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It didn't take long for the Lyft doubters to show up in the equity market
Lyft drops below IPO price as skepticism creeps in on the second day of trading
Updated: April 1, 2019
A driver rides his car in front of the Lyft drivers hub in Los Angeles, California. Apu Gomes/AFP/Getty Images
Lyft Inc. went public Friday in the highest-profile stock sale of the year. It didn’t take long for the doubters to show up in the equity market.
The shares dropped as much as 12 per cent to US$69.12 as of 10:32 a.m. in New York, more than erasing Friday’s gain and falling below its initial public offering price of US$72. Wall Street analysts highlighted concerns about how fast the ride-sharing company can start making money.
While Lyft’s rapidly growing revenue and a large and mostly untapped potential market has many fans, the latest analysts starting their coverage on the stock also noted a possibility of growth slowing down.
Investors hail Lyft shares in IPO, see profits down the road
Lyft shares are going crazy in market debut
Lyft hikes IPO target to $70-$72 a share as excitement rises
“Following years of significant improvement, we believe market share gains and revenue growth are poised to slow as competitive pressures mount in the ride-sharing industry,” Consumer Edge Research analyst Derek Glynn wrote in a note to clients. The analyst initiated coverage on Lyft with an equivalent of hold rating and a US$73 price target, compared with the average price target of US$77.74, according to data compiled by Bloomberg.
Volatility during the first few days after an IPO is not unusual, and may not always be a good indicator of where the company’s valuation might settle after the initial euphoria. However, on an average over a longer term, they seem to be fairly accurate.
While Lyft’s IPO was a much hyped affair, skeptics had sounded warnings earlier, even though investors did not seem to mind that the company was losing money. Lyft disclosed in its IPO filing with the Securities and Exchange Commission that it lost US$911 million on revenue of US$2.2 billion in 2018, compared with a loss of US$688 million on revenue of US$1.1 billion the previous year.
Berkshire Hathaway Inc.’s Warren Buffett expressed his reluctance in a CNBC interview on Thursday, saying he “certainly wouldn’t buy a business for US$25 billion.” Wedbush analyst Daniel Ives last week noted that it was “hard to be bullish” on the stock above US$80.
“Positives for Lyft include a large total addressable market with modest penetration, rapid topline growth, share gains and positioning in the middle of several broader shifts,” Guggenheim analyst Jake Fuller wrote in a note. “All very attractive features, but just not enough to offset our questions around Lyft’s ability to both grow fast and reach its target margins in what is a highly competitive category.”
Wow Air grounded: How to protect yourself if this happens to... Hot Ticket: Canadian (and One Down South) Last Minute-ish Travel Deals
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G-Eazy on His Greatest Accomplishments, Dream Collaboration & How Miami Inspires Him
By David Hochman | January 31, 2019 | People Feature
On the eve of his fourth major-label album release, rapper-producer-hip-hop hottie G-Eazy opens up about life in the music fast lane.
Jersey wool turtleneck, price upon request, at Dior Homme, Design District; braided band with diamonds, price upon request, at beladora.com; watch and signet rings, all G-Eazy’s own.
Gerald Earl Gillum came to music by way of old-school favorites: Beethoven’s Fifth, Vivaldi’s Four Seasons, Dr. Dre’s “Nuthin’ but a ‘G’ Thang.” Before he was known as the rapper G-Eazy, young Gillum soaked up sounds at home in San Francisco’s East Bay, where his grandparents and single mom played lots of classical records, and the kids in the streets and clubs blasted West Coast rap.
Gillum didn’t fit the mold of hip-hop breakout star. Six-foot-four and white with hair slicked back like James Dean, he looked more greaser than gangsta, but his gift with beats and a desire to earn cash and acclaim pushed him toward the mic and the rowdy adoring crowds.
While studying music at Loyola University in New Orleans, he created mixtapes as digital downloads that grew so popular, he was opening for Lil Wayne and Drake before graduating in 2011. He released his first major-label album, These Things Happen, in 2014 and landed his first Top 10 Billboard single the next year with “Me, Myself & I.” World tours, a collab with Britney Spears and TMZ-tracked canoodles with singers Lana Del Rey and Halsey made him full-on famous. Here’s the man who makes it look eazy being G.
Big Fit blazer, $2,125, and Space pants, $1,380, both by Raf Simons at The Webster, South Beach; cotton T-shirt, $130, at Burberry, Design District; bracelet and rings, all G-Eazy’s own.
What was the first moment people took notice of you onstage?
G-EAZY: I was 13 or 14 years old at a little house party for grown-ups with my friend Marty Grimes, who I still perform with. It was his mom’s birthday and she asked the DJ to let us perform. I mostly remember how totally weird it was hearing my voice coming through the speakers over the top of the beat.
You turn 30 in May. Are you more comfortable performing?
G-EAZY: I’m working on my fourth major-label release, but it feels like my 40th because of all the projects I’ve done in my life. On one hand, it’s the most natural thing in the world. But you never get used to it. It’s still surreal.
What do you see as your greatest accomplishment?
G-EAZY: Being able to provide for my family. My mom lost her job as a fine arts professor and suffers from chronic pain that’s hard for her career. I made it my mission to take care of her and send her money every month. Her comfort means everything because she struggled so much to raise my brother and me.
G-EAZY: I don’t have a regular schedule like most people. Often, I’m up making music until 4 or 5 a.m., so I’ll sleep into the next day. But a dream day for me would be waking up in time for brunch with my friends.
Sweater, stylist’s own; cotton T-shirt, $130, at Burberry, Design District; necklace, G-Eazy’s own.
What about a dream collaboration?
G-EAZY: Oh, it would be with Drake, no question. He’s the best we’ve ever seen, in my opinion. His level of success in the music industry is unprecedented as far as being prolific at the highest level for more than 10 years. It’s so hard to stick around. This industry will chew you up and spit you out and can be really cruel. But Drake keeps thriving. He’s like a god to me.
Did you ever have a job outside the music biz?
G-EAZY: Lots of them. As soon as I could work, I worked. At 16, I worked at a hot dog place called Top Dog in Oakland. I ran the register and the grill, cleaned up the place at night; [I was] getting home on school nights at 1 in the morning. But, you know, it taught me the process of running the show myself and knowing what it means to carry the weight. And when you’re making $8 an hour at 16, it means being able to buy Air Jordans when you get your paycheck.
No doubt you’ve made some bigger splurges recently.
G-EAZY: I still collect sneakers, but, yeah, my Ferrari makes me really happy to drive. It’s a black 488 that looks just like the Batmobile. I set it as a goal for myself to buy one, and as soon as I turned in my last album, they delivered it.
How does Miami inspire you as an artist?
G-EAZY: Miami is just an epic place that’s larger than life. It’s literally a city that never sleeps—and you have the beaches and boats. It feels like endless summer here.
Suit jacket with one button, $2,890, crew neck SL T-shirt, $350, boot-cut denim jeans, $690, and Miles booties in python, $1,995, all by Saint Laurent by Anthony Vaccarello at Saint Laurent, Design District; sterling silver body chain, $550, by Martine Ali at Kith, South Beach; bracelet, watch and rings, all G-Eazy’s own.
Describe your ideal look when you’re in town.
G-EAZY: I love wearing party shirts in Miami... like silk button-downs and whatnot. I’ve always been inspired by Leo’s style in the Baz Luhrmann Romeo & Juliet, so it’s a great opportunity to break out the Hawaiian shirts.
What has been your most memorable performance here?
G-EAZY: That’s a tough one because it’s always so much fun, but I’d say probably the night we finished off my last tour. We intentionally put the last show of the run in Miami, and played the Amphitheater with Uzi, Ty, Murda, all the YBN dudes, and P-Lo. By the end of the summer we were like one big family, so that just made the whole show extra special. Then we did the afterparty at E11even and it went off.
G-EAZY: I’m excited about the process of working on this next album, but also of bettering myself and staying in a good headspace. When you’re a performer, especially if you’re touring, life can be kind of like Groundhog Day. You’re performing the same exact songs, and even the crowds start to look the same. That repetition can be a grind, and the grind can really get to you. The key is self-care. It’s hard because you position yourself to be in a place to receive these blessings, but you also have to learn to say no. You need space to quiet down. I’ve seen what happens to artists who burn out, and it’s not pretty. For me, it’s a matter of remembering that little kid who, at 13 or 14, got up onstage. It’s about prioritizing Gerald as much as I prioritize G-Eazy... and in this game, that can be tough.
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10 Amazing Moments in OT History
In 1917, a small group met on March 15-18th in Clifton Springs, New York, and established The National Society for the Promotion of Occupational Therapy. In the United States, we celebrate this as the official start of our profession.
In 2017, we are now celebrating the centennial of occupational therapy. This gives us good reason to look back over the past century and celebrate some of the best moments from OT History.
My 10 Favorite Moments in OT History
1.) The founders included three men and three women, an equal gender division.
In 1917, three men and three women voted into existence a national OT association. This was three years before women were allowed to vote in federal elections!
Our profession still has much work to do in ensuring that our workforce reflects the clientele that we serve, but I am thankful for this inspiration from our origin.
Founders included: Eleanor Clarke Slagle, George Edward Barton, Dr. William Rush Dunton, Jr., Susan Cox Johnson, Thomas Bessell Kidner, and Isabel G. Newton.
2.) The name “occupational therapy” is chosen.
I’ve come to believe that occupational therapy’s name is pure genius.
When the name was settled on, it held together several different movements. The inclusion of “occupation” in our name encompassed the following:
a rejection of rest-cure for tuberculosis,
a rejection of having patients passively languish in institutions,
and an affirmation that the goal of care should be for patients to re-enter into society.
The value placed on occupations also aligned the new profession with the Arts and Crafts movement, which prized the value of traditional craftsmanship as factory production was on the rise.
The inclusion of “therapy” situated our work squarely in the medical field. This was important because women's work in healthcare was just starting to be regarded as professional work (versus private acts of charity.)
To me, our name is a source of inspiration as our profession continues to navigate the many forces that influence our care.
3.) The phoenix is envisioned as the symbol of our profession.
The phoenix is a mythical bird that is reborn from its own ashes (think: Harry Potter). George Edward Barton foresaw this as the symbol of our work and made it the symbol of Consolation House, where he practiced occupational therapy. Under the image of the bird was the tagline “Beauty from Ashes.”
Today the phoenix can be seen on the emblem of OT organizations around the world, the United Kingdom, Hong Kong, and Australia.
4.) OT's unique role in pediatrics is established early.
Pediatric OT has its own unique history, that seems to be underexplored and under-celebrated. I hope to learn more about this history, but for now, I want to give the spotlight to the Curative Workshop that was established in 1919 and is one of the earliest examples of occupational therapy methods being used to serve children with disabilities.
5.) Occupational therapy responds to needs during WWI.
The young profession was quickly drawn into assisting with the war effort. The army began its first use of OT in 1918 at Walter Reed Hospital. Bedridden patients knitted and patients who were ambulatory participated in chair caning, woodworking, printing, and rug making. (Ron Swanson would have been proud.)
Both world wars helped establish occupational therapy’s role in orthopedic care.
6.) Eleanor Roosevelt speaks at Eleanor Clarke Slagle’s retirement reception.
Eleanor Clarke Slagle is considered the “mother of occupational therapy.” She served in elected offices of the Society for the Promotion of Occupational Therapy from 1917-1937.
Slagle was among a new generation of professional women. For me, nothing situates her place in history better than picturing Eleanor Roosevelt speaking at her retirement celebration in 1937.
I do not know the content of Roosevelt’s remarks other than what was summarized in an AOTF newsletter.
“During her remarks, Mrs. Roosevelt lauded the untiring work of Eleanor Clarke Slagle, but could not resist the temptation to speak on the professional activities of women and the importance of advancing the cause of women in society.”
(If anyone has access to her full remarks, please let me know!)
7.) A killer graduation speech is composed.
I love reading the soaring rhetoric from the founders of occupational therapy. Their passion for establishing our profession is so evident in their writing. This expert from a graduation speech delivered in 1929 by Thomas Kidner is my favorite example.
In your chosen field, a part of the noblest work of man—the care and relief of weak and suffering humanity—may you realize in increasing measure the value of certain spiritual things which are the making of life, but which we call by many common names. Kindness, humanity, decency, honor, good faith—to give these up under any circumstances would be a greater loss than any defeat or even death itself.
8.) The World Federations of Occupational Therapists (WFOT) is established.
WFOT was established in 1952 by OT associations from 10 countries.
Today, WFOT has 92 Member Organizations and represents approximately 480,000 occupational therapists around the world.
9.) Sigourney Weaver plays an OT!
Okay. This might just be a personal favorite since I love Sigourney.
Unfortunately, Sigourney's character in the 1988 movie “Gorillas In The Mist” isn't actively working as an OT, but the historical figure was trained as an occupational therapist so I'm going to count it.
Ms. Weaver plays Dian Fossey, who trained and worked as an occupational therapist before moving to Rwanda to study mountain gorillas. Be warned: this is not the feel good movie I was expecting when I checked it out at my local video store a decade ago. There is scandal involved as well as a tragic murder mystery.
10.) The OT services YOU are providing!
While it may not have made the history books yet, the care that you provide individual clients is truly what makes our profession great. May we continue to learn from our past and look ahead with our focus on one thing: providing the best care possible.
Looking to share information about occupational therapy with colleagues and clients? Check out the OT Month Toolkit.
Buy the OT Month Toolkit
Additional OT History Resources
Friedland J. Restoring the spirit: the beginnings of occupational therapy in Canada, 1890-1930. Montréal: McGill-Queen's University Press; 2011.
Peloquin SM. Occupational Therapy Service: Individual and Collective Understandings of the Founders, Part 1. American Journal of Occupational Therapy. 1991;45(4):352-360. doi:10.5014/ajot.45.4.352.
Quiroga VAM. Occupational Therapy: the first 30 years: 1900 to 1930. Bethesda, MD: The American Occupational Therapy Association; 1995.
These moments and resources only scratch the history of our profession. If you are interested in reading more, I strongly recommend othistory.com with posts written by Chris Alterio.
OT ResourcesSarah Lyon, OTR/L March 3, 2017 OT History, What Is OT?5 Comments
Providing OT for Kids in a Private Practice: An interview with Reema Durrani
Sarah Lyon, OTR/L March 27, 2017 Private Practice, Pediatric OT
15 Forms for School-Based OT from The Organizing OT
OT ResourcesSarah Lyon, OTR/L February 9, 2017 Pediatrics, School OT, Documentation, OT Share
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Well, the Intelligent Singaporean is dead. It was a good run, while it lasted.
For those of you who don't know what the Intelligent Singaporean is, well, you obviously don't know the Singapore blogosphere very well. The Intelligent Singaporean, until a few days ago, was a very useful aggregator that regularly provided links to the latest readworthy blog posts about Singapore issues. It was like a central point for exploring what Singapore's sociopolitical bloggers had to say.
Why did the Intelligent Singaporean die? Its owner left a rather cryptic final message. An excerpt:
"Recently certain events have prompted me to re-evaluate the role & relevance of the Intelligent Singaporean in the Singapore socio-political blogosphere. These events have forced me to reconsider whether continuing my aggregation work furthers the original cause of IS.
The original intention of IS was that it would act as a mutual ground of exchange and to facilitate civil discussion about socio-political issues in Singapore. The blogosphere has however evolved rapidly in the intervening year and IS is no longer able to serve the changing needs of the blogosphere today."
Hmmm. Sounds like the kind of message which is intended to let those already in the know, know, and those not already in the know, not know. Well, I don't know, and I shall not speculate.
Guess we will just have to turn to the Singapore Surf now. Which is another website worth visiting.
Some NBC Links
Garuda looks back in time and reminisces about the Rally speeches of three Prime Ministers - Lee Kuan Yew, Goh Chok Tong and Lee Hsien Loong:
"I used to listen to every one of MM Lee Kuan Yew's NDR speeches when he was the PM and each time I could not help but praise him. Every one of his speeches drove something into my heart. I believed in him. I trusted in what he said. Tonight I saw him sitting right in front, facing his own son and watching very enthusiastically and anxiously. He looked very healthy and more alert than SM Goh. I think he may outlive his own sons." - Link.
Eugene reflects on PM Lee's Rally speech on education:
"His voice was wavering but he said it with his heart, “Whichever school you go to, whatever home background you come from, we will help you develop your talents to the fullest.” To some Singaporeans, this might be insignificant or forgettable but to someone who has benefited from the
education system, this promise from a leader is welcoming and reassuring."
Vince Liu ponders the risks and usefulness of the sociopolitical blogging in Singapore:
"I am mindful not to speak much about socio-political issues, especially Singaporean, because largely, what I have to say of the 'big issues' that are happening, are usually covered by people who are usually more articulate than I am, not surprising given the fact that my expertise lies in coding, not writing, not even to mention about the sensitivity of talking politics in Singapore ......... do my views bring about change in the civil society? In all honesty, I hardly think it does."
On CPF, Life, Work and Retirement
For the record, I agree with PM Lee’s views on the aging population. I agree with his proposed changes to the CPF system. When the specific details are announced, I will probably have a few quibbles and disagreements. But by and large, I agree with PM Lee’s general direction.
To be frank, there aren’t many alternatives to choose from. PM Lee’s solutions are not at all brilliant. They are quite obvious. It’s a “not-much-choice” situation.
As I poke around the blogosphere, I hear some people mumbling and grumbling. Their dissatisfaction is with the notion that they’re going to have to work to the ripe old age of 62, or 65, or 67. While I understand the sentiment, I think that these people may not be fully appreciating the issues.
The government is not forcing you to work. If you have enough money, you could choose to stop work at 60, or 58, or 55. As a matter of fact, if you have enough money, you could jolly well retire at 35. Come to think of it, I have ex-classmates who had already become tai tai’s at the grand old age of 30.
In all cases, it’s just that a certain portion of your CPF savings (known as the Minimum Sum) will not be available to you, until you reach 62, 65, or 67 years of age. And even then, you won’t get all of the Minimum Sum at one go. You’ll only get a small instalment, every month for the next 20 years (starting from age 62, 65 or 67).
Some people are peeved because they don’t want to wait till they’re 65 or 67, before they start receiving their monthly instalment. They feel that this rule compels them to keep working until they’re 65 or 67. Ideally, they would like to retire instead at, say, 55 or 60.
What do I think? Well, the monthly instalment is quite small. It was never going to make you feel wealthy. The whole idea of this monthly instalment is just to cover your basic survival needs.
For example, if you turn 55 after 1 July 2008 and before 1 July 2009 (and are able to set aside the Minimum Sum in full), then the monthly instalment you’ll get from age 62 onwards is about $416. That works out to about $14 a day. This will cover three square meals at your neighbourhood HDB coffeeshop. And leave you a few dollars for a kopi and an ice kachang.
If you turn 55 after 1 July 2008 and before 1 July 2009 (and are NOT able to set aside the Minimum Sum in full), you will get even less than $416.
Now, suppose you feel unable to retire at your ideal retirement age of 60, if you do not immediately start getting your monthly instalment. Then in my opinion, you really should not retire anyway. If with your own non-CPF savings, you cannot afford your own three square meals per day (plus kopi and ice kachang), from age 60 to age 65 or 67, then you must be quite broke.
You should probably keep working until you hit the then-prevailing official retirement age. And quite possibly, well beyond that.
Remember – the current life expectancy is around 81 years. There’s a 50% chance you’ll live beyond that. And the national life expectancy is still rising, year after year.
Singaporeans need to start adjusting their mindset about work. They also need to start adjusting their mindset about “old” age. The good thing is that we all grow older gradually, day by day, and not all at once. That means we have plenty of time to slowly adjust our mindsets.
Life expectancies in all developed countries have been climbing steadily through the past century, with no sign of leveling off. PM Lee is peering as far as he can into his crystal ball, trying to see what the future might hold. And he’s making plans for that future.
Our error would be to judge and criticize those plans according to our notions of how human society operates today. Because PM Lee is not preparing for today – he’s preparing for quite a distant tomorrow.
Today when we see a 70-year-old woman, frail, bent over, still working hard in a coffeeshop for meager pay, we feel sorry for her. That sympathy is justified. But if today you are 35 years old and live to be 70 years old in the year 2042, it’s quite probable that you will turn out to be rather different from that 70-year-old woman.
Due to medical advances, it is entirely possible that at 70, you will still be fit, healthy and fully functional. With another 35 years of life left in you. If that is the case, you will be quite happy to still be working at the age of 70. Because 35 years is a very long time to be sitting around and waiting to die.
Inevitably, over time, our views about work, and the role it plays in our lives, will also evolve and change. Currently we think of a working life spanning 35 years as “normal”. In time, we may come to think of a working life spanning 50 or 55 years as “normal”. When that happens, how might society change? Here are some possibilities:
(1) Currently, many modern women delay or avoid marriage / having children, so that they can focus on their career. This idea may gradually become redundant, as the length of the average working life increases. When you have 55 years to build your career, and not just 35 years, the idea of putting your career on the backseat for five or six years to prioritise your family life will become much more agreeable.
(2) Constant learning and relearning will naturally become accepted as a way of life. If you are going to work 50 years, you will probably be around long enough to see everything you learned in the first 40 years of your career become completely obsolete in the last 10 years of your career.
(3) It will become quite common to see people in their 40s or 50s go back to university and study for a new degree, in a completely different field from what they had been working. If you qualify as a doctor at the age of 55 but intend to retire at 75, you still have 20 years to practise as a doctor. That’s long enough to justify the opportunity cost of quitting your engineering job to enter medical school at age 48 or 49.
(4) As industries continually emerge, grow, boom, die or reinvent themselves, more people will from time to time be retrenched, made redundant or otherwise become unemployed. Over a 55-year working lifespan, it may become unreasonable for any individual to expect continuous, unbroken employment.
(5) The older workers of the future are not going to be like the older workers of today. A much higher proportion of the older workers of the future will be well-educated, skilled, trained, trainable and retrainable. Consequently, they will be quite able to compete against younger workers. In fact a very young worker with 1 year's working experience may be at a severe disadvantage compared to a very old worker with 54 years of working experience.
(6) A new species of workers will emerge – I’ll call them the Life Explorers. These are people who earn, save and invest well, within the 1st half of their working life. They accumulate a pool of income-generating assets (with potential for capital appreciation) sufficient to provide fairly indefinite financial security.
For the next 25 or 30 years of their working lives, the Life Explorers work not so much for the money, but for the fun of working, and for the sake of pursuing their various interests in life. Typically they will turn their hobbies into their jobs, or select jobs related to their hobbies.
Professional blogging, anyone? Sign up for my meditation class? Heheh.
PM Lee & The Aging Population
How can Singapore deal with the financial challenges of an aging population? Sounds like a big problem. However, if you think about it, the available measures are fairly obvious:
(1) Pay higher interest on CPF savings
(2) Delay citizens’ withdrawal from their CPF savings
(3) Encourage Singaporeans to work longer and retire later
(4) Make everyone invest in annuities
Okay, that wasn’t too difficult. The devil is in the details, and the actual mechanics will take plenty of working out. But the “big picture” strategy is fairly clear, and PM Lee announced it in his Rally Speech last night. What Mr Wang will explore today are a few scenarios which PM Lee didn’t explicitly touch on.
During his speech, PM Lee mentioned “longevity risk”. This is the risk that you end up living longer than you expected, and therefore you eventually run short of money to support yourself. Furthermore, a high proportion of Singaporeans in their 20s, 30s and 40s today are choosing not to have children at all. Thus many of them will one day become senior citizens literally without any living relatives at all, to depend on.
Harsh as it may sound, the problem is its own solution.
PM Lee described a future where, thanks to advances in medical knowledge and healthcare, people will live longer and longer, with life expectancies climbing to, say, 90 or 100 years or perhaps even more. However, the implicit assumption is that you are able to afford living to such an old age, or that someone else (your relatives, or the state) will pick up the tab.
If you can’t afford this, and if no one else picks up the tab, well, you die. Death is the simple solution to living too long. That’s the brutal truth. (And it’s not so bad really, everyone has to go someday).
It is not necessarily the case that many old people will not be able to afford food and water, and therefore die alone, of starvation, in their little HDB flats. No, not so dramatic or tragic. A more likely scenario is that as they grow older and their savings gradually run out, they find themselves unable to afford the various medical treatments that would prolong life.
For example, let’s say that you are 75 years old. Your heart has developed a valve problem. The doctors recommend a $50,000 operation. They say that if you don’t go for the surgery, well, you are in no immediate danger, but your heart will probably fail sometime in the next five years. On the other hand, if you do go for the operation, they will plonk a new artificial valve into your heart, and it will probably last you another 20 years.
The question then is whether you can afford $50,000. If you can, you get to live longer, perhaps up to the age of 95 years. If you can’t, you’ll die sometime in the next five years.
So essentially your life expectancy (80 years or 95 years) has become a matter of money. Your life expectancy is a function of the medical care available to you, which in turn is a function of the amount of money you have. Ultimately you die, not of starvation, but of a curable heart condition which you could not afford to cure.
My next point is about the likely pattern of wealth distribution in an aging population. It is often said that in an aging population, the working population (that is, the young and the middle-aged) will end up bearing the heavy burden of supporting (either directly or through paying income taxes) the older retired folks.
This is no doubt true, but is there any silver lining for the younger folks? Let’s consider what happens to a person’s assets when he dies.
If you die with a will, then your assets will go, of course, to whoever you named as the beneficiaries in your will (and most people will name their own relatives as the beneficiaries).
If you die without a will, your assets will be divided according to a very specific order stated in the law. For example, if you have a spouse but no children, the spouse takes all. If you have a spouse and children, the spouse takes half the assets, and the other half is divided among the children. If you have no spouse and no children, but do have certain other relatives, then your assets will go, in a certain order, to your parents, siblings, nephews, nieces, aunts, uncles etc.
Now, assume that birth trends in Singapore don’t undergo any drastic change in the foreseeable future. So our population continues to age rapidly. In an aging population, a relatively high proportion of the general population are in the older age-groups.
This means that if in the year 2040 or 2050, you are a middle-aged working adult in Singapore, then the probability is that you will have many more old relatives than young relatives. In other words, the total number of your parents, uncles and aunties will probably exceed the total number of your siblings and cousins, and almost certainly exceed the number of your children, nephews and nieces.
Now as your older relatives start dying off, you will inherit their assets. You may not have been very close to your Auntie Ling (the one you never bothered to visit even during Chinese New Year). Nevertheless she will give you all her assets when she passes away. Why? Simply because she has no one else to give her assets to. After all, Auntie Ling was a typical Singaporean of her generation – she was an only child (or had only one other sibling, whom she outlived), married late (and also outlived her husband), and never had no children of her own. She was literally all alone in the world, except for you. So after she dies, you get everything.
As the population ages, the combined wealth of a relatively greater number of old Singaporeans will become concentrated (after they die) in the hands of a relatively lesser number of younger Singaporeans. This is in contrast to countries with a young population, where the wealth of the recently-deceased will be divided among a greater number of living people.
So in an aging population, there is some economic “silver lining” for the younger folks, after all. In a sense, this alleviates the economic hardship of the relatively younger section of the population, in supporting the relatively older section of the population.
NBC & The PM's Rally Speech
NBC stands for "New Blogger Challenge". The background is here.
Prime Minister Lee Hsien Loong makes his rally speech tonight. Here is your NBC exercise. Blog about his speech (or any part which interests you), and send me your link by Wednesday (you can email mrwangsaysso@gmail.com).
If I find your post interesting, I'll blog about it, and highlight it to my readers too, so that at least some of them will go over to your blog and read it too. That should help make it worth your time and effort to compose the post.
Ideally, you'll either be a new blogger, or a little-known blogger, so that the publicity I give to you will act as a helpful kickstart in getting people to notice your existence.
Shame on the Police
On a Saturday morning, 40 people put on their running shoes and get together to jog along the Singapore River. A nice, healthy activity. However, they get harassed by the police.
Is "harass" a fair word? Judge for yourself. How would you like it if you go jogging with your friends, and you find that undercover cops are following you, and filming you on camera?
And then the police officers ask for your NRIC, and they insist that you were committing a crime under the Miscellaneous Offences Act. And when you ask the police what exactly you're doing wrong, they say that they don't know.
Well, let me tell you what the "crime" was. These 40 people were gay. That is all.
They were not having sex. They were not in the nude. They were not even waving flags or making public speeches. They were at the Singapore River because they wanted to go jogging.
However, because they were gay, jogging suddenly became a crime.
So, to Kelvin Yeo, the police officer apparently in charge of this exercise, I want to ask a few questions.
How do you feel about yourself now? Don't you get bored? Don't you feel stupid? Don't you ever wonder whether you could have a more meaningful job than this?
When you joined the Singapore Police Force, weren't you aspiring to contribute to the security and safety of the nation? By nabbing robbers, murderers, rapists and other dangerous people?
How did you allow yourself to be reduced to this? Harrassing peaceful, harmless joggers on a nice, sunny Saturday morning. Where are you going to do your next stakeout on gay people?
Starbucks? NTUC supermarkets? Bus interchanges? Will it become a crime for a gay person to take the MRT train?
The shame of it. To think that you, a civil servant, are getting paid by taxpayers' money, to waste your time like this.
Chaos in the Financial Markets
Here is an email from one of my readers, Slawek Rogulski:
Hello Mr Wang,
You are no doubt aware of the world financial situation, especially that of the US with the sub-prime mortgages and other exotic instruments starting to lose their value. In your opinion what if any impact on Singapore will this have? Have any funds here had to close or at least temporarily halt withdrawals? And how sound are the local banks? I would appreciate your comments on these issues. Thank you. Regards,
Yes, I am very aware of the current world financial situation. However, for two reasons, I will not comment specifically on the US subprime mortgage situation.
1. There is already an abundance of articles and commentaries in the news and media about the US subprime mortgage situation.
2. No one knows what's going to happen next anyway. That includes Mr Wang.
Me, I'm getting at least 4 jokes per day by email, about Goldman Sachs, Bear Stearns or hedge funds in general. But if you really want to read some serious, and excellent articles on this topic by an anonymous blogger, click here.
Trust that man, he's very good. At the same time, being anonymous, he doesn't have to tailor his commentary to suit any particular vested interest, which he would have to do if he were a known person employed by, say, certain investment banks or hedge funds right now.
As for myself, over the past two months, I've heavily dumped my own fund investments worldwide in the past two months and I'm very long on cash right now. It's been a brilliant bull run, I've made my money over the past two years and I'm out. The party's over, and it sure was fun!
I'm not going bottom fishing yet, because I think we're still a long way from bottom. It is frankly not just about US subprime - it is the market doing a major repricing of credit risk everywhere that credit risk appears. In other words, not just CDOs, but debt in general, and equities too.
Now I'm going to work on my Plan B and Plan C. What shall Mr Wang do, if in three or six months time, his own job (in credit derivatives) vanishes? Poof. Magic, just like a Bear Stearns hedge fund.
Sigh, I may have to become a lawyer again.
The New Blogger Challenge
Like Bernard Leong, I was recently interviewed by Jude Yew, a Singaporean PhD student doing research on the impact of new media during the 2006 General Elections.
However, during the interview, I did not feel very interested in talking about last year's General Elections at all. Internet time moves differently, as I told Jude, and the 2006 General Elections already feels like a distant memory to me. So the interview became a more meandering, loosely structured conversation about socio political blogging in Singapore.
I don't even feel like blogging about the interview. Except to say that during the interview, I expressed disappointment at the lack of depth in serious blogging in Singapore.
In my opinion, a disproportionately high proportion of readworthy blog content is being produced by a very small number of S'pore bloggers. The same few usual suspects.
So the health of the Singapore blogosphere is at risk. It is constantly at risk. All it would take is the departure of a few significant bloggers (eg Alex Au, Aaron Ng, Molly Meek, XenoBoy and a few others) and suddenly the tap would run dry.
I said that it was this serious lack of depth that compelled me to continue my own sociopolitical blogging. If there were a sufficient number of readworthy sociopolitical bloggers in Singapore, I would be quite happy to "retire" or blog instead about my other interests (and I have many).
As it is, I often feel grudgingly compelled to blog about social, political and economic issues in Singapore every now and then. Just to keep the flame alive. Keep people thinking. Ensure that the discussion goes on.
And I still get a steady stream of emails from readers, all the time, and more than I can respond to. Readers who say, "Mr Wang, could you please blog about this, could you blog about that, I would appreciate your views etc etc".
It does make me wonder. Why do I still have to do this? By now, surely I've already done more than my fair share of blogospheric National Service. I wish 20 new, serious, sociopolitical bloggers would appear next week or next month to "replace" me. Yes, 20. Out of one entire nation. Is that really too much to ask?
Go on. Take this as a challenge. Be one of the 20 new, serious, sociopolitical bloggers. Start a blog. Write something readworthy. Then email me or put a link in the comment section of this post. I'll publicise you. And if you want it, I'll help you along with tips and suggestions on how to get at least 10,000 readers a month.
Work, Religion, Money, Psychics and Other Assorted Things
Murabaha; riba; gharar; arbun; wakil; sukuk; fiqh; salam; hadith; haram; musharaka. My new vocabulary.
Caught a plane on Tuesday night to Kuala Lumpur to attend a conference on Islamic finance. In the past five years, Islamic finance has gained more and more prominence, as banks all over the world explore ways to tap into the great amount of wealth in the Middle East. Even DBS has moved (very seriously) into this area - hence we now have The Islamic Bank of Asia in Singapore.
Islamic finance, however, is a topic of which I have very little knowledge. And so, on the brief flight to KL, I found myself attempting to speed-read through an Islamic finance textbook. In the process, I became more intrigued by Islam, than by Islamic finance itself, and made a mental note to find out more about this religion.
Next morning, at the conference, I was one of the few non-Muslims in a predominantly Muslim audience. The conference speaker was a white man, with a very American accent. However, it quickly became apparent that he too was very Muslim. Abdulkader Thomas was his name, and as he went through the course, he spoke Arabic, wrote Arabic, quoted Islamic scholars, and referred often to the Quran and the life and times of the Prophet Mohammed.
Very curiously, at a certain time in the course, Abdulkader briefly alluded to having studied biblical Hebrew during university (could he have originally been Jewish?!), but I did not get any convenient chance to ask him about his unusual spiritual journey through life.
My personal mission was really to explore ways by which modern derivatives (famously described by Warren Buffett as "financial weapons of mass destruction") might be integrated with Islamic finance, and thereby be made palatable to Islamic clients. But it quickly became clear to me that I was on a long trip into uncharted waters. Abdulkader made it quite clear that this was an area with more questions than answers.
I am either on the edge of the next hot innovation in the investment banking world, or at the entrance of a long winding passage leading to a dead end. The religious underpinnings of Islamic finance are, well, very Islamic, and if I don't learn to think more like a Muslim, I doubt if I will go very far with the creation of new Islamic financial products,
Caught some TV from my hotel room this week - watching mostly Discovery Channel documentaries - and there were two which interested me, in particular. The first documentary was about João Teixeira de Faria, more popularly known as John of God, a faith healer in Brazil. This was the first time I'd heard of him, although apparently he has been doing his faith healing for decades and is already very well-known, receiving patients from many different countries.
The documentary showed, in rather graphic detail, John stabbing people with his unsterilised knife, slitting open their stomachs and back muscles etc, and pulling out their cancer tumours, cysts etc with his bare, exposed hands. As we would expect of faith healers, his patients experience no pain, and almost no bleeding, and apparently no post-operation infections either. Like Jane Roberts, John of God is a channeller. He calls upon "spirits of the dead" to enter his body, and use him as a vehicle to carry out the operations - thereafter, John himself has no recollection of how happened.
The second Discovery documentary was entitled Psychic Vietnam. This is about a Vietnamese government project to use a small number of psychics (tested and screened by government officials) to locate the remains of long-deceased, missing Vietnamese soldiers who had died during the Vietnamese war, 30 years ago. Here's a BBC commentary on the show. The actual documentary is quite interesting - it relates how the remains have been sent for DNA testing, and verified to be the remains of the person that the psychic says they are.
Visited the Kinojuniya bookstore at Suria KLCC and was pleasantly surprised to discover that its "Religion" section has much more variety than the one at Singapore's Kinokuniya, and this despite the fact that Malaysia is predominantly Muslim, while Singapore supposedly has more religious heterogenieity.
Two of my new acquisitions are "A Course in Miracles" (this is no ordinary "Christian" book, do click on link to find out how it was allegedly written) as well as "The Life And Teachings of Sai Baba of Shirdi" - India's mysterious, and living, godman (did you know he has a temple in Singapore too, somewhere around Moulmein Road?).
All in all, a rather interesting trip to KL, yielding much serendipitious, varied fodder for my metaphysical grazing.
Salaries in Singapore
I found, through Tomorrow, an interesting blog that's all about salaries in Singapore. Here it is - Salary.sg.
There are lots of interesting posts on that blog, including this nifty one which allows you to benchmark your own annual income (or anyone else's) against the general population of taxpayers in Singapore. Anyone tried typing in PM Lee Hsien Loong's annual income yet? Heheh.
The post featured on Tomorrow was this one - Median Income By Age Group. It tells you the median gross monthly salary of managers (the generalists) and professionals (the specialists), by different age groups. To get a more complete picture, you would want to plow through the original MOM report, but Salary.Sg's graph does give a quick, convenient snapshot.
Retirement, Money and Singaporeans
A Straits Times article, about retirement, savings and Singaporeans' expectations.
ST Aug 11, 2007
Retire? Not so soon, say many
Singaporeans polled
They need to carry on working because of worries
over insufficient savings
By Lydia Lim
SINGAPOREANS are in no hurry to retire and most want to work beyond the official retirement age of 62, some even into their 70s.
It's a case of 'CPF no enough' for many of these workers.
Seven in 10 polled last month in a Straits Times Insight survey on CPF said they do not think their savings in the national pension fund will see them through old age.
Six in 10 of them said the same of their Medisave funds for hospital bills and specified treatments.
The survey of 636 Singapore residents aged 30 and above found that apart from CPF, 77 per cent expect to be able to draw from other sources of retirement income, mainly savings, investments and insurance.
But a significant minority of 23 per cent had nothing else set aside.
One cause for concern is that only one in two Singaporeans has done any financial planning for retirement.
Even fewer, three in 10, have done their sums on how much they need to squirrel away.
What may mitigate against any resulting savings shortfall is their willingness to work beyond the retirement age of 62. Some two-thirds said they plan to do so.
Of these, one-third are willing to work up to age 65, another third up to age 70 and the remaining third into their 70s.
The journalist has got her thinking hat on backwards. The truth can be stated much more simply. It doesn't really matter what the "official" retirement age is. You will go on working as long as you (a) need the money, and (b) are still able to keep working.
Unless you regard suicide as an alternative, you don't have a choice. What were you thinking - that Singapore is a welfare state?
Blue-collar and lower-income workers are the most likely to want to work longer.
Eight in 10 plan to do so, against six in 10 among professionals, managers, executives and business types, or those drawing more than $3,000 a month.
Older Singaporeans are also more likely to want to work past the retirement age than those in their 30s.
The vast majority - 83 per cent - are however against a recent suggestion by ministers to raise the age when they can draw down their CPF minimum sum. It is currently 62.
The only practical significance of the "official" retirement age is that it is also the age when you can start utilising (in tiny little monthly instalments) your CPF minimum sum. For an explanation of how this works, refer to my old post here.
The survey findings also revealed a good amount of ignorance of the workings of the CPF system. Seven in 10 do not know how much they had in their CPF accounts.
And one in two does not know the rate of return on CPF savings.
Of the half who do, most - 63 per cent - are unhappy with the interest rate, which
stands at 2.5 per cent for Ordinary Account savings and 4 per cent for Special and Medisave Account savings.
The top two changes CPF members would like to see are more flexibility in the use of their money, and a higher interest rate on their savings.
Financial experts and Members of Parliament said it is good that Singaporeans feel no false sense of security over their retirement finances.
Manpower Minister Ng Eng Hen emphasised in an e-mail interview that a critical factor in determining what is enough for retirement is how long people work in relation to how long they can expect to live. Average life expectancy has risen from 61 years when CPF was introduced in 1955, to 80 today.
I believe that in the long run, what will catch many people off-guard is how long they end up living. Life expectancies (except in very poor countries) have steadily been rising over many decades and the curves don't seem to show any sign of topping off.
In 1900, life expectancy at birth in the United States was only 47 years. By year 2000, it had climbed to 77 years (an increase of 30 years). In 1950, life expectancy in China was 35 years. By 2000, it had risen to 71 years.
If you google around to check out what the scientists and doctors have to say about new medical discoveries and research and their implications for how long people are going to live, well, you'd probably be quite startled. Anti-aging medicine has become an industry in itself.
The question is - how long can you afford it? Not the medicine. I mean - life itself. Living 10, 20 years longer than you expected means that you need money to support yourself for an additional 10, 20 years. That's a pretty long time.
A volunteer writer from a local environmental group just interviewed me. His article is for a publication that will be released at the time of the next National Youth Environment Forum (yes, we do have such things in Singapore).
Initially I had sensed a little tentativeness on his part. That was probably because he had gone through my blogs and found that I had never really written much about the environment before. He may have been wondering whether I would have anything interesting or insightful to say about environmental issues.
Well, in the end, I don't think he was disappointed. There are many things in the world which Mr Wang hasn't blogged about yet, but that doesn't mean he doesn't have opinions about them, heheh.
Purely by coincidence, I've just come back from a trip to Australia. During that time, I met up with an ecology/environmental volunteer with a special interest in plants. He was a 63-year-old man who cycled 60 km that morning, so as to meet me. The reason why he didn't drive is that he doesn't own a car. The reason why he doesn't own a car is that he does not want to contribute to air pollution and the global consumption of petroleum resources.
He also told me that until last year, he never turned on the heating in his home. If it was cold, he would just wear thicker clothes and sleep with more blankets. Conserving electricity is his other little way of helping to protect the environment. It's only now, when he's starting to get some arthritis in his joints, that he has started turning on the heating during winter.
Until recently, Western Australia was having a prolonged drought right now, and this old man felt that it was a "blessing in disguise". He said that the drought had the benefit of teaching Australians to be more environmentally aware. He proceeded to give me a detailed theory of what the true cost of beef should be, taking into account the cost of the amount of water it takes to raise a cow.
What I saw in this old man was a deep love for Mother Earth and a very strong sense of responsibility for the environment. Do such staunch advocates of the green movement exist in Singapore? Perhaps, but there can't be many.
As I was telling my interviewer, the level of environmental awareness in Singapore will be driven more by economics than anything else. If water and electricity become more expensive; if petrol prices go up; if more shopping centres start charging for plastic bags - these are the sorts of things that will make Singaporeans sit up, take notice and start adopting greener sorts of lifestyles and habits.
Learn more about the old & poor in Singapore. Click here.
The Mandatory National Day Post
A few weeks ago, a free Singapore flag was delivered to my doorstep, wrapped in clear plastic. It's the kind which HDB residents are supposed to hang over their parapets or outside their windows, to exhibit their patriotism to the world, on National Day.
I have a mild adversion about doing such things. I still remember how some citizens, a few years back, were fined for not hanging out their flags properly.
The exact details escape me now. But I think in one case, the chap didn't hang his flag properly, a heavy storm came along, and the flag became crumpled, messy or something like that. The chap didn't bother to tidy up his flag. Later he was fined by the government. Some obscure offence having to do with disrespect to the state flag.
So I looked at my own flag, still in its plastic packaging, and I couldn't decide whether to hang it out or throw it away. Hanging it out would entail a risk of getting fined, a small risk no doubt, but why take any unnecessary risks at all. At the same time, throwing away the flag seemed vaguely wrong and a bit wasteful (I am quite environmentally conscious - I will blog more about this in future). I considered using the flag as a rag, but I was afraid the strong red colour would run.
Unable to decide, I left the flag on the dining table for the time being. A few days later, when I looked around for it, it was gone. I asked Mrs Wang, "Do you know where's that flag?"
"Threw it away," she said.
"You threw it away?"
"Yeah. Down the rubbish chute. Why do you ask? Were you planning to hang it out?"
"No, not really."
"Well then, that's why I threw it away. Our place got too much junk, anything we don't want to use, we just gotta throw it away. Otherwise we kena one big mess, how?"
Mrs Wang is a true blue Singaporean, pragmatic to the bone.
Yesterday my little daughter came back from her playschool with a little national flag painted on her cheek. Apparently the theme in class that day was National Day. All the kids had a little national flag painted on their cheeks or hands.
It was some kind of non-water soluble ink. I was a little annoyed. She looked cute but the ink wouldn't wash off easily. It's still on her face right now. I think it will take another day or two before it comes off completely.
But my mild annoyance really stemmed from the fact that nowadays I doubt whether patriotism is a desirable value to instill in our kids. In fact, I believe that one day, patriotism will become widely viewed as an odd, useless anachronism. Something like the way we regard communism in North Korea and Cuba today.
Globalisation is changing Singapore - and the rest of the world. I see this very clearly in my own work. The world is shrinking quickly and getting more and more interconnected. I believe that the optimal approach would be for the kids to grow up with a very global, international perspective on life. As it is, they are already living in a country heavily populated with non-citizens. I can easily imagine that in the course of their own adult lifetimes, they may well end up living, studying and working for substantial periods of time in half a dozen different countries. They could easily end up holding multiple citizenships or PR status.
The kids need to grow up being very open and receptive to the idea that they may move and move again. Home will be just any place where they stay for more than three or four years. It is important that they are not handicapped by any dubious concepts like patriotism. By any strange notions that they belong to any particular corner of the planet. By any odd idea that they should be loyal to any specific red dot on the global map.
New horizons would open up for them, if they could see themselves as true citizens of the entire world. They must learn to be able to be comfortable, make friends and interact with people of all sorts of different cultures, anywhere in the world. I'm going to have to scrub harder at that little red-&-white smudge, on my daughter's cheek.
Mr Wang will be travelling for several days and is unlikely to blog. See you when I get back.
In the meantime, a reader emailed and asked me to recommend the really "hardcore" readings on the concept of thought affecting reality. Yes, my friend, you're right - Mr Wang hasn't covered the really hardcore stuff yet, and it does get pretty weird. Try Seth, for starters (although the material covered goes beyond TAR). From Wikipedia:
In late 1963, Jane Roberts and her husband, Robert Butts, experimented with a Ouija board as part of Roberts' research for a book on extra-sensory perception. According to Roberts and Butts, on December 2, 1963 they began to receive coherent messages from a male personality who eventually identified himself as Seth. Soon after, Roberts reported that she was hearing the messages in her head. She began to dictate the messages instead of utilizing the Ouija board, and the board was eventually abandoned. For 21 years until Roberts' death in 1984 (with a one-year hiatus due to her final illness), Roberts held regular sessions in which she went into a trance and purportedly channeled messages from Seth. Butts served as stenographer, taking the messages down in homemade shorthand, although some sessions were recorded. These messages from the Seth personality, consisting mostly of monologues on a wide variety of topics, are collectively known as "the Seth Material" (sometimes referred to herein as "the Material") ......
......... "You must watch the pictures that you paint with your imagination, for you allow your imagination too full a reign. If you read our early material, you will see that your environment and the conditions of your life at any given time are the direct result of your own inner expectations. You form physical materializations of these realities within your own mind.
"If you imagine dire circumstances, ill health, or desperate loneliness, these will be automatically materialized, for these thoughts themselves bring about the conditions that will give them reality in physical terms. If you would have good health, then you must imagine this as vividly as in fear you imagine the opposite.
"You create your own difficulties. This is true for each individual. The inner psychological state is projected outward, gaining physical reality -- and this regardless of the nature of the psychological state. ... The rules apply to everyone. You can use them for your own benefit and change your own conditions once you realize what they are.
"You cannot escape your own attitudes, for they will form the nature of what you see. Quite literally you see what you want to see; and you see your own thoughts and emotional attitudes materialized in physical form. If changes are to occur, they must be mental and psychic changes. These will be reflected in your environment. Negative, distrustful, fearful, or degrading attitudes toward anyone work against the self."
Work, Religion, Money, Psychics and Other Assorted...
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Ultimate Sports Day
Ultimate Sports Day is a landmark televised sports series, aimed at unearthing the UK’s most gifted sports talent between the ages of 12-16. Created by MTC Managing Director, Jonathan Marks, the show’s first series was commissioned for 11 episodes, transmitted on BBC2 and CBBC in the lead up to London 2012. USD is currently being repeated on the CBBC channel daily at 11:00am.
The programme commenced with two national ‘boot camp’ selection events. Here, the youngsters were put through their paces and gradually whittled down to four teams representative of each home nation. This ‘X Factor’ style approach was used to engage a wider and more interactive interest from the television audience, while retaining the integrity of sport.
Each team was mentored by one of the UK’s best known sporting stars: Dean Macey for England, Sinead Kerr for Scotland, Christian Malcolm for Wales and Barry McGuigan for Northern Ireland. As the series continued, the teams were pitched against one another in a series of specially devised ‘Ultimate Events’, testing their core sports skill sets.
In the development of the programme, we partnered with the Youth Sports Trust to source the exceptional young talent, and the renowned Professor Greg Whyte to help develop the activities and oversee the competition’s lifecycle.
The project has been strongly supported by a clutch of Olympic stars, including Olympic medallists Phillips Idowu, Amy Williams and Kelly Sotherton who even put their money where their mouths are by taking part in an All Star Special.
During its first series, Ultimate Sports Day had an average 20% audience share. In its short time, the programme has already shown the ability to pique the sporting and competitive interests of the UK’s youth, as well as its potential to deliver a substantial sporting legacy. With such significant success, plans are now afoot to develop the project internationally.
Ultimate Sports Day had great support from some brilliant sports stars, here is what some of them said:
Rebecca Adlington
“What a fantastic programme, I wish Ultimate Sports Day had been around when I was younger. It is great to see kids being competitive whilst learning new skills and having fun. Where do I sign up to be a mentor?!”
Dai Greene
“It’s great to see children from each of the home nations competing for their country and supporting one another, teamwork is important even in the individual sports. Ultimate Sports Day is an aspirational show – long may it continue!”
“The Olympics is a great opportunity to encourage kids to participate in sport but this needs to be maintained after the Games finish. Ultimate Sports Day is the perfect show to encourage kids sporting participation; exciting games, covering all sports skill sets and the chance to learn from some sporting hero’s, why was this not around when I was younger?!”
Discover more about Ultimate Sports Day by visiting the dedicated CBBC website.
Amy Williams Skeleton Experience
Ned Boulting’s Bikeology
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Bradley Cooper & Lady Gaga Set for A Star Is Born
August 16th, 2016 | By Imogen Lloyd Webber
It’s official! Tony and Oscar nominee Bradley Cooper will direct and appear in A Star Is Born…opposite Lady Gaga. According to Deadline, production on the Warner Bros project will start early next year in California.
The long-in-the-works remake had at one point Clint Eastwood to helm and Beyoncé attached to star. Gaga will pen new music for the film.
A Star Is Born first began life as a 1937 film starring Janet Gaynor as a farmgirl-turned-starlet, and Fredric March as an aging movie star. The first musical remake came out in 1954 starring Judy Garland. A second remake was made in 1976 starring Barbra Streisand and featuring the Academy Award-winning song “Evergreen.”
Fall in love with Garland's version of "The Man That Got Away" all over again below!
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Kristin Chenoweth to Return to Stage in My Love Letter to Broadway
September 6th, 2016 | By Imogen Lloyd Webber
The Tony-winning pocket diva is on her way back to the Great White Way! Kristin Chenoweth will return to the stage in My Love Letter to Broadway. The limited engagement concert is scheduled to begin on November 2 at the Lunt-Fontanne Theatre and will run through November 13.
In Love Letter, Chenoweth will perform a handpicked selection of musical theater favorites, including songs from her upcoming album The Art of Elegance, her first album of American Songbook classics. The concert is billed as, "an intimate evening of romance, glamour and laughter."
Chenoweth won a Tony for her performance in You’re a Good Man, Charlie Brown and received nods for originating the role of Glinda in Wicked and for On the Twentieth Century. Other Broadway credits include Promises, Promises. Her many TV credits include an Emmy-winning turn on Pushing Daisies, as well as Glee and The West Wing. Chenoweth's latest album, The Art of Elegance, will drop on September 23.
My Love Letter to Broadway will have music direction by Mary-Mitchell Campbell and costume design by Christian Siriano.
The Lunt-Fontanne Theatre recently played host to Finding Neverland; The Illusionists will play a holiday engagement at the venue from November 25. Charlie and the Chocolate Factory is set to begin previews at the theater on March 28.
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By Dennis Thompson
WEDNESDAY, July 10, 2019 (HealthDay News) -- Most people consider their bed a safe haven, but new research suggests your body heat might trigger the release of potentially harmful chemicals from your mattress.
Mattresses are known to release minute amounts of gaseous chemicals called volatile organic compounds (VOCs). These VOCs come mainly from the polyurethane used in the mattress, but also from other chemicals used in flame retardants and plastics, the researchers said.
Unfortunately, your body heat appears to increase VOC emissions from your mattress, according to tests conducted on eight different types of polyurethane mattresses.
But don't toss out your mattress just yet: The estimated doses of most VOCs remained well below the levels that could cause health effects, researchers noted.
However, some compounds did reach levels of concern for infants and young children, if their ages were considered in exposure calculations, the researchers added.
"There is no reason to panic, and yet it is important to understand that air quality in our sleeping micro-environment is important with regard to our exposure to various pollutants such as VOCs," said senior researcher Yael Dubowski, an associate professor with the Israel Institute of Technology. "Hence, we should make an effort to improve it."
Health effects associated with VOCs range from eye, nose and throat irritation to headaches and organ damage, according to the U.S. Environmental Protection Agency. Some VOCs, including benzene, acetaldehyde and formaldehyde, have been associated with increased cancer risk.
For the study, Dubowski and her colleagues subjected eight different mattresses to simulated sleeping conditions, mimicking the elevated body heat, humidity and carbon dioxide caused by humans when they sleep for even a few hours.
The mattresses had been allowed to air out for at least six months prior to the study, noted Sarah Evans, an assistant professor of environmental medicine and public health at the Icahn School of Medicine at Mount Sinai in New York City.
"Often we think, well, if you let something air out for a little while, you can dramatically reduce the level of chemicals that are off-gassed," said Evans, who wasn't involved with the study. "In this case, even after six months they still saw appreciable levels of off-gassing."
Body heat appeared to increase each mattress' release of VOCs, compared with the levels released when the mattresses were not in use, researchers found.
Estimated exposures remained below the "No Significant Risk Levels" (NSRL) set under strict California environmental laws, researchers noted.
However, if the exposure levels took into account a child's age, the picture took on more concern. For example, compounds linked to cancer such as acetaldehyde, formaldehyde and benzene approached or exceeded age-adjusted levels, researchers said.
The new study was published July 10 in the journal Environmental Science & Technology.
Experts are generally more concerned about children's exposure to VOCs, said Dr. Kenneth Spaeth, chief of occupational and environmental medicine at Northwell Health in Great Neck, N.Y.
Babies in particular spend a lot of time in their crib, lying on foam mattresses that produce these gases, said Spaeth, who had no part in the study.
"By virtue of their age and size, they have heightened vulnerability to potential toxic effects," he said.
Even if these chemicals don't do immediate harm, there is concern that exposure will increase their lifelong risk of cancer, Evans and Spaeth said.
The best way to protect against VOCs is to maintain good ventilation inside your home, by opening windows and using fans, they said.
"Indoor air can have as much as 10 times higher VOCs than outdoor air," Evans said. "Getting fresh air in can really help reduce those exposures."
Consumers also can choose mattresses made of materials other than polyurethane foam, Evans said. Mattresses containing cotton, wool and natural latex will all produce lower levels of gases.
Unfortunately, it can be very difficult for consumers to suss out what's in a mattress and what sort of VOCs those materials might produce, Spaeth said.
"Consumers are in a very difficult position," Spaeth said. "It's very hard to get good information about what a mattress contains, and even if you know that, unless you have a good understanding of the different materials it's hard to know what chemicals might be emitted from those materials.
"The chemicals that are being emitted are not going to be listed in a label that indicates what the mattress is made of," Spaeth said. "These are byproducts of the materials."
The U.S. Environmental Protection Agency has more about volatile organic compounds.
SOURCES: Yael Dubowski, Ph.D., associate professor, Israel Institute of Technology; Sarah Evans, Ph.D., M.P.H., assistant professor, environmental medicine and public health, Icahn School of Medicine at Mount Sinai, New York City; Kenneth Spaeth, M.D., chief, occupational and environmental medicine, Northwell Health, Great Neck, N.Y.; July 10, 2019, Environmental Science & Technology
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The Medical Minute: New therapy often successful at controlling tics
Image: Thinkstock/moodboard
When Dr. Laura Duda goes into an elementary school classroom, she can usually spot one or two children who have a tic – a rapid, involuntary movement or sound such as sniffing, blinking their eyes or scrunching their faces.
Tics are very common in children. Not all children who develop tics receive an official diagnosis, and many outgrow it, according to Duda, a pediatrician at Penn State Children’s Hospital. When one demonstrates both motor and vocal tics for more than a year, they are diagnosed with Tourette syndrome. A new intervention is finding success in helping them control their condition.
Comprehensive Behavioral Intervention for Tics, or CBIT, is a therapy that can lessen the frequency of tics without requiring medicine for many mild and moderate cases.
Dr. Timothy Zeiger, a clinical psychologist at Penn State Health Milton S. Hershey Medical Center, is one of a select group of specialists nationwide certified to provide the therapy.
“Tourette syndrome is a neurologically-based disease, but we know there are environmental factors that can exacerbate the symptoms,” he said. “A lot of these children also have high levels of anxiety and stress, so we work on treating that.”
In the past, cognitive behavioral therapy, biofeedback, relaxation therapy and stress management were the only non-pharmacological tools available to lessen a patient’s symptoms.
With CBIT, the patient works to identify the sensation or feeling that comes before the tic happens.
“I have them describe it, and then we work on developing a competing response for the tic for when they feel the urge to do the tic,” Zeiger said.
Then, they replace the tic with an alternative behavior that can be managed more effectively.
“We have been able to get someone with a motor tic such as a shoulder shrug or a vocal tic such as a throat clear who would do it about 300 times an hour down to less than 10,” he said.
The intervention can be used with children as young as 6, but the child must be able to identify the feeling that comes before the tic in order for it to be effective. Those with the most severe cases can be helped with a combination of CBIT and medication.
Antipsychotic drugs, blood pressure medicines, and more recently, Topamax, have proven useful for controlling tics. But none eliminate them completely, and all of these medications have side effects.
“We try to keep patients off medicine if we can,” Duda said. “CBIT has been shown to be more effective and has fewer side effects.”
Duda and Zeiger say educating families and those who work with children about the condition is often one of the biggest things that can help.
“Typically patients are brought in because the parents notice the tics and get very scared,” Zeiger said. “Sometimes the schools think there is a danger associated with it or that they are going to hurt themselves or others, but that is not the case.”
Teaching those who interact with a child with Tourette syndrome not to give the tics negative attention is important.
“If you tell them to stop doing it, it often increases the child’s level of stress and the tic actually gets worse,” Zeiger said.
He has patients coming from as far as three hours away for treatment with CBIT and sees the benefits they are getting.
“It’s pretty cutting edge,” he said. “We are giving people hope.”
For more information about CBIT therapy, call 717-531-8338 or click here.
Last Updated August 03, 2016
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health, Medical Minute, neurology, psychology, Tourette syndrome
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Horace Ward to receive honorary UGA degree
by Stephanie Schupska
Judge Horace Ward speaks at the Holmes-Hunter Lecture in January 2003.
Athens, Ga. – The University of Georgia will honor retired federal judge Horace Ward—the university’s first African-American applicant—with an honorary doctor of laws degree during its spring graduate Commencement ceremony on May 9 in Stegeman Coliseum.
The Board of Regents of the University System of Georgia approved Ward’s honorary degree during its March 19 meeting.
“Judge Horace Ward’s legacy is a significant one in the history of the University of Georgia,” said President Jere W. Morehead. “He has made substantial contributions to our university community by delivering lectures to our students and sharing his story with our historians. I am grateful to the board of regents for allowing us the opportunity to recognize Judge Ward in this meaningful way.”
Ward’s story with the university started in September 1950 when he applied to the UGA School of Law. He had just completed a master’s degree at Atlanta University, which he received in 1950. The LaGrange native earned his bachelor’s degree from Morehouse College in 1949.
When his application to UGA was denied, Ward sought legal resolution to the matter, starting a quest said to have established an important precedent and tone in the civil rights movement in Georgia in the 1950s.
After earning a law degree from Northwestern University in 1959, Ward returned to his home state and joined the legal team—led by civil rights attorney Donald Hollowell—that represented Hamilton Holmes and Charlayne Hunter-Gault in their landmark efforts to enroll at UGA in 1961.
While a partner in the law firm of Hollowell, Ward, Moore and Alexander, Ward worked on several other significant civil rights cases throughout Georgia, including the Rev. Martin Luther King Jr.’s case in DeKalb County.
In 1964, Ward became the second African-American since Reconstruction elected to the Georgia General Assembly. Ward was re-elected to four terms in the state senate and was appointed to several key committees.
In 1974, he was appointed to the Civil Court of Fulton County, making him the first African-American trial court judge in Georgia. He was elevated to Fulton County Superior Court judge in 1977. Two years later, Ward was appointed to the U.S. District Court for the Northern District of Georgia. Ward took senior status in 1994 and retired from his post in 2012.
Ward was born in LaGrange and graduated as valedictorian from East Depot High School. A veteran of the U.S. Army, Ward served a tour of duty in Korea in the 1950s.
At UGA, Ward’s story serves as the foundation for the Foot Soldier Project for Civil Rights Studies, an interdisciplinary research effort that seeks to uncover and illuminate the history of successful efforts in the state and region that had an impact on the social justice movement. He is the subject of an award-winning biography titled “Horace T. Ward: Desegregation of the University of Georgia, Civil Rights Advocacy, and Jurisprudence,” authored by UGA School of Social Work Dean Maurice Daniels.
Daniels also served as executive producer and senior researcher on “Foot Soldier for Equal Justice, Parts I and II,” both award-winning documentaries that explore Ward’s story, the history of desegregation at UGA and the segregation policies in higher education across the country.
“Through his commitments and contributions to the University of Georgia, this state and this region, Judge Horace Ward has had and continues to have a positive impact on the lives of people in our community and in this state,” Morehead said.
Commencement at UGA Honors / Awards News Release
University invests in lighting and security…
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Employee assistance program vendor
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Venezuelans Are Pissed About Plan for Two-Day Work Week to Combat Energy Crisis
Venezuela is in the throes of an electricity crisis, and President Nicolas Maduro is pulling out all the stops in a desperate bid to conserve what little juice the South American county has left.
On Tuesday, Maduro's government announced that the government's 2 million public employees will only work Monday and Tuesday, and that they will be paid for the days they spend at home.
"There will be no work in the public sector on Wednesdays, Thursdays and Fridays, except for fundamental and necessary tasks," Vice President Aristobulo Isturiz announced. The new schedule will remain in effect until the energy crisis was over.
The declaration was not well received. Protesters took to the streets on Tuesday night, and looters raided shops for food and set fires. More than a dozen people were arrested for looting in Maracaibo, Venezuela's second-largest city, according to state security secretary Biagio Parisi.
Earlier this month, Maduro declared every Friday a national holiday for public sector workers for the following eight weeks. "We'll have long weekends," he said resolutely on state television. Those long weekends are now being extended to elementary school teachers, but employees of public hospitals and state-run supermarkets still have to work.
Related: Every Friday Is Now a Holiday In Venezuela, Thanks to the Energy Crisis
Maduro's big plan to save energy could be backfiring. The Associated Press reported that many people have been "going home to watch TV and run the air conditioning, leading critics to say the furlough is not an effective energy-saving measure."
Maduro said that water levels at the nation's hydroelectric dams have plummeted to dangerously low levels amid the worst drought in nearly 50 years.
Last week, the government also announced its plans to ration power for about four hours a day in 18 of 24 states. "It's necessary," Electricity Minister Luis Motta Dominguez said. "It's a sacrifice."
Those cuts will last 40 days, or until water levels stabilize at the Guri Dam, which provides the majority of Venezuela's electricity. Caracas was spared the power cuts. But over the weekend, residents of El Calvario, a poor area on the outskirts of the capital, protested after they were reportedly left without power for 29 hours. The AP reported that some Venezuelans say the country is beginning to represent the dystopia portrayed in The Hunger Games, where the nation's outer districts suffer to benefit the capital city.
Some have taken to Twitter to express their anger, using the hashtag #MaduroEsOscuridad, which means "Maduro is darkness."
Revoquemos la oscuridad - — Henrique Capriles R. (@hcapriles)April 25, 2016
Drought and low water levels at national dams are not a uniquely Venezuelan problem. What sets Venezuela apart, however, is its over reliance on hydroelectricity. When California's reservoirs began bottoming out, for example, the state turned to natural gas turbines and other avenues for electricity production.
The power outages have exacerbated Venezuela's already grave economic crisis. In 2014, country went into a recession that was compounded by sharply falling oil prices.
While Maduro has blamed the weather phenomenon El Nino for the electricity shortages, critics of his government say he mismanaged the entire situation, failed to develop backup energy sources, and invested poorly. Opposition politicians are currently collecting signatures and attempting to begin a process aiming to oust Maduro from office by the end of the year.
Related: Venezuela's Opposition Can't Pick a Strategy to Oust the President, So It's Trying Three
Watch the VICE News documentary Last Days of Chavez's Legacy: The Fall of Chavismo in Venezuela:
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Father John Misty Debuts Rejected ‘A Star Is Born’ Song, Agrees It Deserved to Be Cut — Listen
Zack Sharf
Indiewire June 17, 2019
“A Star Is Born” fans in attendance at Father John Misty’s June 14 concert in Mississippi got a surprise when the Grammy Award-winning musician debuted an original song he wrote for the movie that ultimately got rejected by director Bradley Cooper and his creative team. The untitled track is a country ballad that one could easily hear Cooper’s Jackson Maine belting.
Fortunately for Cooper, Father John Misty harbors no ill will against the “A Star Is Born” production for not going ahead with his song for the finished film. “That would’ve sucked,” the musician said after finishing his live performance of the song. “I’ve seen that movie. There’s really no place in that movie for that song, unless he was bombing at Coachella or something. The sequel? Now we’re talking.”
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Father John Misty worked with Lady Gaga and Mark Ronson on Gaga’s acclaimed 2016 album “Joanne,” co-writing the lyrics to the tracks “Sinner’s Prayer” and “Come to Mama.” Gaga brought Ronson with her to work on the “A Star Is Born” original music, so it’s not surprising to hear she would do the same with singer-songwriter Father John Misty (real name Josh Tillman). Ronson and Gaga’s work on the “A Star Is Born” original song “Shallow” won them the Academy Award for Best Original Song earlier this year.
Warner Bros. released “A Star Is Born” in theaters last October to a gross of $434 million at the worldwide box office. The film picked up eight Oscar nominations at the 91st Academy Awards, including Best Picture, Best Actor for Cooper, Best Actress for Lady Gaga, and Best Supporting Actor for Sam Elliot. The film’s soundtrack, which Father John Misty got cut from, went platinum in the United States. In addition to its Oscar win, the original song “Shallow” won the Grammy Awards for Best Pop Duo/Group Performance and Best Song Written for Visual Media. The song was nominated in the top categories of Song of the Year and Record of the Year.
“A Star Is Bown” is now streaming on HBO Go. Fans can listen to Father John Misty’s rejected original song in the video below at the 1:20:00 mark.
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US secretary of state arrives in India amid trade tensions
MARIYA AMRAYEVA
Associated Press June 25, 2019
APTOPIX India US
An activist of All India Peace and Solidarity Organization, AIPSO, a left-wing organization, holds a placard during a protest against the upcoming visit of U.S. Secretary of State Mike Pompeo to India, in New Delhi, India, Tuesday, June 25, 2019. Pompeo is scheduled to travel to India after having visited Saudi Arabia and the United Arab Emirates, on a trip aimed at building a global coalition to counter Iran. (AP Photo/Altaf Qadri)
NEW DELHI (AP) — The U.S. secretary of state arrived in India's capital late Tuesday after visiting Saudi Arabia, the United Arab Emirates and Afghanistan on a trip aimed at building a global coalition to counter Iran.
The visit of Mike Pompeo is the first high-level engagement between the two countries since Prime Minister Narendra Modi's re-election in last month's general election. He is scheduled to meet with his counterpart, S. Jaishankar, and Modi on Wednesday amid growing tensions between the two countries over trade and tariffs.
India imposed tariffs on 28 American products including apples and almonds on June 16 in retaliation for the U.S. ending India's preferential trade status on June 1. The Trump administration imposed higher duties on products including aluminum and steel.
The visit also comes ahead of scheduled meeting between President Donald Trump and Modi on the sidelines of the Group of 20 Summit in Japan later this week.
The two countries officials are also likely to discuss India's plans to purchase Russia's S-400 air defense system. U.S. has shown reservations about the deal.
Earlier Tuesday, hundreds of supporters of left-wing groups marched in central New Delhi to protest Pompeo's visit and denounce American policies in the Middle East. They demonstrated as riot police watched along the streets ahead of Mike Pompeo's arrival.
The protesters held banners reading "No war on Iran" and chanted slogans such as "Hands off Iran, hands off!" and "War mongering America, down down."
They urged the Indian government not to cut off imports of oil from Iran, as the U.S. has demanded.
"The relationship that the U.S. wants with countries like India is between a master and a servant," said Arun Kumar, a protester. "We are opposed to that. We want a relationship between equals."
Some other protesters also called for an end of American actions against the governments of Cuba and Venezuela, terming them "imperialism."
Philadelphia mayor fires back: Kenney says Trump would have to 'go back' to hell
WPVI – Philadelphia
Prosecutors drop groping case against actor Kevin Spacey
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If you need magazine customer service or have questions regarding your subscription, please contact us by email: ngmintl@subscription.co.uk
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National Geographic magazine’s distinctive yellow border is a familiar sight. It offers readers a portal to explore the farthest reaches of the Earth and beyond. Yet there is even more to National Geographic magazine than this—an extraordinary purpose that has driven the magazine and its readership for over 130 years.
Since 1888, National Geographic has been igniting the explorer in all of us with a determined commitment to furthering our understanding of the world. Our founders, including Alexander Graham Bell, understood the power of great storytelling to spark curiosity, solve big problems, and push the boundaries of knowledge, and so in October 1888 they printed a 50-cent journal with a plain brown cover. Since then, National Geographic magazine has grown to become the global mouthpiece for the National Geographic Society—a community of bold people with an insatiable curiosity and a passion for exploring and protecting the planet. The magazine and the society are inextricably linked in a unique and powerful partnership that shapes the way people think about the world and themselves.
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Photo: Rebecca Hale
Science, Faith, Virtual Reality and Archaeology meet at National Geographic Museum’s The Tomb of Christ
May 7, 2018 /in Featured, Lifestyle /by Andrew Hamm
Virtual reality headsets let you explore the Church of the Holy Sepulchre. Three dimensional videos take you through the streets of Jerusalem. All of this is an integral part of the National Geographic Museum’s Tomb of Christ exhibit.
With rooms recreated after the church, and panels packed with text and pictures, this exhibit teaches a lot. People in, or traveling to, DC before January 2019 should not miss this chance to meet a new place of mystery, and one that’s fully relevant to today’s divided world.
The exhibit highlights conservation and renovation done by scientists from the National Technical University of Athens on the Edicule in the Church of the Holy Sepulchre. The Edicule is the site within the site — a small shrine built over what’s remembered as the tomb of Jesus Christ, under the impressive dome of a large church in the Ottoman Baroque style.
The place of the Holy Sepulchre has a storied history. Over the past 2,000 years, it’s been a limestone quarry, a Jewish burial ground, a Roman temple to Venus, and multiple Christian churches—destroyed over the years by invaders and natural disasters, only to end up rebuilt. The most recent construction of the church and Edicule occurred in 1808, but the intervening 200 years have weighed heavily on the holy site.
This is where the scientists come in. Professor Antonia Moropoulou and her team have a reputation for saving historic monuments, including the Hagia Sophia in Istanbul and the Acropolis in Athens. Work on the Edicule, however, comes with a twist. The site is governed by the “Status Quo:” an 1852 agreement established by the Turkish sultan, when Jerusalem was under Ottoman rule, that any changes to the Edicule had to be agreed upon by unanimous decision of the six Christian orders that share the church—Greek Orthodox, Franciscan, Armenian, Coptic, Ethiopian and Syrian Orthodox.
Unanimous agreement isn’t easy. The six orders recognized all the way back in 1959 that the Edicule needed restoration. Mosaics were blackened by candle smoke and the walls were weak. Church leaders agreed to renovate on two conditions: the work would not interfere with pilgrims praying at the shrine, and the project would be completed between two Easter celebrations.
Then they waited for a proposal.
And kept waiting.
More than 50 years later, in 2015, church leaders finally received an offer from Moropoulou and her team.
The project used the best in available technology, including ground-penetrating radar, radiometry and robotics. Working by night, the team pulled off a trifecta: restoring the shrine’s original brilliance, reinforcing the structural integrity of the Edicule and contributing to archaeological understanding.
For the first time in centuries—and caught on camera by the National Geographic—researchers removed the stone slab covering Jesus’ tomb. The discovery of Byzantine material confirmed for archaeologists that this same site has been remembered as the location of Jesus’ tomb at least since the fourth century. Other archaeological evidence potentially dates this worship site to the first century.
The exhibit isn’t just about the restoration work, it’s literally a consequence of it. Part of the project involved gathering billions of recorded data points through millimeter-accurate LIDAR scans. With these data researchers created a complete 3D record of the site. This same LIDAR technology that allowed scientists to restore the site is what now allows museum visitors to tour the site through virtual reality.
The exhibit deals openly and respectfully with potentially controversial material—the biggest elephant not in the room. It clearly explains what is known through science, history and archaeological evidence. It doesn’t try to confirm or criticize religious beliefs that might be associated with the site.
“The religious significance of what lies hidden beneath the polished limestone and marble slabs of the church’s Edicule remains a matter of personal faith,” one panel suggests. “But people of all faiths can appreciate the beauty and long history of this storied building.”
The Church of the Holy Sepulchre—home to six different Christian orders, visited every year by believers and nonbelievers of every kind—serves as a microcosm of the whole city of Jerusalem. The city is also home to important Jewish and Muslim sites, including the Wailing Wall and the Dome of the Rock.
For this reason, the National Geographic Museum is also showing a film about Jerusalem the city. Although it’s separate from the Tomb of Christ exhibit (and requires a second ticket), this film provides important context to the experience. The video profiles three articulate teenage women—Jewish, Muslim and Christian. These women introduce viewers to their lives, with an emphasis on their similarities—especially their shared love of their families and city.
The exhibit can be viewed in an hour. The film lasts 40 minutes. And although the exhibit and film cost money (ticket information available at here), the museum also boasts free offerings.
National Geographic Museum: 1145 17th St. NW, DC; 202-857-7700; www.nationalgeographic.org/dc
https://ontaponline.com/wp-content/uploads/2018/05/03_NG_TombofChrist_20171115_022_credit-Rebecca-Hale_preview.jpg 336 650 Andrew Hamm https://ontaponline.com/wp-content/uploads/2019/06/OnTap_Magazine.png Andrew Hamm2018-05-07 16:19:472018-05-07 16:29:26Science, Faith, Virtual Reality and Archaeology meet at National Geographic Museum's The Tomb of Christ
Into A Whole New World: A Q&A with Aladdin’s Kaena Kekoa July 9, 2019
Changing Minds Through Jazz: A Q&A with Mark G. Meadows July 8, 2019
Michael Urie Pulls Double Duty in DC July 1, 2019
The Brewery Tour VIP Giveaway Sweepstakes July 1, 2019
Music Picks: Nas, Cecily, Blink-182 and More June 29, 2019
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Tag Archives: Prudery
Dawn Eden’s Thesis and Defense
Posted on June 15, 2010 by Fr. Angelo M. Geiger
The following is cross-posted here from Dawn Eden’s blog.
My master’s thesis is now available for purchase
Today, in response to requests, I am making my master’s thesis available for purchase by the general public as an eBook. At the same time, it is available for free to priests, seminarians, and lay catechists who work in an official capacity for the Church (e.g. for a parish, diocese, or religious order).
It is titled “Towards a ‘Climate of Chastity’: Bringing Catechesis on the Theology of the Body into the Hermeneutic of Continuity.” (I had made it available briefly before, but decided to pull it until after making my defense, so that I might revise it to incorporate the official readers’ suggestions.)
The 81-page, heavily footnoted thesis is a critique of Christopher West’s presentation that reveals the substance behind recent criticisms of his approach, contains new information (including how the fathers of Vatican II condemned the Jungian phallic interpretation of the Easter Candle ritual), and makes positive suggestions for improving instruction on the TOB.
Those who qualify for a free copy of my thesis are invited to write to request one to be sent by e-mail. Others who would like to read it are asked to donate $10 or more to a fund I have created to finance my doctoral studies in moral theology at the Catholic University of America this fall. Click here to donate, and I will e-mail you the eBook (PDF file).
(Some requests for free copies have come in from people who do not work for the Church, but are “starving students.” I ask them to consider prayerfully the possibility of aiding this “starving student”‘s education by donating the cost of a pizza in exchange for her hard work.)
I greatly appreciate the support of those who read this blog during the years when I maintained it, and of all who have encouraged me in my studies. Your prayers and encouragement keep me going as I begin the long road towards a doctorate and, Deo volente, my further goal of teaching at a small Catholic college.
Following is the speech that I delivered when defending my master’s thesis at the Pontifical Faculty of the Immaculate Conception at Dominican House of Studies, Washington, D.C., on May 19, 2010:
Good evening. I am here tonight to defend my master’s thesis, which is a critique of Christopher West’s presentation of Pope John Paul II’s theology of the body. By “Christopher West’s presentation,” I mean not only his own personal presentation, but also, more generally, the presentation that he promotes through his Theology of the Body Institute, which trains priests and lay catechists to teach his particular interpretation of John Paul II.
I chose this topic, first, because the issues it encompasses—the promotion of the Catholic vision of marriage and family—are close to my heart, and second, because it is highly topical, given that West’s presentation has recently been the subject of public debate among theologians.
In fact, after I completed my thesis, the subject became even more topical with West’s unexpected announcement at the end of March that he was taking a six-month sabbatical, effective immediately. The Theology of the Body Institute, which is the nonprofit created to promote his presentation of the theology of the body, stated that West was taking this leave “to attend to family needs, and to reflect more deeply on fraternal and spiritual guidance he has received in order to continue developing his methodology and praxis as it relates to the promulgation of the Theology of the Body.”
This is noteworthy because it marks the first time West has ever publicly affirmed a willingness to reflect upon his presentation, something that his critics have asked of him for nearly ten years.
My thesis is titled, “Towards a ‘Climate of Chastity’: Bringing Catechesis on the Theology of the Body into the Hermeneutic of Continuity.”
The first half of the title, “Towards a ‘Climate of Chastity,'” is a reference to Humanae Vitae. In that encyclical, Pope Paul VI called attention to “the need to create an atmosphere favorable to the growth of chastity so that true liberty may prevail over license and the norms of the moral law may be fully safeguarded.” That passage was a key text for John Paul II in his Wednesday catecheses on the theology of the body.
The second half of the title, “Bringing Catechesis on the Theology of the Body into the Hermeneutic of Continuity,” refers to a central point of my thesis. Christopher West asserts that the theology of the body is “revolutionary” because “previous generations of Christians” grew up under the burden of a “repressive approach” to sexual issues. His intention is to counter a popular myth—the idea that the Church is, as he puts it, “down on sex.” However, in countering the one myth, he inadvertently fuels another—the idea that, in the wake of Vatican II, we are “building a new Church,” a Church that is fundamentally different from that which preceded it. His praise on Pope John Paul II is predicated on the repeated assumption, sometimes explicit, that the preconciliar Church was stodgy and prudish. While he no doubt intends to promote charity and unity, his approach effectively encourages division and disdain for our past.
That is why I argue that his presentation on theology of the body needs to be reconciled with the “hermeneutic of continuity.” That expression is drawn from the 1985 Extraordinary Synod of Bishops, which stressed that the Second Vatican Council “must be understood in continuity with the great tradition of the church, and at the same time we must receive light from the Council’s own doctrine for today’s Church and the men of our time. The Church is one and the same throughout all the councils.”
Having said that, the very use of the words “hermeneutic of continuity” in my thesis title reflects a paradox inherent in applying theological analysis to popular catechesis and apologetics. West himself almost never resorts to language as obscure to non-theologians as “hermeneutic of continuity.” He directs his words to the ordinary people in the pews. The one who dares to critique him on an academic level risks pretentiousness or even self-parody–like the Times of London music critic who praised a song from the Beatles’ first album for its “Aeolian cadence.”
Nonetheless, I am willing to take that risk, because Christopher West does not present himself as a mere apologist, seeding the ground for faith via rational arguments. Nor does he present himself as merely engaging in catechesis, which, as the Holy See has stated, consists of “transmitting the Gospel, as the Christian community has received it, understands it, celebrates it, lives it and communicates it in many ways.” Rather, Christopher West presents himself as the definitive interpreter of teachings of John Paul II—teachings which, as I will explain shortly, he claims “will lead to a dramatic development of thinking about the Creed.” He is essaying apologetics and catechesis and theology itself. As such, his approach merits serious critical analysis by theologians—especially in light of its overwhelming popularity.
Along with West’s undeniable talent as an author and speaker, there is an element of marketing genius at work. As I noted, he presents himself as the definitive interpreter of Pope John Paul II’s theology of the body. Until last year, when his then-ordinary Bishop Kevin Rhoades and Cardinal Rigali issued a public endorsement of his work, the main evidence that he offered for his teaching authority was that he was fulfilling an imperative laid out by George Weigel in his 1999 biography of John Paul II, Witness to Hope.
Weigel wrote that the theology of the body was a “theological time-bomb set to go off with dramatic consequences … perhaps in the twenty-first century.” He added, “John Paul’s portrait of sexual love as an icon of the interior life of God has barely begun to shape the Church’s theology, preaching, and religious education. When it does it will compel a dramatic development of thinking about virtually every major theme in the Creed.”
From the start of his public career, Christopher West has marketed himself as carrying out this mandate. One sees this most recently in the promotional material for the upcoming TOB Congress sponsored by the Theology of the Body Institute, which was formed to promote West’s presentation. The promotional material states that the conference is “building on the words of papal biographer George Weigel—that this teaching ‘will affect every major theme of the Creed.'” The congress’s workshops are structured around that same premise; the one on catechesis is actually titled, “Catechesis and the Creed in Light of the Theology of the Body.” The overriding implication in that title—and with West’s entire presentation—is that that the Creed is something to be viewed in light of the theology of the body, rather than vice versa.
Having explained why Christopher West’s presentation of the theology of the body merits a theological critique, I will now summarize my thesis.
Chapter One begins with some biographical background on West. As mentioned, a foundational point of his presentation of the theology of the body is that John Paul II’s teachings are “revolutionary” because “previous generations of Christians” grew up under the burden of a “repressive approach” to sexual issues. Because he uses his own experiences to support this point, it is relevant here to explore those aspects of his upbringing that informed his understanding of the attitudes he believes are ingrained in “most Christians.”
West’s understanding of what constitutes a normative Catholic upbringing may be shaped from his experiences during his late teens and early 20s living with his family in the Mother of God Community, a Catholic community in Gaithersburg, Maryland. At that time, during the late 1980s and early 1990s, the community’s leaders exercised puritanical control over members’ lives—including their dating. Eventually, in 1995, James Cardinal Hickey, the Archbishop of Washington, would order reforms to the community to correct its abuses of power. But those changes came too late for West, who, during his time in the community, was subject to its strict rules.
Christopher West told the Washington Post that, after spending years living in the community and submitting to its leaders’ control of his social contacts, his work, and his studies, he realized, “It’s a cult. I’ve been living in a cult.”
Now, one certainly doesn’t have to grow up in a cult to appreciate the dangers of a puritanical approach to sexuality. However, I have found in my research that West’s experiences in the Mother of God Community appear to come into play in his interpretation of John Paul II’s teachings on continence. I will return to this point when I describe the particulars of West’s presentation.
The rest of Chapter One is taken up with a list I compiled, comprising ten major themes of West’s presentation of the theology of the body. In Chapter Two, I examine the criticisms that his presentation has engendered, as well as his responses to those criticisms, and add my own critique. I conclude my critique in Chapter Three, identifying the aspects of West’s presentation that I believe are in most serious need of modification, and recommending specific positive correctives.
I will now briefly list the ten major themes of West’s presentation that I identify in Chapter One:
1. The TOB is an all-encompassing theology that requires theologians and religious educators to recontextualize “everything” about Christian faith and life.West says, “Indeed, a ‘holy fascination’ with our bodies as male and female is precisely the key that opens the holy door to the divine bridal chamber, allowing us to experience what the mystics call ‘nuptial union’ with God.” He also says, “Sex plunges us headfirst into the Christian mystery.”
2. The “sexual revolution” was a “happy fault.” West praises the sexual revolution because, as a reaction against generations of repression and prudery, it “got us talking about our hunger.” What Pope John Paul II did was redirect the discussion in the right direction. So, West says, “The Church looks at the sin of Adam and proclaims, ‘Oh happy fault that won for us so great a redeemer.’ We can look at the error of the sexual revolution and say ‘Oh happy fault that has won for us so great a theology of the body.'”
3. “Dumpster” vs. “banquet.” West likens using pornography to eating out of a “Dumpster,” whereas the joys of sex according to the theology of the body is the “banquet.” West says, “Why was [Playboy magazine founder] Hugh Hefner a successful ‘evangelist’?” West asks. “Because eating fast food is a lot better than starving to death.” Whereas Hefner was “just going to the wrong menu to feed the hungry,” the TOB offers “the banquet of love that truly satisfies.”
4. The nuptial analogy is the primary means by which the faithful should understand their relationship to God—and “nuptial” is to be envisioned in sexual terms. This leads to—
5. “[T]he whole reality of the Church’s prayer and sacramental-liturgical life is modeled on the union of spouses.” In participating in the liturgy, “we are called to deep, intimate, ecstatic joys with Christ the bridegroom.” The faithful who “have eyes to see” are called to be “inebriated,” getting “drunk in the Spirit” on the “new wine” of the “wedding feast of the Lamb.” “In this ‘blessed death’ of holy intoxication, sexual desire passes-over [sic] from lust to an immeasurable love.”
In this regard, West says that the Paschal Candle is intended to be a phallic symbol. I write, later in my thesis, that I was unable to find any source for this in Tradition. Since completing my thesis, I have found evidence that this interpretation is of secular origin and was condemned by the fathers of the Second Vatican Council. [N.B. The revised edition of my thesis that I have made available contains background on the Council’s condemnation of the Paschal Candle “phallacy.”]
6. “The joy of sex—in all its orgasmic grandeur—is meant to be a foretaste in some way of the joys of heaven.”
7. “God created sexual desire as the power to love as he loves.”
8. “Mature purity” enables “liberation from concupiscence.” I will have more to say about this assertion shortly.
9. “The Song of Songs is of great importance to a proper understanding of Christianity.” It shows “[h]ow we come to see the sexual embrace, the deep intimate erotic love of husband and wife, as a passageway into deep transforming intimate union with God.”
10. The meaning of marriage is encapsulated in “intercourse.”
These themes, taken in their entirety, imply that God’s spousal love for His Church should be envisioned by the faithful in an explicitly sexual manner.
Now, there are certain elements of truth in these interpretations that cannot be ignored. To use a favorite phrase of John Paul II—”in a certain sense”—the liturgy is spousal. Likewise, in a certain sense, the sexual union of spouses may be said to image Trinitarian love. If West’s theology stopped there, one could enter into discussion with him over the extent to which, in this day and age, it benefits the faithful to have explicitly sexual imagery introduced into their prayer life. One could also discuss how, in comparing the sexual union of spouses to the beatific vision, one might avoid the risk of either overselling sexual pleasure, or underselling heaven.
The problem, as I see it, is that West doesn’t stop there. He believes that the true message of John Paul II’s theology of the body is that sexual desire necessarily mediates desire for God.
The key word here is “necessarily.” I am not denying that sexual desire can mediate desire for God. For West, however, there is no other way. This is why University of Dallas Professor Mark Lowery, back in November 2001, wrote in the National Catholic Register that, while West’s intention clearly was to convey the truths of the faith, “his overarching lens or perspective” led to “the lurking danger of conveying that Christianity really is all about sex.” In other words, as Lowery put it, instead of Christianizing sexuality, West risked “sexualizing Christianity.”
The implication that sexual desire necessarily mediates desire for God is an undercurrent throughout West’s oeuvre. One sees it particularly in his repeated insistence that every opportunity to sublimate sexual desire is an opportunity for holiness. I cover this in detail in my thesis. The Church has traditionally stated that chastity education should include instruction on avoiding occasions of sin. West states, by contrast, that mature purity is found only in those who are willing to “risk” concupiscence so that they might reap the benefits of “union with Christ and his Church.” By “risking,” he means specifically that men who struggle with lust should practice looking at beautiful women so that they might learn to raise their thoughts and feelings from lust, to joy at encountering the image of God in female beauty.
Now, borrowing a page from West himself—who is known for quoting classic rock songs in his talks—I would call this the Harry Nilsson approach to overcoming lust. Nilsson wrote and sang the hit song “Coconut,” in which a woman puts the lime in the coconut, drinks them both up, and then calls the doctor to complain of a bellyache. The doctor’s prescription is to put the lime in the coconut and drink them both up. The cause is the cure. So it is with Christopher West’s prescription for men who lust after beautiful women: Look at beautiful women.
West’s implication that sexual desire necessarily mediates desire for God also appears clearly Heaven’s Song, his 2007 book that is directed primarily toward aiding the reader’s “sexual healing and integration.” There, West insists “sexual love is the earthly key that enables us to enter into heaven’s song.” He elaborates, “[T] he road to holiness passes by way of sexual healing and integration. The way we understand our bodies and the union of man and woman has a direct bearing with the way we understand Christ’s body and his union with the Church. Hence, if we are to enter in to proper union with Christ and his Church, the diseased images and ideas we have about our own bodies and sexual union must be healed. It can be a long and painful journey—and there is no detour.”
What concerns me is West’s insistence that the “long and painful journey” of sexual healing and integration has to precede holiness. As Mark Lowery noted back in 2001, sexual healing comes from grace—not the other way around.
Moreover, in a point also made by Lowery, grace does not always heal us of everything from which we would like to be healed. It is not a zero-sum game. Self-control is possible with the gift of the Holy Spirit, but, as Paul learned, God does not remove every thorn in the flesh.
A major concern of my thesis is the divergence between West’s presentation and John Paul II’s teachings with regard to continence. I mentioned earlier that West says mature purity is found only in those who are willing to “risk” concupiscence so that they might reap the benefits of “union with Christ and his Church.” To underscore the importance of taking this “risk,” he attacks the notion that an engaged couple wishing to stay chaste should “never spend any extended time alone together.”
Now, the concern that engaged couples may be too chaste seems anachronistic in the wake of the sexual revolution. But remember that West spent his late teens and early 20s living in a community where engaged couples were in fact barred from spending time alone together. So this is a very real concern for him, and he is understandably eager to point out that Catholic teaching permits individuals a certain amount of latitude to responsibly exercise their freedom.
Unfortunately, in his desire to counter puritanical attitudes, West ends up promoting an ideal that has the net effect of promoting puritanism. I discuss this in detail in my thesis, and explain how it is based upon a misinterpretation of both John Paul II and St. Thomas, whose theology is the basis for John Paul’s discussion of the virtue of continence. Essentially, West says that not only must an engaged couple be continent, they must possess the virtue of perfect chastity prior to marriage. That is, they should have no fear of being alone together, because they should have no lust for one another. West said in a talk just last year that an engaged couple who are merely continent cannot be called virtuous because “[t]here is no magic trick on the wedding day that suddenly makes what you do that night an act of love. If you could not be alone together the day before you got married and not sin, there is no magic trick, there is no waving at the wand at the altar, that suddenly makes your sexual behavior beautiful, true, good, lovely, and pure.”
What is wrong with this picture? As I explain in my thesis, what is wrong is, (A) the implication that continence is an insufficient preparation for marriage, and (B) the claim that the sacrament of marriage in no way affects the development of virtue. In fact, the Church does not expect perfect chastity of couples before marriage, precisely because she recognizes that the grace of marriage is what enables couples to transform their imperfect virtue of continence to the perfect virtue of chastity. All that is required of an engaged couple is that they control themselves “in holiness and honor,” as St. Paul writes in First Thessalonians.
By raising the bar so high, to the point where any feeling of lust is proof that one is not ready for marriage, West is effectively promoting the very angelism that he decries. In an age when Catholics—along with singles in general—are marrying later and later, such a misinterpretation of Church teaching has real pastoral implications. I see them when speaking on chastity to young adults. Twice when I have spoken in Manhattan, someone in the audience has asked me, “Why are Catholics in New York City so afraid of dating?”
I was last asked that when I spoke at Columbia University in March. The questioner added, “Catholics here in the city think that they can’t date before marriage—they can only be friends. And these are Catholics who know the theology of the body.”
Young Catholics who are told that they are not ready to marry until they have not only continence, but perfect chastity, are simply avoiding the rituals of courtship. I have since discussed this problem with others, including a priest who is a vocations director, and am confirmed that it is a genuine pastoral issue.
Towards the conclusion of my thesis, in suggesting positive correctives to West’s presentation of the theology of the body, I emphasize the need for catechists to incorporate into the theology of the body the Church’s teachings on suffering. Pope John Paul II himself said, in his final Wednesday address on the theology of the body, that catechesis on the topic would not be complete without addressing “the problem of suffering and death.” If catechists do not account for this—if they present a vision of married life that is all about couples’ sharing in Trinitarian communion, without articulating how they also share in Christ’s sufferings on the Cross—then their words will be like those in the parable of the sower, that fall on rocky ground. As Our Lord said, “Those on rocky ground are the ones who, when they hear, receive the word with joy, but they have no root; they believe only for a time and fall away in time of trial.”
I think it is significant that in 1984, the same year he would complete his catechesis on the theology of the body, John Paul produced his great Apostolic Letter Salvifici Doloris, “On the Christian Meaning of Human Suffering.” In that encyclical, he wrote, “The eloquence of the parable of the Good Samaritan, and of the whole Gospel, is especially this: every individual must feel as if called personally to bear witness to love in suffering.” It is the task of the catechist to seek out the connection between that witness to love mandated by Salvifici Doloris and the witness to love mandated by the theology of the body.
Would you like to read my entire thesis? Please click here to donate $10 or more towards my doctoral studies, and I will e-mail you the eBook.
Posted in Catholicism, Husbands, Marriage, Men, Religion, Wives, Women | Tagged Chastity, Christopher West, Dawn Eden, Human Sexuality, John Paul II, Modesty, Prudery, Theology of the Body | 4 Replies
Father Peter Damian Fehlner on Ratified, Non-Consummated Marriages
Posted on February 13, 2010 by Fr. Angelo M. Geiger
Posted supplementary to my two previous posts (1 and 2):
When are the sacramental graces of marriage received? It has recently became fashionable to state, categorically, that no such sacramental graces are received until a sacramental marriage is consummated, as though a non-consummated marriage is not fully a sacramental marriage. This is simply false. The essence of a sacramental marriage consists in the contract, both as to the celebration of the sacrament and to the permanent state following on that celebration. The first is known as marriage “in fiere” and marriage “in facto esse”. Use has nothing to do with constituting the essence of marriage. This is certainly very logical, whereas the new proposal is hardly that. The conferral of sacramental graces is a presupposition for the holy fulfillment of marriage rights and duties, including use of the marriage act or sexual intercourse. Hence, it is only logical that it be conferred before use of the marriage act. If the sacrament is celebrated worthily, viz., the spouses are in the state of grace, an increase of sanctifying grace follows immediately on the administration of the sacrament, together with the effecting of the marriage bond with the rights and duties which this entails. It is the marriage bond or “vinculum” which is the essence of the marriage state or permanent marriage contract, not the use of the marriage rights. The right to actual graces in order to carry out the duties of the married state which are many besides the use of the marital act is rooted in the vinculum which constitutes a kind of proximate disposition for their conferral at the appropriate time and circumstances. This is clearly the teaching of St. Thomas and is concurred in by St. Bonaventure. Although a few modern theologians consider the vinculum a kind of quasi sacramental character, the majority of theologians prefer to abstain from the use of this terminology. (Cf. F. Sola, SJ. Sacrae Theologiae Summa, volume 4, Madrid 1953, pp. 837-843 for magisterial and theological authorities.) The principal magisterial authorities for this teaching are Leo XIII (Arcanum divinae sapientiae) and Pius XI (Casti Conubii).
Why is the petrine privilege limited to sacramental marriages “ratum sed non consummatum”? A recent opinion claims that this restriction is related to the relative imperfection or incompletion of such a sacramental marriage. Only the consummation of a sacramental marriage makes it fully sacramental, so the theory goes. But this contradicts the long standing explicit teaching of the Magisterium for over a millennium. Any marriage, but especially a “matrimonium ratum”, if intrinsically and fully indissoluble. Intrinsically means that those united permanently by the marriage bond cannot end that bond, nor can the existence of spiritual or psychological frustrations on the part of the spouses, sometimes described as the “death” of a marriage, effect a dissolution of bond. But this has never been meant in the teaching of Christ and of the Church to exclude the possibility of dissolving or ending a marriage by legitimate authorities apart from the spouses. This authority belongs to God because he is the one who instituted marriage and defined the nature of the contract. His authority extends to all marriages, sacramental or merely natural, all of which by his disposition end with death. In one instance, that of the so-called “Pauline privilege” he has when certain conditions are fulfilled decreed the end of a natural marriage “in favor of the faith” in one of the spouses who converts to belief in Christ and is baptized, but the other refuses to live in peace with the converted spouse.
In some special cases Christ has conferred on the successors of St. Peter to dissolve non-consummated sacramental marriages in particular and relatively rare instances. The reason for this delegation is to be found, not in the incompleteness of such a marriage as marriage, but in the imperfect clarity of the sacramental sign, the same rationale underlying the Pauline privilege, the only difference being that in the case of the Pauline privilege the dissolution is effected directly by God himself (no delegation for this has been given either to civil or ecclesiastical authorities). The rationale is this: in these cases the sign value of marriage is either not clearly present (natural marriage) or only partially in the case of a non-consummated sacramental marriage. According to the teaching of Casti connubii, this sign value is twofold: that of Christ with the Church and by extension with souls (a spiritual union) and that of the Divine Word with his human nature (a physical union). The first is realized immediately on celebration of the sacrament, the second only with consummation. The vicarious power to dissolve the bond granted by Christ to the Pope in regard to non-consummated sacramental marriages is limited to those instances where “spiritual death” has occurred (e.g., solemn profession in a religious order) or where this is postulated by the spiritual need of one or the other spouse. But with consummated sacramental marriages the sign value is such that Christ reserves all questions of dissolution of the bond to himself because of the perfection of the sign. Evidently the perfection of the sign is not the equivalent of perfection of the marriage, which must be decided on other criteria, particularly when the virginal marriage of Mary and Joseph is taken into consideration. (cf. the treatise cited above, pp. 826-827; 830)
Posted in Catholicism, Marriage, Men, Religion, Wives, Women | Tagged Christopher West, Father Peter Damian Fehlner, Human Sexuality, John Paul II, Michael Waldstein, Modesty, Prudery, Theology of the Body
Sexing up Canon Law
In response to my last post, “Christopher West: Sexualizing Christianity,” one of his supporters posted a lengthy comment, defending the sexy assertion that the sacramental grace proper to marriage is not confered through the wedding vows but through the act of the consummation of the marriage, so that no sacramental marriage really exists until the spouses engage for the first time in the marital embrace. He (or she) also claims that sacramental grace is also conferred every and each time the spouses engage conjugal act “in a human fashion.”
Since this is so interesting and crucial to the argument, I have chosen to reproduce the comment here and answer it below. Continue reading →
Posted in Catholicism, Husbands, Marriage, Men, Religion, Wives, Women | Tagged Canon Law, Chastity, Christopher West, Human Sexuality, John Paul II, Michael Waldstein, Modesty, Prudery, Theology of the Body
Christopher West: Sexualizing Christianity
Posted on February 8, 2010 by Fr. Angelo M. Geiger
I recently became aware of an exchange between Dr. Mark Lowery and Christopher West that took place in around the turn of the year 2002. Dr. Lowery’s assessment of Mr. West’s work was fair. Like many today, he commended the Theology of the Body apologist for his flair getting across to audiences around the country the reason why “the bedroom needs the Church.” And like many today, he expressed his reservations about the way in which West “sexualizes Christianity.” Lowery intimates that a kind of inversion has taken place in West’s understanding of the relationship between sexuality and Christianity:
Put another way, so clearly does he see how sexuality must be taken up into Christianity that he can give the impression that Christianity has been taken up into sexuality.
Posted in Catholicism, Chivalry, Culture, Husbands, Marriage, Men, Religion, Wives, Women | Tagged Christopher West, David L. Schindler, Dawn Eden, Dr. Mark Lowery, Human Sexuality, Janet Smith, John Paul II, Michael Waldstein, Prudery, Theology of the Body
A Response to Christopher West
Posted on October 30, 2009 by Fr. Angelo M. Geiger
In his long-awaited reply to his critics, West honestly admits that he did not want to say anything until he had received the all clear from the bishops, a boon given in abundance by Cardinal Rigali and Bishop Rhoades. While the bishops’ endorsement is significant, it does not mean that West’s teaching is magisterial or that it is on the level of those who themselves hold the teaching office of the Church. Even a theologian who has gained the endorsement of a pope, such as Hans Urs von Balthasar or Cardinal Walter Kasper, is not considered above respectful criticism when he articulates views that may legitimately be shown to be difficult to reconcile with the Church Fathers and Doctors.
West is gracious for thanking his supporters, but his reference to the “profound consolation” proffered by the faithful is a bit off-putting. He has chosen the path of controversy of his own volition, and for him that it is a matter of truth. Speaking the truth has its consequences, as does making mistakes as a teacher. It must be difficult to the focus of so much criticism, so I do pray for him. Nevertheless, he is considered, the authority on Theology of the Body, even more so now that he has been so strenuously defended. Constructive criticism is in order.
The Pivotal Obfuscation
In my opinion, his concentration on the question of concupiscence is, for the most part, a straw man. It seems evident that since Cardinal Rigali has blessed his entire work without qualification, West considers it is sufficient to reply to what he considers the central issue of contention. Thus, he conspicuously omits any discussion his crusade against prudery or of any of the practical matters that have been dealt with at length by the critics (e.g. the phallic symbolism of the paschal candle, his treatment of interlocutors, his interpretation of his writings of the saints). I will even grant that the question of concupiscence is central to the discussion. However, West mischaracterizes the objections of his critics. Continue reading →
Posted in Blessed Virgin Mary, Catholicism, Culture, Husbands, Marriage, Men, Spirituality, Wives, Women | Tagged Bishop Rhoades, Cardinal Justin Rigali, Chastity, Christopher West, Concupiscence, Father Thomas Loya, Human Sexuality, John Paul II, Modesty, Prudery, Purity, Shame, Theology of the Body | 27 Replies
In Defense of Purity 1
Posted on September 29, 2009 by Fr. Angelo M. Geiger
As promised, here is my first post on Dietrich von Hildebrand’s Purity: The Mystery of Christian Sexuality (originally published as In Defense of Purity). It is probably longer than will be my other posts on the book. We will see. I thought there were some basic ideas about “shame” that I wanted to establish from the beginning. Part of my work here will be to do a comparative study of von Hildebrand’s writing on Purity vis-à-vis John Paul II’s Theology of the Body.
Book I: Purity; Part I: Sex; Chapter I: Sex Distinguished from Other Bodily Appetites
There could be no greater mistake than to explain the tendency to conceal sex as exclusively, or even primarily, an endeavor to hide something disgraceful or ugly (Purity 6).
Catholic tradition describes this tendency to conceal sex as “modesty.” It is a certain kind of shame. We would do well to understand what it is and what it is not.
The shame of English
In his book, Purity: The Mystery of Christian Sexuality, Dietrich von Hildebrand distinguishes between different kinds of shame. Some kinds of shame are, in fact, a reaction against what is “disgraceful or ugly.” Yet not all shame is so. Some kinds of shame are a form of reverence. For example the French word pudeur is translated into English as “shame”; however, it has the nuance of “holy bashfulness” for which there is no equivalent in English.
This limitation of the English language is an impoverishment of our ability to speak of this basic human experience in a precise philosophical way. We call both the fear of the ugly and disgraceful and the awe of the holy and mysterious, “shame.” In other languages this is not the case.
The particular problem with the English word is that it has a primarily pejorative sense. Very few people would ever consider using the word “shame” in reference to a reaction which actually positive. When, for example, we are caught an evil deed we might admit that we are ashamed of ourselves. However, if someone complemented us in public unexpectedly, most of us would not say that we were “ashamed,” but “embarrassed.” But even this latter word is ambiguous, because sometimes were are embarrassed also because we look foolish or out of step.
My use of the phrase “shame on you,” in a previous post was meant to underscore the limitation of our use of the English word. Hence, among English speakers, when we are discussing our reaction to holy things, mysteries and aspects of our lives that are deeply personal and intimate we often use the words “modesty,” and “reverence.”
In matters of sexuality these ambiguities are particularly crucial because of the depth at which we experience our sexuality and, thus, because of the way in which the experience of sexuality, can have tremendously positive and negative values. We might very well be “ashamed” of sex, because we are intuitively or meditatively aware of how holy and mysterious it is, or we might be “ashamed” of sex because our experience of it has been unspeakably debauched and profoundly disrespectful of God, ourselves and others. We might also be ashamed of sex—it is true—because in our sinfulness we are no longer able to perceive its beauty and begin to project onto it the disorder of our own heart. Or finally, we may be ashamed of sex, because we hold the heresy that sex and the body are evil. Whatever our experience in this regard might be, our heart tells us that the matter in question is profoundly important. We cannot afford to confuse these various experiences, because they are truly different and touch directly upon our practice of the virtue of purity.
Our Secret
In the first chapter of von Hildebrand’s Purity, he distinguishes sharply the sex drive from other bodily appetites on the basis of the depth at which we experience these various appetites. Our other bodily appetites such as hunger and thirst are experienced on a relatively superficial level and ordinarily do not become the focus of our deep and serious attention, except when we they become a question of our survival (3).
It is one thing, for example to give one’s attention to the preparation of food in proportion to the general welfare of individuals, say a family and both its nutritional and social needs. It is another to be obsessed with food and the particulars of its preparation. It is still another to become profoundly aware of how dependent we are on food, when one is starving to death. The fact is that we generally experience such bodily desires on a superficial level and only experience them deeply in a moment of crisis.
On the other hand, von Hildebrand says that our sex desire is essentially deep:
Every manifestation of sex produces an effect which transcends the physical sphere and involves the soul deeply in its passion. . . The positive and negative values attaching to sex belong to a level far deeper than those which attach to the other bodily appetites. Indeed, these sexual experiences are characterised by a specific character of mystery . . . (4).
Von Hildebrand says that the depth of sexual experience is established by two factors: the uniqueness of the manner in which body and soul meet in the experience of sex; “the particular intimacy of sex.”
In this chapter of the book, he focuses on the second factor and calls sex “the secret of the individual”:
It is something which the person concerned feels to be altogether private, something which belongs to his inmost being. Every disclosure of sex is the revelation of something intimate and personal. It is the initiation of another into our secret. It is for this reason that the domain of sex is also the sphere of shame in its most characteristic sense. We are preeminently ashamed to unveil this secret to others. Whether and man is modest or immodest depends first and foremost on his attitude to sex (5-6).
It seems to me that von Hildebrand’s analysis accord’s exactly with universal experience of man and is so close to us that generally most people never examine the causes of our reactions. But when we hear a wise man like von Hildebrand express the truth of it, we say, “Yes, that’s it.”
The fact is that our sexuality is tied to our deepest identity as a person and to the mystery of what it means to be a person. We are vulnerable in our sexuality because we are vulnerable as persons who desire to love and to be loved and who never wish to be used. We “expose” ourselves to others in the degree to which it is appropriate to communicate our person and we leave the most intimate revelations to a select few and in some cases to one alone. Our secret is ourselves, and in the end it is the only thing we really can call our own. It is the only real gift we have.
The Spousal Meaning of the Body
Dietrich von Hildebrand’s analysis seems to me to be in full accord with that of John Paul II, though the emphasis is different. Von Hildebrand emphasized the positive aspect of shame relative to the mystery of the person, whereas John Paul II emphasizes the negative aspect relative to the danger of objectifying the person.
When in the Theology of the Body the pope writes about the “spousal meaning of the body” in the context of original innocence, in which man, male and female, were naked and felt no shame, he is speaking of the fact man, male and female, is created for love and is oriented by creation toward making the gift of himself to the other (14.5). It is in this way, as Genesis tells us, that man is created in the image and likeness of God (1:26). In other words the communio personarum (communion of persons) to which man is called is a reflection of the life of the Father, Son and Holy Spirit, the Trinitarian communion of knowledge and love (9.1-3).
This truth is written in the human body, differentiated as male and female, and the bodily union to which man is called in marriage is a sign of the deeper communio personarum of spouses. That deeper communion is charity and the conjugal embrace, as it was intended from the beginning, is not only its sign but through chaste love and sacramental living it becomes a particular means of achieving it (29.3; 131.2-3).
In the state of original innocence the deep meaning of the body was not distorted by the subordination of the gift meant to be loved to its use for selfish gratification. The interiority of man shined outwardly in its entire splendor, with no confusion of its meaning. Not only was the gift unthreatened by the tendencies of fallen nature, but we might also say that for that reason it was less mysterious and more radiant.
Veiling and Unveiling the Mystery
In terms of the importance of this appreciation for the state of original innocence relative to our own state of fallen nature, which we are offered in the Theology of the Body, it is necessary to define and understand the dimensions of the analogy which the Holy Father is using. There is, of course, the sense that Adam and Even represent universal man, male and female, and are a paradigm for the relation of the sexes in general. But there is also the sense in which Adam and Eve as two real persons are created male and female for each other personally. In fact, Eve is specifically created as a person to be the helpmate of the only other human person, Adam. So, it seems to me, that while the relationship of Adam and Eve can be used analogously to represent the relationship of all men and women in general, they are more properly an analogy of the relationship of husband and wife specifically. The importance of this is relative to the origin of shame and, what John Paul II (prior to his elevation to the papacy, as Karol Wojtyla) called the “absorption of shame by love” (Love and Responsibility, San Francisco: Ignatius Press, 1981. 181).
The consideration here is that is that prior to the fall there was only husband and wife, who were, in fact, called to that intimate revelation and communion of persons to which spouses are called. While we might speculate on what the relationship of the sexes in general might have looked like had our first parents not fallen and then proceeded to propagate the human race, I think we are at somewhat at a loss to know what the lack of shame might have been relative to individuals who were not called to reveal the full mystery of their person to others, e.g. unmarried persons, persons relative to others who were not their spouse, persons called to virginity.
Or on the other hand, in a world before shame, were we all called to reveal ourselves completely to each other, even to others who were not our spouses? Does the redemption of the body, then, mean that not only is shame resolved relative to the body but that we are also called now to not fear being vulnerable to a lack of privacy regarding our person?
John Paul II’s description of shame, resulting from the fall of our first parents, emphasizes the need to protect the value of the person and to defend it from being objectified. Shame is, then, a kind of fear, and a “defense reflex” which arises out of our vulnerability caused by the effects of original sin. Now, while John Paul II analysis does tell us what life would be like for spouses if that vulnerability were absent, it does not tell us what the relationship of the sexes would be like in general, since all men are not all spouses of all women.
By their vocation spouse are called to reveal their person and become an unreserved gift to the one to whom they have vowed themselves. But that revelation and gift is not meant for everyone. Since before the fall there were only two people, one male and one female and these two were, in fact, spouses, the state before the fall does not offer us a perfect paradigm for the relationship, say of men and women who are courting, or who may have no relationship at all but must treat each other with the respect of modesty.
While the human body always has a spousal meaning, that meaning as it pertains to my body specifically is not meant to be revealed in the same way to all. And, therefore, a reluctance to reveal too much to the wrong person is merely defensive of personhood against one who might be disposed to use me; it is defensive of personhood toward one who does not properly belong to that level of intimacy.
Vindicating the Mystery of Personhood
In the Theology of the Body John Paul II seems to recognize that shame is not only a defense mechanism against the possibility of being used, but also a vindication of the mystery of personhood:
A person of developed sensibility crosses the limit of that shame only with difficulty and inner resistance. This is clear even in situations that otherwise justify the necessity of undressing the body, for example, in the case of medical examinations or operations (61.2).
In no way does this spontaneous and intuitive “inner resistance” represent prudery or Manichaeism or an ignorance of the truths contained in the Theology of the Body. The Holy Father says that this reaction is found in those of “developed sensibility.” It is perfectly wholesome and compatible with great virtue. In fact, in the context of defending this “inner resistance,” the Holy Father says that original shame “is a permanent element of culture and morality. It belongs to the very origins of the ethos of the human body” (61.3).
According to the Theology of the Body, shame acts as a “veil” over the mystery of personhood in which man discovers himself as the guardian of that mystery and the defender of the “freedom of the gift” (19.2). This action, it seems to me, is not primarily negative, because wherever something is defended against abuse, there is more fundamentally an affirmation of inherent value.
Interesting to note in this regard is that in Love and Responsibility, which is not a document of papal magisterium but is the work of the man Karol Wojtyla, we find more about this positive element of shame than we do in the Theology of the Body. One reason for that may be because the specific context of his remarks on shame in TOB is the examination of our first parents before after original sin in the context of sacred scripture; whereas, in Love and Responsibility Karol Wojtyla reflects on human experience in general.
In Love and Responsibility, Wojtyla vindicates the preservation of privacy in certain matters and argues that the desire for this privacy is not primarily motivated by fear, but by a certain “fittingness.” Fear, indeed, arises when that appropriate privacy is endangered, but it is indirect and secondary (174-175). He says:
The essence of shame goes beyond such fear. It can only be understood if we heavily emphasize the truth that the existence of the person is an interior one, i.e. that the person possesses an interior peculiarly its own, and that from this arises the need to conceal (that is, to retain internally) certain experiences or values, or else withdraw with them into itself (175).
Again, this seems to perfectly accord with what Dietrich von Hildebrand says about the interiority of the person, about sex being the “secret of the individual” and the tendency to protect that secret as one that perfectly corresponds to the mysterious and precious nature of the person.
Emotional Shame
In Love and Responsibility Karol Wojtyla makes the distinction between two kinds of shame relating to sexuality: physical shame and emotional shame. Physical shame seeks to conceal certain parts of the body to the extent that the value of the person is vindicated and defended from being used, while the sexual values are able to “still be a point of origin for love.” Emotional shame seeks to conceal “reactions and feelings” that tend to move one to reduce persons to objects of use by way of their body and sexuality. In particular, but not exclusively, physical shame is the province of women, while emotional shame is the province of men (187).
It is in regard to emotional shame that the popularization of the Theology of the Body has particular resonance, because it is men, more than women, who struggle with issues of sexual temptation. Karol Wojtyla points out that
[t]his internal ‘shame of feelings’ has nothing in common with prudery. Prudery consists in the concealing one’s real intentions with regard to persons of the other sex or with regard to sexual matters in general. A prudish person intent on exploitation tries to make it appear that he has no interest at all in such matters—indeed he is prepared to condemn all, even the most natural, manifestations of sex and sexuality. Such behavior is, however, very often not to be explained as prudery—which is a particular form of hypocrisy, a way of disguising one’s intentions—but by some prejudice or other, perhaps the belief that everything to do with sex can only be an object for use, that sex merely gives the opportunity for sexual release and does not open the way to love between people (188).
In order to understand what belongs to a healthy reaction of a man to the sexual values of a woman one must appreciate fully what Wojtyla is saying here. Wholesome shame is to be sharply distinguished from prudery. And further prudery is not the same thing as the Manichean tendency to devalue or repudiate the goodness of sexuality.
In fact, Wojtyla goes on to say:
True emotional shame cannot possibly be identified with prudishness. Emotional shame is a healthy reaction within a person against any attitude to another person which disregards that person’s essential value, degrading him or her to the level of an object for sexual use (188).
All this points to the fact that the possible reactions of men to the sexual values of women are many and the psychology of those reactions are complex. Certainly, there is nothing in the Holy Father’s writings that would suggest that the tendency to conceal sexual values or to practice custody of the senses relative to sexual values is prudery, or that it only belongs to a lower level of moral behavior. Nor does seem to me that John Paul II says anything to encourage the students of the Theology of the Body to analyze individuals or make generalizations about practical behavior where the individual conscience must be the judge within its own domain.
If I might be indulged for a moment for a bit of cultural commentary, I would say that our age is at particular risk of living shamelessly, not only because of the reduction of people to mere sexual values by so much of culture, but also because the general cultural tendency to keep nothing private. We are almost constantly broadcasting with cell phones, email, instant messaging, text, picture and video messaging, Facebook, Twitter and reality television. Is there anything about our persons that we choose not to broadcast to the world anymore?
Please, no angry comments. This is not a condemnation, just an identification of a risk.
It would be a complex task to unravel the cause and effect relationship. More than likely, the relationship of sexual shamelessness and, if you will, psychological shamelessness is reciprocal. Whatever the case may be, the coincidence of these two aspects should send up a red flag. We are culturally shameless. I cannot help to point out that the cultivation of purity and a healthy, enlightened and exalted view of the body and sexuality will be undermining itself if it minimizes the role of wholesome and sensible shame.
Victorious Secret
In a book published much later (1966) than Purity, Dietrich von Hildebrand, writing the original work in English (Purity was original published in German), choose to speak about wholesome shame in with different vocabulary than he had in the past. In Man and Woman: Love and the Meaning of Intimacy he writes the following:
Shame wants to hide ugly things, whether they are physical or psychical. We feel shame when others speak of our cowardice or our weakness.
But shyness, which is often confused with shame, reveals our reluctance to exhibit beautiful and noble things if they are intimate. . . . This shyness, referring to things which we hide not because we believe them to be ugly but because they are intimate and their specific value calls for secrecy, is absolutely the right response to the sphere of sex (Manchester: Sophia Institute Press, 1992. 58).
So, von Hildebrand opts for the use of the word “shyness” to describe that kind of shame which is protective of one’s secret. That particular word does us the favor of eliminating the connotation of the word “shame” that is so easily identified with prudery and Manichaeism.
Abandoning this kind of shyness is like abandoning mystery. True, one day the mysteries of God will be revealed, but never fully because they are infinite and eternity is not long enough to exhaust them. For an even greater reason, then, are these mysteries to big to be fully revealed in this life. Not even in the great saint, theologian and mystic, Thomas Aquinas, were the mysteries fully revealed, at least not in a way that could be expressed in speech or in a body of teaching. After an extraordinary mystical experience St. Thomas referred to his great work of theology, the Summa Theologiae, as “so much straw.”
If the truth about sex is such great news, because it is so beautiful and sacred, then this is a reason for holy shyness, not a reason to take everything off in public. Such unveiling certainly is not the answer to prudery as von Hildebrand writes:
So, we must understand that the true antithesis to Victorian prudery is a reverent attitude towards sex, seeing in it something great, deep and mysterious, whose existence one should not try to deny, but which by its very nature is intimate, and has the character of a secret (59).
Sex is something deep and mysterious that touches the heart of what it means to be a person and to be called to love and be loved. Holy shyness or modesty is the vindication of those values, or as Karol Wojtyla wrote in Love and Responsibility:
sexual modesty is not a flight from love, but on the contrary the opening of a way towards it. The spontaneous need to conceal mere sexual values bound up with the person is the natural way to the discovery of the value of the person as such (179).
Dietrich von Hildebrand and John Paul II are kindred spirits.
Posted in Catholicism, Culture, Husbands, Knights, Manliness, Men, Motherhood, Mothers, Religion, Wives, Women | Tagged Christopher West, Dietrich Von Hildebrand, email, English, Facebook, Human Sexuality, In Defense of Purity, Instant Messaging, John Paul II, Love and Responsibility, Manichaeism, Modesty, Prudery, Reality Television, Shame, Shyness, Text Message, Theology of the Body, Twitter | 21 Replies
In Defense of Purity
Thanks to Therese, I am now reading Dietrich von Hildebrand’s Purity: The Mystery of Christian Sexuality, originally published under the title In Defense of Purity by Sheed and Ward in 1938. I have decided to blog a bit on the book as I read it. I thought I might publish a post on each chapter.
In fact, I believe that von Hildebrand’s contribution is extraordinarily important for the proper understanding of John Paul II’s Theology of the Body. When I received von Hildebrand’s book, I was elated to find the following endorsement on the back by Dr. Josef Seifert, who helped to clarify some points about shame when I was engaged in a discussion on The Linde several weeks ago:
When first published, von Hildebrand’s books on marriage and purity rediscovered the essence of the true Catholic understanding of sexuality and thereby revolutionized the dominant view of sexuality, which was almost 2000 years old and which was often negativistic and puritan.
Today, von Hildebrand’s thoughts on the spiritual meaning of sex and love are also a key to understanding Pope John Paul II’s grandiose and audacious theology of the body.
This book opened the eyes of countless young people to the mystery and fulfillment of spousal love—and to the horror of impurity which desecrates the mystery.
Together with the theology of the body of Pope John Paul II, von Hildebrand’s writings on purity and sexuality may merit for the Twentieth Century the title of greatest century in Church history with respect to the philosophy and theology of marriage.
Von Hildebrand’s lively and fascinating analysis of love and sexuality will strike you by their beauty and depth, as much today as when the young von Hildebrand wrote this book, which already has made Church history.
If you are looking for an utterly positive understanding of love and sex, which throws into light the great virtue of purity and the greatness of marriage as love-community, this is the book for you.
Interestingly, Dr. Seifert acknowledges and revolutionary quality to both the work of von Hildebrand and John Paul II. However, of course, the meaning of the word “revolution” as it is used here can only be understood in a Catholic sense, as I am sure Dr. Seifert meant it, that is, in the context of the development of doctrine or the hermeneutic of continuity. This is an important point and it is essential for the understanding of the difference between virtue and vice relative to human sexuality and between true modesty and prudery. I am looking forward to a prayerful reading of this masterpiece of a pure and reverent mind.
I will be reading from the 1989 edition, published by Franciscan University Press, Steubenville, under the title Purity: The Mystery of Christian Sexuality. The work is divided into two books, the first having three parts, the second, two:
Book I: Purity
Sex (3 chapters)
Purity (3 chapters)
The Attitude of the Pure in Marriage (3 chapters)
Book II: Virginity
The Nature of Consecration (2 chapters)
Why the Virgin is the Bride of Christ (6 chapters)
Of particular note, von Hildebrand gives his reason for considering purity and virginity in the same work:
The reason for uniting in one study purity and virginity is of a practical nature. Although virginity represents in its significance and value something completely new and autonomous with respect to purity, its inmost nature is only intelligible when we have understood that of the person, which is also the decisive factor for purity.
I will provide parenthetical references to page numbers in my posts.
Posted in Catholicism, Fatherhood, Husbands, Men, Mothers, Wives, Women | Tagged Chastity, Dietrich Von Hildebrand, Dr. Josef Seifert, Human Sexuality, In Defense of Purity, John Paul II, Modesty, Prudery, Purity, Shame, Theology of the Body | 5 Replies
Shame on You. Amen.
Posted on September 1, 2009 by Fr. Angelo M. Geiger
I think the title of this post should be a prayer of blessing. Well, I am being facetious . . . sort of. Or perhaps I have caught a bit of the Christopher West shock-jock bug. In any case, three cheers for good old fashioned shame. Hip, hip, hurray, etc.!
During my hiatus from blogging here I have been busy about many things a la St. Martha. One of those things has been a fruitful discussion at The Linde on The Personalist Project’s web site. Cupuches off to Katie van Schaijik who runs that blog and gave me the opportunity to defend my views.
The Holy is Shameful
There is a shock statement for you that has real apologetical punch, and yet it is perfectly true. Unfortunately, the masters of the anti-prudery crusade, the TOB shock-jocks, just don’t get it, so I need to use my own shock-term in order to make the point to them. Shame is not only embarrassment at what is ugly, it is also modesty and humility in the face of what is holy, beautiful and mysterious.
I am currently trying to get my hands on Dietrich Von Hildebrand’s work, Purity: The Mystery of Christian Sexuality (Steubenville, Ohio: The Franciscan University Press, 1989), originally In Defense of Purity, 7th ed. In the comments on The Linde, Dr. Josef Seifert made reference to this work in which Von Hildebrand distinguishes between different kinds of shame. Dr. Seifert notes that both Karol Wojtyla and Von Hildebrand (as well as Max Scheler) speak highly of sexual shame and “have distinguished it sharply from prudishness.” He points out that whereas Wojtyla commended shame as a way of protecting persons from being objectified and the body from irreverent and lustful attitudes, Von Hildebrand stressed the positive aspects of shame of the beautiful and holy. According to Dr. Seifert, Dietrich Von Hildebrand distinguishes
between shame of something ugly or evil and the shame of something beautiful but so intimate that it belongs to the personal mystery of persons. This is the authentic sense of positive sexual shame which does hide from others those mysteries of love and of the body which only spousal love ought to see or unveil because of its beauty and depth and intimacy. Also in the religious life there are feelings, thoughts or experiences of Saints so sublime that they did not wish to expose them to everybody. . . .
This shame is noble and just as opposite to prudishness (which regards the beauty of the body ugly) as it is to the shame we will and ought to feel when we are seen to perform impure acts or watch porno movies or to act in bad immoral and dishonest ways.
Another commenter, Steve B., quoted Von Hildebrand on the subject of shame from The Devastated Vineyard:
. . . We should experience shame when someone praises our virtue and brings it out into the open, or when we ourselves make public things which are by their very nature intimate. All kinds of being ashamed are deeply human, classical attitudes, especially the shame which encourages us to keep intimate things out of the public eye. It is a stupid mistake to interpret this latter kind of shame, which is especially related to the sexual sphere, as prudery, as contempt of this sphere, as a sign that one views it as taboo. True and noble shame towards the sexual sphere, with which even the pagans were acquainted (just think of the gestures of the hands of many of the Venus figures, which covered the breasts and the pubic region), is a classical human characteristic, an adequate response to the mysterious intimacy of this sphere (28-29, emphasis commenter’s).
The more I engage with people of good will who are understandably enamored of Christopher West’s ability to make a difference in the lives of many thousands of people who are struggling with sexual sins and a lack of peace with their sexuality, the more I am convinced that this wholesome, humble and intelligent kind of shame is under serious attack. That attack, in my view, is all the more serious because instead of directly denying the existence of good shame, it simply minimizes its usefulness on the grounds that apologetical exigencies are more important. While this might sound to some like a valid argument, the result, in my opinion is insidious.
The TOB America Train
Apologetics has the curious quality of being compelling precisely because the apologist has simplified the argument and presented an immediate and clear reason to change one’s judgment, and has done so in an enthusiastic and rhetorically effective way. But while this ability and approach has obvious assets, it can also have real liabilities. Sometimes the most compelling argument is an over-simplification, and the most rhetorically effective and most enthusiastic presentation is an expression of zealotry, which because it is based on an oversimplification is by definition reactionary and misguided. In other words, sometimes the most immediately effective apologetical approach is tantamount to an unbalanced crusade, like a down-swinging pendulum, it has far too much momentum to find equilibrium.
In a sense, I wish I could jump on board the TOB America Train, because I really do think that prudery is a problem. However, when in the interests of providing a powerful argument the apologists for this version of TOB minimize essential distinctions, they shoot the whole effort in the foot, because they begin calling good responses “prudery” so that in the end their effort is transformed from a crusade against prudery into crusade for a fascination with sex.
They say that if we were really on board the train and understood the beauty of sexuality we would want to strip everything and everyone naked as much as possible. This is truly unfortunate, because the result of all this is that the pendulum ends up swinging back and forth. When those truly inclined to prudery hear West & Co. criticize every reaction against stripping they just dig their heels in deeper. And in a sense, why not? Why should we prefer one error over another, especially when our choices are between prudery and sexual over-exposure?
The Sex Crusade
Real prudery—it is true—is unresolved lust. However, the crusaders misappropriate it to every and all reactions of shame. They tell us that anytime one acts with shame in respect to sexual matters it is because they have hidden lust in their hearts and are not being honest about it. Hence, West always gives the following recommendation to those who object to his habit of stripping everything: “Look into your heart and ask yourself why you are uncomfortable with this.”
Unfortunately, this approach is doomed because there are real distinctions between Manichaeism, Jansenism and scrupulosity. The later is not hatred of the body, but pride of judgment and fear of responsibility. All three things can overlap, but they don’t necessarily. The apologetic gurus of our age, I must presume, do not read souls. They should not pretend to.
Likewise, there are real distinctions between shame of sinful things, shame of holy things and lust dressed up as shame (prudery). They are not the same thing and cannot be treated as the same thing without misrepresenting the faith and misleading souls.
As I say, I would like to join forces with the crusaders against prudery, except that I don’t want to be a zealot and I don’t want to shoot my efforts in the foot by engaging in over-simplifications and encouraging a reactionism that will inevitably result—as it has already—in the opposite extreme, namely, an obsession with sex.
I recently read an interview with an actress who was asked about her willingness to take on roles that had a great deal of sexual content and nudity. She defended herself by saying: “it’s kind of an American thing to be uptight about naked bodies.” This is precisely the confusion I am referring to, and in my opinion, the only difference between the crusader’s argument and that of the actress is that the former is dressed up in piety. I even encountered someone apparently favorable to West defending the soft-core pornography of Father Andrew Greeley.
So what about real prudery?
I believe where it exists among Catholics it is usually found in people recently converted who formally lived immodestly and unchastely, or who previously took matters of chastity lightly and went along with the pornified culture. Now reacting against it, not wanting to be an occasion of sin for anyone else and desiring to give good example (especially parents to children), they are inclined to the zealotry of modesty–to their own kind of reactionism. Thus, they place nearly all the emphasis on modesty of dress, manners and eyes, rather than give due attention to custody of the heart.
This is not far from the Islamic ideal that presumes that men are pigs, but that women are really at fault for being shaped like women. Of course, no one would put it that way, but isn’t that the nature of prudery? It cloaks sinister ideas in a mantle of piety and strictness.
The problem is that genuine prudery is in reality the wormy apple. In truth, the genuine article is holy shame, that is, modesty, and it can be easily be confused with rotten prudery by an untrained or superficial eye.
In one or another of my comments on The Linde I brought up the need to cultivate prudence among the faithful as an integral and necessary way to make this discernment. The reasons seem clear to me: 1) because there is a real difference between Manichaeism, Jansenism and scrupulosity; 2) because there is a real difference between shame of sin, shame of the holy and prudery; 3) because without it we oversimplify and promote reactionism and zealotry; 4) because it belongs fundamentally to the nature and practice of true modesty.
Prudery or Prudence
I think that West and his supporters would do well to give this serious consideration, because it seems to me that both forms of zealotry minimize the role of prudence. Those inclined to prudery place all their trust in hard and fast rules that can be measured and enforced with uniformity. They are agitated by intellectual independence and by virtually all diversity within Catholic culture. They do not give due regard for the fact that our counsels are not certain in many areas of life and that good men can disagree about many things, including many things that are important to them. But even this may have more to do with ordinary unresolved scrupulosity than it does with Manichaeism or Jansenism.
On the other hand, the anti-prudery crusaders also minimize the role of prudence, precisely because they pretend to be able to size-up those who disagree with them and label them with Manichaeism, Jansenism and prudery, when, in fact, they really have little or no idea with whom they are really dealing. They also are inclined to say that modesty is purely relative and is almost exclusively a matter of custody of the heart, and in so doing disregard many of the particulars that make up modest or immodest behavior.
For example, the TOB crowd often brings up the African women who live topless nearly all the time. (Although our community works in Nigeria, Benin and Cameroon, I cannot comment intelligently on how prevalent this custom remains in Christianized Africa.) They say the men think nothing of it and that the women have no shame about it. It is all quite innocent and wholesome. No need here for the cultivation of any kind of shame. By this logic one would have to surmise that the customs of pagan Africa are more in keeping with the redemption of the body than our own. This is supposed to be evidence that the external aspects of modesty are all relative.
But the fact is that wherever Christianity has sunk its roots deeply, over time these customs have been given way to what Paul VI called “higher expressions of the mind.” And even if Maria Lactans is a venerable visual tradition within the Church, it is because there is a mean by which prudence can justify limited exposure in appropriate circumstances. It is no justification for the sexualization of culture or the disparaging of natural shame.
In fact, the anti-prudery crusaders are arguing for their own kind of uniformity and lock-step thinking. This is one reason, I think, that some were so inclined to interpret a challenge to West’s ideas as a personal attack. There is no room for divergence and diversity among those who are truly enlightened.
Rules of Thumb
Before I conclude, I want to underscore the importance of prudence in this matter, because I know the tendency to oversimplify and ride the wave of indistinct enthusiasm is much stronger than my abilities to defend prudence. Though I am sure I will not be as convincing as a real soapbox rhetorician, I will give it my best, boring attempt.
Everyone schooled in the fundamentals of Catholic moral theology knows there are three things that are required to make a moral act good:
The object of the act must be good, that is, the act itself cannot be intrinsically evil, like stealing, but must be good in itself, like praying, or at least objectively indifferent, like walking.
The intention of the one acting must be good, that is, the act must not be directed by mind and will to an evil end or with a malicious purpose. Thus, even praying could be evil, if one was knowingly asking God for something sinful.
The circumstances surrounding the act (time, place, manner, etc.) must be such that the one acting may reasonably judge that the act is appropriate to do here and now. Hence, praying is not pleasing to God if one is doing so in a way that prevents him from fulfilling the obligations of his state in life, even though praying itself is good and the person’s intention might be upright.
If any one of these three requirements is not in possession, then the act is not good but sinful or at least imperfect.
In particular, the last point regarding circumstances is the domain of prudence, and this is precisely what we are dealing with when we try to distinguish modesty from immodesty and shame from prudery. If you don’t want to teach people about prudence then never mind talking about prudery, or modesty for that matter, because your listeners will be unable to define them in practice.
Incidentally, this is why rules of thumb have typically been part of the Catholic tradition of moral catechesis. For instance: “the Eucharist is present within a communicant for 15 minutes after receiving communion”; “stealing is a mortal sin when it equals the value of a man’s daily wage”; “a dress isn’t modest unless it extends well below the knee.” It does not seem to me that any of these rules were ever intended as absolute moral imperatives, but neither are any of the questions they are intended to resolve purely subjective and relative. They are rules of thumb precisely because they are to assist us in the cultivation of prudence. The solution is neither to absolutize the rules of thumb, nor to absolutize the relativity of the questions. Absolute uniformity of behavior is neither required nor desirable, because both are based on false premises and concern matters which in some measure are the domain of each man’s prudential judgment.
This is not to say that modesty is purely relative or subjective (in Christian cultures women don’t go topless because of natural, wholesome shame), only that in those matters where good Catholics may disagree the solution is not going to be found in crusades for uniformity (whether in dress or undress) but in the freedom to make independent judgments that are ever more enlightened and generous. In this way, we acknowledge and respect the rightful place of ordinary shame, the higher and objective standard of Christian modesty, the holiness and beauty of both the body and of sexuality, intellectual freedom, a measured diversity of culture, and the legitimate differences of personality, temperament, history and mystery that belong to individual persons created in the image and likeness of God. This is the opposite of zealotry. It is just plain common sense.
Stopping the Pendulum
This approach has the added advantage of pulling that rug out from under reactionary tendencies which are just aggravated by the propensity to use the labels such as prude or skank. More disturbing to me and more frequently occurring than a modesty crusader calling a woman dressed in a trashy outfit a skank, is that same crusader shabbily treating a decent woman or girl who does not meet their standard of uniformity. Both instances offend the dignity of the human person and welfare of souls, but in the second case, the estimation entirely inaccurate.
But this is not only a problem with the modesty crusaders. The anti-prudery crusaders are just as inclined to size people up and examine their consciences (even publicly, as West does). Without having any real idea what is going on in the conscience of someone else, they suggest that ordinary and sincere reactions against unveiling every aspect of sexuality is prudery. What they are looking for is a whole new standard of enlightenment by which they can measure the authentic response to the sexual intuition, and they have their own set of rules that they wish to impose by way of the invocation of authority. Hence, John Paul II is used as the unquestionable authority for all kinds of things he never recommended.
Either way it is shabby treatment and positively anti-personalist behavior. In fact, no one is inclined to change their view of things when they are measured with oversimplified and plainly bogus standards.
Finally, I want to speak directly to men on the question of shame and modesty. John Paul does say that a special burden is placed on the man to see to it that a woman is not made an object (TOB 33.1-2). In this regard men should not project onto women their own disordered desires. Not every woman whose manner of dress a man finds provocative is trying to be provocative. However, that does not mean she is not being thoughtless and a bit selfish. Sometimes women just want male attention. They know exactly how to get it, and sometimes act accordingly, even when their purpose is not lustful.
So there is a mutual burden in this regard, but men with sensitive consciences in matters of purity should not take the depersonalization of women to a new level by projecting onto them their own lust, and like Muslim men expect women to look like something other than attractive and then blame women for their own lack of custody of heart. Again, this is not to say that women’s fashions today in general are not objectively immodest, but it is to say that the preoccupation with the standards of modesty are not altogether helpful to men and the transformation they need to undergo.
In this too, the facile, enthusiastic and clever apologetical argument may be effective but it has also some serious liabilities. The often told story of the two monks who approach a stream and find a damsel there unable to cross is a good example of the problem. Supposedly, one of the monks decided to do the chivalrous thing and carry the girl over the stream. Once across, the monks and the damsel bid their adieus and went their separate ways. After a long time of walking along in silence, finally the other monk said: “Brother, I can’t believe you picked up that woman and carried her over that stream. What were you thinking?” The offender replied: Brother, I put her down a long time ago. It seems you are still carrying her.”
This story, in fact, illustrates something very true, but something that needs to be considered carefully. The second brother’s scandalized heart presumably had lost its peace not because of an offense against God or because of the spiritual peril of the other brother, but because of its own preoccupation with matters of sexuality. The scandalized monk was, in fact, projecting his own problem onto his brother. However, this is no argument that the first monk actually behaved in a prudent fashion. The sword cuts both ways. Modesty is not just a matter of custody of the heart, and while the scandalized brother may well have been a prude, the circumstances of the damsel’s predicament and the monk’s station in life, as well as his own personal story and baggage may have dictated a much different solution.
If as West and his followers suggest the redemption of the body is a matter of self-mastery, why does that mean that ordinary, wholesome shame must go out the window along with prudery? There may be several answers. One is perhaps that in some circumstances souls reach a state in which they attain something akin to original innocence. But West says he is not suggesting that anyone is going to attain that kind of purity. So if prudery is jettisoned and self-mastery is obtained, why does the wholesome shame of holy things have to go as well? In my opinion, it is because the real argument in all this in not about prudery, but about the assertion that the Theology of the Body mandates a new and holy fascination and fixation on sexuality. Unfortunately, this is an invention, and one produced, not by John Paul II, but by Christopher West.
Real Hope
The road to self-mastery is not going to be won by trying to convince the world by flashy but superficial arguments that the Church is not anti-sex when it really never has been. It is not going to be won by teaching men, who need to learn to fight, to seek the path of unrestricted, cushy-soft and allegedly holy eroticism. The road to self mastery is the narrow and difficult road of trial and error, of nuance and distinction, of high ideals and knowledge of one’s weakness, an appreciation for goodness of all that God has created, spontaneity in action, and shame of the ugly and of the beautiful and holy. Men must fight for their chastity. Yes, the message of the Church about sexuality is good news, but it is not a false and shameless hope.
May we all be blessed to see the truth of it. Shame on you. Amen.
Posted in Catholicism, Chivalry, Culture, Girl stuff, Guy things, Husbands, Knights, Marian Chivalry, Marriage, Men, Religion, Spirituality, Wives, Women | Tagged Christopher West, Dietrich Von Hildebrand, Human Sexuality, Jansenism, John Paul II, Manichaeism, Modesty, Personalism, Prudery, Rules of Thumb, Shame, The Personalist Project, Theology of the Body | 12 Replies
Mystics, Martyrs and Rhetoricians
Or the Theology of the Soapbox
What follows in another one of my long expositions on the Theology of the Body. I have to give a loud content warning at the outset. There is some frank talk here about sexuality, or rather, my complaints that there is too much frank talk about such matters. I would have asked Dawn Eden to publish this one, but she has very courageously retired from blogging. I have to commend her on her decision; however, it is not without regret on my part.
I again want to let those I disagree with know that my intentions are honorable and I do not question their integrity or commitment to the faith. I can take my lumps if I deserve them.
In a recent apologia for Christopher West, Father Thomas Loya makes grand assertions:
Christopher West is a bit of a mystic—in the best sense of the word. His work, which seems strange to some, is actually that of a pioneer. And like all pioneers, West is taking a lot of arrows for his courage. In the face of much resistance, West is courageous enough to invite all of us to do just what John Paul II invited us to do: to think and talk in spousal categories. Continue reading →
Posted in Blessed Virgin Mary, Catholicism, Family, Fatherhood, Feminism, Heroes, Husbands, Knights, Manliness, Marian Chivalry, Marriage, Men, Motherhood, Mothers, Pro-Life, Religion, Spirituality, Wives | Tagged agape, Baldichin, Benedict XVI, Bernard J. Pisani, Cardinal Ratzinger, Christopher West, Crucifix, Dawn Eden, Deus Caritas Est, Eamon Duffy, eros, Father Thomas Loya, G.K. Chesterton, Hermeneutic of Continuity, Human Sexuality, Iconostasis, John Henry Newman, John Paul II, Karol Wojtyla, Loincloth, Martyrs, Msgr. George A. Kelly, Mystics, Prudery, Reform of the Reform, Rood Screen, Soapbox, St. Augustine, St. Bernard of Clairvaux, St. Louis de Montfort, St. Theresa of Avila, Theology of the Body, Vatican II, Veil | 22 Replies
John Paul the Great and Hugh Hefner the Magnificent
Posted on May 8, 2009 by Fr. Angelo M. Geiger
Okay, I am glad that a Catholic apologist gets some major exposure in the mainstream media, and I want to repeat again that I believe that those who are popularizing the Theology of the Body are good people and well intentioned. Nevertheless, I take exception to the presentation of Christopher West in this latest interview, precisely for the reasons given in my last post on the subject.
One commenter on that post asserted that the “naked without shame” doctrine contained in the popular catechesis of TOB is really only a “marketing hook,” and that very few, if any, believe that TOB is being proposed as a means of reclaiming original innocence, as suggested by the article I linked to by Father Brian Mullady.
In yesterday’s interview posted on the ABC News website Christopher West compares favorably Pope John Paul II and Hugh Hefner, founder and publisher of Playboy Magazine:
“I actually see very profound historical connections between Hugh Hefner and John Paul II,” said West.
And it’s not just the red slippers?
“No, it’s not just the red slippers.” Each man in his own way, West insisted, rescued sex from prudish Victorian morality.
On Hugh Hefner: ‘I Understand His Ache’
“I love Hugh Hefner,” said West. “I really do. Why? Because I think I understand his ache. I think I understand his longing because I feel it myself. There is this yearning, this ache, this longing we all have for love, for union, for intimacy.” Continue reading →
Posted in Catholic Action, Catholicism, Chivalry, Guy things, Heroes, Knaves, Knights, Manliness, Marriage, Media, Men, News, Religion, Spirituality, Women | Tagged ABC News, Concupiscence, Hugh Hefner, Human Sexuality, John Paul II, Michelangelo, Modesty, Playboy Magazine, Pornography, Prudery, sex, Sistine Chapel, St. Francis of Assisi, Theology of the Body, Virility | 46 Replies
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Jeffrey Costa Select Realty
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Pleasant Hills Real Estate Market Guide
Pleasant Hills is a borough found in Allegheny County, Pennsylvania. It is located 7.49 miles southwest of Pittsburgh. Pleasant Hills was originally part of the vast province of Virginia before becoming part of the newly established Allegheny County in 1788. It was first named Reedsburg by the first landowner, John Reed Jr., and was later incorporated into a Borough in 1947. The municipality has since grown to become one of the most popular suburbs of Pittsburgh. The current name was derived from its characteristic feature of rolling hills and pleasant residents. The municipality has 200-year-old trees at the Pleasant Hills Arboretum.
The borough has a total area of 2.7 square miles of land. According to the 2016 census, the municipality had 8,189 people.
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Pleasant Hills is a perfect place to live in. It offers some of the best shopping malls, places to eat and grocery stores in the region. The presence of fully stocked shopping centers such as Downtown Pleasant Hill, Crossroads Shopping Center, Southland FourSeasons Shopping Center, and Bill Green Shopping Center makes shopping in the borough fun and highly convenient.
There are some really good restaurants for those who love to eat out, with first food services also available. You can get a unique hospitality experience from the Borough’s popular outlets, including Mm Mm Pizza, Atria’s Restaurant, Fortune Star Asian Buffet and Grill, and First Watch-Century III.
Leisure and recreational facilities are available within the municipality. The variety of recreational areas consists of baseball fields, soccer fields, football fields, and playgrounds. There are 3 recreational parks where individuals can go to unwind and these include Mowry Park, Pleasant Kingdom, and Rt. 51 playground.
60.58% of the population at Pleasant Hills affiliate with a religion. 55% are Christians, and 1.37% are Jewish. Famous churches in the borough are Saint Thomas, Freedom Life Center and Pleasant Hills Community Presbyterian Church.
Pleasant Hills boasts of some of the best schools in the region. The Borough is served by the West Jefferson Hills School District, which consists of five schools. Jefferson, McClellan, and Gill Hill elementary schools are for grades K-5. 6-8th graders attend Pleasant Hills Middle School. Then 9-12th graders attend Thomas Jefferson High School.
The school district is well known for high academic standards and competitive athletic programs. Students in high school pay an average tuition of $8,881.41 and those in elementary school pay an average of $8,313.29. The school district is funded by the state basic education funding, real estate taxes and property tax relief.
The municipality has an estimated median household income at $50,289 with a median income for a family at $60,752. The per capita income is estimated to be $25,083. The rate of poverty was 2.9% in 2016. The median list price in Pleasant Hills is $109 per square foot. Compared to the value of Pittsburgh Metro of $114, this value is lower. This value is higher than West Mifflin ($74) and lower compared to South Park ($124) and Jefferson Hills ($126). Foreclosure in this borough stands at 2.7 homes per 10,000. This value is greater than the national value of 1.6 and Pittsburgh Metro’s of 0.9.
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'Twilight Zone' Reboot Casts Seth Rogen for Guest Starring Role
By Michael Hein - March 4, 2019 12:57 pm EST
Seth Rogen has joined the growing cast of the Twilight Zone reboot just one month ahead of its premiere.
Rogen is the latest high profile actor to take a role in the classic anthology series, which is coming to CBS All Access on April 1. The show's official Twitter account made the announcement on on Friday, March 1.
"Enter the fifth dimension with @SethRogen as he will star in an upcoming episode of #TheTwilightZone," it read.
Enter the fifth dimension with @SethRogen as we he will star in an upcoming episode of #TheTwilightZone. The new @CBSAllAccess Original Series premieres April 1. pic.twitter.com/xuQqEEvuYg
— The Twilight Zone (@TheTwilightZone) March 1, 2019
Later in the day, Rogen retweeted a news outlet breaking the story. Like many others who have joined the cast, Rogen was reverent towards the source material, yet he spared some room for a self-deprecating joke in his tweet.
"I’m gonna be on the Twilight Zone, which is one of my favorite shows of all time," he wrote, "and also I look like I’m attending the premier of a pretty classy porno movie in 1974 in this photo."
I’m gonna be on the Twilight Zone, which is one of my favorite shows of all time, and also I look like I’m attending the premier of a pretty classy porno movie in 1974 in this photo. //t.co/mh82c07eLX
— Seth Rogen (@Sethrogen) March 2, 2019
Rogen will be the star of one episode in the reboot series, which tells a self-contained story in each installment. He is listed on the IMDb page for an episode titled "The Wunderkind," along with John Cho, showrunner Jordan Peele and many others. Rogen's casting was first teased late last month, when child actor Jacob Tremblay posted a photo with him on Twitter.
"Just a couple of Canadian Good Boys! We got something coming & I think you're gonna like it," Tremblay wrote with a shushing emoji.
Just a couple of Canadian Good Boys! We got something coming & I think you're gonna like it... ?✌ pic.twitter.com/us1VbVtYRg
— Jacob Tremblay (@JacobTremblay) February 22, 2019
Rogen joins an all-star cast for the reboot, which his helmed by Peele as executive producer, writer and on-screen host. Some of the other big names attached to the show include Kumail Nanjiani of Silicon Valley and The Big Sick, Adam Scott of Parks and Recreation, Steven Yeun of The Walking Dead and Ike Barinholtz of The Mindy Project. All seem to take the remaking of this beloved show very seriously.
"I'm typing this in case these words magically find their way back to a 12 year old me," Nanjiani tweeted last month. "This is a trailer for The Twilight Zone. I'm in it."
The show will consist of ten episodes, with Peele appearing as an omnipotent narrator just as original creator Rod Serling did during the series' original run. The show will be available only on CBS' streaming service, which also hosts the latest Star Trek series, Discovery, the Good Wife spin-off, The Good Fight, and other exclusive shows.
The Twilight Zone premieres on Monday, April 1 on CBS All Acess.
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Connecticut State Division of Criminal Justice
NOTICE: Simsbury Man Charged with Defrauding Hospital Patients
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Current: Report of the State's Attorney for the Judicial District of Fairfield concerning the death of Raylyn George in Bridgeport on August 25, 2005.
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Report of the State's Attorney for the Judicial District of Fairfield concerning the death of Raylyn George in Bridgeport on August 25, 2005.
Investigation | Cause of Death/Autopsy | Involved Officer | Civilian Witnesses | Police Witnesses - Bridgeport Police Department | Conduct of Raylyn George | Scene Investigation/Forensics | Conclusion | Recommendations
I. Investigation
This report pertains to an investigation, conducted under the direction of the undersigned, pursuant to Connecticut General Statute Sec 51-277a. Such an investigation is mandated "whenever a peace officer, in the performance of his duties, uses deadly physical force upon another person and such person dies as a result thereof." While the ultimate finding here is that no peace officer, in fact, caused the death of another person, it is the undersigned’s position that the initial appearance or possibility of such a circumstance requires an investigation regardless.
On August 25, 2005, at approximately 3:15 PM, a telephone call from a confidential informant was received at the Bridgeport Police Department Tactical and Narcotics Team (TNT) office to the effect that there were approximately seven black males, all carrying firearms, hanging out in the area of Building 23, Marina Village. The available TNT officers proceeded to the Westside Precinct Headquarters, conducted a strategy briefing with patrol officers, and continued as a group to Marina Village. All were wearing clearly identifiable Bridgeport Police uniforms. Once at their destination, the police response immediately developed into several separate foot pursuits. One of these chases culminated in the fatal shooting of Raylyn George, age 24, in the rear yard of No 103/105 Park Terrace at approximately 4:00PM.
Pursuant to this Judicial District’s established protocol, the Bridgeport Police Department’s participation was limited to cordoning off the scene and taking the names of potential witnesses pending the arrival of representatives of the State’s Attorney’s Office and State Police personnel, all of whom arrived within minutes of the incident. The swiftness of this response was made possible by the time of day and the proximity of the scene to Troop G and the State’s Attorney’s office. All further investigation was conducted under the direction of the State’s Attorney, by the Connecticut State Police Western District Major Crime Squad, the Office of the Chief Medical Examiner, and the State Forensic Science Laboratory. With the exception of the involved officer, virtually all interviews were conducted during the evening of August 25 and on the morning of August 26. Forensic efforts were conducted as the investigation proceeded.
II. Cause of Death/Autopsy
Mr. George was transported from the scene to St. Vincent’s Hospital where he was pronounced dead at 4:45 PM. His body was transported to the medical examiners facility in Farmington where an autopsy was begun by Chief Medical Examiner H. Wayne Carver at 10:35AM, August 26. This was prior to the availability of scene investigation report, witness’ interviews, or forensic testing results.
On external examination, Dr. Carver found two through and through gunshot wounds. The lesser of the two consisted of an entry wound located five and one-half inches above the right kneecap on the outside of the thigh and an exit wound through the kneecap. Dr. Carver is of the opinion that this type of injury would cause the right leg to immediately collapse and make it impossible to run or walk.
The second (and fatal) gunshot injury was more remarkable. It presented an entry wound one and three-fourths of an inch above and to the rear of the right ear. The wound tract proceeded forward and upward and to the left, exiting above the left eye and just inside the hairline. The wound was of a nature to cause immediate unconsciousness and collapse. Surrounding the entry wound was a pattern of stippling abrasion indicative of a close range shot. Forensic testing demonstrated that, at the time of infliction of this injury, the muzzle of the fired weapon would have been approximately three inches from the point of entry. The wound tract, or angle of trajectory, given a person of Mr. George’s age and apparent health, was within a range of motion consistent with having been capable of self infliction.
When subsequently presented with additional information, Dr. Carver was of the opinion that, in view of the relative debilitating natures of the two injuries, if self-inflicted, the leg wound would, of necessity, have been inflicted first.
III. Involved Officer
The police officer with the closest contact to the death of Raylyn George was P/O Luis Batista, a twenty-two year veteran assigned, at the time of this incident, to the Tactical and Narcotics Team (TNT). In his statement, provided on September 1, Batista reported that he responded to Marina Village from the Westside Precinct with the rest of the task force. Accompanied in an unmarked police vehicle by P/O Robert Simpson (but wearing clearly identifiable police uniforms), he observed three black males standing in the vicinity of Buildings 30 and 31 on Ridge Avenue. Exiting their vehicle, and with sidearms drawn, the officers ordered the three to get on the ground. Two did; the third, eventually identified as Raylyn George, raised his hands and ran West up Ridge in the direction of Columbia Street. Batista took chase, ordering George to stop. George, instead, continued running with his hands still in the air to Columbia where he turned right (South), and proceeded a short distance to the next intersection, turning left (West) onto Park Terrace.
Still pursued by Batista, George proceeded on Park Terrace as far as No.103/105, the second building on the right side. There, George stopped and, keeping his left hand upraised, reached into his waistband with his right hand, and removed a black handgun which he threw upwards and which landed to his right. As Batista walked towards George, the latter moved to his right, retrieved the pistol and aimed it at the officer. Batista advancing, fired three times as George fled out of view, in a southerly direction along the west side of No.103/105. When Batista got to the corner of No.103/105, George was not in sight. As the officer proceeded along the side of the house he heard the sound of gunshots coming from the back yard.
On getting to the back yard, Batista observed George on the ground, slumped with his back leaning against a four foot chain link fence that bordered the East side of the property. George was bleeding from the head and, laying between his right hand and bent right leg was a semiautomatic pistol. At that point , having been directed by arriving officers, he kicked the pistol from George’s reach with the toe of his shoe. Officer Batista was transported to Bridgeport Hospital where his duty weapon, gunbelt and contents were taken into custody. He was next driven home where he surrendered the clothing he had been wearing and finally returned to headquarters to submit to a GSR test.
IV. Civilian Witness
In addition to interviewing potential witnesses whose names were collected by the Bridgeport Police and State Police on August 26, the State Police, continued to comb the area, well into the spring of this year, for additional witnesses. While citizens are often reluctant to come forward, the police were successful in finding a number of persons who were able to provide first hand information. Further, the fact that the incident was to be investigated by the State’s Attorney’s Office and State Police was well publicized in its aftermath. In February of this year, this writer caused the State’s continuing interest in any additional relevant information to be made subject of local print and electronic media news items. When citizens concerned with the investigation subsequently delegated a representative to enquire of the undersigned as to the progress of the matter, the same invitation was extended. To date, no further information has been received. While many persons were interviewed, only the reports of those who were able to provide relevant information follow.
Witness No. 1, (*Follow this link to read the footnote) then a resident of Marina Village, is apparently the person who called in the sighting of "seven black males rolling blunts and showing off their guns." Shortly thereafter, three police officers approached the group from behind. When the latter noticed the police, most scattered, but two complied with the police order to get on the ground. Amongst the fleeing individuals was "Rayray" (Mr. George) who was pursued down Columbia Street by an officer wearing a TNT uniform (Batista). During this, one of the fleeing individuals, apparently not George, fired a single gunshot. Sgt Carl Leonzi, the raid supervisor, also observed this.
The witness followed the pursuit from a distance, observed "Rayray" turned toward the police officer and, she believes, fire several shots at the officer (Scene investigation demonstrates that it was the other way around). She then observed George run behind No. 105/103 Park Terrace from where she heard another gunshot.
Witnesses Nos. 2 and 3 are the aforementioned individuals who complied with the police order to get on the ground. They had been hanging out on Ridge Avenue smoking marijuana when they were joined by "Rayray." Shortly thereafter the police arrived, yelling "get down on the ground." The two did so, but "Raray" ran down Ridge pursued by an officer. After about thirty seconds they heard shots. While neither observed a weapon on George’s person, the latter was clothed in sweat pants and a size 4XXL shirt.
Witness No 4 was sitting in a location where he/she observed a black male run onto Park Terrace from Columbia Street, chased by a police officer. As the black male ran by, he/she did not see anything in his hands. Once on Park Terrace, the officer fired three shots at the fleeing individual who then ran behind No. 103/105 Park Terrace. The officer slowed down before himself proceeding toward the rear of the house.
Witness No. 5 at the time was in a home situated adjacent to No. 103/105. Between approximately 3:30 and 3:40PM, he was on the third floor of the home when he/she heard a number of gunshots that sounded as though they were coming from the area of Columbia Street. He/she ran down to the ground floor front entry where he/she observed a number of police officers coming from Columbia and yelling for everyone to stay indoors. He/she then went up to the second floor and through the house to the second story rear landing. He/she then looked down to the east side of the rear yard of No. 103/105 Park Terrace and saw a black male, with labored breath, sitting against the chain link fence with a black handgun "kind of in his right hand" He/she then saw a policeman approach the individual and kick the gun away.
The witness estimates that it took him/her about eight seconds to initially go from the third floor to the front door and then, when told to get inside, another thirty-two seconds to get to the second floor rear landing. He did not hear any shots from the back yard. These would, of necessity, have been fired as he was heading back upstairs and through to the rear of his home.
Witness No. 6 was also present in an adjoining home. He/she was indoors when he/she heard a number of gunshots which sounded to have come from in front of his/her home on Park Terrace.
The witness went to a rear porch where he/she saw a black male in the previously described position but with the handgun two to three feet from his right hand. He then saw two officers, a black male and a female approach the individual. These officers would have been P/O Simpson and Sgt Pribesh, see subsq.)
Witnesses No. 6 and 7 a husband and wife, were present in No.103/105 Park Terrace when they heard three or four gunshots coming from outside. The husband first went to his front door where he observed police running by. About two minutes later he looked out the back window and saw several police officers in the yard and an individual slumped with his back against the fence. His wife had actually been in a position to observe activity in the back yard but for the fact that she was recovering from a broken back and couldn’t change her position.
*The home of one witness was firebombed on the night of August 26, apparently because he/she had spoken to the police. Consequently his/her entire family was placed in witness protection. As a result, the names of all civilian witnesses are being withheld from this report which, it is expected, will become public.
V. Police Witnesses, Bridgeport Police Department
Sergeant Carl Leonzi was the supervisor of the joint detail that responded to the complaint of a number of armed black males. On arriving at Marina Village, he observed an initial group scatter and proceed on to where P/Os Batista and Simpson were detaining another three individuals. When one (George) took flight south on Ridge, chased by Batista, Leonzi began to assist Simpson with the remaining two (Witnesses Nos. 2 and 3) On hearing a single gun shot from the direction in which George and Batista had run, the Sergeant detailed Simpson to assist. He then heard a series of three or four gunshots and, subsequently, received a radio transmission from P/O Simpson that a party was down.
P/O Robert Simpson arrived on Ridge Avenue with P/O Batista. When one of three individuals who had been ordered to the ground instead fled down the street, Batista took chase. Simpson, assisted by Sgt. Leonzi, remained with the other two. On hearing gunshots from the direction of the chase, the officer ran to assist. As he neared the intersection of Ridge and Columbia, Simpson heard two more shots. On arriving at Park Terrace, he called to Batista who responded from a rear yard. Simpson then ran past No.103/105 and around to the rear of the next house (Nos 99/101) from where he observed Batista standing in the rear yard of Nos.103/105 between fifteen and twenty feet away from a black male who was sitting slumped against the chain link fence that ran along the east side of the property. There was a black handgun laying near the individuals right hand which Simpson told Batista to kick away.
Sergeant Melody Pribesh was the supervisor of the patrol contingent that assisted TNT on the complaint of armed males in Marina Village. On arrival, the Sergeant observed chases proceeding down Ridge Avenue and diverging both left and right at Columbia Street. As she followed to the right towards Park Terrace she heard multiple gunshots coming from that area. Next, after being momentarily detained by a report of activity on Gregory Street (the next intersection after Park Terrace), Pribesh heard additional gunshots ("more than one") coming from the Park Ter. area. She ran in that direction and then followed the sound of yelling to the rear of No.103/105. There, she observed Mr. George slumped against a fence bleeding heavily and labored in breath. A black semi-automatic handgun lay next to George’s right hand. She directed P/O Batista to approach George to kick the weapon away.
P/O Pasquale Speranza was turning onto Columbia Street in his patrol vehicle when he observed a TNT officer running east and chasing a male who repeatedly turned, looking back at the officer, and was holding both hands at his front waist band. As Speranza neared Park Terrace, he heard multiple gunshots. At the intersection, he exited his vehicle and took cover. From there he saw the pursued male run behind No. 103/105 Park Terrace, saw the TNT officer pause and then continue the chase, yelling "drop the weapon." Speranza could not recall whether he heard any additional shots.
P/O Christopher Martin was one of the responding patrolmen but was momentarily detained on a separate stop. After reaching Columbia Street, he parked his vehicle behind that of P/O Speranza. He then exited his car and began walking up Park Street when he heard one or two gunshots fired from somewhere to his right (e.g., the area of the rear of No. 103/105). He then overheard a radio transmission that caused him to reverse direction and run south on Columbia St toward Gregory St. This gave Martin a view into the rear yard of No.103/105 Park Terrace where he observed a TNT officer who he believed to be P/O Batista looking down at the ground.
VI. The Conduct of Raylyn George
The conduct of Mr. George was strongly indicative of a desperate desire not to be apprehended with a stolen firearm. He had, only six weeks earlier, completed a forty-five month state prison sentence. This would have been his eighth arrest. George’s conduct is commensurate with that of others who fled at the sight of police; one was observed firing a weapon as he ran up Ridge Avenue; another was apprehended for Possession of Cocaine With Intent to Sell. By contrast, Witnesses Nos. 2 and 3, who had nothing to hide and complied with the police demand to get on the ground, were briefly detained and released. Clearly Mr. George did everything he could to avoid capture, to the point of attempting to scale a four foot high fence while holding a locked and loaded handgun
VII. Scene Investigation/Forensics
Park Terrace was immediately cordoned off and protected. The State Police began to arrive within two or three minutes of the "person shot" call going out. The Major Crime Squad arrived shortly before 6:00PM. Nothing was disturbed in the interim other than P/O Batista kicking Mr. George’s handgun from beyond his reach and the evacuation of George by emergency personnel to St Vincent’s Hospital. Maintaining the integrity of the scene as much as possible, investigators first searched the scene, then photographed it and finally, collected evidence. They concluded at approximately 4:40 AM, August 26. They returned the next day and continued the search with metal detectors. A copy of the scene diagram is attached hereto
Firearms The firearms of all officers who had participated in the initial detail to Marina Village were inventoried. It was determined that no officer other than P/O Batista fired his weapon during the incident. Batista’s weapon was seized and examined. It was determined that he had fired a total of three rounds.
The weapon recovered in the rear yard of No.103/105 Park Terrace is a Glock 40 cal. semi-automatic pistol. It was stolen in a residential burglary three weeks earlier. The owner reports that the pistol had been stored with the magazine fully loaded (thirteen rounds) but not inserted, and with no round in the chamber. Investigators found ten rounds in the magazine and one in the pistol’s chamber, indicating that only two rounds had been fired.
Ammunition Three nine millimeter expended casings were found on the roadway of Park Terrace. A single expended bullet was recovered from a Ford Explorer vehicle parked in front of No. 109/111 Park Terrace. These were all determined to have been fired in P/O Batista’s weapon. Two expended .40 cal. casings were found close to the location where Mr. George slumped to the ground along the west fence of No. 103/105 Park Terrace. An expended .40 cal. bullet was also found between the same fence and the house. Both casings were determined to have been fired in Mr. George’s pistol; the expended bullet in typically damaged condition, was determined to be consistent with having been fired in it.
Blood A sizeable amount of blood was found in the immediate vicinity where Mr. George collapsed. The only other blood found was along the route on which the deceased was evacuated by stretcher. There have been no reports of any other injured persons. Blood-like stains were located on the barrel, trigger guard and nose of the 40 cal. Glock. This is consistent with close-range back-spatter which is typical of a shot fired from three inches. An examination by the State Forensic Laboratory, however failed to detect the presence of any corresponding blood stains on P/O Batista’s clothing.
Gunshot Residue (GSR) GSR swabbings were taken from Mr. George at St. Vincent’s Hospital, but not until his clothing had been removed pursuant to life-saving efforts. Further, as depicted in photographs, he had expended a large amount of blood, particularly over his right hand. Consequently, only a minimal finding (lead on his left hand) was made. P/O Batista’s hands were swabbed after his clothing had been removed for investigative purposes. The GSR results were negative.
Fingerprints The Glock handgun was preserved for fingerprint analysis. On examination, no identifiable latent prints were found; however, the magazine did have a single print. This has been compared to the known prints of Mr. George, P/Os Batista and Simpson and Sgt. Pribesh and the weapon’s owner, as well as being run through the Automatic Fingerprint Identification System (AFIS). There have been no matches. The identities of the original burglar or anyone else who may have handled the weapon prior to Mr. George on August 25 are unknown.
Fibers The expended 40 cal. bullet found along the west fence of No.103/105 Park Terrace has been examined microscopically. Stuck to its nose and sides is a gray material which is consistent in color with the sweatpants worn by Mr. George. Further testing of the bullet hole on the sweatpants that corresponded with the entry wound on George’s right thigh determined that the distance from the pistol’s muzzle to the wound was between contact and twelve inches.
VIII. Conclusion
Connecticut General Statutes Section 51-277a requires "a determination of whether the use of deadly physical force by the peace officer was appropriate under section 53a-22." No one actually observed Raylyn George at the point when he was shot. Based upon the time line of the aural and visual observations of various witnesses, it is evident that P/O Batista was not even in the rear yard of 103/105 Park place when the last two shots were fired. There is no evidence placing any other person in near proximity to George at any time. The undersigned concludes, on the basis of statements all of police as well as civilian witnesses, as well as the State Police crime scene investigation, all forensic examinations, including the autopsy conducted by the State’s Chief Medical Examiner, that no peace officer fired a weapon that caused any injury to Raylyn George
The precise mechanism of Mr. George’s death remains a matter of conjecture. What is known is that it occurred as he was fleeing police and, likely, attempting to scale a four foot high fence while holding a stolen, locked and loaded handgun in his right hand. Consequently, is no evidence that any peace officer’s actions were inappropriate.
IX. Recommendations
Submitted pursuant to Conn. Gen. Stat. 51-277a on May 11, 2006
Jonathan C. Benedict
Judicial District of Fairfield
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Patrick Mahomes II Kareem Hunt Tom Brady Tyreek Hill Dont'a Hightower Stephen Gostkowski Philip Rivers Andy Reid Duron Harmon Trey Flowers Sports NFL football Professional football Football NFL Playoffs
Kansas City Chiefs Los Angeles Chargers New England Patriots
Patriots preparing for anything in rematch with KC's Mahomes
By KYLE HIGHTOWER - Feb. 13, 2019 04:50 AM EST
New England Patriots defensive back Jonathan Jones (31) warms up with teammates during an NFL football practice, Wednesday, Jan. 16, 2019, in Foxborough, Mass. The Patriots are scheduled to face the Kansas City Chiefs in the AFC championship game, Sunday, Jan. 20, in Kansas City. (AP Photo/Steven Senne)
FOXBOROUGH, Mass. (AP) — In their first meeting with Kansas City, the Patriots had quarterback Patrick Mahomes figured out — at least for a half.
Creative and efficient in leading the Chiefs to a 5-0 start to the regular season, the second-year phenom looked very ordinary in the opening 30 minutes of their Oct. 14 matchup with New England, completing 14 of 23 passes for 164 yards, no touchdowns and throwing two interceptions. It added up to a 24-9 halftime deficit for the Chiefs.
Then the second half began.
Over the next two quarters the 23-year-old picked apart the Patriots' defense, throwing for four touchdowns, including a 67-yard TD strike to Kareem Hunt and a 75-yard TD pass to Tyreek Hill, tying the game at 40 with just over three minutes to play in the game.
It would take some late heroics by quarterback Tom Brady and a game-winning field goal in the closing seconds by Stephen Gostkowski for the Patriots to sidestep KC's comeback effort.
The Patriots have a lot more tape of Mahomes to study for the rematch in Sunday's AFC championship game. They're also hoping both history and the job they did disrupting Philip Rivers and the Chargers in the divisional round can be a starting point in slowing down Mahomes this time around.
Linebacker Dont'a Hightower said going back to what they did right in the first half against Mahomes could be the start of a plan of slowing him down in Round 2.
"We played the first half literally the exact way we wanted to," Hightower said. "We were able to mix things up, keep those guys guessing and keep them on their toes, not letting those guys make big plays.
"With an offense like that, you give (Kansas City coach) Andy Reid any kind of time and he's able to draw up a couple things, and that's something that we learned in the second half was that we've got to play a full 60 (minutes)."
Mahomes will be the sixth first-team All-Pro quarterback to face New England in the playoffs during the Belichick and Brady era.
The Patriots are 4-1 against the previous five. They have seven interceptions in those games, while allowing just six touchdowns. Two of those wins were against Peyton Manning in the AFC playoffs during the 2003 and 2004 seasons.
After coming up short during the regular season, Mahomes will again be looking to become the first opposing starting quarterback under the age of 25 to beat the Patriots under Belichick (25-0).
Mahomes went 2-4 against playoff teams this season, tossing 18 touchdowns and six interceptions in those games.
One of the things that has defined Mahomes in his first year as a full-time starter is his poise in the pocket. That, and his creativity under pressure using his running ability as well as sidearm and even no-look passes at times to keep getting the ball to his playmakers.
It's a big reason why the Chiefs' offense hasn't really missed a beat following the release of Kareem Hunt after video surfaced that showed the 2017 rushing champion knocking over and kicking a woman in a Cleveland hotel hallway in February.
"He's a first-year starter so he's gonna get better and better," safety Duron Harmon said. "I think he's played really good in the beginning of the season, middle of the season, end of the season. He's a guy that's definitely put himself in position to win the MVP. We know that. But we just gotta make it hard on him."
Defensive end Trey Flowers said being fundamentally sound, physical up front and trying to get the offense out of position should go a long way on Sunday.
"They're going to make some plays, but we've got to tackle well. And if you minimize the space with all these skills guys and fast guys, you can kind of get everybody to the ball and get some great pursuit."
Follow Kyle Hightower on Twitter at http://www.twitter.com/khightower
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2010 ACM Turing Award: Leslie Valiant
on Apr 11, 2011 11 October 2017
Last month, the 2010 ACM Turing Award was awarded to British computer scientist Leslie G. Valiant of Harvard University:
For transformative contributions to the theory of computation, including the theory of probably approximately correct (PAC) learning, the complexity of enumeration and of algebraic computation, and the theory of parallel and distributed computing.
Valiant’s fundamental contributions to the development of computational learning theory (in particular, probably approximately correct learning) brought together machine learning and computational complexity, leading to advances in artificial intelligence as well as in natural language processing, handwriting recognition and computer vision.
Read the full award citation.
(also see: the 2009 recipient, as well as the full chronological listing of awards)
ACM Turing Award, Computational learning theory, Leslie Valiant
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Pingback: 2011 ACM Turing Award: Judea Pearl | Computing: The Science of Nearly Everything
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altered states, blueberry, disney, dumbo, fear and loathing in las vegas, psychedelic cinema, taking woodstock
The history of cinema presents us with a considerable number of attempts to recreate the psychedelic experience[1], an experience which confronts the cinematic artist with an extraordinary challenge – to capture a deeply physical, emotional, mental and spiritual experience through the limited means of sound and moving picture.
This short list of cinematic renditions of psychedelic trips is not intended to offer a complete list of the genre. It is only a selection of some of what I consider to be the more interesting and influential trip sequences in the history of cinema. Some of the trips depicted in these videos are magical and enchanted while others are vicious and vile; some are divine and purging while others are funny or just weird. This is of course due to the manifold aspects of the psychedelic experience, which appears in many forms, in life as well as in the movies.
Before the 1960s
The first trips in cinema were animated and often involved animals which got terribly stoned under curious circumstances. Felix the Cat (1927), a pioneering example, is a silent film in which the Felix the cat eats a shoe and a tin can from the garbage and experiences some kind of strange iron poisoning which send him into a delirious world of hallucinations where he is chased around by a giant chicken, sees Santa Claus transforming into a witch, and fights an imaginary cat which keeps turning into a sausage. The trip sequence in this video starts at 4:13.
Another early animated attempt to recreate the psychedelic experience in film can be found in Disney’s Dumbo (1940). Here, the flying elephant drinks magical water out of the well and is transported into a powerful hallucinatory state in which he beholds dancing pink elephants and fractal, kaleidoscopic visions. Peter Stafford’s “Psychedelic Encyclopedia” claims that the chief visualist for Disney’s Fantasia (1940) participated in the mescaline experiments conducted in Germany by Kurt Beringer during the 1920′s; and Artist Paul Laffoley claims that Disney himself experimented with Mescaline “On a regular basis” during his stay in Germany in the 1930′s. So that the relation between 1940s Disney films and psychedelics is still far from clear.
A great number of films dealt with the psychedelics during the 1960s, when the psychedelic movement was in full swing. Most of these films, like “Wild in the Streets” and “The love ins”, were B movies of which tried to capitalize on the hippie phenomenon by turning it into a sensation. Many of these films were done in the tradition of exploitation cinema, indulge in the use of nudity as a cheap thrill and have a rather voyeuristic character.
Roger Corman’s “The Trip” which was based on a script by Jack Nicholson (who is also known for his interest in psychedelics), is a movie dedicated to the description of one long and deeply meaningful trip. Peter Fonda, who plays the protagonist, was known at the time as one of the leading representatives of the burgeoning counterculture inHollywood, and the film sometimes carries a somewhat naïve yet appealing character of trying to make a point for the psychedelic experience.
The Easy Rider cemetery trip scene (here, regrettably, in Italian dubbing) is another classic 1960s cinematic rendition of the psychedelic trip experience. Peter Fonda and Dennis Hopper visit the Mardi Gras festival and then arrive at a cemetery, where they ingest LSD together with two prostitutes. The scene makes use of fish eye lenses, unusual camera angles, background noises and an hectic editing style to capture the psychedelic experience.
Altered States (1980)
The eighties were not a particularly psychedelic decade, however in 1980 Ken Russell directed “Altered States” a fascinating and awfully troubling film which is loosely based on the character of isolation tank pioneer John C. Lilly, who experimented with the conjoined use of LSD and isolation tanks in the beginning of the 1960s.
This film could be called a psychedelic horror film, as it is strewn with incredibly dark visions in which the hero meets the Devil, baphomet and other demonic apparitions. This particular scene is replete with biblical motives and religious symbols, and has an extremely sinister atmosphere. Beside the use of dramatic music, slow motion and esoteric symbols the scene is especially notable for its elaborate use of blue-screen techniques for the recreation of the visionary experience.
Fear and Loathing in Las Vegas (1998)
In 1998 Terry Gilliam released his brilliant version of the book “Fear and Loathing inLas Vegas” written by gonzo writer Hunter S. Thompson, which featured Johnny Depp as the drug obsessed reporter Raoul Duke.
In this unforgettable scene, Duke walks into aLas Vegashotel loaded with an incredible mixture of mind bending drugs. The result is one of the funniest descriptions of an hallucinatory experience in film. Gilliam does extraordinary work in capturing the dynamics of the psychedelic experience, and uses the newly arrived CGI effects to create the visual distortions typical to a psychedelic trip. However, Gilliam has more than just technology going for him. He also has an amazing talent for capturing the highly weird and bizarre form of perception which can turn the world into a carnival of weird mutants during a psychedelic trip.
Blueberry (2004)
“Blueberry” (A.K.A “Renegade”) is a rare film in the sense that it has a unique trip-like feeling from beginning to end. The “Blueberry” trip sequence has already reached a certain cult status on the web and become one of the best known cinematic descriptions of the ayahuasca experience.
While the sequence heavily relies on CGI effects, and is in that sense typical to the digital turn in the cinematic renditions of psychedelic trips – it is also breathtakingly beautiful. The relentless and exquisite movement between different layers and dimensions during the trip recreates the multi-dimensionality of the psychedelic experience in an extraordinary way.
Taking Woodstock (2009)
The “Taking Woodstock” trip sequence, is in my eyes a work of cinematic and psychedelic genius. It manages to capture a graceful psychedelic experience in a delicate and incredibly nuanced way, which is in my eyes, the most sensitive treatment of the psychedelic experience to this day.
This is not incidental, as the makers of “Taking Woostock” actually did thorough research on the subjective effects on psychedelics, and how these could be tastefully and effectively adapted to the screen. The result has been called “a stunner with overlapping pastel lighting effects, green-screen animation, shifting film speeds, lens trickery and undulating CGI…”
Viewing this sequence, I can almost feel what the protagonist is feeling as he slowly enters his psychedelic journey. The sequence pays great attention to the gradual movement into a different order of perception: the sublime glowing of the colors and the orgasmatic shivers of the skin and palpitations of the heart. It enfolds in a way which is typical for many psychedelic experiences: from the womb-like feeling of the caravan, into the magical world outside and onward into a spectacular peak experience where Jake watches the Woodstock crowd turn into one vibrating tissue and his eyes are filled with tears of awe and joy.
[vimeo http://vimeo.com/11696950]
A psychedelic cinematic quest
The attempts to recreate the psychedelic experience in cinema will always be incomplete at best. Capturing such an all encompassing experience through the use of visual and audial means alone is after all a task which can not be performed in an entirely faithful way. However, by examining the history of the psychedelic experience in cinema, one is confronted with the various audacious attempts of performing this task, which teach us not only on the limitations of cinema but also on its ability to act as a mind-altering medium, even to the degree of mimicking the effects of mind-altering substances, a psychedelic cinematic quest which will surely continue to enfold in the coming years, simultaneously with the evolution of media.
[1] When writing of movies which attempt to recreate the psychedelic experience, I am referring here not to movies which have a visually psychedelic qualities such as “2001: A Space Odyssey”, “Charlie and the Chocolate Factory”, “Speed Racer” – but only to films which show one of the protagonists consume some kind of hallucinogenic substance (equivalent to a psychedelic) and then try to recreate his experience for the viewer.
« Culture is not your friend: On the countercultural philosophy of psychedelic thinkers
Avatar: The Psychedelic Worldview and the 3D Experience »
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Kamonwan Wipulakorn
March 23, 2019 April 7, 2019 Pursuit of Excellence Leave a comment Bob IgerChadatip ChutrakulDisneyDisney PlusESPNFox EntertainmentHuluJuree Vichit-VadakanKamonwan WipulakornKobkarn WattanavrangkulSupapan PichaironarongsongkramThai women
https://www.bloomberg.com/news/articles/2019-02-25/women-gain-ground-in-thai-c-suites-not-so-much-in-government
The Asian country where women hold 37 percent of leadership roles, compared with an average of 24 percent globally, may come as a surprise. In this same nation, women make up 40 percent of chief executives and 34 percent of chief financial officers. Further, it ranks first in the world for enrollment of women in higher education with 1.41 women attending a university for every man. Done guessing? It’s Thailand, where women score well in nearly all measures of leadership in the corporate sphere, far surpassing most other Asian countries and gaining good marks globally. Yet even as women are making significant progress in Thailand’s business world, there’s a stark contrast in politics, where they are being left behind. Thailand ranks near the bottom — 181 of 193 countries — in the Women in Parliament list for 2017 by UN Women. Currently, only 13 women are part of the junta’s 240-seat parliament. There’s not a single woman cabinet minister. In the elections this month. there are only 8 women aspirants of the 68 aspirants for the position of prime minister. Thailand’s success in empowering women in corporations is a culture of working women through family businesses; in other words, women have always worked outside the home. Women leaders have more opportunities to run corporate Thailand because the culture allows them to work alongside men in such fields as finance and insurance, while women in politics typically need the support of political parties to break into that male-dominated sphere. For instance, females make up only about 5 percent of the military-appointed legislature — a place where women need backing to get ahead. Some of the notable women in this article are Kamonwan Wipulakorn, Supapan Pichaironarongsongkram, Chadatip Chutrakul, Kobkarn Wattanavrangkul, and Juree Vichit-Vadakan. Thai women are the driving force behind many industries in Thailand and make up a third of senior management positions. Another key factor is that Thai women often stay in the workforce even after having children due to the Thai family structure having the grandparents living in the same household allowing the Thai women to remain a part of the workforce. However, in politics it is not the same because these positions have been historically male dominant. Similar to Kobkarn, Juree was once in government, as a member of the national legislative assembly. “Parliament is a very lonely place for women,” said Juree, who was also was part of the constitutional drafting committee. “It’s easier for men to form a coalition,” she said. As time progresses, and the newer generations come up, I can see politics changing within Thailand.
https://www.businessinsider.com/disney-acquires-fox-71-billion-dollar-deal-2019-3
Disney has closed its $71 billion acquisition of Fox’s entertainment business, putting “Cinderella,” ”The Simpsons,” ”Star Wars,” and “Spider-Man” under one corporate roof. The deal is likely to shake up the media landscape. Among other things, it paves the way for Disney to launch its streaming service, Disney Plus, due out later this year. By buying the studios behind “The Simpsons” and X-Men, Disney aims to better compete with technology companies such as Amazon and Netflix for viewers’ attention — and dollars. Years ago, I had the opportunity to work at Walt Disney World as my first job. During my high school years, I met and worked alongside people from other countries and cultures. It radically changed how I viewed life in my hometown. Even back then Disney was beginning to successfully acquire companies such as ABC which housed ESPN etc. Now with the acquisition of Fox Entertainment, Disney is positioning itself to compete with cable and telecom companies. The acquisition aids Disney control TV shows and movies from start to finish — from creating the programs to distributing them though television channels, movie theaters, streaming services, and other ways people watch entertainment. Disney would get valuable data on customers and their entertainment-viewing habits, which it can then use to sell advertising. Disney CEO Bob Iger said in an earnings call in February that Disney Plus and other direct-to-consumer businesses were Disney’s “No. 1 priority.” With the acquisition Disney also has a controlling stake in Hulu, which will continue to have its general programming format. No pricing has been disclosed for Disney Plus. The streaming service will feature five categories of material: Disney, Pixar, Marvel, “Star Wars,” and National Geographic. Disney charges $5 a month for ESPN Plus, a service that offers programming distinct from the ESPN cable channel. Meanwhile, Fox Corp. — the parts of 21st Century Fox that are not part of the deal, including Fox News, Fox Sports, and Fox Broadcasting — started trading on the Nasdaq under the FOX and FOXA tickers on Tuesday. Personally, I do own a few shares of Disney stock and I’m going to start watching its price a little closer.
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PBS 6
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Four Decades of Perseverance Rewarded with College Degree
An education for Tucsonan Karen Schaffner was a long time coming. by Sophia Paliza-Carre TWEET SHARE
As she walked up to the front of the room to receive the Kathryn Anne Governal Perseverance Award, Karen turned and shouted “I did it!” She received raucous applause from the crowd in response.
This award has been a long time coming. It’s given to a graduating student at the University of Arizona School of Journalism who has persevered in the face of difficult challenges.
Karen Schaffner, 58, is finally graduating with her bachelor’s degree, after stopping and starting her studies over the course of 41 years.
It was her lifelong dream to get her college degree. Life had always simply got in the way and she had prioritized other things– her cultural upbringing, raising her children, taking care of her husband and home and the household budget.
A few years ago, her husband, who had been unemployed for 9 months, came home one day from his new job and asked “what would you do if something happened to me?” Then, Karen decided, it was finally time to go back and finish.
This is her story.
Karen Schaffner has been waiting for her graduation day for a very long time.
Sophia Paliza-Carre, AZPM
“My parents were very traditionally Mexican. When I came of age at that time, in the 70s, it was right when the women's movement was really becoming strong. So they were really really opposed to that. For my brothers, it was become a professional, for me it was marry a professional.”
Karen and her daughter, Misa, after receiving the Kathryn Anne Governal Perseverance Award. Karen's name will also be on a plaque in the journalism school.
Return to school
“And I thought, I can't go back to it. I'm a dinosaur. I don't know anything about social media. I knew what it was, but I didn't know how to tweet, Instagram. None of those things.”
“So, I had my book bag, which I bought special. And my new pens and notebooks. So I was all ready. And the night before my husband and I drove to the university and I walked around until I found the building so I knew where to go. And anyways, that day, I got there real early and I was standing in the hall and I had my little cellphone and I was texting my daughter and, you know, I looked around me and I saw all these young people doing the same thing. And I thought they're as nervous as I am. I'm not the only one who is nervous. And it made me feel better.”
“I looked ahead at the end and I thought, don't look there you won't finish. I just can't look that far ahead.”
“It cost us a lot for me to go. Not just in terms of money... I should be working, not going to school. I should be bringing in money, not costing us money. Jude, my husband, he took a back seat. We both knew this is what's important.’
“It is crazy, all my children are in now, it's been a lot of running to the airport and trying to think about what I’m going to have for dinner, and that sort of thing. This is the first time I've allowed myself to think I did something.”
“On the other hand it's also scary. I don't know what's ahead. I have an internship for the summer, but beyond that I just don't know.”
"Everything is going to change. and I don't know how, and how I'll be affected by it. But that's alright. Let's go for it."
Karen's postcard for Dímelo: Stories of the Southwest.
This story is from a postcard received at El Río Community Health Center. Fill out your own postcard below. Go to www.dimelostories.org for more details on how to participate.
Contesta en Español
Dímelo is brought to you by KUAZ and Finding America, a national initiative produced by AIR, the Association of Independents in Radio, Incorporated. The project is done with financial support from the Corporation for Public Broadcasting, the Wyncote Foundation, the John D and Catherine T MacArthur Foundation, and the National Endowment for the Arts.
MORE: Arizona, Dímelo, News, Higher Education
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Judson Robert Finley 1931-2012
May 8, 2012 August 13, 2015 rafinley
“Such a beautiful dream. I hate to think it all over.” -Hank Williams, Jr. (Lovesick Blues
Retirement Party, 1989
On May 08, 2012, Judson Robert Finley, tireless advocate for the underdog, steadfast friend, warmhearted family man, and musician extraordinaire, quietly left the party he’d loved so well. It will not be the same without his bright, occasionally mischievous smile; his sudden, infectious laughter; his unreserved hugs and reassuring pats on the back.
For the past fifteen years, Parkinson’s Disease had been an unwelcome, increasingly difficult guest at his party, and Jud fought long and hard to hold on to the abilities and activities he enjoyed: photography, homebrewing (“Judweiser”), geology (aka “rock collection”), back roads travel, and above all, music. His last days included plenty of the latter, from the out-of-practice sounds of his daughter’s violin to a private barbershop quartet performance (as arranged, with his family’s heartfelt gratitude, by Sarah House and the Dream Foundation).
Jud was born on July 13, 1931 in Los Angeles, but soon moved with his parents George and Wilberta (“Billie”) Finley and sister June to Santa Barbara. There, at play school, he met [name redacted; you know who you are], his eventual cohort in the Hope Ranch Lemon Pickers and assorted good-natured mischief (trips to Rosarito Beach in 1948-49 to sing western songs on XERB…really?). This was the first of a wide variety of friendships he would make and enthusiastically maintain throughout his life.
What he valued, whether it was an object a job or a relationship, he tried to give it attention and care. He enjoyed fixing things, figuring out how they worked, and devising systems. And, while it might be said he was too reliant upon popsicle sticks and glue when it came to home repairs, when it came to his work on behalf of the disabled, he was brilliant.
After his 1949 graduation from Santa Barbara High School, he briefly attended the University of Redlands, then joined the U.S. Navy in time for the Korean War and, thanks to their refusal to accept the use of his middle name, Robert/Bob became Jud. His favorite postings were in Arizona and Guam; and after his 1954 honorable discharge (Aerographer’s Mate, Second Class) he returned to Arizona, making his home with his first wife and son in the Phoenix area and attending ASU.
He received his Ph.D. in Psychology in 1965, but had already begun work at the Arizona Division of Vocational Rehabilitation, a place he would see through many changes. He was, variously and often simultaneously, Chief Psychologist of the Vocational Evaluation Unit, member of numerous task forces and committees (including the State Board of Psychologist Examiners), Acting Manager of the Rehabilitation Facilities and Resource Development Section, and ultimately, Coordinator of Grants and Contracts. His efforts during these formative years were mighty; his achievements and influence, beyond measure.
Upon his retirement in 1989, he moved with his second wife and daughter to Ashland, Oregon–a place they’d found on one of their quirky, often comical road trips–and turned his photography hobby into a full-fledged business, J.R. Finley Photographics. He also joined the Rogue Valley Harmonizers barbershop chorus, played “gut bucket” in a cowboy band, and fulfilled an unacknowledged life-long dream of performing in a stage production of The Music Man. When photography went digital, he shifted all his attention to “barbershopping,” and so became a vital member of the Harmonizers and at least two active quartets. Even when his vocal chords weakened to the point where he felt he shouldn’t perform, he remained active, giving advice with the help of his perfect pitch and enviable ability to identify any note by ear, while passionately arranging music.
His 2005 decision to “move home to Santa Barbara” with his wife didn’t stop his work with his Oregon friends; it merely slowed it to the speed of the mail. He leaves behind two large binders packed with original four-part-harmony versions of songs such as “Hit the Road, Jack” and “Sentimental Journey” to name but a few.
Wherever Jud went, he made friends–and this includes the last weeks of his life, when he moved into Alexander Court, spent time at Cottage Hospital, and lastly when he was cared for so graciously at Sarah House. His time there—peaceful and loving—was a gift for which his family will be forever grateful.
To have known him is to miss him terribly, but he wouldn’t welcome much sorrow. In his own words:
Please tell folks I loved them but didn’t know much how to show it. Tell ‘em I believed in helping other people at all times, like the Scout Oath says, but didn’t always do it. Tell ‘em I tried to be a good Dad, Husband, Employee, and Person, and hope that it showed. Then, there ought to be a party with plenty of music, eats (including beef enchiladas and hot sauce!), and then everyone ought to get on with livin’.
Jud is survived by his wife of nearly 40 years, Alice; his son, Jon, with children Krista and Tim; his daughter, Rebecca; his brother-in-law Bill Lipe with children Carrie, Jessie, and David, and their families; and his many dear friends.
Should it be desired, memorial contributions may be made to Sarah House (PO Box 20031, Santa Barbara, CA 93120; www.sarahhousesb.org) and/or Visiting Nurse and Hospice Care Foundation (805-965-5555 or www.vnhcsb.org).
Arrangements by Welch-Ryce-Haider Funeral Chapel.
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Summer of the (Animated) Bat, Part 1
Posted on November 12, 2016 by rfunkad in Cup o' Joe // 0 Comments
So you may recall that in the summer of 2015, I celebrated getting the complete 1960’s Batman series by spending the summer watching both it and live action movies that ranged from the 60’s to today. I had plenty of fun with that, so I decided to do another version of it. I spent this past summer watching as much animated Batman as I could get my hands on. Here’s what I found…
(BLOGGER’S NOTE: This list includes ONLY the Batman animated series and any movies that spun off from them. It does NOT include stand-alone animated movies, such as the recent adaptation of The Killing Joke. But hey, there’s always next summer, right?)
THE ADVENTURES OF BATMAN (1968) and THE NEW ADVENTURES OF BATMAN (1977)
Both of these came from Filmation, a company that, along with Hanna-Barbera, largely dominated Saturday morning cartoons in the 60’s and 70’s. There’s a ton of similarities between the two. Per Filmation’s apparent creed, they were cheaply produced and made ample use of stock shots (particularly the 60’s series.) In fact, some of the 70’s stock shots were direct re-creations of those from the 60’s series. Both shows featured iconic voice actors. The 60’s version had Olan Soule and Casey Kasem as Batman and Robin. They would go on to voice the characters during the various incarnations of The Super Friends. The 70’s series featured Adam West and Burt Ward returning to the roles. (I would’ve loved to have seen the conversation those guys had with their agents. “What the hell, man? Ten f’n years and all you land me is another Batman series? You gonna finish that sandwich?”)
While no one would describe the 60’s series as gritty, the 70’s version has a decidedly lighter tone. This is mainly due to the addition of Batmite, a tiny traveler from another dimension with a voice that sounded like a cross between Lou Costello and a cat getting ass-raped as it’s being fed through a woodchipper. Apparently, the idea was that kids couldn’t relate to super heroes, but COULD relate to someone whose purpose was to be an annoying little bastard. It’s a mentality that led to s**t like Scrappy Doo.
SCOOBY-DOO MEETS BATMAN (1973)
Speaking of which, long before said annoying little bastard was added, everyone’s favorite mentally-challenged dog teamed up with the Dynamic Duo. This “movie” is actually two episodes of The New Scooby Doo Movies, a Saturday morning series from the early 70’s in which Scoob and the gang teamed up with various celebrities or fellow animated characters. Both of these episodes include The Joker and The Penguin, who are downgraded from super-villains to bumbling dips**ts. The first story involves the two trying to steal a flying suit from a Professor Flaky. The Professor has a tendency to mix up things he says before correcting himself (ex. “It’s The Poker and Jenguin. I mean, The Joker and Penguin.”) It’s fine at first, but after hearing him do it with EVERY line for nearly 45 minutes, I was openly rooting for the villains to kill him…and eat him. The second story reduces the super-villains to dupes being used by a counterfeiter to pass phony bills. That aside, the second story is clearly better, as it involves an actual mystery and has more story. The first is largely an excuse for the Scooby gang’s usual bulls**t hijinks.
The New Scooby Doo Movies was the product of Hanna-Barbera studios. While they didn’t seem to have Filmation’s fetish for stock shots, they didn’t exactly break the bank on the animation, either. Everything generally looks like what Carl Sprang might have drawn if he’d been drinking all weekend. Continuity is treated like a cute idea, as we’re given moments like Batman being barehanded and wearing a ring in one shot and then having his gloves back on in the next (I guess they’re trying to tell us Batman’s a klepto.) Characters have a tendency to freeze in position for awkwardly long periods of time. Batman’s cowl makes no sense, as it’s open at the neck and the mask just seems to stop at his jawline. Robin’s mask is so big in some shots that it looks like he’s wearing an early version of wraparound sunglasses. The voice talent, on the other hand, is solid. As he did with the 60’s animated series and Super Friends, Olan Soule provides the voice for Batman. And Casey Kasem does good work doing double-duty as both Robin and Shaggy. (If you didn’t know in advance, you might have a hard time realizing it was the same actor for both voices.) Ultimately, though, I can’t imagine anybody under the age 40 finding this interesting and even for those who do, only as a nostalgia item.
BATMAN: THE ANIMATED SERIES (1992) and THE NEW BATMAN ADVENTURES (1997)
This is the Holy Grail for Batman fans. Not just in the animated category, but in the whole of Batman on screen (with the possible exception of Nolan’s film series.) Gorgeously animated in the same mix of classic and modern styles that dominated Burton’s films, the series is less quirky, but no less dark. Visually, it incorporated art deco and film noir elements into a setting that also used modern technology, achieving the same timeless feel of Burton’s Batman (which in turn had been influenced by the look of Terry Gilliam’s Brazil.) It’s a melange of styles that works even better in animated form than in the live-action films; the elements blending so smoothly that you simply accept that world for what it is.
In terms of the storytelling, the show runs far deeper than any of its predecessors. In fact, there are plenty of times in which I wound up asking myself, “This is a kid’s series, right?” Episodes like “Beware The Grey Ghost” pack a genuine emotional punch, as do episodes focusing on Two-Face, Mr. Freeze and Clayface. The origin of Clayface, as depicted in the series, is genuinely disturbing and at no time do the creators back off the impact of The Joker’s antics. With all of these mature elements in place, it’s small wonder that Fox gave the show a try in prime time (an experiment they pulled the plug on WAY too quickly.)
The voice talent was highlighted by Kevin Conroy (as The Batman) and Mark Hamill (as The Joker). Conroy was solid, providing the perfect amount of gravity and differentiating subtly between his depictions of Batman and Bruce Way. Hamill was a revelation as The Joker (though only a slight one to the few who’d seen his work as The Trickster in the 90’s Flash TV series.) He was able to be both funny and loathsome (often in the same sentence.) Hamill’s ability to make you laugh at, but never be charmed by The Joker puts his work up there with Jack Nicholson and Heath Ledger as the best portrayals of the character. The series had a raft of talent providing guest voices, including Ron Perlman (Clayface), Roddy McDowell (The Mad Hatter), Ed Asner (Roland Daggett), John Vernon (Rupert Thorne), Kate Mulgrew (Red Claw), Helen Slater (Talia) and Marliu Henner (Veronica Vreeland). A particular favorite was Adam West as the washed-up TV star Simon Trent, formerly The Grey Ghost.
The Animated Series is most noted for introducing the character of Harley Quinn, a former Arkham Asylum psychiatrist whose mind is warped by The Joker. She becomes his sidekick and girlfriend, though the relationship is tempestuous at best. (Shocking, really. One would imagine The Joker to be a more caring and giving lover.) Voiced by The Animated Series‘ voice director Arleen Sorkin, the character quickly grew from walk-on to sidekick to member of the Rogue’s Gallery to full-on member of the DC Universe. Sorkin’s by-turns hilarious and demented work played no small part in that, as she’s clearly become the template for all future portrayals of Harley Quinn.
The New Batman Adventures aired on the WB (later CW) Network a few years after Fox cancelled The Animated Series. It was put together by the same creative team and voice talent. Word is that creator Paul Dini wanted the call the series Batman: Gotham Knights, perhaps intending to position it as a new series altogether. Warner Brothers shot the idea down, deciding they could package DVD releases of the new series with the previous one, thus giving the impression that The New Batman Adventures was a continuation of The Animated Series. Sadly, The New Batman Adventures was less a continuation of the old series and more a pale imitation of it. The animation style was less rich and the art deco elements were toned down, thus removing the sense of style that dominated The Animated Series. The focus also moved to the supporting cast, particularly Batgirl, Robin, Nightwing and Nightwing’s mullet. The writing and voice acting remained strong, but the altered look of the series made it seem like a continuation in name only. Not bad, but not a revelation, either.
BATMAN: MASK OF THE PHANTASM (1993)
Mask of the Phantasm was a direct-to-video movie spun off from The Animated Series. It presented a new villain in the form of The Phantasm, a vigilante whose killings of various mob bosses are actually blamed on the Bat. It also explored, in flashback form, a young Bruce Wayne’s doomed love match with a woman named Andrea Beaumont. As could be expected, the two storylines are not unrelated, coming together in a way that forces Bruce to question his commitment to being Batman and what such a thing stands for.
The film makes use of the rich visual style found in The Animated Series. While the backstory involving Bruce and Andrea is interesting, it’s curiously muted. The attempts at emotion fall a tad short because there’s never been a defining love of Batman’s life, ala Lois Lane and Superman, Iris West and The Flash or even Mary Jane Watson and Spider-Man. As a result, one of the story’s defining qualities falls a tad flat and the film never feels like much more than a 75 minute version of the TV series. The voice cast, though, is stellar. Series regulars Kevin Conroy (Batman), Bob Hastings (Commissioner Gordon), Efrem Zimbalist Jr. (Alfred) and Robert Costanzo (Harvey Bullock) are all here, along with Mark Hamill (and his always-stellar take on The Joker), Dana Delaney as Andrea, Abe Vigoda as an aging mob boss and Stacey Keach as Andrea’s father.
Like the 1966 live-action Batman film, Mask of The Phantasm had the problem of existing concurrently with a running series. However, unlike the ’66 film, it doesn’t feel like this one, in terms of visual style, character development or plot, takes us any place that The Animated Series hasn’t already gone.
BATMAN & MR. FREEZE: SUB-ZERO (1998)
Originally intended for release in 1997 but pushed back to create distance from the live action Batman and Robin debacle, Sub-Zero was, as I noted in last year’s blog entry, a better take on the Mr. Freeze story than Joel Schumacher’s abomination. The plot deals with Freeze and a sleazy doctor kidnapping Barbara Gordon (Batgirl) for the purpose of harvesting one of her organs to save Freeze’s comatose wife. (Believe it or not, in Batman continuity, this was not the worst thing ever to happen to Batgirl.) Batman and Robin rush to the rescue while Freeze struggles with his own conscience and the forces that have driven him to become a super-villain.
Timing-wise (and it appears continuity-wise) the film falls between The Animated Series and The New Adventures. Visually, it’s in the same boat. The animation isn’t as rich as The Animated Series, but not as stripped down as its successor. The visual flow of the story is similar to Burton’s films; almost as if the animated movies were determined to provide what the live action movies were f**ing up. It adds some computer animation to heighten the excitement and it works quite well, particularly in a chase scene where Barbara is kidnapped. The voice acting is great, as always, though I found Michael Ansara’s Freeze a tad hokey.
Ultimately, Sub-Zero succeeds because it finds an emotional element to the story that’s largely missing from (and when present, poorly executed by) Batman and Robin. Freed from the dictum that as many terrible yuks as possible must be added to the film, Sub-Zero is able to focus on the complexity of its villain; how such a villain is often just a hero turned sideways by circumstance. If only Joel Schumacher had been interested in such a thing…
COMING IN PART 2: The animated Bat enters a new century…and Beyond.
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Runglobal Australia
Aussies named for 50kms Rio line up
Posted on January 9, 2016 by Kate Dzienis Leave a comment
Jared Tallent in the men’s 20kms race walk final at the IAAF World Athletics Championships in Beijing on August 23, 2015. Image – Getty Images.
CANBERRA, ACT:
Triple Olympic medal holder Jared Tallent was yesterday (January 8) confirmed as part of the Australian Olympic team for the 2016 Rio Games, along with 34-year-old veteran Chris Erickson and Erickson’s student athlete Brendon Reading.
At the London Games, Tallent was beaten by accused Russian drug cheat Sergey Kirdyapkin in the 50kms race walk and this year he will aim to claim the gold he so deserved in 2012.
A decision has not yet been made in Kirdyapkin’s court case, where he may be stripped of his gold medal.
Tallent, 31, told the Australian Olympic Committee he was intent on winning the gold this time around.
“This one’s going to be pretty special after what happened at the last Olympics,” he said.
“I’m so well prepared I can get some redemption in Rio.”
Tallent is also chasing selection in the 20kms race walk division and was thrilled to hear his fellow colleagues would be by his side every step of the way – literally.
“It’s a great group and we’re all great friends and these are the best guys to be on the team with in this event,” he said.
Erickson’s history includes participating in the 20kms walk at both the 2012 London Games and 2008 Beijing Games, and placing 13th in the 50kms event at the 2015 IAAF World Athletics Championships.
Rio will be his first time competing in the Olympic 50kms event – his favoured distance, and the father of two revealed he felt like somewhat of a rookie.
“I’m extremely stoked to be going to my third Games but for me I somewhat look at it like it’s my first Olympics again,” he said.
“I finally get my chance at the 50 which is my preferred event and the other satisfying thing is to be selected at the earliest possible opportunity as well.
“It’s nice to be able to have a full preparation over the next seven months and really look to have the performance of my life in Rio and push for that top eight.”
Race walking is in Erickson’s genetics, with his father Tim Erickson representing Australia at the 1978 and 1982 Commonwealth Games.
Athletics is expected to be the largest section of the 2016 Australian Olympic team.
The next selections for athletics will follow the 20kms walk trials in February.
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Amy Poehler and Nick Offerman Craft New NBC Reality Competition
As if you hadn’t enough trouble keeping The Handmaiden and The Handmaid’s Tale separate, Amy Poehler and Nick Offerman are adding a new wrinkle. The Parks and Recreation pair will host The Handmade Project, a new NBC reality competition for craft-making.
Per The Hollywood Reporter, Poehler and Offerman will return to their NBC roots for the six-episode reality competition, which itself will measure “artisanship and the makers who can create amazing things with their hands.” Eight makers will compete to build crafts for the hosts and a panel of judges, while Poehler herself said of the project:
I’m thrilled to be celebrating artists who make things by hand, and I’m looking forward to finally conquering my fear of paper mache.
Added Offerman:
People who make things are my favorite kind of folk. Practical, clever and terrific in a pinch. That makes me tickled pink to have a front-row seat at this prodigious display of talent, and admiring and cheering on an amazing crop of American makers. Plus, Amy and I have a strong tradition of tomfoolery, so let’s see if we don’t have some good fun.
The series arrives as part of Poehler’s overall deal with Universal Television Alternative Studio, though no premiere has yet been determined. Stay tuned for the latest in the meantime.
‘Parks and Rec’s Leslie Knope Writes to America After Election 2016
Filed Under: Amy Poehler, NBC, Nick Offerman, Parks and Recreation
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Jun 29, 2017 · 08:00 pm
Scroll Staff
Missing JNU student case: CBI offers Rs 10 lakh reward for information on his whereabouts
The next Delhi High Court hearing in the matter is on July 17.
The Central Bureau of Investigation on Thursday announced a reward of Rs 10 lakh for anyone who came forward with information on the whereabouts of missing Jawaharlal Nehru University student Najeeb Ahmad, reported ANI. The Delhi High Court had transferred the case to the CBI on May 16. The next hearing in the matter is on July 17.
While handing over the case, the court had ordered the agency to appoint an officer no lower than the rank of a deputy inspector general of police to handle the investigation. The case was handed over to the CBI after Ahmad’s mother had filed a petition, and the police had said they had no objection to it.
The 27-year-old biotechnology student was reported missing on October 15, 2016, after a spat with members of the Akhil Bharatiya Vidyarthi Parishad. He was initially described by university officials as an “accused” in the events of that night, but after he went missing, the police had registered a case of abduction and offered a reward for any information on his whereabouts.
Following orders from Home Affairs Minister Rajnath Singh, the Delhi Police had also formed a special team to find Ahmad. The police had failed to make any major breakthrough since his disappearance, triggering criticism and protests against the authorities.
JNU student Najeeb Ahmed missing case: CBI announces Rs. 10 lakh reward for information to locate him.
— ANI (@ANI_news) June 29, 2017
Najeeb Ahmad
In Tamil Nadu, beheading of a 14-year-old is suspected to be a caste crime
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Connect to the Knowledge of a Community of Cancer Experts
About Patient Power - A Cancer Resource
Patient Power News and Perspectives
Meet the Patient Power Team
Patient Power® is a service of Patient Power, LLC, based in Seattle with team members around the world. Patient Power was founded by two health communications pioneers, Andrew and Esther Schorr. They previously founded HealthTalk.com, a leader in support for people with chronic illnesses and cancer. Patient Power® is devoted to helping you, the cancer patient or survivor and your family through knowledge, to get the best medicine and return to or maintain good health.
Andrew lived that. In 1996 through a routine blood test he was diagnosed with leukemia (CLL). By reaching out to other patients and connecting with doctors who specialize in his illness, he participated in a clinical trial, received "tomorrow's medicine today" and now, 19 years after diagnosis, remains in deep remission and takes no medicines.
Like all too many cancer patients, Andrew developed a second cancer, in 2011, myelofibrosis. But, again, by connecting with the most modern medicine he continues to live a full life. While Andrew's success won't be everyone's story, he and our entire team, are committed to helping each person we touch approach their illness in a way that gives them the best chance of good health: getting smart about their diagnosis, seeking out the best healthcare providers, getting second and even third opinions on what approach to take – including, if appropriate, participating in a clinical trial, and drawing on others for support.
Patient Power® is built on a library of programs, organized into health centers, which continues to grow as we attend medical conferences and produce new interviews throughout the year. These programs feature top medical experts from some of the world’s leading medical institutions, dedicated advocates and inspiring, knowledgeable patients. We invite you to watch and learn from these programs let us know what you think, either by taking a short survey after the program or contacting us directly.
Financial support for our efforts comes from Andrew and Esther's own funds, key medical centers, and industry sponsors who have no editorial control. Patient Power® is not selling anything and has no agenda other than to help you live well.
The opinions expressed on this site are Andrew's, our other contributors and guests, and from visitors like you. They do not necessarily reflect the opinions of our sponsors or any outside organization.
Please consult your own doctor for medical advice that is most appropriate for you.
For more on Andrew’s story and his commentary on current cancer issues, please visit his blog and check out his book, The Web-Savvy Patient: An Insider’s Guide to Navigating the Internet When Facing Medical Crisis.
Page last updated on May 9, 2019
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The Beatles is the ninth studio album by English rock group the Beatles, a double album released in 1968. It is also commonly known as "The White Album", as it has no graphics or text other than the band's name embossed (and, on the early LP and CD releases, a serial number) on its plain white sleeve.
The album was written and recorded during a period of turmoil for the group, after visiting the Maharishi Mahesh Yogi in India and having a particularly productive songwriting session in early 1968. Returning to the studio, the group recorded from May to October 1968, only to have conflict and dissent drive the group members apart. Ringo Starr quit the band for a brief time, leavingPaul McCartney to play drums on two tracks. Many of the songs were by less than the full group, some of them "solo" recordings, as each individual member began to explore his own talent.
Upon its release in 22 November 1968, the album received mixed reviews from music critics, who criticized its satirical songs as unimportant and apolitical amid a turbulent political and social climate. However, it reached number 1 on the charts in both the United Kingdom and the United States. The album has sold over 20 million[citation needed] copies worldwide and has since been viewed by critics as one of the greatest albums of all time. In September 2013 after the British Phonographic Industry changed their sales award rules, the album was declared as having goneplatinum.[3]
Contents Edit
[hide] *1 Background
2 Recording sessions
2.1 Division and discord in the studio
2.2 Instrumental contributions
2.3 Other musicians
2.4 Technical advances
3.1 Compositions not included
4 Editing concerns and release
4.1 Mono version
4.2 Packaging and tape configurations
6 Cultural responses
7 Commercial performance
11 Release history
Background[edit] Edit
See also: The Beatles in India
The Beatles were at the peak of their global influence and visibility in late 1968. Sgt. Pepper's Lonely Hearts Club Band, released the previous year, had enjoyed a combination of commercial success, critical acclaim, and immense cultural influence that had previously seemed inconceivable for a pop release. Time, for instance, had written in 1967 that Sgt. Pepper's constituted a "historic departure in the progress of music—any music,"[4] while Timothy Leary, in a widely quoted assessment of the same period, declared that the band were prototypes of "evolutionary agents sent by God, endowed with mysterious powers to create a new human species."[5] The Beatles was the first album that the group undertook following the death of their manager, Brian Epstein, and the first released by their own record label, Apple.
Most of the songs were conceived during a Transcendental Meditation course with Maharishi Mahesh Yogi in Rishikesh, India in the spring of 1968. The retreat had required long periods of meditation, initially conceived by the band as a spiritual respite from all worldly endeavours—a chance, in John Lennon's words, to "get away from everything."[6] Both Lennon and Paul McCartney had quickly found themselves in songwriting mode, however, often meeting "clandestinely in the afternoons in each other's rooms"[7] to review the new work. "Regardless of what I was supposed to be doing," Lennon would later recall, "I did write some of my best songs there."[8] Close to forty new compositions had emerged in Rishikesh, twenty-three of which would be recorded in very rough form at Kinfauns, George Harrison's home in Esher, in May 1968.
The Beatles had left Rishikesh before the end of the course, with Starr and then McCartney departing, and Lennon and Harrison departing together later. According to some reports, Lennon left Rishikesh because he felt personally betrayed by rumours that Maharishi had made sexual advances toward Mia Farrow,[9][10] who had accompanied The Beatles on their trip. Shortly after he decided to leave, Lennon wrote a song called "Maharishi" which included the lyrics, "Maharishi/You little twat"; the song became "Sexy Sadie". According to several authors, Alexis Mardas (aka "Magic Alex") deliberately engineered these rumours because he was bent on undermining the Maharishi's influence over each Beatle.[11][12][13] In a 1980 interview, Lennon acknowledged that the Maharishi was the inspiration for the song: "I just called him 'Sexy Sadie'."[14]
The album's working title, A Doll's House, was changed when the English progressive rock band Family released the similarly titled Music in a Doll's House earlier that year.
Recording sessions[edit] Edit
[1][2]Abbey Road Studios in 2006.
The Beatles was recorded between 30 May and 14 October 1968, largely at Abbey Road Studios, with some sessions at Trident Studios. Although productive, the sessions were reportedly undisciplined and sometimes fractious, and they took place at a time when tensions were growing within the group.[15] Concurrent with the recording of this album, the Beatles were launching their new multimedia business corporation Apple Corps, an enterprise that proved to be a source of significant stress for the band.[citation needed]
The sessions for The Beatles marked the first appearance in the studio of Lennon's new girlfriend and artistic partner, Yoko Ono, who would thereafter be a more or less constant presence at all Beatles sessions.[16] Prior to Ono's appearance on the scene, the individual Beatles had been very insular during recording sessions, with influence from outsiders strictly limited. McCartney's girlfriend at the time, Francie Schwartz, was also present at some of the recording sessions, as were Pattie Harrison and Maureen Starkey, the other two Beatles' wives.[17]
Author Mark Lewisohn reports that the Beatles held their first and only 24-hour recording/producing session near the end of the creation of The Beatles, which occurred during the final mixing and sequencing for the album. The session was attended by Lennon, McCartney, and producer George Martin.[18]
Division and discord in the studio[edit] Edit
Despite the album's official title, which emphasised group identity, studio efforts on The Beatles captured the work of four increasingly individualised artists who frequently found themselves at odds.[18] The band's work pattern changed dramatically with this project, and by most accounts the extraordinary synergy of the Beatles' previous studio sessions was harder to come by during this period. Sometimes McCartney would record in one studio for prolonged periods of time, while Lennon would record in another, each man using different engineers.[18] At one point in the sessions, George Martin, whose authority over the band in the studio had waned, spontaneously left to go on holiday, leaving Chris Thomas in charge of producing.[19] During one of these sessions, while recording "Helter Skelter", Harrison reportedly ran around the studio while holding a flaming ashtray above his head, "doing an Arthur Brown."[18]
Long after the recording of The Beatles was complete, Martin mentioned in interviews that his working relationship with the Beatles changed during this period, and that many of the band's efforts seemed unfocused, often yielding prolonged jam sessions that sounded uninspired.[15] On 16 July recording engineer Geoff Emerick, who had worked with the group since Revolver, announced that he was no longer willing to work with them.[18]
The sudden departures were not limited to EMI personnel. On 22 August, Starr abruptly left the studio, explaining later that he felt that his role was minimised compared to that of the other members, and that he was tired of waiting through the long and contentious recording sessions.[15] Lennon, McCartney, and Harrison pleaded with Starr to return, and after two weeks he did. Upon Starr's return, he found his drum kit decorated with red, white, and blue flowers, a welcome-back gesture from Harrison.[15] The reconciliation was, however, only temporary, and Starr's exit served as a precursor of future "months and years of misery", in Starr's words.[15] Indeed, after The Beatles was completed, both Harrison and Lennon would stage similar unpublicised departures from the band.[15] McCartney's public departure in 1970 would mark the formal end of the band's ensemble although Lennon had previously announced to McCartney that he was leaving the band. McCartney described the sessions for The Beatles as a turning point for the group. Up to this point, he observed, "The world was a problem, but we weren't. You know, that was the best thing about the Beatles, until we started to break up, like during the White Album and stuff. Even the studio got a bit tense then."[15] Of the album's 30 tracks, only 16 have all four band members performing.
Instrumental contributions[edit] Edit
According to Lewisohn, McCartney played drums on "Dear Prudence" because Starr had left the group while the song was being recorded.[18] Lewisohn also reports that, in the case of "Back in the U.S.S.R.", also recorded during Starr's absence, the three remaining Beatles each made contributions on bass and drums, with the result that those parts may be composite tracks played by Lennon, McCartney and/or Harrison.
Other musicians[edit] Edit
Though not formally credited on the album, Eric Clapton played lead guitar on Harrison's "While My Guitar Gently Weeps".[20] Harrison explains in The Beatles Anthology that Clapton's presence temporarily alleviated the studio tension and that all band members were on their best behaviour during his time with the band in the studio.[15] Harrison, who had invited Clapton to the sessions, soon reciprocated by collaborating with Clapton on the song "Badge" for Cream'slast album Goodbye. Harrison, too, was not formally credited at first, but was identified as "L'Angelo Misterioso" on the cover.
Clapton was not the only outside musician to sit in on the sessions. Nicky Hopkins provided electric piano for the single cut of "Revolution" (recorded during these sessions). Several horns were also recorded on the album version of "Revolution 1". "Savoy Truffle" also features the horn section. Jack Fallon played a bluegrass fiddle on "Don't Pass Me By",[21] and a team of orchestral players and background singers appeared on "Good Night" (which was Beatle-free except for Starr's vocal).
Technical advances[edit] Edit
The sessions for The Beatles were notable for the band's formal transition from 4-track to 8-track recording. As work on the album began, Abbey Road Studios possessed, but had yet to install, an 8-track machine that had supposedly been sitting in a storage room for months. This was in accordance with EMI's policy of testing and customising new gear, sometimes for months, before putting it into use in the studios. The Beatles recorded "Hey Jude" and "Dear Prudence" at Trident Studios in central London, which had an 8-track recorder.[18] When they learned about EMI's 8-track recorder, they insisted on using it, and engineers Ken Scott and Dave Harries took the machine (without authorisation from the studio chiefs) into the Number 2 recording studio at Abbey Road for the band's use.[18]
Songs[edit] Edit
Although most of the songs on any given Beatles album are usually credited to the Lennon–McCartney songwriting team, that description is often misleading, and rarely more so than on The Beatles. With this album, each of the four band members began to showcase the range and depth of his individual songwriting talents, and to display styles that would be carried over to his eventual solo career. Indeed, some songs that the individual Beatles were working on during this period eventually were released on solo albums. According to the bootlegged album of the songs recorded at Kinfauns, George Harrison's Esher home, these include Lennon's "Look at Me" and "Child of Nature", eventually reworked as "Jealous Guy"; McCartney's "Junk" and "Teddy Boy"; and Harrison's "Not Guilty" and "Circles."[22][23]
Many of the songs on the album display experimentation with unlikely musical genres, borrowing directly from such sources as 1930s dance-hall music (in "Honey Pie"), classical chamber music (in "Piggies"), the avant-gardesensibilities of Yoko Ono and John Cage (in "Revolution 9"), country-style music (Ringo Starr's "Don't Pass Me By"), a western-style saloon ballad ("Rocky Raccoon"), and the lush sentimentality of Henry Mancini's film scores (in "Good Night"). Such diversity was largely unprecedented in global pop music in 1968, and the album's sprawling approach provoked (and continues to provoke) both praise and criticism from observers.[24] "Revolution 9", in particular, a densely layered eight-minute-and-thirteen-second sound collage, has attracted both interest and disapproval from fans and music critics over the years.
The only western instrument available to the group during their Indian visit was the acoustic guitar, and thus many of the songs on The Beatles were written and first performed on that instrument.[25] Some of these songs remained acoustic on The Beatles (notably "Rocky Raccoon", "Blackbird", "Julia", "Cry Baby Cry", "I Will" and "Mother Nature's Son") and were recorded in the studio either solo, or by only part of the group.
Compositions not included[edit] Edit
A number of songs were recorded during these sessions but were not issued on The Beatles, including Harrison's "Not Guilty" (which he re-recorded for his eponymous 1979 album, George Harrison), Lennon's "What's the New Mary Jane", and McCartney's "Jubilee" (later retitled "Junk" and released on his first solo LP).[26]
Others included "Mean Mr. Mustard" and "Polythene Pam" (both of which would be used for the medley on Abbey Road); "Child of Nature" (recorded with drastically different lyrics as "Jealous Guy" for Lennon's Imagine); "Etcetera" (a McCartney composition); "The Long and Winding Road" (completed in 1969 for the Let It Be LP); "Something" (which ended up on Abbey Road); and "Sour Milk Sea" (which Harrison gave to friend and Apple artist Jackie Lomax for his first LP, Is This What You Want).[citation needed]
Other songs recorded for, but ultimately left off The Beatles received significant exposure via bootlegs, notably Harrison's "Circles" (which he eventually re-recorded as a solo track and released on his 1982 album, Gone Troppo) and "Not Guilty" (which he also eventually re-recorded as a solo track for his 1979 album George Harrison), and Lennon's manic "What's the New Mary Jane".[citation needed] More recently, the song "Revolution 1 (Take 20)", a previously unknown track, surfaced in 2009 on a bootleg and is supposed to connect "Revolution 1" and the avant-garde "Revolution 9" (both of which appeared on The Beatles) in an attempt by Lennon to record one long version of "Revolution" before ultimately splitting the two songs up.[27]
The White Album session versions of "Not Guilty" and "What's the New Mary Jane", and a demo of "Junk", were ultimately released on the Beatles Anthology 3 album in 1996.
Singles[edit] Edit
Although "Hey Jude" was recorded during the White Album sessions it was not included on the album and instead was originally issued as a single nearly three months before the album's release (it would, however, make its LP debut two years later as the title cut of the post-Abbey Road compilation album otherwise known as The Beatles Again). "Hey Jude's" B-side, "Revolution", was an alternate version of the album's "Revolution 1". Lennon had wanted the original version of "Revolution" to be released as a single, but the other three Beatles objected on the grounds that it was too slow.[15] A new, faster version, with heavily distorted guitar and a high-energy keyboard solo from Nicky Hopkins, was recorded and was relegated to the flip side of "Hey Jude". The resulting release – "Hey Jude" on side A and "Revolution" on side B – emerged as the first release on The Beatles' new Apple Records label.[26] It went on to be The Beatles' most successful single, with world sales over 5 million by the end of 1968 and 7.5 million by October 1972.[26] No singles were taken from The Beatles in either Britain or America, but "Ob-La-Di, Ob-La-Da" backed with "While My Guitar Gently Weeps", both from the album, became a double-sided smash in Australia, spending five weeks at Number One in the beginning of 1969.[citation needed]
Editing concerns and release[edit] Edit
The Beatles was the first Beatles album released by Apple Records, as well as their only original double album. Producer George Martin has said that he was against the idea of a double album at the time and suggested to the group that they reduce the number of songs in order to form a single album featuring their stronger work, but that the band decided against this.[28] Interviewed for the Beatles Anthology, Starr said that he now felt that it should have been released as two separate albums (that he appropriately named The White Album and The Whiter Album). Harrison felt on reflection that some of the tracks could have been released as B-sides, but "there was a lot of ego in that band." He also supported the idea of the double album, to clear out the backlog of songs that the group had at the time. McCartney, by contrast, said that it was fine as it was ("It's great. It sold. It's the bloody Beatles White Album. Shut up."), and that its wide variety of songs was a major part of the album's appeal.[29] The Beatles was released on 22 November 1968.
Mono version[edit] Edit
The Beatles was the last Beatles album to be released with a unique, mono mix, albeit one issued only in the UK and a few other countries. Twenty-eight of the album's 30 tracks ("Revolution 1" and "Revolution 9" being the only exceptions) exist in official mono mixes. Several of these mono mixes are quite different from the stereo versions. Perhaps most notably, the mono mix/edit of "Helter Skelter" eliminates the fade-in at the end of the song (and Ringo Starr's ending scream "I've got blisters on my fingers!"), and the mono mix of "Yer Blues" has a longer fadeout than its stereo counterpart.
Beatles albums after The Beatles (except Yellow Submarine in the UK) occasionally had mono pressings in certain countries (such as Brazil), but these editions—Yellow Submarine, Abbey Road and Let It Be—were in each case mono fold-downs from the regular stereo mixes.
In the US, mono records were already being phased out; the US release of The Beatles was the first Beatles LP to be issued in stereo only.
The mono version of The Beatles was made available worldwide on 9 September 2009, as part of the Beatles in Mono CD box set.
Packaging and tape configurations[edit] Edit
[3][4]A vintage circa-1970 pressing of The Beatles. Note the serial number and the album title is embossed, rather than printed.
The album's sleeve was designed by Richard Hamilton, a notable pop artist who had organised a Marcel Duchamp retrospective at the Tate Gallery the previous year. Hamilton's design was in stark contrast to Peter Blake's vivid cover art for Sgt. Pepper's Lonely Hearts Club Band, and consisted of a plain white sleeve. The band's name was discreetly embossed slightly below the middle of the album's right side, and the cover also featured a unique stamped serial number, "to create," in Hamilton's words, "the ironic situation of a numbered edition of something like five million copies."[citation needed] Indeed, the artist intended the cover to resemble the "look" of conceptual art, an emerging movement in contemporary art at the time. Later vinyl record releases in the US showed the title in grey printed (rather than embossed) letters. Early copies on compact disc were also numbered. Later CD releases rendered the album's title in black or grey. The 30th anniversary CD release was done to look like the original album sleeve, with an embossed title and serial number, including a small reproduction of the poster and pictures (see re-issues).
The album's inside packaging included a poster, the lyrics to the songs, and a set of photographs taken by John Kelly[30] during the autumn of 1968 that have themselves become iconic. This is the only sleeve of a Beatles studio album not to show the members of the band on the front.
LP packaging varied somewhat by territory. Original copies of the LP released in the UK, for example, opened from the top rather than the right side, and were numbered starting at 10,000. (Later pressings opened conventionally from the right side, and did not bear a unique number.) Some South American editions did not feature the Kelly photographs in the gatefold, instead including uncredited performance photographs of the band from circa 1964–65 (the Beatles are clean-shaven and wearing matching suits in the photos, as Brian Epstein insisted they do in performance during this period).
Tape versions of the album did not feature a white cover. Instead, cassette and 8-track versions (issued on two cassettes/cartridges in early 1969) contained cover artwork that featured high contrast black and white (with no grey) versions of the four Kelly photographs.[31] In both the cassette and 8-track versions of the album, the two tapes were sold in a black slip-cover box that bore the title, "The Beatles", and the outline of an apple, embossed in gold.[32] This departure from the LP's design not only made it difficult for less-informed fans to identify the tape in record stores, but it also led some fans at the time to jokingly refer to the 8-track or cassette not as the "white album" but as the "black tape." In 1988, Capitol/EMI re-issued the 2-cassette version of the album, still with the same cover artwork as the original cassettes, but without the black slip-cover box. The mid-1990s Canadian Apple/Capitol version of the 2 cassette set (C4-46443A/B) does have the appropriate plain white inlay cards with "The Beatles" Part 1/Part 2 lettering across the bottom of the inlay.
Capitol/EMI initially issued reel-to-reel editions of The Beatles, as well. These also used the black-and-white Kelly portraits as cover art, and were available in two configurations: as two separate volumes similar to the cassette and 8-track editions, and as a single twin-pack tape. Capitol/EMI ceased manufacturing of pre-recorded reel tapes in North America in late 1969, and subsequently licensed the album (along with several other Beatles recordings) to Ampex for reel-to-reel distribution. The Ampex reel-to-reel tape version of The Beatles, released in early 1970 (in two separate volumes, and again using the Kelly cover artwork), is particularly noteworthy in that it features eight tracks in edited form: "Dear Prudence", "Glass Onion", "Don't Pass Me By", "Why Don't We Do It In The Road?". "Yer Blues", "Helter Skelter", "Cry Baby Cry" and "Revolution 9". These are unique to the album's Ampex reel-to-reel version, and have not been issued since.
In the autumn of 1978, the album's tenth anniversary, EMI reissued the album as a two-record set pressed on white vinyl in limited quantities of only 150,000 copies. In 1981, Mobile Fidelity Sound Lab (MFSL) issued a unique half-speed master variation of the album utilising the sound from the original master recording. The discs were pressed on high-quality virgin vinyl.
A painting of the band by "Patrick" (John Byrne) was at an earlier point under consideration to be used as the album's cover. The piece was later used for the sleeve of the compilation album The Beatles' Ballads, released in 1980.
Critical reception[edit] Edit
Retrospective reviews
The A.V. Club A+[33]
Blender [34]
The Daily Telegraph [35]
Encyclopedia of Popular Music [36]
Pitchfork Media 10/10[37]
PopMatters 9/10[38]
The Rolling Stone Record Guide [39]
Slant Magazine [40]
Upon its release in November 1968, The Beatles received mixed reviews from music critics,[41] most of whom viewed its mild, playful satire as unimportant and conservative.[42] Time magazine wrote that the album comprises the "best abilities and worst tendencies" of the Beatles and found it skillfully performed and sophisticated, but lacking a "sense of taste and purpose."[43] Nik Cohn, writing in The New York Times, considered it "boring beyond belief" and described "more than half the songs" as "profound mediocrities."[44] Robert Christgau of The Village Voice said that the album is "their most consistent and probably their worst", and referred to its songs as a "pastiche of musical exercises".[45] Critics also complained about a lack of unity among the songs and criticized the Beatles for using eclecticism and pastiche as a means of avoiding important issues during a turbulent political and social climate.[46] Jon Landau, writing for theLondon Daily Times, argued that the band uses parody because they are "afraid of confronting reality" and "the urgencies of the moment".[42]
In a positive review, Tony Palmer of The Observer claimed that, "if there is still any doubt that Lennon and McCartney are the greatest songwriters since Schubert," the album "should surely see the last vestiges of cultural snobbery and bourgeois prejudice swept away in a deluge of joyful music making".[47] Richard Goldstein of The New York Times felt that their songwriting had improved and they relied less on the studio "magic" of Sgt. Pepper and Magical Mystery Tour.[48] Alan Smith of NME derided "Revolution #9" as a "pretentious" example of "idiot immaturity", but assigned the benediction "God Bless You, Beatles!" to "most of the rest" of the album.[49] Jann Wenner of Rolling Stone called it their best album and asserted that they are allowed to appropriate other styles because their ability and identity are "so strong that they make it uniquely theirs, and uniquely the Beatles. They are so good that they not only expand the idiom, but they are also able to penetrate it and take it further."[50]
The Beatles has since been regarded as one of the best albums of all time.[51] In 2003, Rolling Stone ranked it number 10 on its list of the 500 greatest albums of all time.[52] In a retrospective review, Neil McCormick of The Daily Telegraph also viewed the album as one of the greatest and found it "so eccentric and interesting" that "even its sketchiest oddities somehow gain power amidst the cornucopia of ideas and performances."[35] Allmusic editor Stephen Thomas Erlewine also felt that the album is interesting for "its mess" and wrote that each song is an "entity to itself, as the band touches on anything and everything they can", which "makes for a frustratingly scattershot record or a singularly gripping musical experience, depending on your view".[24] In The New Rolling Stone Album Guide (2004), Rob Sheffield gave the album five stars and said that, despite "loads of self-indulgent filler", listeners often pick different highlights, which is "part of the fun".[53] Slant Magazine's Eric Henderson claimed that The Beatles remains one of the band's few albums that "resists reflexive canonisation, which, along with society's continued fragmentation, keeps the album fresh and surprising."[54] Chuck Klosterman, writing in The A.V. Club, said that the album found the band "hitting on all 16 cylinders" and called it a "masterwork".[33]
Cultural responses[edit] Edit
Ian MacDonald, in his book Revolution in the Head, argues that The Beatles was the album in which the band's cryptic messages to its fan base became not merely vague but intentionally and perhaps dangerously open-ended, citing oblique passages in songs like "Glass Onion" (e.g., "the walrus was Paul") and "Piggies" ("what they need's a damn good whacking"). These pronouncements, and many others on the album, came to attract extraordinary popular interest at a time when more of the world's youth were using drugs recreationally and looking for spiritual, political, and strategic advice from The Beatles. Steve Turner, too, in his book A Hard Day's Write, maintains that, with this album, "The Beatles had perhaps laid themselves open to misinterpretation by mixing up the languages of poetry and nonsense."[55] Bob Dylan's songs had been similarly mined for hidden meanings, but the massive countercultural analysis ofThe Beatles surpassed anything that had gone before.[56] Sociologist Michael A. Katovich writes that the album's release "engendered a collective appreciation of it as a 'state-of-the-art' rendition of the current pop, rock, and folk-rock sounds."[1]
Even Lennon's seemingly direct engagement with the tumultuous political issues of 1968 in "Revolution 1" carried a nuanced obliqueness, and ended up sending messages the author may not have intended. In the album version of the song, Lennon advises those who "talk about destruction" to "count me out". As MacDonald notes, however, Lennon then follows the sung word "out" with the spoken word "in". At the time of the album's release — which followed, chronologically, the up-tempo single version of the song, "Revolution" — that single word "in" was taken by many on the radical left as Lennon's acknowledgment, after considered thought, that violence in the pursuit of political aims was indeed justified in some cases. At a time of increasing unrest in the streets and campuses of Paris and Berkeley, the album's lyrics seemed to many to mark a reversal of Lennon's position on the question, which was hotly debated during this period.[56] However, the recording chronology belies the interpretation that from the single to the album Lennon moved from a definite position to one of ambivalence, since despite the single's earlier release it was the album version that was recorded first.[57]
Cult leader Charles Manson persuaded members of his "family" that the album was an apocalyptic message predicting a prolonged race war and justified the murder of wealthy people.[58]
In October 1969, a Detroit radio programme began to promote theories based on clues supposedly left on The Beatles and other Beatles albums that Paul McCartney had died and been replaced by a lookalike. The ensuing hunt for clues to a cover-up, that The Beatles presumably wanted to suppress (and simultaneously publicise), became one of the classic examples of an urban legend.
On the 40th anniversary of the album's release, Vatican newspaper L'Osservatore Romano wrote that it "remains a type of magical musical anthology: 30 songs you can go through and listen to at will, certain of finding some pearls that even today remain unparalleled."[59]
In early 2013, the Recess Gallery in New York City's SoHo neighborhood presented We Buy White Albums, an installation by artist Rutherford Chang.[60] The piece was in the form of a record store in which nothing but original pressings of the LP was on display.[61] Mr. Chang created a recording in which the sounds of one hundred copies of side one of the LP were overlaid.[62]
Commercial performance[edit] Edit
As it was their first studio album in almost eighteen months (and coming after the blockbuster success of Sgt. Pepper's Lonely Hearts Club Band) expectations were high at time of release of The Beatles. The album debuted at number 1 in the UK on 1 December 1968[63] (becoming their third album to do so, after Help! and Revolver). It spent seven weeks at the top of the UK charts (including the entire competitive Christmas season), until it was replaced by The Seekers' Best of the Seekers on 25 January 1969, dropping to number 2.[63] However, the album returned to the top spot the next week, spending an eighth and final week at number 1.[63] It then spent another four weeks in the Top 10, and then dropped in the charts more quickly than Sgt. Pepper. The White Album was notable for blocking The Beatles' follow-up album, Yellow Submarine, which debuted (and peaked at) number 3 on 8 February 1969, the same weekThe White Album was dominating the second position on the charts. In all, The Beatles spent 24 weeks on the UK charts, far fewer than the more than 200 weeks for Sgt. Pepper.
In the United States, the album achieved huge commercial success. Capitol Records sold over 3.3 million copies of The White Album to stores within the first four days of the album's release.[64] It debuted at number 11, jumped to number 2, and reached number 1 in its third week, spending a total of nine weeks at the top. In all, The Beatles spent 155 weeks on the Billboard 200. According to the Recording Industry Association of America, The Beatles is The Beatles' most-certified album at 19-times platinum and the tenth-best-selling album of all time in the United States. (Each sale is counted as two sales, because The Beatles is a double record set. Therefore, at 9.5 million records, it is the band's third-best-selling-album in the US.)
Track listing[edit] Edit
All songs written and composed by Lennon–McCartney, except where noted.
Lead vocals[56]
1. "Back in the U.S.S.R." McCartney 2:43
2. "Dear Prudence" Lennon 3:56
3. "Glass Onion" Lennon 2:17
4. "Ob-La-Di, Ob-La-Da" McCartney 3:08
5. "Wild Honey Pie" McCartney 0:52
6. "The Continuing Story of Bungalow Bill" Lennon 3:14
7. "While My Guitar Gently Weeps" (George Harrison) Harrison 4:45
8. "Happiness Is a Warm Gun" Lennon 2:43
9. "Martha My Dear" McCartney 2:28
10. "I'm So Tired" Lennon 2:03
11. "Blackbird" McCartney 2:18
12. "Piggies" (Harrison) Harrison 2:04
13. "Rocky Raccoon" McCartney 3:33
14. "Don't Pass Me By" (Richard Starkey) Starr 3:51
15. "Why Don't We Do It in the Road?" McCartney 1:41
16. "I Will" McCartney 1:46
17. "Julia" Lennon 2:54
Side three
1. "Birthday" McCartney and Lennon 2:42
2. "Yer Blues" Lennon 4:01
3. "Mother Nature's Son" McCartney 2:48
4. "Everybody's Got Something to Hide Except Me and My Monkey" Lennon 2:24
5. "Sexy Sadie" Lennon 3:15
6. "Helter Skelter" McCartney 4:29
7. "Long, Long, Long" (Harrison) Harrison 3:04
Side four
8. "Revolution 1" Lennon 4:15
9. "Honey Pie" McCartney 2:41
10. "Savoy Truffle" (Harrison) Harrison 2:54
11. "Cry Baby Cry" Lennon, with McCartney 3:02
12. "Revolution 9" Speaking from Lennon, Harrison, George Martin and Yoko Ono 8:22
13. "Good Night" Starr 3:13
Personnel[edit] Edit
John Lennon – lead, harmony and background vocals; acoustic, lead, bass and rhythm guitars; keyboards (electric and acoustic pianos, Hammond organ, harmonium and mellotron); extra drums and assorted percussion (tambourine, maracas, cymbals, thumping on the back of an acoustic guitar, handclaps and vocal percussion); harmonica, whistling and saxophone; tapes, tape loops and sound effects (electronic and home-made)[18]
Paul McCartney – lead, harmony and background vocals; acoustic, lead, rhythm and bass guitars; keyboards (electric and acoustic pianos and Hammond organ); assorted percussion (timpani, tambourine, cowbell, hand shake bell, handclaps, foot taps and vocal percussion); drums (on "Back in the U.S.S.R.","Dear Prudence", "Wild Honey Pie", and "Martha My Dear"); recorder and flugelhorn; sound effects[18]
George Harrison – lead, harmony and background vocals; acoustic, rhythm, bass and lead guitars; Hammond organ; extra drums and assorted percussion (tambourine, handclaps and vocal percussion) and sound effects[18]
Ringo Starr – drums and assorted percussion (tambourine, bongos, cymbals, maracas and vocal percussion); electric piano and sleigh bell (on "Don't Pass Me By"), lead vocals (on "Don't Pass Me By" and "Good Night") and backing vocals ("The Continuing Story of Bungalow Bill")[18]
Guest musicians
Eric Clapton – lead guitar on "While My Guitar Gently Weeps"[20]
Mal Evans – backing vocals and handclaps on "Dear Prudence",[65] handclaps on "Birthday",[66] trumpet on "Helter Skelter""[20]
Jack Fallon – violin on "Don't Pass Me By"[67]
Grant Mansell – drums on "Martha My Dear"[68]
Pattie Harrison – backing vocals on "Birthday"[66]
Jackie Lomax – backing vocals and handclaps on "Dear Prudence"[65]
Maureen Starkey – backing vocals on "The Continuing Story of Bungalow Bill"[68]
Yoko Ono – backing vocals, brief lead vocals and handclaps on "The Continuing Story of Bungalow Bill",[68] backing vocals on "Birthday",[66] speech, tapes and sound effects on "Revolution 9"[69]
Ted Barker – trombone on "Martha My Dear"[70]
Leon Calvert – trumpet and flugelhorn on "Martha My Dear"[70]
Henry Datyner, Eric Bowie, Norman Lederman, and Ronald Thomas – violin on "Glass Onion"[71]
Bernard Miller, Dennis McConnell, Lou Soufier and Les Maddox – violin on "Martha My Dear"[70]
Reginald Kilby – cello on "Glass Onion"[71] and "Martha My Dear"[70]
Eldon Fox – cello on "Glass Onion"[71]
Frederick Alexander – cello on "Martha My Dear"[70]
Harry Klein – saxophone on "Savoy Truffle"[72] and "Honey Pie"[73]
Dennis Walton, Ronald Chamberlain, Jim Chest, and Rex Morris – saxophone on "Honey Pie"[73]
Raymond Newman and David Smith – clarinet on "Honey Pie"[73]
Art Ellefson, Danny Moss, and Derek Collins – tenor sax on "Savoy Truffle"[72]
Ronnie Ross and Bernard George – baritone sax on "Savoy Truffle"[72]
Alf Reece – tuba on "Martha My Dear"[70]
The Mike Sammes Singers – backing vocals on "Good Night"[74]
Stanley Reynolds and Ronnie Hughes – trumpet on "Martha My Dear"[70]
Tony Tunstall – French horn on "Martha My Dear"[70]
John Underwood and Keith Cummings – viola on "Glass Onion"[71]
Leo Birnbaum and Henry Myerscough – viola on "Martha My Dear"[70]
Geoff Emerick – engineer,[56] speech on "Revolution 9"[75]
George Martin – record producer and mixer;[56] string, brass, clarinet, orchestral arrangements and conducting;[56] piano on "Rocky Raccoon"[76]
Ken Scott – engineer and mixer[56]
Barry Sheffield – engineer (Trident Studio)[56]
Chris Thomas – producer;[56] Mellotron on "The Continuing Story of Bungalow Bill",[68] harpsichord on "Piggies",[77] piano on "Long, Long, Long"[78] Saxophone arrangement on "Savoy Truffle"[79]
Certifications[edit] Edit
Sales/shipments
Argentina (CAPIF)[80]
Listed as Album Blanco
Platinum 60,000x
Listed as The White Album
Gold 30,000x
Australia (ARIA)[81]
2× Platinum 140,000^
Canada (Music Canada)[82]
Italy (FIMI)[83]
Gold 30,000
New Zealand (RMNZ)[84]
2× Platinum 30,000^
United Kingdom (BPI)[85]
Platinum 300,000^
United States (RIAA)[86]
19× Platinum 9,500,000^
sales figures based on certification alone ^shipments figures based on certification alone xunspecified figures based on certification alone
BPI certification awarded only for sales since 1994.[87]
Release history[edit] Edit
United Kingdom 22 November 1968 Apple (Parlophone) LP PCS 7067/7068
United States 22 November 1968 Apple, Capitol LP SWBO-101
Worldwide reissue 10 October 1987 Apple, Parlophone, EMI CD CDP 7 46443 2
Japan 11 March 1998 Toshiba-EMI CD CP25-5329-30
Japan 21 January 2004 Toshiba-EMI Remastered LP TOJP 60139-40
Worldwide reissue 9 September 2009 Apple Remastered CD 0946 3 82466 2 6
Worldwide reissue 13 November 2012 Apple Remastered LP 094638246619
Retrieved from "https://rock.fandom.com/wiki/The_Beatles_(White_Album)?oldid=10721"
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Indiana University Indiana University Indiana University
15.06.14, Christie, Muslims and Crusaders
Christopher MacEvitt
The Medieval Review 15.06.14
Christie, Niall. Muslims and Crusaders: Christianity's Wars in the Middle East, 1095-1382, from the Islamic Sources. Seminar Studies in History. London: Routledge, 2014. pp. xl, 186. ISBN: 9781138022737 (hardback) 9781138022744 (paperback).
macevitt@dartmouth.edu
The recent efflorescence of scholarship on the crusades can perhaps no longer be called recent, seeing that it is now entering into its third decade. The general surveys and narrative histories, particularly those published in English, have followed the well-worn path focusing on crusading in the Middle East from the perspective of the Franks. A few books have approached the subject from a Muslim perspective: first and most popularly, by Amin Maalouf in The Crusade through Arab Eyes (New York, 1983), and then in a more comprehensive and scholarly way by Carole Hillenbrand in The Crusades: Islamic Perspectives (Edinburgh, 2000). More recently, Paul Cobb has written a broad history of Muslim-Christian conflict in The Race for Paradise: An Islamic History of the Crusades (Oxford, 2014). Niall Christie's work builds on this tradition by offering a concise general history that is ideal for undergraduate courses.
Part of what makes Christie's book so useful is what he does not do. In contrast to most books (particularly those written from the perspective of the crusaders), his does not waste many words on the political and military events of the crusades and of the Frankish principalities. These have been narrated ad nauseam since the time of William of Tyre. Instead of yet another description of how the armies of the First Crusade crossed Europe and the Levant and of the battles they fought along the way, Christie provides a concise summary of the events of the period under discussion, and focuses instead on the significant historiographical issues at hand. For example, the third chapter on "The First Crusade and the Muslim Response, 1095-1146," devotes just two pages to a description of events in that period, and then moves on to think about and read the relevant Muslim sources, conceptions of the crusaders' motives, and jihad and counter-crusade. Brevity is Christie's academic superpower--the entire chapter is only eleven pages long.
The book contains nine chapters and a conclusion spread over 119 pages. Following an introduction, the second chapter gives a broad overview of the Islamic world before the crusades. The third chapter is discussed above (covering the First Crusade and the Muslim response), while the fourth chapter focuses on "Nur al-Din and Saladin, 1146-1174." The fifth chapter, "Victory and Stalemate, 1174-1193," covers the remainder of Saladin's career. The sixth chapter, "War and Peace in the Twelfth-Century Levant," steps away from the chronological perspective to address the question of relations between Muslims and Franks, showing the wide variety of interactions between them. The seventh chapter discusses "The Successors of Saladin, 1193-1249," which gives the readers a helpful exploration of the Ayyubids and their dynamic with the Franks. Chapter Eight turns to "The Mamluks, 1249-1382," and a final chapter surveys the broader impact of the crusades in both the medieval and modern periods.
In addition, the book provides a variety of useful addenda: a timeline, a Who's Who consisting of some forty-seven individuals from Shajar al-Durr to Usama ibn Laden [sic], a glossary of names and terms, a guide to Muslim nomenclature, marginal notes on definitions throughout the book, the ever essential maps, family trees, and best of all for teaching purposes, a handy collection of twenty-one translated Muslim sources in the appendix. Many of these are available elsewhere, but the book offers several that are difficult to find in translation or are otherwise unavailable. Particularly useful are the translation of al-Mas'udi on the Franks (Document #3), a selection of Arabic poetry written in reaction to the First Crusade (Document #5), Ibn al-Qaysarani and 'Imad al-Din al-Isfahani on Frankish women (Document #15), and Ibn Wasil and Sibt ibn al-Jawzi on the handover of Jerusalem to Frederick II (Document #16).
Christie takes a cautious approach to his topic; the book is not intended to advance any new arguments about the period. It instead provides a general overview of the scholarly debates for a reader with little background in the subject. The book does a better job of this for the twelfth century than the thirteenth. Chapter four on Nur al-Din and Saladin, for example, discusses Emmanuel Sivan's presentation of Nur al-Din as la plaque tournante, the pivot through whom jihad assumed a central importance in campaigns against the Franks, and draws on the work of Yasser Tabaa on among others on the architectural articulation. The chapter on the Mamluks, in contrast, gives less historiographical context. The book does offer some important lessons even to historians versed in the field. The first is the emphasis on analysis rather than on chronology. Not only does this make sense given the materials already available for the study of the crusades, but it also is a good model for medievalists broadly. While events and facts are important to teach students, in the end the skills that we most often are trying to impart are the ability to read sources critically and to analyze them. Christie's text gives student the model and the tools to do so.
It is perhaps ungenerous to criticize a book I have already praised for its brevity for what it fails to cover, but the only such lacuna I can really lament is the lack of focus on material culture. Christie's notes and references show that he is familiar with much of the secondary literature, particularly in reference to architecture, and he does discuss castle building and a few other material objects (a coin of Baybars, the Mamluk bridge at Lydda, Nur al-Din's minbar destined for the Al-Aqsa Mosque, all of which also admirably illustrated). But archaeology and art history form an essential part of our ability to understand the medieval Middle East, and in many ways show the complexity of Muslim-Christian exchange to its fullest. A (short) chapter on such material would add depth to the entire book, and such a chapter's discussion of “The Problem of the Sources” would be a particularly useful one for students.
Medieval Review Support Fund
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Tag Archives: Ready Player One Alan Silvestri
https://sideshowsoundtheatre.com/wp-content/uploads/2017/08/sideshow-tell-8-7-2017.mp3Hello the internet and welcome to episode 84 of Sideshow & Tell, your newscast where your host Ian Crabb and special guests, bring you all the happenings from the world of film and television music, composers and movie news! This week sees the welcome return of Tiffany Jordan. First of all, Ian and Tiffany discuss the latest soundtrack releases including Spider-Man: Homecoming by Michael Giacchino and War for the Planet of the Apes by Michael Giacchino, from Sony Masterworks, Valerian and the City of a Thousand Planets by Alexandre Desplat, from EuropaCorp, and finally, The Emoji Movie by Patrick Doyle, by Sony Classical. The pair also bring us the news that composer Alan Silvestri has taken over composing duties from composer John Williams on Ready Player One, composer John Williams will be scoring the upcoming historical drama The Papers, and the Netflix series Sense 8 will be getting a two-hour series finale scored by composers Johnny Klimek and Tom Tykwer after it’s unfortunate cancellation earlier this year. Your new favourite podcasting duo wrap up SAT84 with a Home Video Pick and deliver their Pick of the Week by composer Hans Zimmer from WaterTower Music!
2:45 Spider-Man: Homecoming
6:41 War for the Planet of the Apes
12:05 Ready Player One
16:16 The Papers
20:34 Sense 8
28:52 Valerian and the City of a Thousand Planets
39:33 The Emoji Movie
This entry was posted in Podcasts and tagged Dunkirk Hans Zimmer, Film Music News, Gifted Rob Simonsen, Ready Player One Alan Silvestri, Sense 8 Johnny Klimek and Tom Tykwer, Soundtrack News, Soundtrack Podcast, Soundtrack Releases, Spiderman Homecoming Michael Giacchino, The Emoji Movie Patrick Doyle, The Papers John Williams, Valerian Alexandre Desplat, War for the Planet of the Apes Michael Giacchino on August 7, 2017 by Sideshow Sound Theatre.
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Tag Archives: Eid ul-Fitr
Eid ul-Fitr Should Foster Brotherhood in the Muslim Umma and Provide Spark of Hope For the Less Privileged
“A Muslim must play an active role in helping his family and the brotherhood of believers. The object is not to achieve status, wealth and power, but to contribute to society’s overall development. This implies moral responsibility to help the weaker, less fortunate members.” — His Highness the Aga Khan, Toronto, May 14, 1987. [1]
A new Moon occurs when all of the Sun’s light is reflected away from Earth, and the side of the Moon facing Earth is barely visible, as illustrated in the above photo. Sometimes the dark face of the Moon catches Earth’s reflected glow and returns that light. The phenomenon is called earthshine. This Astronaut Photograph was taken on July 31, 2011, on board the International Space Station and is provided by the ISS Crew Earth Observations Facility and the Earth Science and Remote Sensing Unit, Johnson Space Center.
The festival of Eid, also known as Bairam or Eid Ramadan is one of the most joyous days in the Islamic calendar. It is an occasion for celebration and rejoicing for Allah’s Bounty upon mankind for His revelation of the Holy Qur’an during the month of Ramadan. It is also a time for individuals to express their gratitude to Allah for having given them the strength, courage and resilience to complete the fast, and thus fulfilling the duty enjoined upon them by Allah.
On this joyous occasion, we convey our heartiest felicitations and Eid Mubarak to all our readers as well as Muslims around the world, with the fervent hope and prayer that peace and harmony should prevail over many areas of the Muslim world afflicted by horrible conflicts, which are resulting in the loss of lives and contributing to unbearable hardships and struggles. The Islamic ethic of forgiveness, generosity, and peaceful co-existence and unity through dialogue are keys by which conflicts can be resolved, whereby every Muslim can aspire for a life of material and spiritual well-being and happiness.
The excerpts produced in this post from the Holy Qur’an and the hadith as well as from the farmans, writings and speeches of Hazrat Ali (a.s.) and Mawlana Hazar Imam (His Highness the Aga Khan) are foundation blocks for building harmonious societies around the world. The acts of charity and generosity mentioned in the quotes will facilitate those who are underprivileged to manage their own destinies, thereby leading them to a life of dignity, befitting Allah’s greatest creation.
PROFOUND TEACHINGS OF ISLAM
Conceptual image for the holy month of Ramadan and Eid al Fitr. Photo: Istockphoto
“It is not righteousness that you turn your faces towards the East and the West, but righteous is the one who believes in Allah and the Last Day, and the angels and the Books and the prophets, and gives away wealth out of love for Him to the near of kin and the orphans and the needy and the wayfarer and to those who ask and set slaves free.” — Holy Qur’an, 2:177
“And whatever good you may spend on others is for your own good, provided that you spend only out of a longing for God’s countenance.” — Holy Qur’an, 2:272
“You will not enter paradise till you believe, and you will not believe till you love one another. Let me guide you to something by doing which you will love one another: Salute and sundry among you.” — Tradition of the Prophet Muhammad (s.a.s.)
“A great river is not made turbid by a stone. A religious man who takes to heart an injury is as yet, but shallow water. If any misfortune befalls you, bear with it, that by forgiving others you may yourself obtain pardon. O my brother! seeing that we are at last to return to earth, let us humble ourselves in ashes before we are changed into dust.” — Hazrat Bibi Fatima (a.s.). [2]
“…As the world gets smaller, it is fundamental that people should work together and not against each other, and try to be a little more generous than you have been in the past. If people have made mistakes, forgive them their mistakes. If people have harmed you, forget and forgive. Do not hold grudges. Do not turn around and say, ‘he hurt me yesterday, so I will hurt him today’. This is not the spirit of Islam…” His Highness the Aga Khan, Farman Mubarak, Mumbai, 1969, Precious Gems.
“…when you are studying the Qur’an, when you are studying the history of Imams, when you are studying the history of pre-Islamic Arabia, I would like you to take from this history that which will help you to live within the spirit of Islam. This means to live honestly, to live purely, to know that you are brothers and sisters, to be available at all times when one or the other needs help, to be generous, to be honest. These are the qualities which you can trace throughout Qur’an-e Shariff, throughout the life of the Prophet, throughout the lives of the Imams. And this is something which I would like you to follow, not only in letter but also in spirit, because it is this spirit which cannot be changed, and which I would like my spiritual children to understand fully…” Farman Mubarak, His Highness the Aga Khan, Karachi, November 29, 1964. [3]
“There are those who enter the world in such poverty that they are deprived of both the means and the motivation to improve their lot. Unless these unfortunate ones can be touched with the spark which ignites the spirit of individual enterprise and determination, they will only sink back into renewed apathy, degradation and despair. It is for us, who are more fortunate, to provide that spark.” — His Highness the Aga Khan, speech, Housing and Development, Mumbai, January 17, 1983.
Date Re-posted: June 3, 2019.
We welcome your feedback. Please click Leave a comment
[1] Quoted in Ilm, July 1986, page 17.
[2] Ilm, Volume 13, Number 1, July 1990, page 45-46.
[3] Farman Mubarak Pakistan Visit 1964, published by the Ismailia Association for Pakistan, quoted also in Ilm, Volume 13, Number 1, July 1990, page 38.
Posted By: Malik Merchant, Editor Category: Festivals and Celebrations, Hadith, His Highness the Aga Khan IV, Holy Qur'an, Islam, The Holy Qur'an Tags: Brotherhood, Eid ul-Fitr, Muslim Umma, Spark of Hope
Eid ul-Fitr Should Provide Spark of Hope For the Less Privileged, and Foster Brotherhood, Forgiveness and Generosity in the Muslim Umma
“The poor are not mere inanimate, unmotivated, units of deprivation. They are living, thinking people like the rest of us.”
Mawlana Hazar Imam, His Highness the Aga Khan, 49th Ismaili Imam
Historical photo: Muslims offering the Eid ul Fitr prayers at the Sheikhantaur Mosque in Tashkent. Photo created/published between 1865 and 1872. Credit: The US Library of Congress.
(Selections from the Holy Qur’an, the hadith and teachings of Shia Ismaili Imams)
Conceptual image for the holy month of Ramadan and Eid ul Fitr. Photo: Istockphoto. Copyright.
“Have a tender heart, as tender as a fistful of green grass; be not arrogant and stiff as a tree upright in a forest. A tree is toppled in a storm, but grass bends and sways happily with the wind.” Hazrat Ali (a.s.), Kalam-e-Mawla, 8:67
“Islam is not passive. It does not admit that man’s spiritual needs should be isolated from his material daily activities. A Muslim must play an active role in helping his family and the brotherhood of believers. The object is not to achieve status, wealth and power, but to contribute to society’s overall development. This implies moral responsibility to help the weaker, less fortunate members.” — His Highness the Aga Khan, Toronto, May 14, 1987. [2]
“The poor are not mere inanimate, unmotivated, units of deprivation. They are living, thinking people like the rest of us.” — His Highness the Aga Khan, Aiglemont, March 16, 1983.
“On the occasion of my Silver Jubilee, I would be deeply happy if the members of my jamat, wherever they are and whatever their age, would reaffirm in a visible and united manner their commitment to the principles of Islam which bind all Muslims together, and which are unique example to all mankind: Belief in Allah, the fulfillment of His message to man, respect and support for His greatest creation, man himself. In this way let us establish even sounder foundations for a good and proper life and let us extend our support to those living in the developing areas of the world.” — His Highness the Aga Khan, 1982. [4]
A new moon at Mackerricher State Park, California, USA. Photo: Istockphoto. Copyright.
Date posted: Friday, July 17, 2015.
[4] Talika Mubarak of Mawlana Hazar Imam, Silver Jubilee, July 11, 1982, quoted in Ilm, July 1990, page 55.
Posted By: Malik Merchant, Editor Category: Festivals and Celebrations, Hadith, His Highness the Aga Khan IV, Islam, The Holy Qur'an Tags: 1st of Shawwal, Brotherhood, Crescent or new moon, Eid ul-Fitr, Forgiveness Generosity, Id ul Fitr, July 17 2015, Simerg
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Kinga Frojimovics
Die Beziehung zwischen der Pester Israelitischen Gemeinde und der IKG Wien. Vom ‚Anschluß’ bis zum Beginn der Deportationen 1941
The Relations between the Jewish Community of Pest and the Israelitische Kultusgemeinde Wien (IKG) from the 'Anschluß' until the Beginning of the Deportations, 1938-1941 In 1938 the Jewish Community of Pest (PIH)] and the Israelitische Kultusgemeinde Wien were the two largest Jewish communities of Central Europe. By 1938, the two Jewish communities had cultivated strong relationships with one another for over a century. However, the nature of the relationships between the two Jewish communities had changed drastically in 1938.
As a consequence of the increasingly worsening official anti-Jewish discrimination, ties of social and legal aid had exclusively replaced any other kinds of relationships. Religious life, chiefly issues of kashrut, social aid for members of the community, as well as Emigration from Austria after the 'Anschluß', and issues concerning one’s Hungarian citizenship after the anti-Jewish legislation had been central to the mutual work of extending social and legal aid to one another.
A systematic study of the relationships between the two largest Central European Jewish communities between 1938 and 1941 will enable us to understand how these increasingly adversely influenced central institutions of Jewish life attempted to assist their members and one another during the first phase of the Holocaust. To show how the two communities collaborated and tried to help each other is crucial, since these Jewish institutions are routinely portrayed even in historical works as isolationist bodies that were utterly uninvolved and uninterested in the problems of the Jewish world in general. The study will explore how their ties between 1938 and 1941 (until the beginning of the mass deportation of Viennese Jews) influenced the behaviour of the two communities and their members both in the later phases of the Holocaust and its aftermath. The ties of legal and social aid provided a viable model as well as a context for later patterns of relationships within and also without the Jewish world.
Irina Scherbakowa
Erinnerung versus Verdrängung am Beispiel Russland. Vom schwierigen Umgang mit der Vergangenheit
There is a paradox saying in contemporary Russia that a country's past cannot be predicted: the image of the Russian or Soviet past is always influenced by the interpretation of the current political situation. In order to be able to understand why Russia is once again in the smothering hold of an “unpredictable past” and why one's attitude to Stalin is still, 62 years after his death, the sole measure for a person's position on democracy and liberal values, we must take a closer look at the social conditions during the second half of the 1980s. This paper addresses that task. Its particular focus is the construction of an official state ideology from contradictory historical images by the ruling elites in contemporary Russia.
Miloslav Szabó
Ein ‚antislowakischer' Oscar-Film? Zur Darstellung des Holocaust im tschechoslowakischen Film Obchod na korze
During the clerical-fascist Slovak State, "Tóno" Brtko, a docile and poor carpenter, is offered the possibility to 'aryanise' the small Main Street sewing accessories shop of Rozália Lautmannová. Torn between his good-natured principles and his greedy wife Evelyna, he finally agrees to take over the shop by making the deaf and senile lady believe he is her nephew arriving to help her out. Yet he then discovers that the business is bankrupt, and Ms. Lautmannová is only relying on donations from the Jewish community. While letting his wife believe he is making money from the shop, he gradually becomes a supporter of the old lady. More and more, a cordial relationship between the two evolves. When the Slovak authorities finally decide to deport the Jewish population of the small town, Tóno, in a deep conflict with himself and his values, finally opts for hiding Ms. Lautmannová – a decision which turns into tragedy. Obchod na korze won the 'Oscar' for Best Foreign Language Film in 1966. The film was presented on the occasion of a VWI-Visuals presentation on 29 January 2015 in Vienna's Admiralkino.
Paul Weindling: “That’s not fair, Daddy”. On Being a Second and Third-Generation Applicant to the Austrian General Settlement Fund
Download PDFSince the 1950s, the Republic of Austria insisted it had settled all the claims of its Jewish citizens regarding their properties stolen under the Nazi regime. From the late 1980s, with the help of personal recollections and case studies, it became ever clearer that this was often not the case, and that the Austrian authorities had in many instances – often deliberately – handled matters of restitution carelessly. Many losses were not addressed in Austrian restitution and compensation measures. In the course of the re-evaluation of the role of Austrian citizens in the Nazi era which took place in the 1990s, and in the wake of the Washington Agreement of 2001, a General Settlement Fund for Victims of National Socialism was established. Its purpose was to bring about a comprehensive resolution to open questions of compensation and to acknowledge Austria’s moral responsibility for losses of assets suffered by the victims of the Nazi regime in Austria between 1938 and 1945 in the form of voluntary payments. This article describes the inconsistencies and ordeals an applicant is confronted with in the course of a justified claim for restitution, based on personal experiences, but presented in a scholarly framework.
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'Spooks' - Meet The Newbies: Sophia Myles
16 September 2010 | Written by Catriona Wightman
Yesterday we brought you a chat with new Spooks cast member Laila Rouass, and today it’s the turn of Sophia Myles! She’s joining the show as Beth, a new spy in the team. We caught up with Sophia to find out more about her character and working on Spooks.
Were you a fan of Spooks before you joined the show?
“I’d never seen an episode! I’ve seen a few now. I went back right to the start and watched the first series, and then the series just before this so I knew where I was coming in.”
Can you tell us a bit about Beth?
“She was head-hunted by MI6 when she was 18 as a student in Edinburgh University studying English. So she went through all the training at MI6 when she was 18. She passed everything with flying colours, and actually Harry Pearce met her back then. She’s actually based on a real-life woman, who I’ve met. She was very rebellious so she decided at the last minute that she didn’t want to go and work for the government. But she was passionate about security and intelligence so she went into the private sector instead. First she went off to Columbia but most of her 20s was spent in the Middle East – she owned a private company and had like 600 SAS soldiers working beneath her by the age of 26. She’s come back to London and I think looking for a bit more stability, so she applies for a job.”
You said Beth’s based on a real person. What was it like meeting her?
“Amazing. I’ve got a crush on her!”
It’s been said that the theme of this series is deception. Does Beth trust people?
“I think in this particular field of work, no-one reveals their true nature on the surface. So I think anyone working in this industry would be wise to not believe what they hear or what they see is true. I think she has a pretty good instinct. Probably her closest ally is [her fellow new spy] Dimitri [played by Max Brown], just because they’re the same age. I think from day one because they join at the same time, they’re both like the new kids at school together. And I probably think of everyone he’s the most likely person she would want to go out with and have a dinner with or something out of work. I think they’re most likely to be friends in real life.”
How does Beth get on with the rest of the team?
“I think from Beth’s perspective, because she’s known Harry for 12 years previously, she feels very, very comfortable already with him. And she instantly finds it very easy in Dimitri’s presence. It’s like joining a school three years late. Of course everyone’s going to be a bit wary of you to start with. But I think both Dimitri and Beth prove themselves pretty quickly to be good eggs.”
Did you get to film a lot of action scenes?
“Yeah, loads! We never stop running! We’re all runners, we get quite competitive. I thought I was doing well getting three times round my local park once or twice a week! The boys get adrenaline rushes from guns and cars, and I feel nothing. Give me a horse and I’ll be happy!”
Spooks isn’t concerned about killing its main characters off. Does that worry you at all?
“You know from day one that’s part of the deal. So you’d be an idiot not to expect your death at some point because that’s the way they roll on this show.”
The new series of Spooks begins on Monday at 9pm on BBC One.
Tagged as Spooks
PreviousWhat’s On TV (UK)
NextEvening Standard (UK)
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The Bath Chronicle
Dracula swoops in for filming
30 August 2006 | Written by E. Cooney
The blood-sucking vampire Dracula swooped on Bath yesterday as the city centre was transformed into a film set.
The 90-minute BBC television drama featuring Hustle star Marc Warren as Dracula and Poirot’s David Suchet as his nemesis Van Helsing is expected to be screened after Christmas. It is the third time in a year North Parade Buildings has been used by film crews. But Dracula promises to be very different to the costume dramas usually filmed in the city.
The script was written by Bath writer Stewart Harcourt, and is based on Bram Stoker’s 1897 novel. It explores the darker side of London and incorporates the life of the author, who is believed to have died from syphilis.
“The film looks fantastic,” said Mr Harcourt. “It’s very realistic, very sexual and very violent. When I was asked to do it I thought it was exciting, but what I thought was more exciting was Bram Stoker’s life.”
Mr Harcourt’s three children are appearing as extras in the film, but will probably not get to see it, said Mr Harcourt, who wrote TV series Hearts and Bones and is working on an adaptation of Frankenstein, which was penned by Mary Shelley in Bath.
“Bath is fantastic for this period of history and it’s inspirational,” he said.
Producer Trevor Hopkins added: “This production is about the subculture of Victorian society – sexual immorality, the cracks in the mirror. It’s very dark. It’s not cape and fangs.”
Abbey Green was transformed into a bustling daytime scene for the final shots of the film. The Bath Sweet Shop became a bookseller and publishers, and the Pink Lemons Too boutique was covered in chairs for sale.
North Parade Buildings – where filming took place after dark – became the headquarters the Brotherhood of the Undead cult.
The Georgian terrace was used for BBC Four’s Beau Brummel in March, and as a reconstruction of Jack the Ripper’s London for National Geographic TV in July.
Now a major Jane Austen drama could soon use the city as a backdrop. The film commissioner for Bath and north east Somerset, Maggie Ainley, is in final talks over an ITV1 adaptation of Persuasion.
The city previously starred in a 1995 BBC version of Persuasion and a 1980s version of Northanger Abbey. It also formed the London backdrop for the 2004 Hollywood version of Vanity Fair.
Filming for Dracula will finish on Monday. Scenes have been shot in several other locations in the south west, including Dyrham Park.
Tagged as Dracula
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News Campaigns Materials
SCWC Responds to Governor Brown’s State of State Address
Governor Highlights Balanced Approach Needed to Secure Statewide Water Supply
Los Angeles, CA - Governor Jerry Brown today delivered California’s State of the State Address, in which he laid out his priorities for California in 2016. In his address, the Governor noted that California’s economy and all those who live and work in the state depend on a reliable and secure water supply. He underscored the importance of investing in our water conveyance system in addition to moving forward with other critical water supply projects such as stormwater capture, groundwater cleanup, recycling and desalination.
“We applaud the Governor for highlighting the critical need to invest in water infrastructure. In Southern California, we continue to move towards additional creative water supply enhancements like conservation efficiency, stormwater capture, recycling, desalination and groundwater cleanup but we need California WaterFix. At the end of the day, we must fix the Delta because it’s the linchpin to California’s water planning.”
Charley Wilson
Southern California Water Committee
Established in 1984, the Southern California Water Committee is a nonprofit, nonpartisan, public education partnership dedicated to informing Southern Californians about our water needs and our state’s water resources. Spanning Los Angeles, Orange, San Diego, San Bernardino, Imperial, Riverside, Ventura and Kern counties, the SCWC’s members include representatives from business, government, agriculture, water agencies, labor and the general public. Visit us at www.socalwater.org and find us on Facebook and Twitter.
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Whatever you call it, it’s home
DEC 21 / 17
Why we’re not celebrating Tuponia’s 150th
The Canada brand is one of the most recognized national brands around the world, partly due to its reputation for natural beauty, partly due to its inspired deployment of its wordmark and other marketing techniques.
A 2015 ranking of the top national brands put Canada at fifth overall, just behind Japan, Switzerland, Germany and Sweden—not bad company to keep! In addition to the visual identity, Canada scored high marks from international travellers for its reputation as a tourist destination, high standard of living, natural beauty and public safety.
As we mark the 150th anniversary of Confederation, let’s take a look at how the branding of “Canada” has changed over time.
c. 15,000 BCE to Present
For the original inhabitants of what is today called Canada, this sprawling landmass went by dozens of different names. In more recent times, “Turtle Island” has become a common name used among Indigenous peoples to describe the territory bound by the Arctic, Atlantic and Pacific oceans.
French explorer Jacques Cartier appropriates the Huron-Iroquois word “kanata,” meaning “village,” to describe the region around modern-day Québec City, but slips up and spells it “Canada.” You’ve probably seen the Heritage Minute.
The first “official” use of the name “Canada” comes into effect when Québec gets split up into the colonies of Upper Canada and Lower Canada.
Two years before Confederation, no one had settled on a name yet for what to call what was then “British North America.” Politician Thomas D’Arcy McGee made the compelling case for “Canada” thusly:
“I read in one newspaper not less than a dozen attempts to derive a new name. One individual chooses Tuponia and another Hochelaga as a suitable name for the new nationality. Now I ask any honourable member of this House how he would feel if he woke up some fine morning and found himself instead of a Canadian, a Tuponian or a Hochelagander.”
The British North America Act makes it official: Dominion of Canada, it is! Technically, the British Union Jack was the official flag of Canada at the time, but the “red ensign,” a red flag with the Union Jack in the top left corner, was flown more widely.
Banff National Park is established as Canada’s first national park, and is instrumental in advertising Canada to the rest of the world as a paradise of rugged mountains, soaring trees and pristine lakes.
The enterprising immigration minister Clifford Sifton advertises Canada in Europe as “The Last Best West,” a reference to the perception that all the good land in the US had already been settled. Of course, the Canadian Prairies had been “settled” for thousands of years by then, but we have a history of conveniently overlooking such facts.
A royal proclamation establishes Canada’s coat of arms, as well as the country’s national colours: red and white.
Tired of dealing with the colonies, the British government downloads a lot of powers and responsibilities to Canada via the Statute of Westminster, helping Canada begin to get out of the shadow of the British Empire.
After much debate and a wide range of options, the National Flag of Canada—better known as the Maple Leaf—is adopted by the Canadian government. Prime Minister Lester B. Pearson had sought a new flag for Canada based on his experience brokering the end to the Suez Crisis, during which Egyptian negotiators took umbrage over Canadian peacekeepers sporting the Union Jack on their uniforms.
In addition to the new flag, the Canadian Government Travel Bureau adopts the “Canada” wordmark, designed by Toronto’s Jim Donoahue, to promote Canadian tourism abroad.
Salute the fallen: flags that never made the cut.
Trudeaumania, Expo 67 and Canada’s 100th birthday mark Canada’s arrival to the world as not just a bunch of mountains, lakes and trees.
Under the Federal Identity Program, the Canadian government makes Helvetica its official typeface due to its “versatility, excellent legibility and contemporary design.”
An update of the tourism wordmark—using a modified Baskerville typeface with the Canadian flag over the last “a”—gets adopted government-wide as an official symbol. According to the Treasury Board Secretariat, “The objective of adopting the Canada wordmark was to have a unified federal identity that is applied consistently across all departments. This ensures that the public can easily recognize the Government of Canada and its programs, services, facilities, assets, activities and uniformed officials.” By now, you’ve probably seen it thousands of times on everything from tax returns to film credits.
Canada publishes its first-ever comprehensive manual of design standards, in a neat and tidy 16 volumes. Perfect for a light beach read!
Stephen Harper’s Conservative government earns some derision for changing “The Government of Canada” to “the Harper government” on federal communications. On a potentially related note, the Government of Can—er, the “Harper government”—unveils millions in federal spending to mark the bicentennial of the War of 1812, and restores the “Royal” names and insignia to the branches of the armed forces.
Ottawa designer Raymond Larabie releases a modified version of his “Mesmerize” typeface ahead of Canada’s 150th birthday, which is soon adopted by the federal government as the official font of Canada 150. To reflect a broader understanding of Canadian identity, Larabie designed the characters and glyphs needed to properly incorporate Indigenous languages such as Cree, Inuktitut and Anishinaabemowin.
Mike Barber
Mike Barber is an editor at Goods & Services Branding, where he’s normally heard cursing under his breath about passive sentences. No, not your passive sentences, of course, those are special and perfect just the way they are. Someone else’s. In an earlier life, he reported for a news wire service, dabbled in digital journalism and experimented with government.
Your Roots are (still) showing
#effortless or #elaborate?
Branding chops
The name is the game
Staying “flawsome”
Stranger danger
Message from the editor
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The Four Season 2 Finale Recap: Did The Right Artist Win?
This is it: The Four Season 2 finale!
After a fun opening number and some advice from the judges, finalists James Graham, Leah Jenea, Whitney Reign, and Sharaya J were ready to hit the stage for the final night of competition!
Each of the Final Four performed a song, and the winner (chosen by the audience) was allowed to select their opponent for the next round.
Whitney kicked off the competition with “Lady Marmalade”. It was one of her weaker vocal showings, but she did display a lot of star power and it was fun to watch. Leah Jenea followed with “True Colors”. It was on the quieter side but still made for another captivating performance from Leah. Sharaya J rapped over “Juicy” and it was another great number from her and a great showcase of her determination to taste victory. James was last with “Rock With You” and this one fell flat with the judges, who said he just couldn’t live up to Michael Jackson’s iconic original version of the song.
After all the performances, the audience voted and the winner of Round 1 was…Sharaya! She chose to challenge Whitney, leaving Leah and James to battle it out in a rematch of their duel two weeks prior.
This stage of the finale saw Final Four paired off to battle each other for a spot in the top 2.
The first battle was between Sharaya and Whitney, with the latter starting things off with “A Million Reasons”. While this was a much better performance vocally, the passion and special Whitney flare wasn’t as evident as usual. Sharaya did a rap over “Cops Shot The Kid” and was also briefly off her game, but managed to pull it back together in the end to become the judges’ choice as the winner of the battle.
Up next was Leah vs. James. Leah sang “Golden” and we got to see a different side of her with her upbeat choice of a number. James countered with Adele’s “Hello” and showed a lot of range in his abilities. The judges were torn between the two, but ultimately chose James to advance to the final duel.
It all came down to this: a head-to-head battle between James and Sharaya – two members of the Original Four. (But not before a performance from Season 1 winner Evvie of her brand new single!)
Sharaya was up first with “Say Less”, a song she wrote that really showed who she is and what she’s about as an artist. James selected Coldplay’s “Fix You” as his final number of the season, and it was a great choice since it was a slow song that built into something to show off his pipes.
The judges praised both artists for their journeys over the course of the season, and Sharaya announced her recovery from breast cancer! Once again, the panel was torn, but in the end the winner of The Four Season 2 was…James Graham!
While I know James was a fan favorite, I was personally a little more mixed on him. Some performances I would really dig, and others fell a little bit flat for me. While I enjoyed his performance in the last battle slightly more than Sharaya’s, I took note that the judges were making their decisions tonight taking the entire season into account, and based on that I would have chosen Sharaya to win. She was probably the most consistent throughout the show, with even her lesser performances not dipping too far down in quality from her better ones. I also found her to be more fresh unique as an artist that James (and I could say the same about Leah as well).
Congratulations to James on the win, and here’s hoping we also see several of this summer’s contestants picked up by industry professionals. We certainly saw a lot of talent this season, and I’d hate to seeit go to waste!
Tags diddy dj kahled fergie Meghan Trainor The Four: Battle for Stardom
PREDICTION: Zhavia & Zayn Will Beat Lady Gaga at the ‘Teen Choice Awards’…Here’s Why!
This Is Not A Drill: ‘The Four’s’ Diddy Announces Return Of ‘Making The Band’
The Talent Recap Show: Did Meghan Trainor Make the Right Choice on ‘Songland’?
Meghan Trainor’s ‘Songland’ Pick is a BOP! Here’s Our Episode 5 Recap
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Dutch Law DBA – The Purpose, the Consequences and the (in)securities
Now that the proposed Deregulation Assessment Working Relations Act (DBA) has passed Parliament the VAR Certificate has become a relic from the past.
In more than 10 years of its existence, clients who hired contractors who were in possession of a VAR-wuo or VAR-dga, were protected against any possible PAYE liability (tax and social security contributions). If it turned out that the contractor was in fact to be considered an employee of the client, the financial consequences were entirely for the account of the contractor, whereas the client remained protected. This unlimited protection no doubt played an important role in the significant increase of flexible labour we have seen over the last few years.
However, presumed abuse by fake self-employed contractors caused politicians to call for an adjustment of the system. The VAR Certificate was issued based on assumed future facts and circumstances. Even though these facts and circumstances in practice often turned out to be different, because of the unlimited protection of the client, actual application of the relevant legislation proved to be difficult.
DBA has become effective as of 1st May 2016 however there was a ‘transition period’ up until Jan 2018. During the transition period both the client and the contractor had an obligation to make sure that the working relationship, where necessary, was transformed in such a way that it met with the new legislation. The Dutch authorities, even during the transition, made it clear that penalties would apply for any company that breaches the new rules.
Implementation of the DBA rules has now been pushed back to Jan 1st 2020, however as with the transition period up until now, companies seen to be in breach of the proposed DBA rules will be subject to fines and the liability of back taxes.
The new DBA Act intends to offer certainty to both the client and the contractor about the classification of the working relationship, focusing on the relationship the ‘End User’ client has with the temporary worker. When a self-employed setup is being looked at the new legislation must be considered and then, when secure in the knowledge that you are the right side of the new DBA rules, a Model Agreement can be issued. Model Agreements are official contracts used for self-employed engagements and are sent off by the contracting party (company who is engaging with the contractor) to be approved by the Dutch Government. As a member of Bovib (Brancheorganisatie voor intermediairs en brokers) TCP has been deeply involved in drafting an industry specific agreements for intermediaries that were sent to the Dutch authorities for their approval. By using this agreement, as well as carrying out the relevant due diligence for the placement of contractors with our clients, we are managing the risks that can arise from this kind of placement.
What are the authorities focusing on when assessing Employed / Self-Employed?
The elements to be taken into account when assessing the working relationship are linked to the criteria for employment, these being primarily (but not limited to) 1) does the client have authority over the contractor, 2) is the contractor tied to this one client 3) is the contractor providing their own equipment.
In order to be classified as self-employed it is important that the agreements between parties contain the following clauses or clauses of similar meaning:
The contractor accepts full responsibility for the correct performance of the work. He will be liable for any damage relating to his performance and will indemnify the client against all claims for compensation.
The contractor plans and performs the work independently. He does not come under the management and control of the client. The client neither gives instructions nor imposes regulations relating to presentation, interaction with the client’s competitors or other clients, working hours and corporate identity by means of a corporate dress code, logos on company vehicles and business cards.
The contractor takes care of his own tools, equipment and training.
The contractor is working for a number of different clients at the same time. Has several sources of income
If the agreement contains these or similar clauses it will very likely be approved by the Authorities. Should the work indeed be performed in accordance with these clauses the working relationship cannot be classified as employment and the client cannot be held liable for PAYE.
However, should the work not be performed in accordance with the clauses in the Model Agreement the authorities could still claim employment, causing the client to be liable for PAYE. In such a situation employment can only be assessed retrospectively.
The role of the intermediary
As the focus is on the relationship between the End User Client and the contractor, the risks and liability can sit entirely with the client. The role of an intermediary like TCP in this case can be used to help manage the risks involved.
By using TCP’s Model agreement, as well as carefully carrying out the necessary back office due diligence, TCP can ensure the compliance of the placement from start to finish and so manage the risk to the End User client.
The risks involved when placing a self-employed contractor on site with your client are essentially related to ‘Deemed Employment’. If the Dutch Tax and Customs Administration suspect that DBA is being deliberately ignored in any way then they will look to assign a party as the employer, subject that party to retrospective tax and social security as well as apply penalties/fines. As the worker/contractor is on site with the End User Client they are certainly at most risk.
Model Agreements can help manage this risk however, simply having a Model Agreement in place is not enough. DBA must be seen to be being met throughout the placement.
The Dutch are taking this pretty seriously and are carefully reviewing companies that look to have Model agreements authorized. Between 2016 and 2017 over 4000 applications were made to the authorities to have Model agreements approved, of which over 1000 were rejected.
How TCP can help
TCP manages the hiring of contractors and makes sure that contracts are compliant, whether that is the contract between the contractor and TCP or the (framework) agreement between TCP and the client.
When dealing with a true self-employed contractor we will, during the term of the assignment, constantly be monitoring working conditions. Thus making sure that the work is being done in accordance with the contract (that excludes employment). By doing so we protect the client against a potential PAYE liability whereas the contractor does not need to worry about his status as a self-employed contractor.
If you would like to find out more about how TCP can help, please contact a member of our sales team on +44 208 5800 800.
© 2019 TCP Solutions Ltd
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Home » Sports » ITF $15,000 Men’s Tennis Tournament: Vasisht-Prajwal duo goes down in semis
ITF $15,000 Men’s Tennis Tournament: Vasisht-Prajwal duo goes down in semis
Mysuru lads C. Vasisht and S.D. Prajwal Dev, representing India in the $15,000 ITF Men’s Tournament at Uganda, went down in the semi-finals in the Men’s Doubles event on Friday. Kaza Vinayak Sarma and M. Goran Markovic combined well to beat C. Vasisht and S.D. Prajwal Dev 6-3, 7-5 in a semi-final tie which lasted for one hour and 21 minutes.
In the quarter-finals, Prajwal and Vasisht beat Lorenzo Bocchi & Tomasso Gabrieli of Italy 7-6 (7), 6-1. In the first round, the duo beat Anton Chekhov (Rus) & Aaron Cortes Alcaraz (Esp) 6-3, 6-4.
In the Men’s Singles event, top-seed Ivan Nediko (Rus) beat city lad Prajwal Dev 6-1, 7-5 to enter the semi-finals.
In the pre-quarterfinals, Prajwal Dev beat Jayesh Pungliya 6-4, 6-1 and in the first round, he beat Boris Aguma (Uga) 6-1, 6-1.
Vasisht lost to Kaza Vinayak Sarma 6-7(5), 5-7 in the Men’s Singles first round tie.
C. Vasisht S.D. Prajwal Dev Tennis
Ph.D awardees
AITA Championship Series: Manish from Mysuru enters semi-finals
8 × = forty
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In, I guess
At the beginning of the EU campaign I started a "bullshit arguments" tag, with the thought that I might highlight any particularly tendentious, emotive or illogical tactics used by either side. I haven't kept it up, though, because it would have meant transcribing pretty much every news bulletin in its entirety.
I was, and am, far from enamoured of the EU, and was genuinely on the fence at the start. However, I will now almost certainly vote to stay in, because no even vaguely acceptable alternative is available. To vote to leave has become synonymous with a vote against immigration, against workers' and environmental protections, and for economic neo-liberalism. It's very clear that all these - laced with coded and not-so-coded racism - are what we'd get in the event of an Out vote.
It absolutely didn't have to be that way: there are other models that an independent Britain might have followed, but at this time there is no group both willing and able to bring them to existence, or even to talk about them as a possibility. So, the choice is: EU, warts and all; or else a UK stripped of everything that's actually valuable and worth having about the EU. It's not really a choice, is it?
Tags: bullshit arguments, current affairs
heleninwales
Coming second to whom? The multi-billionaires buying up all the new-build luxury apartments in London aren't European. They're Russians and Chinese. Leaving the EU won't make a scrap of difference to the upward pressure on house prices caused by this sort of property speculation.
If you mean immigrants, as I said before, less than half of our immigrants currently come from the EU. The majority (51%) come from non-EU countries. So if the government can't or won't stop non-EU immigration while we're in the EU, why should they stop it if we left? If businesses want cheap labour and native British people won't work for those wages, they'll import workers either legally or illegally. You're living in dreamland if you think that leaving the EU will magically stop foreigners coming here to work.
As for me, I'm voting remain because we in Wales do well out of the EU because it funds various important projects that we desperately need. I don't trust the Westminster government to replace that funding because they didn't care about the regions before we entered the EU and they don't need our votes in order to get elected, so they don't need to keep us happy. As far as Westminster is concerned, the regions don't exist.
I suspect your slogan is, "I want my country back." Though where you think it's gone or who stole it, I don't know. Wales was stolen by force (the castles are still there) and then the country's resources were plundered to make a few people very rich. In the 1980s, Thatcher screwed the miners and devastated the South Wales valleys by following free market principles. (It was cheaper to import Australian coal (note that Australia is not an EU country!) than to mine it here in Britain.) Finally, the life is coming back into South Wales. Railways and stations have reopened allowing people to travel to where the jobs are. Who paid for those projects? Why, the "evil" EU of course, along with the devolved Welsh assembly. So I'll be voting remain for good sound economic reasons.
ron_broxted
I don't live in the West End. I understand Wales wanting in (plus Scotland, a second referendum on way, I supported Yes last time). I am not a UKIPper, only agree with zero immigration. Make it too hot for Polacks to stay.
All the Poles I've met have been pretty pleasant people, many with excellent English and (for what's it's worth) a willingness to work. Some I count as my friends. Why would I want them to go back to Poland? Perhaps it's to make room for the influx of elderly British emigrants who'll be returning from retirement Spain and France to clog up the NHS wards once those governments decide to make it "too hot" for the British immigrants to stay?
(By the way, please don't use terms such as 'Polack' on this blog.)
2016-06-19 02:29 pm (UTC) (Link)
I have been thinking of the nature of prejudice (before I logged on). I have some Polish pals, they speak fluent English and wash. Down at the DSS it is another story, Stanislaus gets to the head of the housing queue and has interpreters on £200 per hour. The million or so English in Spain are scum, they refuse to learn Spanish and want a mini Hackney replicated, only with sunshine and "no darkies". Polack is merely Ashkenazim Yiddish for Polish. Wladislaw usually refers to Jews as "Korva zydowa" (fucking yids) and the whole EU referendum was caused by Blair/Brown and their contempt of the white working class.
vschanoes
Yiddish is the language of the Ashkenazi, so no need to specify. You're mistaken about "Polack." You can look that up on Wikipedia. It is considered a derogatory slur in the US and the UK.
Yes there is, Eastern or Western Yiddische. I never hear the P WORD over here in Britain, Irish in America use it. Wiki is not much of a citation.
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Terrelle Graham Reviews
Films. Video games. Television.
Godzilla: King of the Monsters – Movie Review – A colossal monster mash up.
Posted on May 31, 2019 May 31, 2019 by terrellegrahamreviews
It’s no secret. I loved Gareth Edwards’s 2014 Godzilla and I still do til this day. It’s a masterpiece of scale that features breathtaking visuals and a well tuned sense of suspense and build up. That build up was a controversial aspect, because many felt the titular monster didn’t appear enough. Well Godzilla: King of the Monsters feels like a direct answer to those complaints.
The narrative picks up five years after the events of the previous film, with Monarch scientist Dr Emma Russell (Vera Farmiga) and her daughter Maddison (Millie Bobby Brown) being kidnapped by a group of eco terrorists, who aim to gain control of a new device she invented that will change the way humans can interact with Godzilla. Once new titans start to rise and threaten the existence of human life her ex husband, Dr. Mark Russell (Kyle Chandler) and Monarch realise they must make Godzilla their ally in order to save the world.
Whilst the story is admittedly not that strong, it plays much better when you view it from the perspective of a B-Movie, or a live action anime featuring an onslaught of Kaiju mayhem. The characters at times make questionable decisions that only seem to exist, as a method to bring the audience to the next monster match up. The grounded reality established in the first film has been adjusted to a more sci-fi driven world, where for example there’s a secret underwater base and a McGuffin that is capable of communicating with the monsters. The more I think about it, the more I notice the story and the established world falls in line with some of Toho’s classic movies from the 60’s and onwards. I do believe this was an intentional choice on the filmmakers part to honour the legacy that came before it, by keeping the plot fairly simple albeit a little over the top, instead of focusing heavily on logic and other things to make the narrative more serious as a whole. One aspect that absolutely didn’t work for me is the humour. I didn’t laugh once, despite the many attempts through out. The one liners and jokes just weren’t that inventive which is a shame, because they could’ve made some of the longer dialogue scenes more entertaining.
The great news is everything audiences will be paying to see, absolutely delivers ten fold. The monsters are showcased in all their glory through out the film and they invoke a sense of wonder and awe each time you see them. Each one comes with their own distinct characteristics and abilities which makes it easy to find things to love about all of them. By this point Godzilla is viewed as Earth’s protector but his relationship with the humans isn’t that simple during the first half. One of the best scenes in the film featured Godzilla approaching the Monarch underwater base, with the aim of intimidating everyone on the inside. It’s a wonderfully tense moment that made me question Godzilla’s motives and whether he was coming to protect or destroy. Mothra is simply beautiful to look at, she has been brought to life with so much grace and attention to detail, which made her scenes feel incredibly majestic. How they utilise her within this story is perfect, and fans of her will be extremely pleased with how she’s handled. Rodan is lethal and a clear dominant force in the skies, hurtling over cities and causing mass destruction due to the whirlwind of air and fire that comes from his wings. His key action sequence showcased him making great use of his powers in order to dispatch a squadron of jets. It is truly exhilarating. The interesting thing with Rodan is he is a neutral, who is looking for an alpha to bow down to, which means the side in which he stands on is never truly set in stone.
That brings me to the last of the four titans, King Ghidorah. From his first scene he is introduced as an intelligent and intimidating threat. Magnificent in size with a devastating array of abilities. The artistic design of Ghidorah makes it impossible not to admire him. A golden three headed hydra that conjures up humongous storms as he travels. He’s described as an ancient rival of Godzilla and through the action set pieces we witness how much havoc and damage he can cause, even to Godzilla himself. A creative choice was made to allow three different actors to perform motion capture for each of Ghidorah’s heads. This was an effective choice because it makes the three separate personalities very noticeable. The main head is the most aggressive and the clear leader of the three, whilst one of them is fierce and the other one is a little curious. When you see them in action you’ll understand what I mean and it totally works. It gives the terrifying monster a lot of personality.
The majority of the cast were all fine in their roles. The script may have overpopulated the story with characters though, because a large majority of them fall to the side quite quickly and don’t get a whole lot to do. I like what Millie Bobby Brown brought to the role of Madison. She handled her moments of drama well, and showcased great emotional range when it was needed. I can certainly see her becoming a big movie star in the future. Vera Farmiga did feel a little wasted here, because Dr. Emma Russell is one of the characters I have the most issues with. Her motivations seem a little all over the place, and there’s places they attempt to go with her that were just all too predictable. Dr. Mark Russell portrayed by Kyle Chandler was also fine. He did make the emotional strain of his family relationship felt, but he lacked the charisma needed to carry a film of this nature as a lead. It was nice to see Ken Watanabe return as Dr. Ishiro Serizawa. He gets a lot more to do in this film than the last, and he has a pivotal scene with Godzilla that I thought was beautiful.
Michael Dougherty has a clear love for the legacy of this franchise and it shines through with his direction. At times he does struggle to keep the energy flowing through the dialogue scenes, but that’s mainly due to the dialogue in the script (which he co-wrote) being very exposition heavy. But once he gets to unleash the monsters he feels right at home with all the carnage. His work alongside the director of photography, Lawrence Sher is for the most part astonishing. There’s some wonderful perspective shots of humans on the ground with the colossal monsters fighting around them, and moments like that really drew me into the intensity of the action. Most of the time they stage the monster sequences with a fantastic sense of grandeur, which really takes your breath away. Their work wasn’t perfect though, as there were a few times where the shots could’ve been framed better to capture the monsters fighting, as it was a bit of a struggle to see what was occurring sometimes. That being said I must say hats off to them for the final shot of the film, which looks like a stunning piece of art.
Bear McCreary’s pulse pounding score is a thing of beauty. He splices his own original music with interpolations of the classic Toho themes for these monsters. It’s something that fans will appreciate greatly, but even if you aren’t familiar with the original themes, they’re utilised at the right moments in order to get you amped up for the action. The sound department deserve a lot of praise. During the monster battles there can be a lot of audio occurring at once, but the sound mix is superb. They made sure to heighten and balance the sounds of the Monsters amongst the destruction that was occurring around them. The overall sound design was fantastic too, which each monster carrying their own assortment of recognisable noises and roars.
This instalment expands upon the mythology of Legendary Pictures’ Monster Verse in some very satisfying ways, and the filmmakers accelerate the world building of this cinematic universe with great success. There are far more callbacks to the previous Toho movies than I had ever expected. These range from Easter eggs and references, all the way to surprising plot points from the older films, that have been merged within this story. There is also a post credits scene which you’ll want to stay for. It’s nothing crazy but the implications it provides for where the future of this franchise will go, is definitely something that fans will be excited for.
Godzilla: King of the Monsters honours the 65 year legacy of the franchise and delivers an exhilarating experience that demands to be seen on the biggest cinema screen you can find. The spectacle is grand, the visuals superb and the monsters are utterly breathtaking.
(4 Stars out of 5)
-T. Graham.
Godzilla: King of the Monsters – Starring Vera Farmiga, Kyle Chandler, Millie Bobby Brown, Charles Dance and Ken Watanabe.
Directed by Michael Dougherty.
Now showing in cinemas.
Posted in FilmTagged Film Review, Ghidorah, Godzilla, Godzilla: King of the Monsters, Kaiju, King Ghidorah, King of the Monsters, Kong, Monster Verse, Mothra, Movie Review, Review, Rodan, UKLeave a comment
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Home » Knowledge Base » Changes in Bird Habitat Utilisation around the Horns Rev 1 Offshore Wind Farm, with Particular Emphasis on Common Scoter
Changes in Bird Habitat Utilisation around the Horns Rev 1 Offshore Wind Farm, with Particular Emphasis on Common Scoter
Title: Changes in Bird Habitat Utilisation around the Horns Rev 1 Offshore Wind Farm, with Particular Emphasis on Common Scoter
Authors: Petersen, I.; Fox, A.
National Environmental Research Institute (NERI)
Static Device
Birds, Seabirds, Waterfowl
Wind Energy general, Offshore Wind
Petersen, I.; Fox, A. (2007). Changes in Bird Habitat Utilisation around the Horns Rev 1 Offshore Wind Farm, with Particular Emphasis on Common Scoter. Report by National Environmental Research Institute (NERI). pp 36.
This report presents an analysis of recent changes in waterbird habitat utilisation around the Horns Rev 1 wind farm, with particular emphasis on Common Scoter.
Ornithological investigations of waterbird numbers and distribution in the study area around the Horns Rev 1 wind farm were initiated in 1999. As part of a demonstration programme on the environmental feasibility of offshore wind farms a total of 34 surveys of bird distributions were conducted in the period from 1999 until 2005. In late 2005 and early 2006 additional six surveys were conducted in relation to the Horns Rev 2 EIA process.
Results from the demonstration programme concluded that the distribution of divers and Common Scoter were adversely affected by the presence of the wind turbines at Horns Rev.
In late 2006 and early 2007 Vattenfall A/S maintenance crews and helicopter pilots reported increasing numbers of Common Scoters present within the wind farm site. On that background a series of four surveys of waterbird distribution in the area was programmed during January to April 2007.
Data from surveys in January, February, March and April 2007 showed that Common Scoter was the most numerous bird species in the study area, with a total of 356,635 observed birds. Herring Gulls (7,661), Eider (5,674) and diver sp. (511) were other numerous species in the area.
Common Scoters dramatically changed their distribution in the study area during the period from 1999 to 2007 for reasons other than the presence of the turbines. Therefore a comparison of distribution of this species pre- and post-construction of the wind farm, using a traditional BACI concept, was impossible. The analyses presented here thus build on data from the January to April 2004 to 2007.
During three out of four surveys in 2007 more Common Scoters than during any previous surveys were recorded within the foot print of the wind farm. On 25 January 2,112 birds, on 15 February 4,624 birds, on 3 March 1,359 and on 1 April 35 Common Scoters were encountered in the wind farm area.
Analyses of Common Scoter encounter rates in six 2x2 km grid cells within the wind farm area compared to encounter rates in 14 grid cells in the periphery of the wind farm site showed no significant difference for the three early surveys, while significantly lower encounter rates within the wind farm during a survey on 1 April. Based on the summed data set from 2007 there was no significant difference between encounter rates in the wind farm site and the periphery.
Analyses of Common Scoter cumulative distance frequency distributions in 500 m intervals from the wind farm centre point out to a radius of 6 km for each of the years between 2004 and 2007 showed that gradually higher percentages of the birds present within this radius were recorded within the wind farm site. The same pattern was found when analysing the proportion of birds within 3 km of the wind farm centre point to the total number of birds present within 6 km of the centre point, most dramatically amongst the proportion of individuals occurring within the area, which progressively increased from 10% in 2004 to 50% in the results from the survey in 2007.
We therefore conclude that Common Scoter may indeed occur in high densities between newly constructed wind turbines at sea, but this may only occur a number of years after initial construction. We still cannot exclude the explanation that this reflects changes in food supply rather than a change in the behaviour of the birds themselves.
As Common Scoters were virtually absent from Horns Rev prior to the construction of the wind farm it is difficult to judge how many birds the wind farm site would support by 2007, had the wind farm never been constructed. The use of spatial modelling tools may help elucidate whether the present found numbers of birds represent 100% of what could be expected in the absence of the wind turbines, given the nature of the habitat. Such an exercise was beyond the scope of this report.
Spatial modelled density surfaces of Common Scoter, including estimated total numbers within the study area, will be presented in a separate report for each of the four surveys conducted in 2007.
There was no sign that divers, previously concluded to avoid the area of the wind farm and its surroundings, had changed their distribution relative to the wind farm.
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The Vocation of Teaching and the Penn State Scandal
By Paula Marantz Cohen | November 22, 2011
My husband and I were on our way to Paris for our honeymoon when there was a commotion toward the front of the plane. It filtered back to us that someone was sick, and my husband, who had just finished his residency in internal medicine, immediately went forward and spent the rest of the trip ministering to a young woman who had gone into diabetic shock. I will always remember my Paris honeymoon for that plane trip, when I was left for seven hours at the back of the plane while my husband saved someone’s life.
My husband’s action was not simply a function of his morally upright character, morally upright though I think he is. It was also a function of his training as a physician. A doctor is supposed to step forward when someone is in distress. In recent years we hear reports of physicians, fearful of litigation, who shirk this duty, but they are exceptions. Doctors who don’t provide aid when the occasion demands it violate the sacred code of their profession.
Let us turn now to the Penn State scandal. Educators in this case failed to intervene where many people were apparently in distress. This failure has been explained in moral terms, and, certainly, one cannot discount the moral element. We assume that any morally upright person who knew about what is reported to have been going on in that locker room would have intervened on behalf of the abused child, just as we assume that anyone on that airplane to Paris would have tried to help the sick woman. But there is an additional responsibility that comes with being a teacher—an understanding of moral duty not in absolute terms but in vocational ones.
The university president, athletic director, head coach, and graduate assistant coach (a confusing appellation, if ever there was one) apparently failed in their moral duty to alert the police that young people were being abused. But the emphasis on morality misses part of the point. Teaching–of which coaching and college administration should be a subset—are professions that are supposed to support learning, much the way that medicine is a profession supporting health. As part of this mandate, teachers have a responsibility to intervene when learning is inhibited or under attack. Doctors not only support good health, they also intervene to alleviate sickness. Why isn’t the mission of teaching (and coaching and the administration of education) seen in the same terms?
Part of the reason is that education is a less clear-cut vocation than medicine. We are not speaking of physical calamities like cardiac arrest or diabetic shock, but more amorphous ones involving child welfare (though sexual abuse, in the case in question, is clear-cut enough). More to the point, however, medicine is a vocation that has traditionally garnered more respect than teaching, and as a result, it has been able to hold its practitioners to a higher standard. This standard extends beyond the patients who visit doctors’ offices to people in general. As members of their profession, they feel obliged to intervene and help whenever and wherever a medical emergency arises. You might say that any decent person would intervene, but that misses the degree to which we learn our sense of appropriate behavior within vocational parameters and are abetted or inhibited in this behavior by the institutions that employ us.
Joe Paterno took a holier-than-thou attitude with respect to his vocation, but this was not what gained him respect. He wasn’t revered because he was an educator but because he won football games. (We can put aside for the moment what role athletics should play in an educational curriculum—that is a topic for another column.) That Paterno made more money than the president of Penn State—and, more tellingly, far more than the most effective and devoted teacher there—says something about the values of that institution and, beyond that, about the values of the society in which that institution is a part. We don’t respect teachers as much as we respect doctors. Perhaps that is a factor in those instances when they don’t look beyond the narrow purviews of teaching, scholarship, and coaching football to something larger: the protection and promotion of the well-being of those being taught.
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Home > node > Australia's Impressionists, National Gallery
Australia's Impressionists, National Gallery | reviews, news & interviews
Australia's Impressionists, National Gallery
The visual discoveries of France applied in the open landscapes of a young nation
by Marina VaizeyWednesday, 04 January 2017
Tom Roberts, 'A Break Away!', 1891 © Art Gallery of South Australia, Adelaide Elder Bequest Fund 1899
Painted in 1891 by Tom Roberts, A Break Away! shows us a flock of maddened, thirsty sheep careering down a hillside stripped of grass by drought, accompanied by rollicking sheepdogs and cowboy shepherds on horses. If those sheep pile on top of one another into the puny stream at the bottom of the hill, injury – even death – will occur. The perspective is vertiginous, and the scene almost visibly pulsates with energy.
It is one of Australia’s best-loved paintings (main picture), emblematic of the growing prideful nationalism of a new country – well, new to Europeans who ignored, blighted and almost completely destroyed the 50,000-year-old culture of the native aborigines. It is a highlight of an unusually refreshing exhibition of landscapes and cityscapes of that so-called Lucky Country, Down Under on the other side of the world, where Christmas is summertime.
England’s First Fleet arrived in 1788, with the first permanent settlements by westerners, and its centenary in 1888 provoked strong feelings of national pride. Federation was finally accomplished for the whole continent in 1901. So, in the waves of nationalism and constitutional consolidation that was taking place all over the world in the 19th century, Australia was not that far behind; nor, with its tiny population almost all concentrated in the cities – Melbourne was one of the richest in the world – was its art backward in coming forward to inhabit the mainstream.
Nevertheless, in spite of the huge but ramshackle survey of art from Australia at the Royal Academy in 2013, its leading lights are still little known outside their home country. The timing of this small but concentrated and specialist showing should help us open our eyes as we escape briefly from London's weather and global worry to revel in these refreshing, enthusiastic examinations as a newly confident group of artists flexed their visual muscles to look at their surroundings. Nearly 50 paintings, most from the leading museums of Oz, give a fair overview of a trio of young but ambitious artists of the time and their passion for both city streets and vast country vistas. Almost all date from the 1880s and 1890s and encompass the famous "9 by 5 Impression" exhibition, held in 1889 in Melbourne, which took its name from the dimensions of the lids of the cigar boxes which were used instead of canvases. It was in Melbourne in the late 1880s that the Heidelberg group was formed, the artists travelling out from the city to camp at its edge, in the country, in a place called Heidelberg – and to paint, both out there in the landscape and back home in the studio.
They are unpretentious but so vivid and captivating, painted with an acute observation
The group could easily have been widened, but the intensity of the concentration on just the four artists makes for helpful clarity. They are hybrid artists, travellers all: the precocious Charles Conder (1868-1909) was born in England, and only spent six years in Australia (1884-1890) studying art and painting, prodigiously precocious. The Australian Arthur Streeton (1867-1943), master of the landscape, was in later life to spend 23 years in England before returning home. He was hailed early on as embodying the beginning of (Western) art in Australia. Tom Roberts (1856-1931) studied at London’s Royal Academy and was profoundly influenced by Whistler (himself, of course, also a hybrid, claimed by both America and England): he brought the lessons he had absorbed from the new movement of Impressionism back to Australia, but even he in later life left Australia to spend some 20 further years in England.
The wealthy Australian John Russell (1858-1930) went away entirely, returning to Sydney only in old age: he was friends with Van Gogh, whose portrait he painted. Living for years in the artists’ colony on Belle Isle in Brittany, Russell was close to Monet and mentored Matisse. His subject matter is French, his style an amalgam of Impressionism and post-Impressionism, with encrusted brush strokes and a flirtation between representation and – well – imaginative impressions. He is now comparatively little known in Europe – he destroyed much of his own work – and has been called Australia’s lost Impressionist. Oddly, the one prominent Australian Impressionist Frederick McCubbin who also exhibited in the "9 by 5" show is not included, although it was he who hardly ever left Australia.
Arthur Streeton’s glorious Golden Summer, Eaglemont, 1889, shows his gold and blue palette; the rich land, the sheep and their shepherd going home in the early evening. His Purple Noon’s Transparent Might, 1896 (pictured above right), is a beguiling look over a vast landscape, a river valley, the river sinuously twisting and turning, a range of mountains blurred by mist in the distance, all under a huge overarching sky.
There is a wall of the "9 by 5 Impression" paintings, and other small sketches, city scenes of London and Australia, country and city, and of course larger paintings, fully-formed so to speak. But all share a sensibility: they are unpretentious but so vivid and captivating, painted with an acute observation of solid structures, crowds, country bridges, railway stations, city streets, harbour side, meadows, bathed in changing light. Tom Roberts’ Allegro con Brio: Bourke Street West is a much larger painting, a crowded city scene of a dusty street with people and horse-drawn carriages, framed by unpretentious buildings, their verandas hinting at strategies to combat the inescapable heat. Roberts and Streeton both paint the sea, the land coming down to meet the water: endless beaches, cliffs, wooded hills. And Charles Conder paints a fashionable beach at a resort, in A Holiday at Mentone (pictured above), its inhabitants fully, and elegantly, dressed, strolling, in 1888.
Go to this show, and be refreshed and surprised: it was a time when art was becoming truly international, almost a kind of lingua franca. The investigations initiated by those French visual revolutionaries were contagious, providing an impetus that broadened the vocabulary of art, taken up with intelligent discernment, skill and enthusiasm on the other side of the world.
Australia’s Impressionists at the National Gallery to 26 March
Read more visual arts reviews on theartsdesk
It encompasses the famous '9 by 5 Impression' exhibition which took its name from the dimensions of the lids of the cigar boxes which were used instead of canvases
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theartsdesk in Australia: The oldest civilisation on show
Impressionists in London, Tate Britain review - from the stodgy to the sublime
Drawn in Colour: Degas from the Burrell Collection review - guilty pleasures at the National Gallery
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Les Rencontres d’Arles 2019 review - strength in tradition To celebrate its 50th year, the photography festival takes a long view
BP Portrait Award 2019, National Portrait Gallery review - a story for everyone The annual prize takes the pulse of contemporary portraiture
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Félix Vallotton: Painter of Disquiet, Royal Academy review – strange and intriguing An avant-garde artist who paints like Holbein
Cutting Edge: Modernist British Printmaking, Dulwich Picture Gallery review - a cut above Excellent exhibition sheds light on linocuts of neglected Grosvenor School Modernists
Francis Bacon: Couplings, Gagosian Gallery review - sex and power in double figures A small selection focuses on the painter's radical figure paintings
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Edouard Vuillard: The Poetry of the Everyday, Holburne Museum, Bath review - dizzying pattern and colour An artist's world encompassed
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NTT DATA Services Soaks Up Some Sun
Blog /NTT DATA Services Soaks Up Some Sun
NTT DATA Services employees recently gathered outside the offices of the Plano Parkway Campus to beat the heat and enjoy a company ice cream social. But ice cream wasn’t the only big draw, as City of Plano Mayor Harry LaRosiliere was on-hand to meet and greet IndyCar driver Tony Kanaan, from the Chip Ganassi Racing team. Tony was in the Dallas area for the Rainguard Water Sealers 600, an annual race held at the Texas Motor Speedway. NTT DATA has enjoyed the privilege of sponsoring Tony for the past five years, and hosting him — and his No. 10 IndyCar — provided a rare opportunity for employees and their families to enjoy some one-on-one time with the winner of the 2013 Indianapolis 500 and the 2004 IndyCar Series Champion.
As a newly hired intern, I was given my first real opportunity to freely converse with all of my new fellow workmates in a friendly and open setting. My position as a Market and Communications intern has given me the opportunity to flex my social media muscles as well as develop both my communications and public relations skills, such as learning to blog. But, because of the ice cream social, I was given the opportunity to move outside of my space and meet employees outside of my circle, which gave me fresh and different perspectives and insights about the company.
Employees, along with their families, enjoyed their cold treats, as a live DJ played hits from the early ‘70’s Classic Rock to the present day. Drumsticks and push pops provided cool relief as everyone soaked in the sun and enjoyed the fun. Both the environment and vibe were uplifting, providing a welcome break from the mostly indoor day-to-day work. There’s nothing better than going outside on a summer day and enjoying some good music and ice cream.
To top off the event, Tony Kanaan made an appearance. The Brazilian driver signed autographs and helped announce the names of the winners of the raffle, who were given four tickets for the weekend’s racing events. Joining Tony at the raffle was the City of Plano Mayor Harry LaRosiliere. The two guests were a welcome sight as employees were given chances to interact with the two big fans of NTT DATA.
Apart from greeting fans, Tony brought along his car for employees and their families to see. Kanaan’s Number 10 IndyCar has a Dallara DW12 chassis with a 2.2 liters twin turbo Chevrolet mated to a Xtrac transmission. The weight of the car is: 1570 lbs in oval spec, 1600 lbs road/street course spec. The power output of 625 to 675 HP varies with boost spec per track. NTT DATA will be the primary sponsor for both the No. 10 and No. 9 car, driven by Scott Dixon, for the Rainguard Water Sealers 600. Hear what Tony had to say about the race.
Along with Kanaan’s car, two other vehicles were available for friends and family to climb aboard for photos. One was a vintage motorcycle with a sidecar, and the other was a bathtub on wheels – safe to say few got inside the bathtub.
All-in-all, the employee ice cream social was a great success, as family, friends, and employees gathered outside the office for a visit. Many reacquainted themselves with co-workers they haven’t seen recently. And it was nice to meet family members rarely seen around the office. The inviting atmosphere, mixed with a plethora of friendly conversation, made for what many would call a perfect afternoon.
I thoroughly enjoyed meeting the many people that work at this company. Having only joined NTT DATA Services in late May, this ice cream social was a perfect opportunity to turn a few unknown faces into memorable ones. From Tony Kanaan’s visit all the way to the free ice cream, there couldn’t have been a better event on a hot Texas summer day.
John Hazzard
John is on the Marketing & Communications team at NTT DATA Services. He currently attends Saint Louis University, where he majors in Business, with a focus in Marketing and minor in Creative Writing. He has years of sports writing under his belt, predominantly focusing on soccer. His work has been featured on websites, including Sports Illustrated and the Bleacher Report.
Retailers Refocus on Customer Oriented Solutions New Forrester Report
Bridging Accounts Payable Gaps With Technology
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Vale: Steve Dunleavy
June 25th, 2019 By David Knox 2 commentsFiled under: News,
Australian journalist Steve Dunleavy, who made a name for himself in the US as host & reporter for A Current Affair, has died, aged 81.
“It just was very sudden,” his son Sean Dunleavy said. “But he was home, it was peaceful. But we don’t know what the cause of death was.”
Born in Sydney in 1938, Dunleavy’s media career spanned more than 40 years, with his trademark tabloid style, until his retirement in 2008.
He started at The Sun in Sydney as a copy boy in 1953 and then headed over to The Daily Mirror.
He headed overseas in 1966 where filing for newspapers in the UK until he took a job at the New York Post, owned by Rupert Murdoch.
At one stage he was set to be the topic of a Hollywood movie with rumours Paul Hogan or Mel Gibson might play a role.
Source: Nine
Tags: A Current Affair
bh June 25, 2019 3:16 pm
Wasn’t he also the inspiration for the Robert Downey Jr character in Natural Born Killers?
roaringdave June 26, 2019 8:22 am
He was.
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Remain’s of Australia’s most infamous bushranger ID
Executions, Gaols, Murder, Twisted History
The headless remains of Australia’s most infamous criminal, Ned Kelly, have been identified. Victoria state Attorney General Robert Clark said that a team of forensic scientists identified Kelly’s remains among those exhumed from a mass grave at Pentridge prison in Melbourne in 2009. Kelly led a gang of bank robbers in Victoria in the 19th century. Today he is considered by many Australians to be a Robin Hood-like figure who stood up to the British colonial authorities of the time. He was executed in 1880, but his final resting place had long been a mystery. “To think a group of scientists could identify the body of a man who was executed more than 130 years ago, moved and buried in a haphazard fashion among 33 other prisoners, most of whom are not identified, is amazing,” said Victoria Attorney General Robert Clark. The Sydney Morning Herald reported that investigators revealed that an almost complete skeleton of the outlaw was found buried in a wooden ax box. Clark said DNA analysis and other tests were used to confirm the skeleton is Kelly’s. The Morning Herald said DNA samples were taken from Melbourne school teacher Leigh Olver, who is the great-grandson of Kelly’s sister Ellen. Kelly’s skull was stolen from a display case at the Old Melbourne Gaol in 1978. A 2009 claim by a West Australian farmer, Tom Baxter, that he had Kelly’s skull was eventually rejected, but led to the investigation that uncovered his bones. The Morning Herald said that investigators believed that Kelly’s remains were transferred from the Old Melbourne Gaol to the Pentridge prison in 1929, then exhumed with the remains of 33 other people during the investigation in 2009. Baxter had handed the Victorian Institute of Forensic Medicine what he said was the stolen skull, which featured the inscription “E. Kelly” on its side — Kelly’s actual first name was Edward. Baxter has not revealed how he got ahold of the skull. Scientists at the institute set out to determine who the skull belonged to, and to identify Kelly’s full remains among the tangle of skeletons exhumed from the Pentridge site. Through CT scans, X-rays, anthropological and historical research and DNA analysis, the team finally identified one skeleton as Kelly’s. Most of its head was missing. Stephen Cordner, the institute’s director, said the DNA left no doubt the skeleton was Kelly’s. Tests on the remains also uncovered evidence of shotgun wounds that matched those Kelly suffered during his criminal rampage. “The wear and tear of the skeleton is a little bit more than would be expected for a 25-year-old today,” Cordner said. “But such was Ned’s life, this is hardly surprising.” As for Baxter’s “E. Kelly” skull? Not Ned’s. The whereabouts of Kelly’s skull remain a mystery, Cordner said. Descendant Olver told reporters in Melbourne that he hoped his notorious ancestor will finally be laid to rest in a place of dignity. “It’s such a great relief to finally have this side of the story resolved,” Olver said. Kelly’s story has been documented in several books and movies, including a film starring Rolling Stones frontman Mick Jagger and another starring late actor Heath Ledger. Kelly’s use of homemade armor to protect himself from police bullets was even given a nod during the 2000 Sydney Olympics, when actors on stilts dressed in similar armor were featured in the opening ceremony. “I think a lot of Australians connect with Ned Kelly and they’re proud of the heritage that has developed as a result of our connection with Ned Kelly and the story of Ned Kelly,” Olver said. “In our family, he was a hero.”
https://twistedhistory.net.au/wp-content/uploads/2016/08/image-15.jpg 477 474 Limelight https://twistedhistory.net.au/wp-content/uploads/2018/10/Twisted-Logo-Tranparent-no-shadow.png Limelight2018-08-04 23:26:312018-08-09 23:26:41Remain's of Australia's most infamous bushranger ID
Trappers Death
Melbourne Murder Tours, Murder, On This Day
On This Day – June 27, 1934
Charged with having murdered Daniel George Robinson, a trapper, on June 27, 1934, Albert James McKenzie (28), farm labourer, appeared in the City Court before Mr. Maclean, P.M., today. Supporting a police request for a remand, Sergeant Madin said it was alleged that Robinson was shot with a shotgun in his hut in the Wombat Ranges at Tolmie and that his body was placed under a log in the bush, where his skeleton was discovered on September 28. McKenzie was arrested on the murder charge on Wednesday afternoon by Detective-Sergeant O’Keefe, Senior Detective Sloan, Senior Constable Barrett and Detective Garvey. McKenzie was remanded to appear at the City Court on October 14. He did not ask for bail.
https://twistedhistory.net.au/wp-content/uploads/2016/06/692182-200_trapper_enlargement_tcm16-38357.jpg 867 695 Limelight https://twistedhistory.net.au/wp-content/uploads/2018/10/Twisted-Logo-Tranparent-no-shadow.png Limelight2018-06-27 18:00:002018-06-27 00:34:18Trappers Death
King Alfred’s Skeleton
On This Day, Twisted History
ON THIS DAY ……. 30th March 1891
Workmen on the railway to Mansfield, under construction at the time, unearthed a skeleton. No one was quite sure who it was but locals thought it was probably King Alfred, an aboriginal tribal leader who had been elevated to regional status by the early landholders in the area. When Alfred died, he was buried near the spot at Merton where the excavations were being made.
https://twistedhistory.net.au/wp-content/uploads/2016/03/11297710_263653057299163_1580778761_n.jpg 298 380 Limelight https://twistedhistory.net.au/wp-content/uploads/2018/10/Twisted-Logo-Tranparent-no-shadow.png Limelight2018-03-30 22:46:282018-03-30 22:46:28King Alfred's Skeleton
Skeleton at Bendigo
ON THIS DAY…… 30th August 1898
An enquiry was opened, on the 30th August 1898 at Bendigo into a mystery attached to the finding of the skeleton of a man under an old blue blanket at Five-mile Creek. A patient at Bendigo Hospital said he knew two mates at Five mile Creek. They had a quarrel, and one bolted from the district. He supposes the skeleton must be that of the mate who probably was murdered. The medical evidence of the examination of the skeleton was to the effect that some of the bones of the jaw were missing, and one was indented as with slugs. The enquiry was adjourned until the following day .
https://twistedhistory.net.au/wp-content/uploads/2016/08/Richard-III_4.jpg 530 800 Limelight https://twistedhistory.net.au/wp-content/uploads/2018/10/Twisted-Logo-Tranparent-no-shadow.png Limelight2017-08-30 00:00:492017-09-14 01:22:09Skeleton at Bendigo
The Trial of the Geary’s
ON THIS DAY – FEBRUARY 28, 1854
The trial of Patrick and Margaret Geary for the murder of a shepherd in 1854, was commenced at the Old Court House, Melbourne. Mr Adamson prosecuted on behalf of the Crown, and Messrs Molesworth and Sirr represented the prisoners respectively. The presiding judge was his Honour Mr Justice Pohlman. Mr Adamson opened the case in a concise address to the jury, in which he explained the circumstances of the crime with which the prisoners were charged, and the evidence which would be called to endeavour to substantiate it. Andrew Murray was the first witness called. He stated: I am a squatter residing at St.Kilda, and had a brother named Hugh Murray. His station was situated on the Corangamite, and was north of mine. Beyond his was Mr Calvert’s station. I knew a man named Thos. Brookhouse, who was a shepherd in the employ of my brother Hugh. I know the prisoner Patrick Geary, who was also employed by my brother as a shepherd. Geary and Brookhouse were both in my brother’s employ in 1854. Geary’s hut was nearest to the home station, and about three quarters of a mile from Brook- house’s. The hut occupied by Geary was 11 or 12 miles from the home station. On the west, Lake Corangamite was about three miles from both huts. The huts are no longer in existence, but I have pointed out the site of them to constable Killen. I remember Brook- house being missing. He had a sheep dog. When Brookhbuse was reported missing, I went with others in search of him, and spent about a fortnight in the search. On the morning that we first set out, I visited Brookhouse’s hut, which then presented the appearance of his having left it with the intention of returning as usual. The breakfast things had not been removed, and the place appeared to be undis- turbed. The dog was about the hut. We followed the dog, thinking that he might lead us to where Brookhouse would be found, but he frequently stopped, and we ultimately gave up the search. My brother and myself, as well as the owners of all the neighbouring stations, lost a large number of sheep that year. On the 31st of August, 1869, constable Killen came to me, and in consequence of what he said to me I ac- companied him to the spot where Brookhouse’s hut had stood. We also went to a man named George Ball, who was engaged in building a stone wall about half a mile distant. He, and a hoy in his employ named Bayliss, took us to the place where the bones of a man had been found, and which a constable took possession of. Brookhouse was a small, natty tidy little man, having thin sharp features and a prominent chin. He was about 50, or perhaps more. John Shayp, a farmer, living near Ondit, about 12 miles from Colac, deposed: I know the two prisoners. In 1854 I was in the em- ploy of Mr John Calvert, as shepherd. I visited Brookhouse’s hut when the search was commenced, and saw a tea cup, and saucer, a basin, a teapot, and, I think, a knife on the table. The hut was swept clean, and every- thing in order, as if he had not been long ab- sent. When we approached the hut the dog ran away, I think in the direction of south. Brookhouse, I should say, was forty-eight or fifty years of age. He was about as old as I am now. I left home when I was twenty-four years of age, and have been in this country thirty-two years. I am 6ft 8in in height, and he was within an inch lower. We often com- pared our height, and I told him he would never do for a soldier. (A laugh.) He used to wear a blue serge shirt outside, and a black red- striped silk handkerchief. His hat was usually a sou’-wester. The clasp-knife produced is like one he used to have slung to his pocket. He used also to carry a similar knife. The piece of striped cotton produced is like the inside shirt he used to wear. The piece of neckerchief produced is similar, I believe, to the one he used to wear. I can observe the stripe. The bit of hat shown me appears to be a bit of a sou’-wester. At Colac I saw the skeleton found, with the boots on, and at once recognised the remains as those of Brookhouse. The boots on the bones produced I have not the slightest doubt were worn by Brookhouse. He used to have the lace-holes very close to each other. In 1854, a stranger would not pass my hut perhaps for two months. Two other witnesses were examined, and the case was not concluded when the court rose.
Patrick Geary, Margaret Geary, Old Court House, Melbourne, Molesworth, Mr Justice Pohlman, Mr Adamson, Andrew Murray, St.Kilda, Hugh Murray, Calvert’s station, Patrick Geary, Lake Corangamite, constable Killen, shot, murder, George Ball, Bayliss, John Shayp, Ondit, John Calvert, shepherd, Colac, skeleton, Brookhouse
https://twistedhistory.net.au/wp-content/uploads/2016/02/12773083_10207958252136186_403198268_o.jpg 865 1150 Limelight https://twistedhistory.net.au/wp-content/uploads/2018/10/Twisted-Logo-Tranparent-no-shadow.png Limelight2017-02-28 00:00:212017-02-09 01:46:37The Trial of the Geary's
Human Skeleton Found
On this day …….. 25th of January 1949
Farmers who uncovered a human skeleton at Bannockburn, near Geelong, on this day in 1949, may have solved the mystery of John Lang, farmer labourer, who disappeared in the district nearly 50 years ago. Lang, after his disappearance, became the centre of several legends in the Moorabool Valley district, round Bannockburn. After his wife died about 20 years ago, their cottage fell into ruin and some local, residents swore it was haunted by Lang’s ghost. Mrs Lang refused to believe her husband was dead and kept a light burning in the cottage window to light, his way home. At the time of his disappearance it was believed Lang had been murdered and buried, or that he had fallen into a creek and been drowned. The skeleton was found today, buried under heavy stone and rubble, while a farmer was digging out a rabbit warren. The bones were sent to the Government Pathologist for report.
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Remain’s of Australia’s most infamous bushranger ID’d
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Swan Lake, Op. 20, Suite: Scéne (moderato)
Label: X5 Music Group
Die Zauberflöte (The Magic Flute), KV 620: Overture
Suite for Orchestra No. 3, BWV 1068 in D Major: Air
Violin Partita No. 3 in E Major, Bwv 1006: Preludio
Symphony No.5 in C minor, op.67 "Fate", 1. Allegro con brio
Liebestraum No.3 in A flat major, op.62, O lieb so lang' Du lieben kannst
Brandenburg Concerto No.3 in G major, BWV 1048, 1. Allegro
Concerto for Piano and Orchestra No. 21, Kv 467 in C Major: Andante
Concerto for Mandoline, Strings and B.c. No. 1, F 5, R 425 in C Major: Allegro
Symphony No. 40, KV 550 in G Minor: Allegro Molto
Cavatina
Concerto for 2 Violins, Strings and B.c. No. 3, BWV 1043 in D Minor: Vivace
Adagio in G Minor for strings and organ
Bagatelle for Piano in A minor "Für Elise", WoO No.59
Cantata BWV 208: IX. Schäfe können sicher weiden (Sheep may safely graze)
Overture to Egmont, Op. 84
Fugue for solo Guitar, BWV 1000 in A Minor: Fugue
Vocalise No.14, Op. 34, for cello and piano: Lentamente
Symphony No. 94 in G Major, "The Surprise": Andante
Nocturne No. 2, Op. 9 in E Flat Major
Turandot - Nessun dorma
The Planets, Op. 32 - IV. Jupiter, The Bringer Of Jolity
Concerto for Viola, Strings and B.c. in G Major: Largo
Dies irae: Tuba mirum
Symphony No. 5: IV. Adagietto
Concerto for Violin and Orchestra Op. 64 E minor: I. Allegro molto appassionato
String Quartet, Op. 1: Adagio
Concerto Grosso in G minor "Christmas Concerto", op.6/8: 2. Allegro
Symphonie No. 9, "From the New World": II. Largo
Cello Concerto No.1 in C Major (Hob Viib:1), 2nd Mvt: Adagio
Piano Sonata No.11 in A major, K.331: III. Alla Turca - Allegretto
3 Gymnopédies - Gymnopédie No. 1: Lent et douloureux
Concerto for Piano and Orchestra, Op. 16 in A Minor: Allegro molto moderato
Thaïs: Meditation
Hungarian Dances: No. 5 in G Minor
Adagio for Strings
Ave Maria (after J.S. Bach)
Suite Bergamasque No. 3, L 75: Clair de lune
Rhapsody in Blue
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Brussels shines the spotlight on contemporary art
March 20, 2018 swamiupendra 0 Comments
Brussels has become a hub of contemporary art. Few cities in world can boast of such a huge art scene as Brussels, be it in any form. The capital is fertile place for creativity and discovery. International artists are charmed by its many beautiful spaces dedicated to art. Collectors from all over the world, for their part, regularly visit the capital to find that one piece that makes all the difference. Several players help enrich the art scene: the WIELS, BOZAR, MIMA, the Centrale for Contemporary Art, the CAB Foundation, the Villa Empain, and let’s not forget the future Kanal Foundation either. Between museums and art centres, galleries and artists’ collectives, fairs and other events, Brussels is sharing its passion for art.
Salon Beurs Show at Art Brussels
Every year, Brussels celebrates contemporary art from April to May. From the unmissable Art Brussels fair to the Private Choices exhibition, not to mention the Affordable Art Fair, events will be showcasing contemporary art with both domestic and international artists taking centre stage. Here is a quick look at the fairs, exhibitions and unmissable events of the next few months.
Art Brussels
Art Brussels is celebrating its 50th birthday: This year’s fair is full of innovations. Since its creation, Art Brussels has developed into one of the biggest contemporary art fairs in Europe. The fair is an unmissable date on the international artistic calendar. No less than 147 galleries featuring art from 32 countries. Art Brussels has never been so international, although the number of Belgian galleries has also increased.
Dates: From 19 to 22 April 2018
Venue: Tour et Taxis
Poppositions
POPPOSITIONS 2017 Exhibition view ©Renato Ghiazza
Recognising the crucial role of contemporary art fairs within a globalised market, Poppositions aims to revitalise the ways that pieces are hung and presented, always experimenting and discovering ground-breaking ways of selling. It is more than a fair, it is an exhibition involving a continuous critical dialogue, whilst guarding against stand-based layout. The title of this year’s fair, In Watermelon Sugar, was borrowed from that of the post- apocalyptic novel of the same name by Richard Brautigan, published in 1968.
Venue: Former Coppens Studio
ACAF
Since 2006, the special feature of this fair is that the artists themselves do the exhibiting. ‘Accessible Art Fair (ACAF) brings original art, with a mix of photography, design and sculpture, to a public that has been buying art since 2006.
Date: 19 April to 22 August 2018
Venue: Nonciature du Sablon
Blast from the past: Contemporary Art- Brussels’ cultural heartbeat in April
The Brutal Play
The CAB Foundation presents The Brutal Play, a collective exhibition curated by Matthieu Poirier, who is gathering sculptures by ten artists, from the constructivist period through the minimalism of the sixties, to the present day.
Dates: Until 26 May 2018
Venue: CAB Foundation
Unexchangeable
It is often said that there is nowhere else that has as significant a proportion of art collectors as Belgium. It is striking, however, that with such potential, so few partnerships are formed between public museums and private collections. By means of a selection of historic and museum-quality works from the 80s and 90s, on loan from private collections in Belgium, the exhibition focuses on the value of a work of art. This exhibition tells the story of a pivotal time in the history of art, during which artists changed the paradigm of the uniqueness of a work of art through concepts such as the simulacrum, simulation and equivalence.
Venue: Wiels
Private Choices
The Private Choices exhibition lifts the veil over an important sector of the art field: collections of contemporary art and the art lovers who initiated them. More than ever before they play a major role in a constantly growing art world. This project showcases 11 Brussels collections gathering together works by Belgian and international artists, famous artists, and young creators, in an attempt to reveal the uniqueness of each of them. Through the choices made in collaboration with the collectors, what is revealed is a part of their vision of art and of life.
Dates: Up to 27 May 2018
Venue: CENTRALE for contemporary art
The Boghossian foundation presents its new exhibition entitled Melancholia at the Villa Empain. It addresses the origins and manifestations of melancholia. Existing in East and West since antiquity, it continually sends human beings to their lost origins, filling them with regret for a world that has passed.
Dates: 15 April to 19 August 2018
Venue: Villa Empain
Promesses d’un visage [Promises of a face]
©TravelMagazine
The Promesses d’un visage exhibition takes you back through more than six centuries of portraiture, through paintings, drawings, sculptures and photographs from the collections of the Royal Museums of Fine Arts of Belgium, as well as guest pieces. An object representing power or challenge, an instrument for social recognition or the expression of the subject’s rebellion, the portrait is a genre which has undergone a number of metamorphoses over time, right up to the habit of the selfie. Bouts, Memling, Rubens, Van Dyck, Gauguin, Ensor, Chagall, Delvaux, Bacon, Tuymans, Borremans, Fabre, Vanfleteren…
Dates: 23 April to 15 July 2018
Venue: Royal Museums of Fine Arts of Belgium
Voici des fleurs [Here are some flowers]
This exhibition pays homage to the work of Akarova (1904-1999), a renowned interwar era Brussels woman who devoted her life to music, dance, choreography, painting and sculpture. La loge is inviting contemporary artists to exhibit their own works side by side with Akarova’s works, and to make their own connection between her ideas and the dynamics of production.
Dates: 19 April to 30 June 2018
Venue: La loge
Opening of the Kanal Foundation
The Kanal Foundation will be opening its doors on 5 May for a year before the refurbishment work begins. This future museum of contemporary art and architecture will be housed in the former Citroën garage a stone’s throw from the Senne. Throughout the year, this cross-disciplinary exhibition will be offering screenings, concerts, performances and exhibitions of works taken mainly from the Pompidou Centre collections. It is a chance to see pieces never before seen in Belgium in this raw space before it is closed for refurbishment work. The coming exhibitions will also present pieces by Brussels artists created especially for the occasion.
Date: Starting from the 5 May 2018
Venue: Fondation Kanal
So if you love contemporary art, you have many reasons to plan a trip to Brussels in coming months.
Have you witnessed the Art scene in Brussels? Share your experiences in the comments section below.
Spread the Love! Share the post!!
Tags: art, Art Brussels, Art exhibitions, Art Fair, belgium, BOZAR, brussels, Contemporary Art, culture, Europe, Flanders, Kanal Foundation, tourism, travel, WIELS
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Read Next: 'She's Gotta Have It' Canceled After Two Seasons at Netflix
August 10, 2016 8:21AM PT
John Saunders, Veteran ESPN Broadcaster, Dies at 61
By Variety Staff
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John Saunders, the veteran ESPN broadcaster of more than 30 years, died early Wednesday morning at his home in Hastings-on-Hudson, N.Y. He was 61.
Saunders’ wife called 911 after finding the ESPN host unresponsive, Hastings-on-Hudson Police Chief Anthony Visalli confirmed to Variety, which TMZ first reported. He was not breathing and was pronounced dead at the scene.
Saunders’ cause of death is unknown. A spokesperson with the Westchester County Medical Examiner told Variety that it rejected the case because there were no signs of foul play or trauma.
The broadcaster joined ESPN in 1986. In addition anchoring “SportsCenter,” he was also the host of “The Sports Reporters.” Throughout his career he would go on to become the voice of college basketball and the WNBA, as well as the MLB All-Star game and World Series. He hosted the Stanley Cup playoffs between 1993 and 2004 on ESPN.
“John was an extraordinary talent and his friendly, informative style has been a warm welcome to sports fans for decades,” said ESPN president John Skipper in a statement.
“He was one of the most significant and influential members of the ESPN family, as a colleague and mentor, and he will be sorely missed. Our thoughts are with his loved ones at this extremely difficult time.”
Saunders was born in Canada where he grew up playing hockey, which eventually earned him a scholarship to play at Western Michigan University.
In the late 70’s he was a news director and sports anchor for several Canadian stations. Then, in the early 80’s he moved back to the U.S. to work as a sports anchor at WMAR-TV in Baltimore.
Outside of his broadcasting career, Saunders was a founding member of the V Foundation for Cancer Research and also served on the board of directors.
Saunders is survived by wife Wanda and daughters Aleah and Jenna.
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Frank Deford, who cultivated a distinct style of sports journalism at Sports Illustrated and National Public Radio, had died. He was 78.
Deford’s wife confirmed to the Washington Post that he died on Sunday in Key West, Fla.
During his lifetime Deford was the author of over a dozen books, most recently “Over Time: My Life as a Sportswriter” in 2012. His 1981 novel “Everybody’s All-American” was adapted to screen by Taylor Hackford in a 1988 film starring Jessica Lange, Dennis Quaid, and Timothy Hutton. Deford was the screenwriter for two films — “Trading Hearts” (1987) and “Four Minutes” (2005). The acclaimed journalist has several television credits including his time as a correspondent for “Real Sports with Bryant Gumbel” on HBO between 1995 and 2015.
Gumbel commented on Deford’s death: “I’m stunned by Frank’s passing. Yes, he’d been ill, but just a week ago, he’d joked to me about finally being released from the hospital. In addition to being an immense talent, he was a consumate gentleman, a dear friend, and a beloved, original member of our Real Sports family. Frank was a giant in the world of sports. His loss is immeasurable.”
Deford began working for Sports Illustrated after graduating from Princeton in 1962, and went on to enjoy a tenure of over 50 years. He was ultimately named senior contributing writer by the publication.
In addition to the written word, Deford’s voice became a dependable part of NPR’s “Morning Edition” from 1980 until he retired in May 2017, shortly before his death. He leaves behind an astonishing 1,656 commentaries for NPR, according to the broadcaster.
Deford was a member of the National Association of Sportscasters and Sportswriters Hall of Fame, and was named Sportswriter of the Year six times. He was the recipient of both an Emmy and a George Foster Peabody Award.
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Status of Treaties
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STATUS AS AT : 17-07-2019 07:16:32 EDT
A. Custom Matters
7. Additional Protocol to the Convention concerning Customs Facilities for Touring, relating to the Importation of Tourist Publicity Documents and Material
New York, 4 June 1954
28 June 1956, in accordance with article 10.
Registration :
11 September 1957, No. 3992
Signatories : 25. Parties : 74. 1
Text : Certified true copy
United Nations, Treaty Series , vol. 276, p. 191.
The Convention was adopted by the United Nations Conference on Customs Formalities for the Temporary Importation of Private Road Motor Vehicles and for Tourism, held at the Headquarters of the United Nations, New York, from 11 May to 4 June 1954. It also adopted the Additional Protocol to the said Convention, relating to the Importation of Tourist Publicity Documents and Material, and the Customs Convention on the Temporary Importation of Private Road Vehicles. The Conference was convened by the Secretary-General of the United Nations in accordance with resolution 468 F (XV)2 adopted by the Economic and Social Council of the United Nations on 15 April 1953. For the text of the Final Act of the Conference, see United Nations, Treaty Series , vol. 276, p. 191.
Participant 3, 4
Ratification, Accession(a), Succession(d)
9 Aug 2010 a
31 Oct 1963 a
4 Jun 1954
6 Jan 1967 a
30 Mar 1956
5 Mar 1971 d
7 Oct 1959 a
15 Aug 1974 a
4 Sep 1963
16 May 1963 d
2 Jun 1993 d
4 Apr 1957
18 Jun 1958 a
Germany 6, 7
15 Jan 1974 a
15 Feb 1957 a
3 Apr 1968 a
11 Nov 1963 d
2 Dec 1954
18 Dec 1957 a
16 Mar 1971 a
16 Sep 2005 a
1 Dec 2005 a
7 May 1958 d
29 Jul 1968 d
23 Oct 2006 d
7 Mar 1958
26 Jun 1961 d
1 Dec 1964 d
19 Apr 1972 a
12 Mar 2001 d
3 Sep 1981 d
5 Sep 1958 a
Syrian Arab Republic 13
11 Apr 1966 d
United Kingdom of Great Britain and Northern Ireland 3, 14
Declarations and Reservations 15
(Unless otherwise indicated, the declarations and reservations were made
upon ratification, accession or succession.)
The Democratic and Popular Republic of Algeria does not consider itself bound by the provisions of article 15 of the Protocol concerning compulsory arbitration and declares that the agreement of all the parties in dispute is required for the sub mission of each individual dispute to arbitration.
Bulgaria 16, 17
Bulgaria16,17
The Revolutionary Government of the Republic of Cuba does not consider itself bound by the provisions of paragraphs 2 and 3 of article 15 of the Protocol.
Czech Republic5
"Fiji shall not be bound by Article 2 of the Additional Proto- col in so far as it refers to unframed photographs and unframed photographic enlargements; but undertakes to allow the tempor- ary duty and tax free admission of these articles under the provi- sions applicable to Article 3 of the Protocol."
"The Hungarian People's Republic does not consider itself bound by the terms of paragraphs 2 and 3 of article 15 of the Protocol."
"Notwithstanding article 3 of the Additional Protocol the duty-free temporary importation into Malta of display material (e.g., showcases, stands and similar articles), sound recordings and flags, shall be subject to the making of a deposit with the Comptroller of Customs equivalent to the amount of duty payable on the goods allowed to be temporarily imported or to the giving of a security for such duty."
Poland 17, 18
Poland17,18
The Romanian People's Republic does not consider itself bound by the provisions of article 15, paragraphs 2 and 3, of the additional Protocol. The position of the Romanian People's Re- public is that a dispute concerning the interpretation or application of the Additional Protocol may be submitted to arbitration only with the agreement of all the parties in dispute and that only persons nominated by unanimous agreement of the parties in dispute may act as arbitrators.
The Government of the Union of Soviet Socialist Republics, considering that disputes concerning the interpretation or application of the Additional Protocol to the Convention concerning Customs Facilities for Touring can be decided by arbitration, declares that a dispute may be submitted to arbitration only with the agreement of all the parties in dispute and only persons nominated by unanimous agreement of the parties in dispute may act as arbitrators.
A dispute may be submitted to arbitration only with the agreement of all the parties in dispute.
"Notwithstanding Articles 2, 3 and 4, the Government of Uganda reserves the right to require temporary importation per- mits in respect of any item specified therein which may be or be come dutiable at any time."
United Republic of Tanzania 19
United Republic of Tanzania19
"Notwithstanding articles 2, 3 and 4 of the Additional Proto- col, the Government of the United Republic of Tanganyika and Zanzibar [Tanzania] reserves the right to require temporary im- portation permits in respect of any item specified therein which may at any time be dutiable."
Territorial Application
Date of receipt of the notification
Belgium 21 Feb 1955 Belgian Congo and Trust Territory of Ruanda-Urundi
Netherlands 10 7 Mar 1958 Netherlands Antilles, Netherlands New Guinea and Suriname
New Zealand 11 21 May 1963 Cook Islands (including Niue)
Portugal 4 18 Sep 1958 Overseas Provinces
30 Mar 1983 Macau
United Kingdom of Great Britain and Northern Ireland 3, 14, 20 7 Aug 1957 Cyprus, Federation of Malaya, Jamaica, Malta, North Borneo, Seychelles, Sierra Leone, Singapore, Somalian Protectorate, Tonga and Zanzibar
14 Jan 1958 Brunei, Antigua, Mauritius, Sarawak, St. Vincent, Gambia, Montserrat, Federation of Nigeria, British Solomon Islands Protectorate, Gibraltar, Virgin Islands, Grenada, St. Helena and Dominica; and Kenya, Uganda and Tanganyika with reservations
16 Jun 1959 Barbados
12 Sep 1960 British Honduras
11 Nov 1960 Hong Kong
9 Jan 1961 St. Christopher-Nevis-Anguilla
15 Sep 1961 Trinidad and Tobago
5 Feb 1962 British Guiana
On 16 June 1975, the Government of Switzerland declared that the provisions of the Convention apply to the Principality of Liechtenstein so long as it is linked to Switzerland by a customs union treaty.
Official Records of the Economic and Social Council, Fifteenth Session, Supplement No. 1 (E/2419), p. 9
The Secretary-General, received on 6 and 10 June 1997 communications regarding the status of Hong Kong from China and the United Kingdom of Great Brtiain and Northern Ireland (see also note 2 under “China” and note 2 under “United Kingdom of Great Britain and Northern Ireland” in the “Historical Information” section in the front matter of this volume). Upon resuming the exercise of sovereignty over Hong Kong, China notified the Secretary-General that the Convention will continue to apply to the Hong Kong Special Administrative Region.
On 29 September and on 19 October 1999, the Secretary-General received communications regarding the status of Macao from China and Portugal (see also note 3 under “China” and note 1 under “Portgual” in the “Historical Information” section in the front matter of this volume). Upon resuming the exercise of sovereignty over Macao, China notified the Secretary-General that the Convention will continue to apply to the Macao Special Administrative Region.
Czechoslovakia had acceded to the Protocol on 8 March 1967, with a reservation. For the text of the reservation, see United Nations, Treaty Series , vol. 596, p. 544. See also note 1 under “Czech Republic” and note 1 under “Slovakia” in the “Historical Information” section in the front matter of this volume.
See note 1 under “Germany” regarding Berlin (West) in the “Historical Information” section in the front matter of this volume.
See note 2 under “Germany” in the “Historical Information” section in the front matter of this volume.
In a notification received on 4 April 1974, the Government of Greece stated that it accepted the decisions, recommendations and dec- larations contained in the Final Act of the Conference.
See note 1 under "Montenegro" in the "Historical Information" section in the front matter of this volume.
See note 1 under “Netherlands” regarding Aruba/Netherlands Antilles in the “Historical Information” section in the front matter of this volume.
See note 1 under “New Zealand” regarding Tokelau in the “Historical Information” section in the front matter of this volume.
The former Yugoslavia had acceeded to the Additional Protocol on 10 July 1958. See also note 1 under “Bosnia and Herzegovina”, “Croatia”, “former Yugoslavia”, “Slovenia”, “The Former Yugoslav Republic of Macedonia” and “Yugoslavia” in the “Historical Information” section in the front matter of this volume.
Notification by the United Arab Republic. See also note 1 under ”United Arab Republic” in the “Historical Information” section in the front matter of this volume.
In a notification received on 4 March 1959, the Government of the United Kingdom gave notice of the withdrawal of the reservation to article 2 and informed the Secretary-General that "the United Kingdom has been giving full effect to article 2 of the Additional Protocol since the 1st of January 1959 . . .". For the text of that reservation, see United Nations, Treaty Series , vol. 276, p. 204.
In a communication received on 16 September 1968, the Government of Japan notified the Secretary-General that, in accordance with paragraph 7 of article 14 of the Protocol, it "reserves the right of not extending to the States making reservations the benefit of the provisions to which such reservations apply".
Subsequently, in a communication received on 6 May 1994, the Government of Bulgaria notified the Secretary-General that it had decided to withdraw the reservation made upon accession to article 15 (2) and (3). For the text of the reservation, see United Nations, Treaty Series , vol. 348, p. 358. See also note 16 in this chapter.
The Governments of Italy and Switzerland have notified the Secretary-General that they object to this reservation.
On 16 October 1997, the Government of Poland notified the Secretary-General that it had decided to withdraw its reservation with regard to article 15 of the Additional Protocol made upon accession. For the text of the reservation see United Nations, Treaty Series , vol. 367, p. 334. See also note 16 in this chapter.
In a communication received on 2 August 1965, the Government of Portugal notified the Secretary-General that, in accordance with paragraph 7 of article 20 and paragraph 7 of article 14, respectively, of the Convention and Additional Protocol, Portugal reserves the right of not extending to the United Republic of Tanzania the benefit of those provisions of the Convention and the Additional Protocol to which apply the reservations made upon accession by the United Republic of Tanzania.
With the following reservation: "Notwithstanding articles 2, 3 and 4 of the Additional Protocol, the Governments of Kenya, Uganda and Tanganyika reserve the right to require temporary importation permits in respect of any item specified therein which may at any time be dutiable."
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NFL Draft RB breakdown: Alabama’s Josh Jacobs likely 1st-rounder, but who’s next? | TribLIVE.com
Steelers/NFL
NFL Draft RB breakdown: Alabama’s Josh Jacobs likely 1st-rounder, but who’s next?
Joe Rutter
Sat., April 13, 2019 7:30 a.m. | Saturday, April 13, 2019 7:30 a.m.
Penn State running back Miles Sanders runs a drill at the NFL football scouting combine in Indianapolis, Friday, March 1, 2019.
The NFL Draft will be conducted April 25-27 in Nashville, Tenn. Each day leading up to the first round, the Tribune-Review is compiling a positional preview of the top draft prospects.
Today: Running backs
1. Josh Jacobs
Alabama, 5-10, 220
Because of Alabama’s deep crop of running backs, Jacobs never was a workhorse for the Crimson Tide. His junior season in 2018 included 640 yards rushing on 120 carries and 11 touchdowns. He also had three receiving touchdowns and one as a kickoff returner. He could be the only running back taken in the first round.
2. Miles Sanders
Penn State, 5-11, 211
Another runner to exit after his junior season, Sanders (Woodland Hills) is hoping his one season as the primary running back at Penn State was enough to impress scouts. With Saquon Barkley gone to the NFL, Sanders rushed for 1,274 yards and nine touchdowns while averaging 5.8 yards per carry. He was voted Penn State’s offensive MVP.
3. Damien Harris
His best season occurred as a sophomore when Harris rushed for 1,037 yards. As a senior, while splitting carries with Jacobs, Harris rushed for 876 yards and nine touchdowns while averaging 5.8 yards per carry.
4. David Montgomery
Iowa State, 5-10, 222
Montgomery posted back-to-back 1,000-yard season as a sophomore and junior at Iowa State before declaring for the draft. He had 1,216 yards rushing (4.7 average) last season with 13 touchdowns in 12 games.
5. Devin Singletary
Florida Atlantic, 5-7, 203
Despite his height, Singletary carries a mid-round grade. At Florida Atlantic, he had a nose for the end zone, scoring 32 rushing touchdowns in 2017 and 22 last season. He rushed for 1,920 yards as a sophomore and gained 1,348 as a junior before he opted out of his final season.
6. Darrell Henderson
Memphis, 5-8, 208
Henderson finished second in the nation with 1,909 rushing yards last season as a junior, which prompted his decision to declare for the draft. A first-team All-American, Henderson averaged 8.9 yards per carry and scored 22 touchdowns. Henderson also rushed for 1,154 yards as a sophomore.
7. Justice Hill
Oklahoma State, 5-10, 198
After back-to-back 1,000-yard seasons and leading the Big 12 with 1,467 yards as a sophomore, Hill’s numbers dipped in his junior year in 2018. He finished with 930 yards (5.9 average) and nine touchdowns while missing two games to a rib injury.
8. Rodney Anderson
Oklahoma, 6-0, 224
Anderson was slowed by injuries during his time at Oklahoma, including his redshirt senior season when he played in just two games before injuring his right knee. His only full season came in 2017 when he rushed for 1,161 yards and 13 touchdowns while averaging 6.2 yards per carry.
9. Trayveon Williams
Texas A&M, 5-8, 206
Williams exceeded 1,000 yards in his freshman and junior seasons, and he declared for the draft after gaining 1,524 yards last season. He scored 15 touchdowns last year while averaging 6.1 yards per carry. He also returned kicks for the Aggies.
10. Benny Snell
Kentucky, 5-10, 224
Snell is the great nephew of Matt Snell, who helped Joe Namath and the New York Jets to the upset of the Baltimore Colts in Super Bowl III. He created his own niche at Kentucky by exceeding 1,000 yards rushing in all three of his seasons. As a junior, he rushed for 1,449 yards and 16 touchdowns.
Qadree Ollison & Darrin Hall
Pitt, 6-1, 228 & 5-11, 225
They shared carries last season for the Panthers, but only Ollison was invited to the NFL Combine. Ollison rushed for 1,213 yards and 11 touchdowns in 2018. Hall was right behind with 1,144 yards and 10 scores. Both players are considered late-round prospects.
Best fit for Steelers
Mike Weber
Ohio State, 5-10, 211
Weber is considered a third-day prospect, and that’s about the time the Steelers might target a running back, if they do at all. Weber was one of several running backs the Steelers brought in for a predraft visit. He had 954 yards and five touchdowns as a junior before declaring for the draft.
Joe Rutter is a Tribune-Review staff writer. You can contact Joe by email at [email protected] or via Twitter .
Categories: Sports | Steelers
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Deo_Shao_Thesis.pdf
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Master Thesis Project 30p, Spring 2012
A Proposal of a Mobile Health Data Collection
and Reporting System for the Developing World
Deo Shao
Annabella Loconsole
Banafsheh Hajinasab
Examiner:
Marie Friberger
E-mail: deoshayo@hotmail.com
E-mail: annabella.loconsole@mah.se
Malm University, Department of Computer Science.
E-mail: banafsheh.hajinasab@mah.se
E-mail: marie.friberger@mah.se
Data collection is one of the important components of public health systems. Decision
makers, policy makers and health service providers need accurate and timely data in
order to improve the quality of their services. The rapidly growing use of mobile
technologies has increased pressure on the demand for mobile-based data collection
solutions to bridge the information gaps in the health sector of the developing world. This
study reviews existing health data collection systems and the available open source tools
that can be used to improve these systems. We further propose a prototype using open
source data collection frameworks to test their feasibility in improving the health data
collection in the developing world context. We focused on the statistical health data,
which are reported to secondary health facilities from primary health facilities. The
proposed prototype offers ways of collecting health data through mobile phones and
visualizes the collected data in a web application. Finally, we conducted a qualitative
study to assess challenges in remote health data collection and evaluate usability and
functionality of the proposed prototype. The evaluation of the prototype seems to show
the feasibility of mobile technologies, particularly open source technologies, in
improving the health data collection and reporting systems for the developing world.
Keywords: Data collection, Mobile technologies, Open source frameworks, The
developing world and Health data.
Popular science summary
This master thesis project investigates the challenges of health information systems in the
developing world1. Through literature review and qualitative study, we study health data
flow in health systems and challenges associated with health data collection methods.
The objective is to understand the challenges and propose technology-based solutions
that can improve the data flow between different levels of health systems. We further
review the available technologies for data collection and evaluate their suitability in
improving health data collection process in the developing world. In this study we chose
open source (open standards)2 data collection frameworks to propose a prototype for
health data collection to gain global technical support and allow future extensions of the
prototype. After reviewing several open source data collection frameworks3 we selected
open data kit (ODK)4 to propose our prototype. The proposed prototype could improve
data collection and reporting system from primary health facilities 5 to secondary health
facilities6. There are several aspects that could be improved by the prototype; the aspects
are data accuracy and data processing time. We collected reviews from health data
experts and non-experts from developing countries as part of the evaluation study on the
proposed prototype. The evaluation result showed that the prototype could improve the
The developing world is also known as third world, is the term used to classify the less economically
developed countries, these countries are mostly found in Africa, Asia and Latin America.
Open Standards: Are standards that are maintained in open forums through open process. In
technology perspective, these standards are used to maintain uniformity of different components and allow
users to adopt products with high degree of flexibility of using the technology. Open standards in
technology context are collectively termed as open source technologies (technology that is free of charge
available publicly )
Open source data collection frameworks: These are set of software components (tool kits) developed
from open standards that are used for data collection.
4 Open data kit (ODK): Is the open source data collection framework that is used for mobile data
collection.
5 Primary health facilities: Is operational level of health care system. It consists of health care centers
(point of care) such as hospitals and dispensaries.
6 Secondary health facilities: Is the management level of health care system where strategic plans and
decision are made.
health information systems in the developing world. This study has uncovered challenges
in health data collection methods and technologies that can be used to improve data
collection process in the context of the developing world. Moreover, we have motivated
the use of open source technologies in improving health systems of the developing world.
Primarily, I would like to thank the almighty God for the endless blessings and grace that
has been reason for this achievement.
Secondly, I would like to express my gratitude and heartfelt thanks to my supervisors
Annabella Loconsole and Banafsheh Hajinasab for their guidance, motivations and
kindness throughout my thesis. I could not do much without your guidance and support.
I would like to express my sincere thanks to my examiner Marie Friberger for her
guidance, constructive and invaluable suggestions that helped me to reach this
achievement. Your support was invaluable and key for the success of this thesis.
I would like to convey my sincere thanks to Daniel Spikol for his advice and support
that boosted my research idea. Your advice was important for this achievement.
I also take this opportunity to thanks my friends and colleagues for their support and
feedback throughout my thesis. I thank you all.
I am thankful to people who participated in my qualitative study for their responses
and cooperation. Your response to my questionnaire was important to the success of my
thesis.
I also express my gratitude and hearty appreciation to Dotto Mgeni for making her
support available in all my pursuits. Your encouragement and support fueled the success
of my thesis. Thank you very much.
I would also like to express my gratitude to my lovely parents who have been tireless
in encouraging and supporting me throughout my studies. Your wisdom and love has
been motivation for my success. God bless you always.
Lastly but not the least, I would like to thank my scholarship donor Erasmus Mundus
ACP for granting me with the opportunity to pursue masters degree.
1 Introduction......................................................................................................................... 13
1.1 Motivation ............................................................................................................... 14
1.2 Research goals ......................................................................................................... 15
1.3 Research delimitations ............................................................................................. 16
1.4 Results ..................................................................................................................... 16
1.5 Outline ..................................................................................................................... 17
2 Research methodology........................................................................................................ 18
2.1 Literature review...................................................................................................... 19
2.2 Design and creation ................................................................................................. 21
2.3 Evaluation study ...................................................................................................... 22
2.3.1 Study method....................................................................................................... 23
2.3.2 Planning and preparation of the evaluation ......................................................... 23
2.3.3 Participants of the evaluation study..................................................................... 23
2.3.4 Execution of the evaluation study ....................................................................... 24
2.3.5 Threats to validity................................................................................................ 24
3 Background and related works ......................................................................................... 25
3.1 Health information systems in the developing world .............................................. 25
3.2 Reporting systems.................................................................................................... 27
3.3 Gaps found in the literature ..................................................................................... 29
4 Mobile data collection technologies ................................................................................... 30
4.1 Challenges of the available health data collection methods .................................... 30
4.2 Mobile technologies in health systems .................................................................... 32
4.3 Mobile data collection methods ............................................................................... 33
4.4 Google Android platform ........................................................................................ 35
4.5 Benefits and drawbacks of using open source technologies .................................... 36
4.6 Open source frameworks for data collection ........................................................... 37
4.7 ODK related work.................................................................................................... 41
5 A prototype for mobile data collection and reporting ..................................................... 43
5.1 Scenario of health data collection and reporting system ......................................... 43
5.2 Design of the proposed prototype ............................................................................ 45
5.3 Requirement specification of the proposed prototype ............................................. 45
5.3.1 Stakeholders ........................................................................................................ 45
5.3.2 Use case diagrams ............................................................................................... 46
5.3.3 Functional Requirement ...................................................................................... 48
5.3.4 Non Functional Requirements ............................................................................. 49
5.4 Developing the prototype ........................................................................................ 50
5.4.1 Design decision ................................................................................................... 50
5.4.2 Components of the prototype .............................................................................. 50
6 Evaluation of the prototype ............................................................................................... 58
6.1 Discussion of the questionnaire results.................................................................... 58
7 Conclusion ........................................................................................................................... 61
7.1 Summary .................................................................................................................. 61
7.2 Discussion ................................................................................................................ 62
7.3 General implications of the study findings .............................................................. 64
7.4 Contribution to previous work ................................................................................. 64
7.5 Limitations of the proposed prototype ..................................................................... 65
7.6 Future work.............................................................................................................. 65
Appendix I: Sample form of diseases reporting [62] ........................................................... 67
Appendix II: Sample form of diseases reporting ................................................................. 68
Appendix III: Questionnaire used for qualitative study part. ........................................... 69
References ............................................................................................................................... 74
FIGURE 1: STEPS IN CONDUCTING LITERATURE REVIEW [15]. ...................................................................................... 20
FIGURE 2: STEPS OF THE PROTOTYPE DEVELOPMENT [17]. ........................................................................................ 22
FIGURE 3: LEVELS OF HEALTH CARE SYSTEM AND THE DATA FLOW [1]. ......................................................................... 26
FIGURE 4: DHIS INFORMATION CYCLE IN HEALTH FACILITIES [30]................................................................................ 28
FIGURE 5: ANDROID DEVELOPMENT ARCHITECTURE [40] ......................................................................................... 36
FIGURE 6: DATA FLOW IN HEALTH SYSTEMS [31] ..................................................................................................... 44
FIGURE 7: USE CASE DIAGRAM FOR HEALTH DATA STATISTICIANS................................................................................. 47
FIGURE 8: USE CASE DIAGRAM FOR HEALTH SERVICE MANAGER .................................................................................. 47
FIGURE 9: GENERAL ARCHITECTURE OF THE PROTOTYPE ............................................................................................ 51
FIGURE 10: STOCK LEVEL REPORT FORM DISPLAY AND THE CORRESPONDING XFORM DEFINITION SCREENSHOT. ................... 53
FIGURE 11: A SAMPLE SCREENSHOT OF THE FORM MANAGER MENU............................................................................ 53
FIGURE 12: A SAMPLE SCREENSHOT OF THE FORM MANAGER IN WEB APPLICATION ........................................................ 54
FIGURE 13: A SAMPLE SCREENSHOT OF THE DATA MAPPING ON ADMINISTRATION MODULE ............................................. 55
FIGURE 14: SAMPLE SCREENSHOT OF THE BAR GRAPH OF DISTRICTS AGAINST MALARIA REPORTED CASES ............................ 55
FIGURE 15 : THE MAIN COMPONENTS OF THE PROPOSED PROTOTYPE .......................................................................... 57
TABLE 1: MAPPING RESEARCH QUESTIONS TO THE RESEARCH METHODS ....................................................................... 18
TABLE 2: RESEARCH ACTIVITIES [16] ..................................................................................................................... 21
TABLE 3 : CHALLENGES OF EXISTING HEALTH DATA COLLECTION METHODS .................................................................... 32
TABLE 4: MOBILE DATA COLLECTION TECHNOLOGIES ................................................................................................ 34
TABLE 5: COMPARISON OF DATA COLLECTION FRAMEWORKS...................................................................................... 40
TABLE 6: ROUTINES IN HEALTH INFORMATION SYSTEMS [31] ..................................................................................... 44
TABLE 7: MATCHING OF THE FUNCTIONAL REQUIREMENTS AND THE GAPS TO BRIDGE...................................................... 49
TABLE 8: OVERALL RESPONSE OF THE QUESTIONNAIRE .............................................................................................. 60
LIST OF ACRONYMS
ODK Open Data Kit
OpenMRS Open Medical Record System
EHR Electronic Health Record
mHealth Mobile Health
HIS Health Information System
HMIS Health Management Information System
ICT Information and Communication Technologies
IT Information Technologies
SMS Short Messaging Service
NGO Non Government Organization
J2ME Java Platform Micro Edition
GPRS General Packet Radio Service
Wi-Fi Wireless Fidelity
KML Keyhole Markup Language
RQ Research Question
MHDK Mobile Health Data Kit
ACM Association of Computing Machinery
HTML Hypertext Markup Language
JSP Java Server Page
order to improve the quality of their services. The demand to health quality data is high
as it is used as input to vital decision-making processes that have impact to
socioeconomic and environmental behavior monitoring. Health data is used as input on
health systems in policy making process, analyzing and predicting the health outcomes
such as mortality and diseases outbreaks [1]. Furthermore health data is critical important
in determining health service coverage and shortcomings and therefore help the process
of proper allocation of resources. In the resource limited settings like in the developing
world, evidence based decision-making is important to serve for the available resources.
Health management information systems (HMIS) in most developing countries are not
efficient and this is probably due to unreliability of health data which cause
underreporting to the managerial level where decisions and plans are made [2].
In the developing world, socioeconomic barriers and geographical reasons have
hindered the availability of potential health data. These barriers have affected the data
collection methods, which are mostly manual, and paper based. Data collected through
these manual methods are not standardized and therefore these are difficult to process for
analytical and data mining purposes [3]. In recent years human population in the
developing world has been reported to grow in high rate due to several factors such as
improvement of health services, especially maternal health which has been the impact of
foreign aid [4]. This growth of human population has raised more challenges to health
practitioners in dealing with large volumes of health data. Health data processing
between different levels of health care systems have been affected by this growth as
manual aggregation of large volume of data is now a tedious work and has high error
rate. In addition to that, the critical shortfall of the health workers in these regions affects
the effort of improving the data collection and analyzing process. Poor data collection
methods have lead to lack of clear understanding of the flow of health data. If the flow of
health data is not clearly understood by the decision makers, fulfillment of the plans and
the policies that are created to improve health services may be difficult [2].
With the advancement of mobile technology, the demand of advanced and mobile
phone based methods of collecting data have increased and therefore researchers have
been devoted to study how this technology can improve the data collection process. This
advancement has caused the cost of purchasing and operating a cellular phone device to
be affordable to low income communities in such a way that there is an exponential
growth of cellular subscribers. According to ITU (International Telecommunication
Union) statistics on number mobile phone subscribers globally, it was expected the
number of cellular phone subscribers to reach five billion by the end of the year 2010.
Seventy percent of the cellular phone subscribers globally live in middle and low income
countries [5].
Several studies have proposed mobile technology as the candidate technology in
improving remote data collection in the developing world and even in isolated regions of
developed world [6][7]. The discussion on the use of mobile technology in data collection
have been motivated by the advancement of modern cellular technologies, which enables
mobile devices to carry more capabilities in memory, processing speed and visual
display. Furthermore the mobile phones are portable and have long lasting battery life
that could support remote collection of data in various geographical locations compared
to laptops computers [8].
Though there are many research works already proposing methods for collecting
health data remotely in the developing world, there is need to review and improve these
methods using the newer technologies.
This study have been highly motivated by the research findings reported by Mechael et
al. [3] on barriers and gaps affecting mhealth (mobile health) in the developing world.
There is a lot of research done so far in data collection using mobile technologies.
However, with the advancement of mobile technologies few researchers have attempted
to investigate the use of new phone technologies in collecting health data, especially in
the developing world. Moreover there are available open source frameworks for data
collection such as open data kit (ODK)7, EpiSurveyor8, FrontlineSMS9 and RapidSMS10
that could be used to improve data collection process at low cost.
With these factors, we are motivated to investigate the available mobile technologies
and open source frameworks, which can improve health data collection and reporting
systems in the developing world.
1.2 Research goals
The main objective of this study is to investigate and analyze the challenges associated
with health data collection and reporting from primary to secondary health facilities (see
Figure 3 in Section 3.1). The understanding of these challenges will help in investigating
and evaluating available mobile technology and open source tools that can address the
challenges in remote data collection and reporting.
Specific objectives are
1. To investigate the challenges of using available paper based and mobile health
data collection methods and reporting systems from primary health facilities to
secondary health facilities in the developing world.
2. To investigate the available mobile technologies and open source tools that can be
used to collect and report the health data remotely.
3. To improve the collection and reporting of aggregated health data in the
developing world through mobile technologies and open source frameworks from
primary to secondary facilities.
To meet the above objectives this research aim to answer the following research
questions (RQ).
RQ1: What are the challenges with the available paper based and mobile based health
data collection and reporting methods from primary health facilities to secondary
health facilities?
Available at http://opendatakit.org/
Available at http://www.episurveyor.org
Available at http://www.frontlinesms.com/
Available at http://www.rapidsms.org/
RQ2: What are the available open source mobile technologies tools that can be used
to collect health data remotely?
RQ3: How can mobile technologies and open source frameworks improve the
aggregated health data collection and reporting process from primary to secondary
facilities?
1.3 Research delimitations
The general scope of this study is bounded to open source technologies because of their
stability, which are fuelled by the support from large community of developers
worldwide. Furthermore, acquisition of open source technology solutions could be
relevant for the developing world as it requires less financial effort and has large support
to make it stable and viable [9].
The specific scope of this study is limited to mobile health data collection, we have
focused only in investigating mobile technology, and the available open source
frameworks in improving the process of collecting and reporting health data from
primary health facilities to secondary facilities (see Figure 3 in Section 3.1). We focus on
collection of statistical data that is reported to managerial level to enhance data driven
decision-making and policy-making process. For the reason of limited time, the other
types of health data such as patient level data are out of this scope.
1.4 Results
This master thesis provides knowledge of the challenges that impede health data
collection and reporting systems from primary health facilities to secondary health
facilities in the developing countries. Moreover, the prototype for mobile health data
collection has been developed to test the applicability of the available mobile
technologies in improving health data collection and reporting systems in the developing
world. The reason for developing this prototype has been highly motivated by the
suggestion given by Sen and Bricka [10], that there is a need for academic researchers to
test the emerging mobile technologies in solving community problems especially in the
developing world health data. The overall contribution from this study is contribution to
knowledge of mobile health data collection and reporting system from primary health
facilities to secondary health facilities in the developing world.
1.5 Outline
This report has been organized into chapters. Chapter 2 describes the research
methodology. Chapter 3 presents the background and challenges health information
systems, Chapter 4 presents the mobile technologies and open source frameworks for
data collection. Chapter 5 presents the proposed prototype, Chapter 6 presents the
evaluation of the proposed prototype and the summary of the this study are presented in
Chapter 7.
Research methodology according to Creswell [11] is defined as general guideline for
solving a problem or systematic way of solving a problem through design of novel
solution. There are different kinds of research approaches; these include qualitative
approach, quantitative approach, design science approach and mixed approach (a mixture
of qualitative methods and quantitative methods).
In this study, a combination of three methods has been used because of the nature our
research questions that require multiple methods to get them answered. Combining
methods offers great promise on flexibility of the research and draw strengths from
multiple methods and therefore allow the research to answer more broader questions that
are not confined to only one method [12]. We performed a literature review, design and
creation and finally we conducted a qualitative study to evaluate the results of our
creation. Table 1 describe summary of the approaches used to address the research
Table 1: Mapping research questions to the research methods
Literature Review Questionnaire Design and Creation
(See Section 2.1) (See Section 2.3) (See Section 2.2)
RQ1: Review the literature on Asking health
What are the the current health information systems
challenges with the information systems in the (HIS) experts and other
available paper developing world and stakeholders from the
based and mobile investigate the challenges developing world; What
based health data on health data collection is the main method of
collection and methods (paper and collecting and reporting
reporting methods mobile-based methods). health data? What kinds
from primary health See Chapter 4. of health data is
facilities to reported from health
secondary health facilities to
facilities? management levels?
What is the frequency
of reporting health
data? What are the
challenges that hinder
the success of HIS in
their countries?
See Chapter 4.
RQ2: Review the literature on
What are the the open source mobile
available open data collection
source mobile frameworks. Compare the
technologies tools reviewed frameworks by
that can be used to their capabilities in
collect health data collecting data and
remotely? supporting technologies.
RQ3: Review the scenario on Describe the Design a prototype
How can mobile health data collection in the functionalities of the for health data
technologies and developing world. The prototype to HIS collection from
open source scenario was chosen due to experts. Ask them primary health
frameworks previous experience of the about the usability in facilities to secondary
improve the author with the selected improving health data health facilities using
aggregated health scenario. Investigate the collection in their open source
data collection and data flow between different countries. The mission framework (for this
reporting process health care system levels was to test the study we chose ODK
from primary to and data type collected in feasibility of the to develop).
secondary each level. Identify the prototype in improving See Chapter 5.
facilities? stakeholders and capture the health data
their requirements from the collection are reporting
selected scenario. from primary health
See Chapter 5. facilities to secondary
facilities in the
developing world.
2.1 Literature review
Due to the fact that m-services (mobile services) is an emerging field, many researchers
have been devoted to conduct studies in various application areas. However few studies
have been carried in the developing world on mhealth applications in general [13].
Although a lot of research is done in developed world it is not approriate to address
mhealth problems in the developing world, because resources are scarce and shared by
large community [14].
We performed a literature review to gain an understanding of the challenges of paper
based and mobile based health data collection, which addressed RQ1.
Thereafter we put our literature review focus on the mobile technologies and available
open source frameworks that can be used to improve health data collection and reporting
process from primary to secondary health facilities. The review helped to gain
understanding which addressed RQ2.
According to Oates [15], there are about 7 steps (see Figure 1 in Section 3.1) in
reviewing literature critically. The steps are searching, obtaining, assessing, reading,
evaluating, recording and writing a review (see Figure 1). The process of reviewing
literature started with searching the literature from several digital libraries such as Google
scholar, Science direct and ACM library by using the keywords which was extracted
from the research goals. The keywords used in our search were Data collection,
Mobile technologies, Open source frameworks, Developing world, Health data,
Health information system and Health care system. We then assessed the found
literature by going through the abstract and the conclusion parts to see if they suit our
study. We also use refence follow up technique to obtain the materials which were
referenced in the found literature, this helped to expand our understanding by getting
more explanations on the reviewed concepts. The priority for reviewing articles of the
same concept was given to the latest published articles to ensure that knowledge of the
state of art is gained. The third step was to read and record the review of the concepts
from each of the selected literature. The sources of materials reviewed are mostly
academic papers, books and technical reports.
Figure 1: Steps in conducting literature review [15].
2.2 Design and creation
The nature of this study is to design a prototype for mobile health data collection and
reporting for the developing world. This follows a design and creation approach, an
attempt to create things that serve human purposes; it is technology oriented. March and
Smith[16] have defined a research framework to model research activities in studies that
follow a design and creation approach. In this framework there are four main artifacts
that are mapped to the four main activities.The artifacts are constructs, model, method
and instantiation11. The activities are build, evaluate, theorize and justify. In this study we
followed this framework to properly conceptualize and represent all the techniques to the
solution. The activities are building and evaluating the instantiation of the prototype for
mobile health data collection in the developing world. This method addressed RQ3.
The procedure of developing a prototype started by studying the open data kit
framework and thereafter followed by design of custom functionlities for mobile health
data collection.Table 2 summarizes the activities that have been undertaken in this study.
Table 2: Research activities [16]
Build Evaluate Theorize Justify
Instantiation X X
The process of designing the proposed prototype followed four steps of a prototyping
model [17] shown in Figure 2. We started by identifying the stakeholders (users) through
a scenario of the data collection and reporting systems in the developing world, and
Instantiation: Is the realization of the artifacts in their environment.
Construct: Is the formulation of vocabulary of a domain that describes a domains problem and used to
specify their solution.
Model: Is a set of preposition expressing relationship among constructs.
Method: Is a set of steps to perform task.
literature review.We identified the requirements of the users through literature review and
also using author experience on health system of the developing world.The prototype was
then developed through a series of customizing, testing and debuging of the source code
to suit health data collection. Due to time constraints, we could not perform a testing of
the prototype in the actual environment (health system in developing countries).We
evaluated the prototype through questionnaire by asking health information system
experts from the developing world about functionality and feasibility of the prototype in
their countries.The procedures of the evaluation process are presented in section 2.3.
Figure 2: Steps of the prototype development [17].
2.3 Evaluation study
Evaluation is an invaluable component of the research process.According to Hevner et al.
[18] there are different ways in which IT artifacts can be evaluated, the ways are
functionality, completeness, usability, consistency, accuracy, performance, reliability and
how it fit with the context.The evaluation process of this study aimed to evaluate the
functionality and usability of the proposed prototype through a qualitative method.The
evaluation results helped us to reveal the challenges of the mobile based data collection
methods and also pin point the users suggestions that could be used for improving the
prototype in future.
2.3.1 Study method
The selected method for this evaluation part is email survey. According to Eysenbach and
Wyatt [19], email survey is the preferred method in qualitative study when participants
are scattered and the data is required fast in readily analyzed form. Also online survey is
well suitable when there are time and budget limits. Therefore we chose this method to
conduct our qualitative study for general evaluation of the research objective.
2.3.2 Planning and preparation of the evaluation
The execution of the evaluation study started with planning and formulation of questions
that assess the current situation of health data collection and possibility of improving the
situation through mobile technology. The main objective was to evaluate the feasibility of
the proposed prototype in health systems of developing countries. One of the limitations
that we faced in this evaluation part is inability to conduct an observational study with the
actual stakeholders of the prototype. Therefore we created a questionnaire that included
the description of the prototype to help respondents to get knowledge of the prototype
before answering the questions. The questionnaire was divided into three sections; the
first section presented the introduction and a short description with screenshots of the
proposed prototype to familiarize the respondents with the main objective of the
prototype and its functionality. The second section presented general questions that aimed
to understand the challenges of health data systems and assess feasibility of mobile
applications for data collection. The third section presented a set of questions that aimed
to evaluate health data collection process and the proposed prototype. The questionnaire
is presented in Appendix III.
2.3.3 Participants of the evaluation study
The participants of this study were selected by the criteria of being citizens of developing
countries and with the assumption that they have some knowledge of health systems in
their countries. The priority was given to the people who have knowledge of the health
systems in developing countries. Therefore we targeted public health international
students, medical researchers and health service managers. We found contacts of the
participants through colleagues and organizations websites. The participants were from
Kenya, India, Ghana, Tanzania, Ethiopia, Zambia, Malawi, Uganda and Fiji. However
the majority of the contacted people were not directly working with health data systems
but had knowledge of how health systems work in their countries.
2.3.4 Execution of the evaluation study
The questionnaire was initially reviewed by few colleagues and then distributed to more
than 25 participants through email. The majority of the participants started to respond
after two days with a filled questionnaire. Some of the participants who had no
knowledge of health information systems failed to answers some questions that required
understanding of the way health systems work. Out of more than 25 participants who
were contacted, we received 15 responses, including 4 responses from health data
systems experts and the 11 from non experts.
2.3.5 Threats to validity
Threats to validity are the influences that may constrain the ability of interpreting data
collected in a qualitative study to draw conclusion. There are at least three main kinds of
validity which must be taken care from these threats. The types of validity are internal
validity, external validity and construct validity [20]. In evaluation of the proposed
prototype, we have minimised threats to construct validity by including descriptions,
screenshots of the proposed prototype and minised ambiguity in formulating
questionnaire questions to help participants to get clear understanding of the studys
objective. The external threat to validity of our evaluation result is threatened because
majority of the participants of the evaluation study had no direct experience or working
with health information systems of developing countries. This was the threat we accepted
in this study because of time constraints to conduct this study with actual stakeholders in
real scenario. Therefore we further call for future work to evaluate the prototype with
actual stakeholders.
3 Background and related works
This section describes the background of the health information systems and reporting
systems in developed world.
3.1 Health information systems in the developing world
Health information systems (HIS) are the systems for collecting and processing health
data from various sources. HIS have become a crucial component for strengthening the
health systems in developing countries. There has been tremendous growth of these
systems in recent years; this has been the result of advancement of technologies, which is
taking place all over the world. HIS emergence has therefore lead to shifting from paper
based to computer-based ways of processing health information. This shift has increased
the opportunities of manipulating patient data efficiently. However, it has also raised
challenges of technological complexity in using the advanced tools of processing health
data. The usage of health data is extended not only for patient care and administrative
purpose but also for planning and decision making in improving health service. Health
care workers nowadays deal with large amount of data, a situation that has high risk to
errors, and increase the cost of accessing and using the data. Demand of technology based
tools that could ease the data input and manipulating process is vital and is relevant in
increasing the performance of health professionals. Ubiquitous network infrastructure
which in now available worldwide open up doors for new health information systems that
could allow capturing of different types of data everywhere [21]. However
implementation of HIS has been in challenging developing countries due to
uncoordinated structures of their health organizations that cause unnecessary
fragmentations of health systems, inconsistency and redundancy in reporting [22]. The
lack of shared standards in data collection methods cause the gaps in reporting health data
as it might lead to important data not to be reported. Furthermore lack of coordination
between health care system levels in reporting health data lead to poor utilization of the
collected data which might therefore affect the quality of service that is offered by HIS
[23].
In order to improve the coordination between health care systems levels, the flow of
necessary information needs to be understood. The flow of health data from the lower
level (primary health facilities) to higher level (secondary facilities) needs reliable data
from the lower level. The upper levels where strategies and plans are made rely on the
information collected from the lower level (operational level). Proper data collection
methods allow regular monitoring of health information systems[1]. Figure 3 shows
different levels of health care system and the need of data in each level.
Figure 3: Levels of health care system and the data flow [1].
Adequate and timely information at the top level is of crucial importance towards
improving strategic plans of managing the primary facilities. Lack of adequate
information may lead to negative impacts to the health system such as underreporting of
important data [23]. Data collection units at the operational level needs to be equipped
with appropriate technologies that can lead to availability of adequate and timely
information. Health data systems in remote areas of the developing world have been
facing the problems in reliability of data and therefore hamper the delivery of quality of
health services [24]. The use of mobile technology seems to be effective as an enabling
technology for resource limited settings such as in the developing world [25][8][26].
However, most of the previous researchers have studied the use of PDAs, which are
nowadays regarded as an old technology compared with the new emerging mobile
technologies of cell phones, smartphones and computer tablets.
PDAs have limitations on kind of data they can capture compared to smartphones and
cell phones for example they cannot capture GPS data and they have small memory size
compared to smartphones [27]. Furthermore, the networking capability of PDAs is
constrained compared to smartphones, which have advanced networking capabilities such
as 3G and Wi-Fi support, which can allow capturing of multimedia data such as images
and video data. In health data collection perspective smartphones and cell phones could
offer more capability compared to PDAs [27].
Basing on what has been done, we have explored opportunities of exploiting this
advancement of ICT (Information and Communication Technologies) to improve health
data collection process in the developing world.
3.2 Reporting systems
There are different kinds of information that are reported to health managerial level in
developing word health systems. The categories of the information required include
population (health surveys), morbidity and mortality, health service activities, facilities,
employee information, medical distribution and financial information. Information in the
developing world health systems is used to improve health services, especially in
increasing accountability and plans progress monitoring [28]. There have been efforts of
improving the health reporting systems in developing countries, however the demand of
improving data collection methods is high due to advancement of technologies and
increase of population [29].
Health Information Systems Programme (HISP)12 are the pioneers of developing
health systems in developing countries, one of their product for reporting health data is
District Health Information System (DHIS)13. DHIS is free and open source software
which has been be introduced in many developing countries to serve for collection and
HISP (Available at : http://www.hisp.org/) is the initiative that aims at improving health care systems by
enhancing the capacity of health care workers in making decision.
Available at : http://dhis2.org/
aggregation of routine data that could help health service managers in making
decentralized informed decisions. DHIS aimed to address key problems in reporting such
as fragmentation and inconsistencies in reporting. Despite of adopting DHIS, the data are
still collected manually using paper based systems and tally sheets. The collected data are
then sent to the sub-district center after every month where they are feed into the DHIS
software. At the sub-district level, the DHIS software generates reports which are sent to
the higher levels of management (see Figure 3 in Section 3.1) that data analyzes the data.
The methods in which data are collected and aggregated increase the risk of low quality
of data and has been reported to affect the decisions that are made based on the data [30].
Figure 4 shows the information cycle in health facilities of the developing world.
Figure 4: DHIS information cycle in health facilities [30].
Since DHIS has been introduced in many developing countries health care systems,
we are motivated to draw our requirements from the workflow of this system and seek for
a way to improve the reporting mechanism using the advantage from newer technologies.
3.3 Gaps found in the literature
Despite of several efforts that have been made to address the health data collection
challenges using mobile technology, the demand for improvement is vital. The
introduction of newer technologies opens new opportunities of improvement. The
following are the gaps found in the previous way of collecting and reporting health data
in the developing world.
Gap 1: There is fragmentation of health information system due to un-
coordination between different levels of health care systems [22].
Gap 2: The current way of reporting health data from health facilities to
management levels is subject to underreporting due to involvement of human
being in collecting and aggregating data [30] [31].
Gap 3: The current way of reporting health facilities routine data to the
managerial level is not timely and may lead to delay of crucial decisions that
could be more effective [31].
Gap 4: Although there have been many opensource frameworks (see Table 5 in
Section 4.6) that could ease efforts to data collection, few studies have
attempted to build prototypes from these frameworks.
4 Mobile data collection technologies
This section presents the review of the mobile technologies and the available open source
frameworks for data collection. We start by understanding the challenges with the
existing paper based and mobile-based health data collection methods in the developing
4.1 Challenges of the available health data collection methods
There are several challenges that affect collection of health data in the developing world.
One is the limited number of health experts; there is critical shortfall in health officials in
the developing world and therefore this makes the process of effective data collection
more tedious [5][25][13]. In addition to that, socioeconomic constraints that face these
regions make the effort of training enough statisticians difficult and therefore the paper
based data collection methods become inefficient because of lacking enough skilled
people to manually collect and analyze the health data [1].
Despite of the limited number of workers, the health infrastructures are not enough to
save the human population which is reported to grow exponentially in these regions [4].
Geographical infrastructure and limited resources in highly populated communities are
the barriers that impede the speed of health data collection using paper based methods
Another is the lack of reliable communication infrastructure; communication
infrastructure in the developing world is not stable and is often compromised by weather
and natural calamities such as floods and earthquakes. This causes delay of health
surveys and also sometimes become expensive as it involves more workers and increases
the cost of transporting the manually filled forms [7].
Paper based data collection tools such as questionnaires have a large degree of error
and are subject to data loss. Data processing using this method is reported to be more
time consuming and cumbersome which does not guarantee quality of the outcome [33].
This has then lead to delays of surveys due to time lag between data collection and
availability of data for analysis. In addition to that, digitizing paper-based collected data
is difficult and it is subject to lack of data quality.
The evaluation study that was conducted by Missinou et al. [34], found mobile devices
such as PDA to be more effective compared to paper based data collection methods. In
this study, PDA was found to be less time consuming and with more data precision
compared to paper based method. However in the study conducted by Ganesan et al. [35]
it was reported that mobile phones are more efficient in data collection compared to PDA
due to their advanced features in memory, long lasting battery life and networking
capability.
In general health data collection and reporting systems in the developing world are
mostly affected by economic barriers in these regions. These barriers impede the efforts
of improving health services such as improving access to health data and reporting
systems to enable effective data driven decision and policy making for health service.
Lack of resources such as human resource make the effort of collecting and reporting
health data cumbersome and therefore causes inconsistency and underreporting of the
health data. Table 3 presents a summary of the challenges of health data collection and
reporting systems in developing countries collected from literature review and
questionnaire survey (Section 2.3 describe the questionnaire survey).
The use of mobile technology could bridge this gap in a low cost and effective manner
by allowing gathering of data remotely through trained personnel in the community. The
modern mobile devices have shown to carry more capabilities that could overcome the
barrier of limited resources in public health sector in the developing world. Furthermore,
the use of mobile phones promises more efficiency and more quality of the data
collected. Perera [32] says With these advantages of Mobile-based systems it is
undoubtedly suitable to consider developing paradigm-shift application infrastructure to
overcome problematic issues in present healthcare systems. In Section 4.2, we review
the application of mobile technologies in improving health systems of the developing
Table 3 : Challenges of existing health data collection methods
Literature review Questionnaire survey
The current methods of Paper based and partial computerized Paper based methods
collecting and reporting methods [31] [30].
health data.
Time for collection and There are defined frequencies of 1. Monthly
reporting health data reporting health data based on type of 2. Quarterly
from primary health data and where there data is reported. 3. Weekly
facilities to secondary The frequencies are in terms of weekly, 4. Yearly
facilities. monthly, quarterly and annually [31]. It depends on kind of
Kind of data collected Facility records, birth and death 1. Number of diseases cases
and reported from registers, outpatient records [1]. reported in health facilities
primary health facilities 2. Medical equipments
to secondary health (medical assets)
facilities. 3. Medical stock level
Users of health data Health statisticians and health Doctors, government and
managers [31]. medical researchers.
General challenges of 1. Limitation of resources such as 1. Low data accuracy due of
data collection and human resources and health data the paper based method in
reporting systems. processing tools [5][25][13]. data collecting.
2. Lack of reliable communication 2. Delays in reporting crucial
infrastructure to support the transfer information to the
of data from remote health facilities managerial level.
to management levels (district 3. General lack of capacity
level). for data collection and
3. Lack of data accuracy and processing (few health
consistency of reporting health workers)
data. 4. Poor record keeping
4. Fragmentation of health methods and mostly are in
information system due to un- paper forms
coordination between different 5. Poor health infrastructure
levels of health care systems [30] which is exploited to serve
[31]. large population hampers
5. The existing electronic data the health data collection
collection methods are mostly SMS efforts.
based and they have limitations on
data capturing capabilities [36].
4.2 Mobile technologies in health systems
The dramatic advancement of mobile technology has geared new opportunities of
improving social lives in developing countries. The societies are now becoming mobile
oriented and therefore, there is an increased pressure on the efforts of exploiting this
technology in improving social services. Usage of mobile technologies in developing
countries could now be able to handle many existing problems of their health systems;
data collection process is one of the aspects that can be fuelled by exploiting mobile
technology as enabling technology in improving the accuracy and efficiency of the
process as whole [37].
The general benefits of exploiting mobile technologies in health care systems includes
assurance of quick processing of the collected data and it does not require complicated IT
infrastructure to set up. Moreover, mobile applications are usually simple in terms of
usability and can be adopted by users without any special IT skill. Finally, the financial
cost of developing mobile application is relevant and can be afforded by many
organizations in developing countries. However there are also challenges in adoption of
mobile technologies such as privacy and security of the health data in ubiquitous
networks14 [38].
4.3 Mobile data collection methods
There are numerous ways of collecting data from remote areas, these include paper-based
methods and electronic based methods. Paper based methods are mostly used in low-
income regions due to limitations of resources such as electric power and IT
infrastructure that could not allow usage of electronic methods such as computer software
for data collection. Despite of having many disadvantages such as lack of accuracy and
time consuming, the paper based method has been useful in conducting all kind of
surveys because of its flexibility, does not require electric power, and does not require
technological skills.
Electronic methods are sophisticated methods, which are used to enable collection
and storing of data. These methods involve the use of mobile devices such as PDAs, cell
phones, smartphones, netbook, notebook, tablets computers. Electronic methods offer
more capability and efficiency compared to paper based data collection methods. The
advantages of electronic methods allows complex data management with accuracy
assured, require less time to collect and analyze large volume of data, the logic of
entering data can be programmed to avoid capturing of data that will not be analyzed,
Ubiquitous network is the network that allows users to have access to the application programs
wherever they are using mobile devices.
data collected through these methods can be standardized and therefore allow easier
aggregation and analysis process [39]. Table 3 shows the mobile data collection
technologies and type of data that can be captured.
Table 4: Mobile data collection technologies
Device/ Description Type of data that can Data format
Technology be captured
Paper based Paper based method: It is the way of Text data Structured
collecting data by using pen and paper.
Cell Phones Cell phone: It is the portable wireless Text data, Audio data Unstructured
device that has basic telephony
functionalities such as making calls,
receiving calls, send and receive text
messages.
PDA PDA: It is the portable device enabled Text data, Images Structured
with internet connection, storage and data, Video data,
digital visual display capabilities used to Audio data
conduct simple computing tasks.
Smartphones Smartphone: It is the device that offers Text data, Images Structured
telephony functionalities and adds more data, Video data,
features such as web access, ability to Audio data, GPS data
send and receive emails, reading and (latitudes, longitudes)
editing documents.
Netbook Netbook: It is the small portable Text data, Images Structured
wireless device with less processing data, Video data,
power that offers basic functionalities Audio data, GPS data
such as word document editing and (latitudes, longitudes)
browsing the internet.
Notebook Notebook: It is the small portable
device with more processing power
compared to netbook.
Tablets Tablets Computers: It is the portable
computers computer small than laptop and has
touch screen keyboard to perform tasks
that can be performed by laptop or
desktop computers.
Data collection technologies have been further geared by the growing and
advancement of smartphones technologies that offer larger screen size, more memory and
high computing speed which facilitate capturing of data in short time compared to the
time consumed by other methods. Furthermore, the GPS technology that is nowadays
integrated with smartphones, gives more opportunities of using smartphones as data
collection tool. The integrated GPS functionality allows accurate location information
capturing of respondents of where the data is collected [10]. This revolution of cellular
phones technologies have been championed by the emergence of many mobile device
development platforms that have attracted many developers to get involved in developing
mobile applications. There are several mobile device platforms in the market, the
available platforms include Symbian, Windows, RMI Blackberry, Apple iPhone, Linux
and Google Android mobile platforms [40]. In recent years, the Google Android platform
has attracted the development of many applications since it is the only open source
platform for mobile devices. Since we are investigating open source technologies that
could improve health data collection process, the Google Android platform is our choice
for this study.
4.4 Google Android platform
Google Android platform is an open source software platform for mobile devices, it is
composed of operating system and open libraries that are free of charge worldwide to be
used by researchers and developers [10]. Being an open source software platform means
it has a large supporting community to improve the software and fix bugs and that has
been one reason that the Android platform gained popularity in recent years. The
architecture of Android is comprised of four main layers each with its own functionality.
The layers are the application layer, which contain core applications such as email and
SMS program, the application framework layer, which provide standard structure for
specific operating systems, the libraries layer, which contains a set of procedures that are
invoked by applications, and the kernel Linux layer where the applications are executed
[40]. Figure 5 depicts the Android development architecture.
Figure 5: The Android development architecture [40]
Another important feature that makes this platform popular out of the others is its
ability to optimize the usage of memory. Multiple processes can run in the Android
platform, each process consuming low memory [40]. This feature gives us more
confidence on the suitability of this platform in data collection as health data collection
forms may require more memory that could not be offered by other platforms.
4.5 Benefits and drawbacks of using open source technologies
Open source technology is the philosophy of developing and improving software through
open and public forums by sharing the source code. The success of open source
technologies was fueled by the emergence of the internet which has then increased the
demand of more collaboration between software developers [41]. According to Fuggetta
open source technology is a promising strategy for improving maturity and quality of
software development activities [42]. Fuggetta further asserts that putting source code in
a public view allows different developers to examine the code, fix bugs, and therefore
make the software reliable and stable. In the economic perspective, open source
technologies are free of charge, can be modified and redistributed without license. This
make open source based software affordable and managed with low cost [43].
The challenge of open source software is on keeping track of the software versions,
because there are many developments going on at the same time. This causes open source
software to be less competitive in software market compared to proprietary software [43].
However, with standardized development frameworks such Google project hosting
service, it is easy to track versions and the changes made in each version through
centralized way of sharing source code.
4.6 Open source frameworks for data collection
There exist several open source projects that seek to improve the data collection process.
A number of data collection toolkits have been developed and released under general
public license (GPL).These frameworks have a large community developer and reviewers
support worldwide that share source code and improve them. We have found in the
literature, seven SMS based and electronic form based data collection frameworks which
have been used in various scenarios of data collection. We review these frameworks in
the following subsections.
Open Data Kit (ODK) is an open source software program which facilitates digital data
gathering and compilation of data [44]. ODK was developed purposefully to bridge the
information gaps in resource-constrained regions such as the developing world by taking
advantage of mobile phones subscriptions growth in these regions. ODK platform has
two main modules, which are ODK collect and ODK aggregate. ODK collect is the client
side module, which can run in any Android device such as smartphones, netbook,
notebooks and tablet computers. ODK collect forms are constructed using the XML
language. ODK aggregate is the server side module, which gathers all data collected
from ODK collect module. ODK aggregate can be hosted either in local server or in
cloud server to enable multi location data collection. ODK aggregate offers other
services of manipulating data such as visualization of data in various forms and mapping
the data with locations. ODK supports data of all types including text, video, images,
audio, GPS data and barcode data [45].There are several case studies in which ODK has
several application areas ranging from enterprises to community level solutions, some of
these application areas are government, business, health sector and education sector
[25][46].
FrontlineSMS is an open source SMS based platform, which offers collection of data
through text messaging. It further offers other functionalities to manipulate the collected
data such as visualization. This platform was purposed to offer standalone SMS oriented
services to governmental and non-governmental organizations at low cost [47].The
important feature of this platform is that it does not require internet connection in
collecting data. FrontlineSMS platform is installed in a computer to receive, store and
auto-forward messages based on the user settings. FrontlineSMS platform can be
configured to perform auto-responding to the incoming messages based on the user
defined keywords to individual clients or to group of clients. This platform has been
applied in different scenarios which involve messaging services through cell phones, for
example in medical appointments and remainders [48].
EpiCollect is an open source software platform for mobile data collection. It facilitates
collection and visualization of data through multiple mobile smartphones. Unlike ODK
that is supported by only Android enabled devices, EpiCollect is supported by Android
and iPhone smartphones. EpiCollect can gather all kind of data types including text,
audio, video, images and locations. The important feature of EpiCollect, which is similar
to ODK, is that it is not reliant to network connectivity; data can be collected offline and
synchronized later to the server when there is network connectivity. This feature makes
data collection suitable in regions where internet connection is not available [49].
RapidSMS is the SMS-based open source data collection framework that helps mobile
collection and aggregation of data. The framework offers functionalities of capturing data
through SMS and managing data through a web interface. It supports all kind of mobile
phones, which have capability of sending and receiving text message. RapidSMS does
not required any client software to be installed in a mobile phone, it makes use of the
SMS application that comes with a device. This feature has geared RapidSMS to be used
in large surveys in developing countries such as Nigeria15, Ethiopia16, Senegal17 and
Available at : http://www.rapidsms.org/case-studies/nigeria-monitoring-supplies-in-a-campaign-setting/
Malawi18 where many basic phones are mostly used. RapidSMS has been used in several
studies including national surveillance, response monitoring and supply chain [50][51].
Open X Data is an open source data collection framework, which has been championed
by the community of academic researchers and developers from various universities
across the world. Open X Data support low-end java enabled phones to collect data
remotely in low budget settings. It provides a way to visualize and manage the gathered
data though a web interface. Open X Data framework has been used in several case
studies such as early warning systems and mhealth projects in developing countries [52].
Nokia Data Gathering is the mobile data collection tool that offers functionalities of
gathering simple data (textual data). This platform has two main modules, client side
module software, which is installed in mobile phone, and the server side module
software, which is used to manage collected data. Survey forms are created from the
server software and sent to the mobile phone where data is collected. This platform
support only Nokia handsets. The key features that are found in this platform include,
survey question editor that enables creation of different kind of questions such as
multiple choice, exclusive choice, text and image. Furthermore it offers ability to trigger
questions based on the responses [53].
JavaRosa is an open source mobile data collection tool that is used to speed up collection
and aggregation of field data remotely. JavaRosa is a J2ME implementation of
OpenRosa19 specification of data collection for mobile devices. It uses GPRS20 protocol
to send data from the mobile devices to the storage server [54]. JavaRosa has been using
Available at : http://www.rapidsms.org/case-studies/supply-chain-management-during-food-crises/
Available at : http://www.rapidsms.org/case-studies/senegal-the-jokko-initiative/
Available at : http://www.rapidsms.org/case-studies/malawi-nutritional-surviellence/
Available at : http://openrosa.org/
GPRS is the data access technology in 3G mobile networks.
in several cases in the developing world such as Tanzania in management of childhood
illness via remainders and remote support [55], and in supporting community health care
workers (CHWs) [56].
In general, all reviewed data collection frameworks have to carry capabilities to improve
the traditional paper based methods of collecting data. The reviewed frameworks can be
evaluated in terms of type of data they can collect, handset support, and network protocol
support and data storage capability. In Table 5, we compare the mobile data collection
frameworks based on the findings of Jung [57]. After comparing the features of each
framework, we selected the open data kit (ODK) for developing the proposed prototype
for health data collection (see Chapter 5).
Table 5: Comparison of data collection frameworks
Tool License Data type Handset Network Protocol Data Storage
type Collected Support Support
RapidSMS Open source Text(SMS) Basic Phones GSM(SMS) Local Storage
FrontlineSMS Open source Text(SMS) Basic Phones GSM(SMS) Local Storage
Open X Data Open source Text, Images, Java Phones GSMS(SMS), Local Storage
Video, Audio, GPRS(WAP),
GPS Bluetooth
Open Data Open source Text, Video, Android GPRS, Wi-Fi Hosted Storage
Kit Audio, GPS,
Nokia Data Open source Text, Images, Nokia Phone GPRS, Wi-Fi Local Storage
Gathering Video, Audio, (Java enabled)
Java Rosa Open source Limited by Java enabled GPRS Local and
headset and Phones hosted storage
EMIT Proprietary Text via forms Java enabled GPRS Hosted Storage
EpiCollect Open source Text, Images, Android, GPRS,3G,Wi-Fi Hosted Storage
GPS iPhone
4.7 ODK related work
Several efforts have been done by several researchers in improving data collection using
the open data kit framework and the ubiquitous infrastructure.
Piette et al. [25], assert that mobile technologies and open source frameworks together
can improve health service. They propose a software that combines OpenMRS (Open
Medical Record System)21 and ODK (Open Data Kit)22 in management of non-
communicable diseases (NCDs). Adoption of this tool in mhealth was found to improve
patient management, access to health resources, access to information and health
In another research which was keen to evaluate the efficiencies of adopting the use of
ODK in data collection in resource limited settings, Rajput et al. [46] found the use of
ODK to be more cost effective compared to paper based methods. Paper based collected
data was requiring extra efforts in integrating to medical record systems. The evaluation
on the use of PDAs in this study found PDAs to have limitations such as inability to
capture GPS data and synchronization of data with external data storage devices.
Aanensen et al. [49] research on the use of smartphones with web application show a
promising successful future of the new mobile technologies such as Android in
improving the data collection process. Unlike PDA, which was found to encounter
weakness, especially in the security of collected data, the approach of linking
smartphones with web applications has improved the security of data in large extent.
Once the data is collected by the smartphone application it is synchronized to the web
application where analysts can quickly accessed it. This does not only offer security but
also timely reporting and quality of the data is maximized compared to the old fashions
of collecting data and ensure data locality. In our study we move one more step by
evaluating available open source frameworks that can reduce the effort of setting up a
mobile data collection system.
Based on the reviewed open source frameworks for data collection and mobile
technologies, it is clear that the development of mobile applications is on the high peak
Available at :http://openmrs.org/
Available at :http://opendatakit.org/
attracting developers and researchers to explore and develop solutions to bridge
information gaps. The advancements have gone further in developed regions compared to
developing ones. There is still need for academic researchers to test the applicability and
usability of these growing technologies in improving information systems of the
developing world as it was suggested by Sen and Bricka [10]. We develop and evaluate a
prototype for health data collection for the purpose of testing and to build understanding
of how the available tools can serve for health data collection in the developing world.
Chapter 5 describes the development process and the components of the proposed
prototype.
5 A prototype for mobile data collection and
This chapter present the proposed prototype based on the understanding from the
literature review and the scenario of how data collection and reporting systems work in
the developing world. The scenario was chosen due to the previous work of the author
with this scenario.
5.1 Scenario of health data collection and reporting system
The study on health information systems integration in developing countries (case of
Tanzania) [31] reveled that health data flow in starts from the health facilities and goes to
the district, then to the regional and finally to the national level. The data are collected
using paper and pen methods and rarely using computerized methods such as
spreadsheets. At the health facilities, the data are collected using cards and later recorded
into registers. Registers are then used to generate tally sheets, which are compiled and
filled into forms called book 223 (see Appendix I). Book 2 report forms are further
reported to district level where they are compiled through DHIS and generate new forms
called book 10. Book 1024 forms are then manually submitted to the national level where
they are further aggregated and analyzed. Figure 6 shows the flow data and the process at
each level.
Book 2 is the compiled report of tally sheets showing the number of reported cases of a disease in a
health facility.
Book 10 is the compiled report of diseases statistic reports from different districts which is reported to
regional level of the health system.
Figure 6: Data flow in health systems [31]
All reports from the health primary facility are submitted to the district health
information system (see Section 3.2). The sample form, which is used by health facility to
report diseases statistics to the district level, is shown in Appendix I. There are different
routines of reporting health data from one level to another within health information
system. Table 6 shows the routines the reporting health data from health facilities to
management levels.
Table 6: Routines in health information systems [31]
Data Flow Frequency
Reproductive Child Health (RCH) Normal To Regions: Quarterly
To National: Annually
Expanded Programmes Normal To Regions: Monthly
Immunizations (EPI) To National: Monthly
Malaria Skip Regions To District: Quarterly
From this scenario and the general case described in Section 3.2, we understand the
data flow and the frequency of reporting data between different levels of health systems.
From this understanding, we design a prototype for a mobile data collection. Section 5.2
presents the design process.
5.2 Design of the proposed prototype
From the found gaps through literature review and the scenario of health data reporting
system, we are motivated to design a prototype for health data collection and reporting by
using opensource frameworks alongside newer technologies. The aim is not only to
bridge the gaps but also to test the newer technologies in solving community problems.
The specific target that this study attempt to hit is collection and reporting of health data
from the primary facilities to secondary facilities (see Figure 3 in Section 3.1). We
attempt to bridge the information gap between primary facilities and secondary facilities
to allow timing and consistency in reporting routine health data. Based on our review of
seven frameworks (see Table 5 in Section 4.6), we selected the Open Data kit framework
backed with the Android platform. The reason for this selection is motivated by the
features such as unlimited capability of capturing data of all types and openness of its
source code. In budget-limited settings such as in the developing world, open source
technology solutions could be more relevant. ODK has proved its capability in scenarios
reviewed in chapter 4.
5.3 Requirement specification of the proposed prototype
Requirement specification is an invaluable part of software engineering, which defines
the requirements in a formal way to avoid problems of ambiguities along the
development process. In this section, we present stakeholders, functional and non-
functional requirements of the proposed prototype.
5.3.1 Stakeholders
Identifying system stakeholders is an important aspect of the software development as it
guides the requirements engineering process [58]. In this section, we identify the key
stakeholders of the proposed mobile health data collection. The identification process was
guided by the general knowledge drawn from the literature review, which was carried in
chapter 3 and the scenario presented in chapter 4.
Health data statisticians: These are the health record management experts at the
primary health care facilities whose duties are to track the health routine data and
report to the high levels (see Figure 1 in Section 3.1). In mobile health data collection
systems, these stakeholders shall be able to collect and report the health routine data
through electronic forms, which will be accessible from the mobile client software.
Health system managers: These are the decision and policy makers at the secondary
health facilities whose tasks are to visualize, analyze and make informed decisions to
improve the health services.
Other stakeholders: We identified other possible stakeholders during the
questionnaire survey carried in this study. The suggested stakeholders are doctors,
medical researchers and government agents. However due to the time limitation, we
could not incorporate these users in the proposed prototype. Therefore, we call for the
future work to investigate the requirements of these users and include in future work
on the prototype.
5.3.2 Use case diagrams
It is important to properly model the users characteristics in order to understand the roles
and variation between users [59]. Use case modeling is the way of showing how the
system stakeholders will interact with the system. In this section, we present the system
use cases.
Use case diagram for health data statistician
The proposed prototype for mobile health data collection will allow health data
statisticians to perform some activities with the data. Figure 7 shows how health data
statisticians will interact with the system. After login to the system, the health data
statistician will be able to perform several tasks such as downloading the forms from the
server, fill in the forms, modify the forms and send the completed forms to the web
application. The web application manage users authentication and validate the received
forms.
Figure 7: Use case diagram for health data statisticians
Use case diagram for health service manager
The proposed prototype for mobile health data collection will allow health managers to
perform some activities on the data that could help them to make decisions and plans.
Figure 8 shows how health services managers at the secondary facilities will interact with
the system. After login to the system, the health manager will be able to perform the tasks
such as uploading Xforms and visualize and managed data submissions.
Figure 8: Use case diagram for health service manager
NB: Some use case in figure 7 and figure 8 have the same names but they are not the same.
5.3.3 Functional Requirement
Functional requirements are the specific statement of service that defines how the system
should react to particular inputs and how it should behave in particular situations. In this
section we present these statements of service which correspond to the requirement
analysis which were found from the literature and summarized in Section 3.5.
F1. The server module of the prototype shall provide interfaces to visualize and aggregate
Motivation: Visualization of the gathered data in various formats is important for
decision and policy makers. Aggregation and dynamic queries could ease the
process of analyzing data for further usage.
F2. The mobile health data collection prototype shall provide pre-designed forms to
gather health data from a mobile phone.
Motivation: Usability, portability and ability to store charge are the key features
that qualify mobile phones in collecting data from remote areas and where electric
power is limited. The proposed prototype will provide a way of collecting data
through mobile phones using pre-designed forms and offer a feature to send the
finalized forms to the database.
F3. The mobile health data collection client module shall provide interface to report
health routine data through forms that are downloadable from the server side module
of the prototype.
Motivation: Centralizing data collection forms could enable common format of
data that need to be reported from each health facility. This will bridge the gap of
fragmentation in health information system that was found in the literature.
The matching of the functional requirements and the gaps found in the literature is
presented in Table 7. Gap 4 is not included in Table 7 because of being in different level
of abstraction.
Table 7: Matching of the functional requirements and the gaps to bridge
Gap 1 Gap 2 Gap 3
F1 X
F3 X X
5.3.4 Non Functional Requirements
Non functional requirements are the system quality related statements that define the
constraints on the services offered by the system [60]. In this section we describe these
statements that will help understanding the pattern of the development process of the
proposed prototype.
Availability: The mobile health data collection prototype shall operate in Android
mobile device. A web application shall operate in any HTML enabled web browser of a
computer or mobile phone.
Motivation: Android framework as stated earlier is the underlying platform that
has been used to develop the proposed prototype; therefore we are limited to
Android enabled devices and HTML browsers for web application interfaces.
Security: The mobile health data collection prototype shall provide access to only
authorized users with username and password authentication method.
Motivation: Security is an important aspect of any information system. Users of
the proposed prototype will be registered in a web server and authenticated using
username and password when they want to have access to server services such as
downloading blank forms from the server and sending finalized forms to the
Usability: The mobile health data collection prototype shall be easy to use and not
require special computer skills.
Motivation: Mobile phones are nowadays common devices and are used by many
people without any technical skills. The proposed prototype shall be easy to use as
it will stand as other mobile applications. The electronic forms will have labels to
guide users on what and where to fill data. The web application interfaces also
will be user friendly and will require simple skills in managing data.
5.4 Developing the prototype
In this section, we describe the development process of the functionality of each module
of the proposed prototype.
5.4.1 Design decision
In designing of the proposed prototype, we have made decision on the technologies.
There are different technologies that could be used to develop the prototype. The options
are J2ME or Java-Android for mobile client and PHP or JSP for administration module.
However due to the fact that we developed this prototype on top of the ODK framework,
we were constrained to the specifications of ODK in terms of implementation language
and development tool kits. The technologies that were used for development of the
proposed prototype are:
1. XML for designing the electronic data collection forms.
2. Android software development kit (SDK) for creating Android executable
application.
3. Java language for backend side of modules.
4. Google API for deploying and testing of the administration module.
5. JSP, HTML and CSS for designing the web interfaces of the web application.
5.4.2 Components of the prototype
The proposed prototype is divided into modules and sub-modules. Figure 9 show the
modules and sub-modules.
Figure 9: General architecture of the prototype
Client Module (MHDK Collect)
In the development of the client module, we used Google APIs libraries for Android and
ODK framework. We imported the ODK collect framework source code from the ODK
developers community site25 source code into Eclipse IDE. We designed the custom
functionalities of getting blank forms from the web server to a mobile phone and also
filling the forms and sending the forms to the server. In this study we renamed the
original ODK collect to MHDK collect since we have added custom designs for health
data collection.
The prototype was tested in a both Android virtual device and real device. We
downloaded the executable Android file (.apk file) from the project folder (bin sub folder)
and install it in a real Android device. In this study, we have tested this prototype in HTC
Sensation and HTC Desire Android mobile phones.
Available at : http://code.google.com/p/opendatakit/downloads/list
Data gathering forms (Xforms)
We created XML forms (XForms) which are used to collect data from the mobile phone.
For the case of this prototype, we created two main forms that could help to collect data
from the primary health facilities and report to secondary facilities (district level). The
forms are health facility (for stock level status) and diseases statistics (for reported
diseases in the primary facilities). The terminologies used to label data elements in our
Xforms were found from the sample form reviewed in this study (see Appendix I and
Appendix II). However, the terminologies are flexible depending on the kind of data
needed to be captured, for example, data related to medical stock level and diseases
statistics. The data elements that are defined in Xforms are automatically created in the
database when the XForm is uploaded to the administration module. The Xforms are
designed using XML editors such as ODK build26 which offers flexible visual form
design, however it may require further manual hand coding of the form logic (the order of
filling the data in a form).
The Xforms are created by the health managers and uploaded to the administration
module of the prototype. The health statisticians then download the Xforms through
client module in a mobile phone and collection. The filled Xforms are then sent to the
administration module where health managers can visualize and process data for
management purposes such as decision and policy making. The flexibility of the form
design allows the prototype to work with various terminologies (data elements) and allow
integration data from different sources (different primary health facilities). The flexibility
on terminologies used in data collection forms allows easy way of setting uniformity of
data formats and therefore increase coordination of different levels of health information
system. Therefore, the proposed prototype may be used to capture health data of various
types depending on the demand. Figure 10 shows the sample form display in a mobile
phone and the XForm definition.
Available at : http://build.opendatakit.org/
Figure 10: Stock level report form display and the corresponding XForm definition screenshot.
Form Manager
This is the main window, which contains links to perform different operations on forms.
The operations include, getting blank forms from the server, filling blank forms and
sending finalized report forms to the server. The collected data can be stored temporarily
in a mobile phone and sent later to server in case of unavailability of internet connection.
Figure 11 shows the screenshot of the form manager that will be displayed in a mobile
Figure 11: A sample screenshot of the form manager menu.
Administration Module (MHDK viewer)
In developing administration module, we used Google app engine as web server and
reuse ODK aggregate source code to design custom functionality for health data
ODK aggregate
ODK aggregate is web application that provides interfaces to manage data collection
forms and the collected data. The operations on management of data are visualization of
data through maps and simple graphs, customizable data filters that allow the generation
of custom reports. Furthermore, collected data can be exported to Comma Separated
Values (CSV) format and visualized in other applications such as MS excel27. Figure 12
shows a screenshot of a form management interface in ODK aggregate. This web
interface can be accessed through HTML web browsers. We have tested this application
in both computer and phone HTML browsers. The phone HTML browser seems to have
limitations on the visualization of graphs and charts. We could not attempt to investigate
the other options such as coding the web application version for mobile phone due to
time limitation and therefore it is left for the future work.
Figure 12: A sample screenshot of the form manager in web application
Available at : http://office.microsoft.com/en-us/excel/
The collected data can be visualized in two ways, which are maps and simple graphs.
Figure 13 and Figure 14 shows how the data can be visualized in maps and graphs
Figure 13: A sample screenshot of the data mapping on administration module
Figure 14: Sample screenshot of the bar graph of districts against malaria reported cases
Hosting the Administration Module
In this study, we chose Google app engine to deploy and host ODK aggregate (MHDK
viewer) because it is based on open source technologies and which is a non functional
requirement of the ODK framework. Google app engine is the cloud computing28 service
that offers software as a service (saas). It allows users to deploy and host web
applications on Google infrastructure. Google app engine as other kinds of cloud
computing environment such as Amazon web service (AWS)29 and Microsoft Azure
service (MAS)30, it offers easy building and maintaining of applications. Currently
Google app engine offers free of charge building and deploying up to 10 applications per
one developer. The startup package with Google app engine is 500MB disk space for all
10 applications and 5 million page views per month for free of charge [61]. In the design
of the proposed prototype, we first created a Google app engine account and created
application that would host the ODK aggregate (Administration module).
General components of the prototype
The prototype has several components that work together to improve the efficiency of
mobile health data collection. The component are XML forms authoring tools, ODK
aggregate (MHDK Viewer), Mobile phone client software (ODK collect).
The prototype has a client module, which is composed of mobile application to gather
data, administration module, is composed of web application to manipulate gathered data,
and form authoring tools to design data gathering forms (XML forms). Figure 15 shows
how the different components relate to each other.
Cloud computing is the kind of computing service that provides software data access and storage
service that can be accessed everywhere regardless of physical location of the end user (Computing
everywhere)
Available at: http://aws.amazon.com/
Available at: http://www.windowsazure.com
Figure 15 : The main components of the proposed prototype
Prototype source codes
Open source software projects can be said as revolutionary process of releasing software
and open access of the source codes to the community [43]. In proposing prototype for
mobile health data collection, we followed open source technology philosophy.
Therefore, we created an online repository to share the source codes. The source code of
the prototype is hosted in Google project hosting service with the name Mobile-
Collect31.
Available at : http://code.google.com/p/mobile-collect/
6 Evaluation of the prototype
This chapter presents the evaluation of the proposed prototype. The evaluation of the
prototype was conducted through questionnaire survey. Section 2.3 presented the
procedures of the evaluation study.
6.1 Discussion of the questionnaire results
The first part of the evaluation study, intended to assess the challenges in health
information systems including data collection methods. The summary of the response
from the participants is as follows.
First is the collection of incomplete or incorrect data due to lack of understanding of
the flow of health data. This is then subject to inconsistency and underreporting of the
health data to the management level.
The general lack of capacity for data collection and processing; there is a critical
shortfall of expertise in health sector of developing countries. This causes the efforts of
collecting and processing health data to be difficult and result to delays in reporting
crucial information.
Large population with limited resources; one of the things that impede developing
countries from growing up is limitation of resources. In health systems, few available
resources are used to serve large population, this cause inefficiency in the whole process
as few workers are dealing with large volumes of data.
The study has also found out that most of the developing countries uses paper based
methods in collecting and reporting health data and their health systems are partially
computerized. Due to lack of enough expertise in technology based systems, the available
health workers face difficulties in using efficiently the computer systems for managing
health information.
We were keen to understand what kind of data is being collected with the current
methods. We then found that, there are several kinds of health data that are collected; the
kinds include number of cases of diseases such as malaria and cholera, morbidity and
mortality data and drugs stock data. These data are collected and computed to generate
reports which determine the situation of a particular disease at particular place. The
health data are also used as notification for abnormal and infectious diseases to alert the
management to take action as soon as possible. Moreover the health data are used to track
the drugs stock level and help the management to plan better to avoid stock run out.
In evaluating the proposed prototype, participants were confident in supporting the
idea of introducing mobile based tools of collecting health data due to the fact that mobile
devices are easy to use and affordable by the developing countries. The participants said
that the Android platform is not common in their regions but it is catching up and could
take over in future. One participant said Android is not common enough but soon that
wont be a problem. The participants were confident at answering yes on the usability
and applicability of the proposed prototype in their countries. Health information systems
experts who were involved in this study reported existence of other technology based
data collection systems in place but are not efficient as most of them lack technical
supports and therefore they are not commonly used. One health data expert said Several
platforms have been developed and tested in Tanzania. They have shown high potential of
improving collection and transmission of data although they lack technical support for
updates and bug fixing.
Furthermore as part of future improvement and implementation of the proposed
prototype, participants of this study suggested the involvement of more stakeholders such
as medical researchers at the data processing module and addition of more ways of
analysing collected data to improve maximum utilization of health data. Participants
suggested the proposed prototype to include a way of doing descriptive analysis on the
reported health data to improve the work of decision makers. Interestingly, participants
were suggesting features which are already included in the prototype such graphs to
analyze data. This assured us about the feasibility of the prototype in real scenario.
In general all participants supported the idea behind the proposed prototype and show
their hopes that the prototype is applicable in their countries. The health data expert who
was contacted in this study quoted saying I believe this application could be very useful
in developing countries and also could save time, resources and workload. The overall
response for each question from the questionnaire is summarized in Table 8.
Table 8: Overall response of the questionnaire
QUESTION OVERALL RESPONSE
What are the main challenges that face 1. Low data accuracy due of the paper based
health information systems in your method in data collecting.
country? 2. Delays in reporting crucial information to the
managerial level.
3. General lack of capacity for data collection and
processing (few health workers)
4. Poor record keeping methods and mostly are in
5. Poor health infrastructure that is exploited to
serve large population.
6. Lack of coordination between different levels of
health information systems
What kinds of data are reported from 1. Number of diseases cases reported in health
health facility to the management levels facilities
(secondary facilities)? 2. Medical equipments (medical assets)
3. Medical stock level information
4. Financial information
What is the frequency of reporting health 1. Monthly
data (e.g. Monthly, weekly, quarterly, 2. Quarterly
yearly)? 3. Weekly
4. Yearly
5. It depends on kind of reports
How long does it take to collect and One week to one month
aggregate health data using the current
method (eg.1 day, 1 week, and 1
month)?
Who are the most common users of Health service managers, doctors, government
health data (e.g. doctors, patients,
government)?
We have designed a mobile platform to All participants said Yes
collect and visualize health data; do you
think this could improve the current way
of collecting health data?
The proposed prototype offers health 1. Data filtering or query capabilities to answer
data mapping and simple graphs for specific questions
analysis. What other features that could 2. Ability to collect additional data if required for
be included in future to improve analysis specific cases or instances
process?
The proposed prototype involves only 1. Medical researchers at the data processing level
two main stakeholders (health 2. Medicine suppliers
statisticians and health managers). What
are other stakeholder do you think they
should be involved?
The proposed prototype has 1. Report of human resource available at the health
implemented two forms for capturing facility
diseases statistics in health facilities and 2. Report of health service asset at the health
tracks the medical stock level at the facility
health facility. What are other type of 3. Financial information report
reports do you think are important to be
implemented in future?
This chapter presents the summary, discussion and conclusion of the study.
In this master thesis project we have investigated the use of mobile technologies in
improving health data collection and reporting systems of the developing countries.
Through literature review, we have analyzed the current data collection and reporting
methods (see Chapter 3 and Chapter 4). Furthermore, we have briefly compared the
mobile technologies and the data collection open source frameworks (see Table 5 in
Section 4.6). Requirement analysis of the proposed prototype was through literature
review and the actual scenario of data collection and reporting process in developing
countries (case of Tanzania).
The proposed prototype focus on collection of the statistical data, which are reported
from primary health facilities to secondary health facilities. The overall aim is to improve
the health service through improved data driven decision and policy making process.
Timely and appropriate data are essential for effective decision and policy making
process [28]. The communication infrastructure in the developing world is not
sustainable, manual reporting of health data from remote health facilities is difficult and
lead to delay of plans and decisions. We focused on mobile technologies and open source
frameworks, which can improve data collection and reporting process. The proposed
prototype has been developed to test the applicability and usability of the available
mobile and open source technologies in improving the reporting process.
The evaluation study showed the proposed prototype seems to be applicable for
improving the health data collection and reporting systems in the developing world.
However, there is a need for further evaluation of the prototype in actual environment
(health systems in the developing world) and using requirements from the primary source
(health data experts) to model the functionalities that meet the requirements.
7.2 Discussion
Current practice of collecting health data is through paper based methods where physical
forms are filled with data and collected manually. The transcription of data for analysis is
difficult and lead to low quality of data especially when the data volume is large.
Furthermore, the supervision of multiple data collections from multiple locations is
difficult and may lead to large time lag for data to be available for usage. The proposed
prototype has implemented electronic data collection forms that are easy to manage for
remote health data collection from multiple areas. In addition, the proposed prototype has
implemented data viewer module where collected data can be visualized and manipulated
for analysis purpose. Compared with paper based methods, which require extra efforts of
filling the forms and thereafter enter the data manually in computer software such as MS
Excels and spreadsheet, the proposed prototype has linked the data collection feature and
data manipulation feature. Therefore, the proposed prototype may reduce difficulties in
data collection and minimizes the time lag for data to be available for usage. Data
transcription with proposed prototype is simplified as the data is feed directly to the
database through a mobile phone; therefore human data transcription errors can be
minimized and increase data accuracy.
The proposed prototype seems to have capability of capturing data of all type such
text, audio, video, images, barcodes, and GPS data; therefore it add more flexibility in
kinds of data that can be collected than other frameworks such as RapidSMS,
FrontlineSMS and Pendragon forms which have limitation in capability of collecting
data. Furthermore, proposed prototype is customizable (flexible form design) and can be
deployed in user defined settings compared to other mobile data collection frameworks
which are close source and do not offer options to work with user defined settings such as
custom data collection forms and other data visualization options.
The flexibility on terminologies used in data collection forms allows easy way of
setting uniformity of data formats and therefore increase coordination of different levels
of health information system. Therefore, the proposed prototype may be used to capture
health data of various types depending on the demand.
The framework selected to design the proposed prototype (ODK) is based on open
source technologies, which allow future development with less effort, which can be
affordable and manageable by the economy of the developing regions.
Answering the research questions
data collection and reporting methods from primary health facilities to secondary health
Through literature review and qualitative study, we have found challenges that
impede health data collection and reporting systems.
With paper-based methods, data accuracy and consistency in reporting is difficult to
maintain. The limitations of resources such as human resources and the growth of
population in the developing world put health data workers in tedious situation of
dealing with large volumes of data through paper-based methods.
With paper based methods, it is hard for the health service managers to track health
data from remote health facilities. This may lead to delays in generation of important
reports that could help decision makers and policy makers in improving the health
Despite of several efforts of improving health data collection process through mobile
technology, the available solutions are proprietary based and they lack enough
support to users.
RQ2: What are the available open source mobile technologies tools that can be used to
collect health data remotely?
To answer this research question we have critically analyzed several data collection
frameworks based on their capability in capturing data with consideration of the
developing world settings. We have evaluated several data collection frameworks
(see Section 4.6). The evaluation process assessed the mobile data collection
frameworks technologies based on their data capturing capabilities, data types, and
platform support and storage capability.
RQ3: How can mobile technologies and open source frameworks improve the aggregated
health data collection and reporting process from primary to secondary facilities?
To answer this research question, a health data collection prototype has been
proposed. The prototype has been developed from the open source framework
selected after evaluating several available frameworks. The proposed prototype has
implemented electronic health data collection forms to test how the mobile
technology can be used to improve the health data collection and reporting process.
Furthermore, the prototype has implemented a way health managers can visualize
collected data for analysis and decision making purpose. The collected data can be
visualized through data mapping and simple graph features. Moreover, the prototype
can be used to depict the flow of health data from primary health facilities to
secondary health facilities in the developing world and can be used as blue print for
future actual implementation in real settings.
7.3 General implications of the study findings
The realization that mobile phone based health reporting systems are feasible in the
developing world has important implications for health reforms in these parts of the
world. It has already been observed that the use of mobile phone for communication is
prevalent in the developing world and that the current paper-based reporting systems are
not sustainable. There is thus the need for pilot projects to adopt new models such as the
prototype proposed in this research in a controlled and experimental process in the field.
This will provide the needed data sets for the review of the prototype and for streamlining
future research works.
7.4 Contribution to previous work
The overall contribution from this study is knowledge of how mobile technologies can
improve health data collection and reporting process using open source frameworks.
Comparing with previous work which studied the use of mobile technology such as
PDAs [49][46], OpenMRS [25] and cellular phones for data collection, this study has
attempted to evaluate and test the use of emerging mobile technology (Android) for
remote data collection. Unlike previous studies which did not draw much attention on
open source technology solutions, this study has investigated the applicability of open
source technologies in improving health data reporting systems of the developing world.
Previous work on mobile-based health data collection systems has focused on capturing
remote data through SMS, which has limitation in capability of capturing data. For
example one SMS can collect only maximum of 160 text characters [36]. With the
proposed prototype, one electronic form can capture unlimited amount of all data type
including text, video, audio, barcodes and GPS data. Furthermore, SMS based data
collection systems required users to have knowledge of the SMS format, for example
leaving space between data elements. Electronic forms that have been implemented in the
proposed prototype are user friendly and can let user fill the proper data in proper input
box (structured data). The data visualization interface of the proposed prototype may help
the decision makers to quickly access data.
The empirical contribution from the proposed prototype is to serve as a blue print of
the actual implementation of the systems that could improve data collection and reporting
from health facility to district level.
7.5 Limitations of the proposed prototype
The proposed prototype has been developed basing on the requirements from secondary
sources such as literature, therefore it could not be deployed directly in the field rather it
can be used to depict the general process of the health data reporting using mobile
technology. Furthermore, the proposed prototype works only on Android based mobile
phones and the current administration module has been tested to work on Google Cloud
only. For the prototype to be successful on the field there is need for a series of field tests
and modifications that do not fall under the scope of the current project.
7.6 Future work
The future studies in this research area could attempt to develop the proposed prototype
using data and specifications from the primary sources (actual stakeholders). Such works
could also focus on enhancing health data visualization to improve the analysis process.
For example, enable data visualization through mobile phone screen (mobile interface for
data visualization). The health data analysis process could also be improved in such a
way that some of the decisions to be automated can be based on the collected data. For
example, once the drugs stock level goes below certain value, the system can be triggered
to provide alerts and suggestions to the health service managers about how to handle the
stock run out. Furthermore, the future studies could look at the way different health data
systems can be integrated to avoid duplication of data and maintain consistency reports.
In addition to that, future work could attempt to investigate ways of coordinating
different health information systems levels to avoid fragmentation of flow of information
through centralization of health data centers. Moreover, there are still rooms for
investigating how open source frameworks could enhance other health management
services in the developing world. For example, studies are needed to evaluate the
applicability of different open source software packages for health service management
Security to health data is another area future studies can look. The advancement of
ICT increases vulnerability of the privacy and security of health data, especially sensitive
health data (statistical data) which might have great impact to the health service. Future
work can investigate ways of securing health data in the ubiquitous networks and other
health data transmitting networks.
Appendix I: Sample form of diseases reporting [62]
Appendix II: Sample form of diseases reporting
Appendix III: Questionnaire used for qualitative study
This questionnaire is prepared by Deo Shao a student undertaking Master of Computer
Science (MCS) at Malmo University -Sweden. With the guidance of my supervisor
Annabella Loconsole, I need to conduct a qualitative study to understand challenges of
remote health data collection and reporting systems in the developing world and also to
evaluate the proposed prototype for mobile health data collection. Your participation in
this research study will be highly appreciated.
Your response to this questionnaire will be treated with confidentiality. Your response is
very important to me as this will lead to the final write-up of my thesis. The questionnaire
should not take too long to complete.
Thank you very much for your time. Please do not hesitate to contact me with the email
below if you have any questions concerning this questionnaire.
Email: deoshayo@hotmail.com
Proposed prototype description
We have designed a prototype for mobile health data collection that will serve decision
and health policy makers in their works. The proposed prototype has focus on reporting
health data from primary facilities (hospitals, dispensaries, health canters) to secondary
facility (district health managerial level). The focus is more on statistical data that could
help health managers in making decisions and policy of improving health services. The
prototype has been deployed in Google cloud and tested. Below are sample screenshots
showing the main functionality of the application.
A sample screenshot of the data mapping in a web browser
Sample screenshot of the bar graph of districts against malaria reported cases
Mobile application main menu
Electronic form for collecting data
General Architecture of the prototype
Questions: Multiple choice you may highlight the answers.
1. Nationality: ..............................................................................
2. Have you ever worked in health sector?
a. Yes b. No
If you answered Yes in which position? .......................
3. How is health data collected in your country?.....................
a. Paper methods
b. Mobile device
c. Computer software
d. I dont know
4. To what extent is mobile technology used in your country?.......................
a. Wide b. Intermediate c. Low
5. Do you think mobile device applications could easy health data collection and
reporting process?.................
a.Yes b. No
6. Which kind of mobile phones are common to your country?................
a. Smartphones. b. Cell phones. c. Both.
7. Which mobile platform do you use?..................
a. Android phones (Android)
b. Nokia phones (Symbian)
c. Blackberry phones (Blackberry)
d. Windows phones (Windows)
e. iPhone (iOS)
f. Other phones
8. Do mobile networks cover the most part of your country?...................
a. Yes b. No c. I do not know
Evaluation of the proposed prototype
9. Is the health information systems computerized in your country?...............
10. What are the main challenges that face health information systems in your
country?
11. What kinds of data are reported from health facility to the management levels
(secondary facilities)?
12. What is the frequency of reporting health data (e.g. monthly, weekly, quarterly,
yearly)?
13. How long does it take to collect and aggregate health data using the current
method (eg.1 day, 1 week, and 1 month)?
14. Who are the most common users of health data (e.g. doctors, patients,
15. We have designed a mobile platform to collect and visualize health data; do you
think this could improve the current way of collecting health data?
16. The proposed prototype offers health data mapping and simple graphs for
analysis. What other features that could be included in future to improve analysis
17. The proposed prototype involves only two main stakeholders (health statisticians
and health managers). What other stakeholders do you think should be involved?
18. The proposed prototype has implemented two forms for capturing diseases
statistics in health facilities and tracks the medical stock level at the health
facility. What other type of reports that you think are important to be implemented
in future?
19. The proposed prototype has been developed in the Android platform. Do you
think that this platform is now common in your country and could be proper
platform for developing community applications?
20. Any other comments or suggestion.
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Only 11% of Americans correctly estimate their ideal daily calorie requirements, according to one survey. The rest of us tend to overestimate, says Bonnie Taub-Dix, RD, a spokesperson for the Academy of Nutrition and Dietetics. Let's say you assume that consuming 2,000 calories per day will allow you to reach your target weight, but it really takes 1,800: Those extra 200 are enough to keep an additional 20 pounds on your frame.
Chronic migraines were what first inspired Amanda Tagge to start exercising. “I was hoping to find some relief from my headaches and working out did help but I realized that if I really wanted to feel better I needed to revamp my health habits overall and lose weight,” she says. The more she changed, the better her headaches got and she lost 70 pounds in the process which helped her feel even better. Focusing on all the ways her health was improving kept her going even when the scale wasn’t moving.
You know the drill: Replace refined, overly processed foods with more natural, whole foods. Sure, all foods fit, but they don’t all fit equally. Here’s why: Every time you eat, your metabolism increases as your body works to process your meal. Studies that compare the metabolic boost of calorie-matched whole foods to processed ones find that your body can burn up to 50 percent more calories after a meal made with more real food ingredients compared to a similar meal made with more processed fare. The fact is, your body has to work harder to break down whole foods in order to grab the raw materials it needs so if you exist on a lot of packaged foods and fast foods (think: chips, donuts and drive-thru fare), it’s going to be tougher to lose weight and keep those pounds from coming back.
Counseling and community: In-person group meetings typically meet at a community center or business on regular basis. Participants might engage in a group discussion, breakaway groups or one-on-one sessions with other members or program counselors. Some weight loss programs rely on internet-based forums and communities or mobile applications for meal planning, counseling, group interaction and support.
You may think you're vigilant about watching what you eat, but research shows that stolen bites and tastes can rack up a few hundred uncounted calories, which can put on pounds fast. Eating while distracted can cause mindless eating, too. When women who normally watched their portions had lunch in different situations, they ate 15% more (72 additional calories) while listening to a detective story, compared with when they ate alone and free of any distractions, found a study in the American Journal of Clinical Nutrition.
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So she started researching. She found something called the 21-Day Meal Plan, which seemed like it would work with their lives. The plan showed them what foods they could eat and what they should skip. They started by cutting sugar, junk and processed foods and added vegetables, fruit, legumes, whole grains and lean meats, such as chicken and turkey. In the first week, Parent noticed a difference.
Get all that? Basically, the differences between groups were minimal. Yes, the low-fat group dropped their daily fat intake and the low-carb group dropped their daily carb intake. But both groups ended up taking in 500 to 600 calories less per day than they had before, and both lost the same average amount of weight (12 pounds) over the course of a year. Those genetic and physical makeups didn’t result in any differences either. The only measure that was different was that the LDL (low density lipoprotein) was significantly lower in the low-fat group, and the HDL (high density lipoprotein) was significantly higher in the low-carb group.
For even more impressive effects on body composition: aim for exercise forms which elicit a positive hormonal response. This means lifting really heavy things (strength training), or interval training. Such exercise increases levels of the sex hormone testosterone (primarily in men) as well as growth hormone. Not only do greater levels of these hormones increase your muscle mass, but they also decrease your visceral fat (belly fat) in the long term.
Trying to lose weight? Having trouble? Women often find it harder than men to shed excess pounds. In part that's because women's bodies have a tendency to "hold on" to a certain amount of fat. But in some cases the problem can be traced directly to certain habits and lifestyle traps - including many that can easily be remedied. Here are 10 weight-loss traps to watch out for:
Illescas-Zarate, D., Espinosa-Montero, J., Flores, M., & Barquera, S. (2015, April 19). Plain water consumption is associated with lower intake of caloric beverage: Cross-sectional study in Mexican adults with low socioeconomic status. BMC Public Health, 15, 405. Retrieved from https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-015-1699-0
Remember that in order to keep the pounds off and maintain your happy weight, you need to develop a healthy lifestyle. That means forming a routine and keeping up the habits so you can hang on to them for life. "I forced myself out of bed at 5:30 a.m. four to five times a week to run," says Erin Bowman who has kept off 69 pounds. "My first few were horrible. But I stuck with it, eventually trading my run-walk intervals for steady 45-minute jogs," she says.
The customized support and abundant resources come at a price. This varies based on the intensity of your weight loss goals; we paid $60 per month. (We made an account before purchasing and received a 50% off offer by email to incentivize our membership. Tease them in the same way and see if you get the same deal.) If you want to get a look at all these perks before you purchase, you can try Noom free for 14 days.
Eat Breakfast Every Day. One habit that's common to many people who have lost weight and kept it off is eating breakfast every day. "Many people think skipping breakfast is a great way to cut calories, but they usually end up eating more throughout the day, says Elizabeth Ward, MS, RD, author of The Pocket Idiot's Guide to the New Food Pyramids. "Studies show people who eat breakfast have lower BMIs than breakfast-skippers and perform better, whether at school or in the boardroom." Try a bowl of whole-grain cereal topped with fruit and low-fat dairy for a quick and nutritious start to your day.
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Sasha Alexander Net Worth 2019, Bio, Wiki, Age, Height
Sasha Alexander is a known Serbian-American actress who became popular all over the world with her role as Kaitlin Todd in “NCIS” and later as Dr. Maura Isles in “Rizzoli & Isles”.
Early life:
She was born on May 17, 1973 in Los Angeles in California to parents who are both of Serbian ancestry. Her birth name is Suzana S. Drobnjaković but she eventually changed it into Sasha Alexander.
She has a brother named Alexander. Alexander is a commom Russian and Serbian name.
Sasha began acting in the seventh grade and got involved in almost all school productions.
Once she acted as a leading female in the production of “Baby” at her school. The same day her partner who was also the leading male actor decided not to show up at the play and she was left all alone in front of the audience.
That hasn’t stopped her to use her skills as a comedian and she played out the whole play by acting both roles.
The audience was stunned by her performance and that gave her the wings to continue her dream. She knew that she has theatre in her blood.
She was also an avid ice skater, greatly talented but had to quit her skating career due to a knee injury.
She continued acting both in high school and in college. Sasha tried herself as a band singer in 1987 (when she was 14). The band was called “Everything Nice”.
She is a graduate of Southern California’s School of Cinema-Television where she studies directing. Kappa Alpha Theta was her college sorority.
She always wanted to be involved in Shakespeare’s festival programme so she relocated to New York. With her role of Katherine in “The Taming of the Shrew” she received great critics and a place on the Royal Shakespeare Company opened for her.
Career development:
Sasha starred getting a lot of offers and played in a lot of festivals, and besides that she has written numerous productions, such as “Lucky 13”, a comedy with Harland Williams and Lauren Graham. She also acted in this film.
She was involved in many aspects of movie making, not only in acting. She produced an independent comedy film called “X-Girlfriends.” She also starred in it.
In 1997 she was a cast member in “Supply & Demand”, “Battle of the Sexes” and “Visceral Matter.”
She co-starred in a TV drama “Dawson’s Creek” in 1998. Her role in this popular series was as Gretchen Witter who dated the leading character. She was a cast member of this series almost two years.
In 1999 she acted in “Twin Falls Idaho” and in “Wasteland”.
She also starred in “Greg the Bunny”, but the series ended quickly. In this role, of a Lesbian reporter she did her first onscreen kiss with another woman, Sarah Silverman.
Some of the movies she worked on or played a role in were: “All Over the Guy” , “The Last Lullaby” and “Yes Man” (where she acted alongside Jim Carrey). “Yes Man” is a comedy based on the memoir by British humorist Danny Wallace and produced and directed by Peyton Reed.
In Jeffrey Goodman’s “Last Lullaby” ( 2008) she starred alongside Tom Sizemore.
She once played in CSI in an episode called “Alter Boys”.
Sasha also starred as Dr. Jackie Collette in “Presidio Med” , a CBS series.
She became widely popular for her role od NCIS special agent Caitlin Todd in 2003. Her career in NCIS role ended in 2005 when she was killed by a terrorist. It is known that she asked for her departure from the show.
She also appeared in a few episodes if JAG.
In 2006 she gained a small role in “Mission Impossible III.
She shortly joined the acting crew on “The Nine” and she was in one episode of “Friends” (where she interviewed Joey).
“He’s Just Not That Into You” in 2009 was also a very successful film in which she played where the leading roles were given to Jennifer Aniston and Ben Affleck.
In 2010 she started playing one of her most famous roles – she became Dr.Maura Isles in a popular “Rizzoli & Isles” series, where she acted as the medical examiner. The other leading role in the series, a detective Jane Rizzoli, was played by Angie Harmon who became her best friend there.
In “Shameless”, which was produced by “Showtime” she played a college professor.
She won the People’s Choice Award for Favorite Cable TV Actress forr her great work in “Rizzoli & Isles”.
She has an award from San Diego Film Festival Award which she received for her work on “The Last Lullaby”.
Personal life:
In 1999, when she was 26, she married Luka Pecel, an American film director, but the mariage was ended in a few weeks.
Eight years later she married Edoardo Ponti, a known movie director and the son of Sophia Loren and Carlo Ponti. Sophia Loren is a known actress and his father Carlo was a film producer.
Sasha and Edoardo got married in 2007 at the Russian Orthodox Church in Geneva in Switzerland.
Together they have two kids: a daughter Lucia Sophia Ponti born in 2006, and a son called Leonardo Fortunato Ponti, born in 2010. Both children were born in Geneva.
Sasha is involved in a lot of activities and she is keeping her body in shape by her healthy diet and exercise.
She uses ice-skating and dancing for her routine exercise and learns her kids to skate too.
Meditation is her another tool to keep her body in balance.
She is very rich and owns large properties. She is the face of Cover Girl cosmetics. Sasha owns a few restaurants and has has her own brand of Vodka. It us called “Pure Wonderalexander US”.
She released her own perfume called “With Love from Sash”.
She loves travelling and she plans visiting China and Japan in the near future. It was hard to travel when her kids were young but now it is much easier.
Full name: Suzana Drobnjaković
Date of birth: May 17, 1973
Birthplace: Los Angeles, California, U.S.
Weight: 57 kgs
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Models, TV Stars
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Archive for Western
Westworld 2016
A dark odyssey about the dawn of artificial consciousness and the evolution of sin. Set at the intersection of the near future and the reimagined past, it explores a world in which every human appetite, no matter how noble or depraved, can be indulged.
Science Fiction | Western
Little House on the Prairie 1974
Little House on the Prairie is an American Western drama television series, starring Michael Landon, Melissa Gilbert, and Karen Grassle, about a family living on a farm in Walnut Grove, Minnesota, in the 1870s and 1880s.
Drama | Western
Wynonna Earp 2016
Wyatt Earp's great granddaughter Wynonna battles demons and other creatures with her unique abilities and a posse of dysfunctional allies - the only thing that can bring the paranormal to justice.
Western | Action & Adventure | Sci-Fi & Fantasy
Have Gun – Will Travel 1957
Have Gun – Will Travel is an American Western television series that aired on CBS from 1957 through 1963. It was rated number three or number four in the Nielsen ratings every year of its first four seasons. It was one of the few television shows to spawn a successful radio version. The radio series debuted November 23, 1958. The television show is presently shown on the Encore-Western channel. Have Gun – Will Travel was created by Sam Rolfe and Herb Meadow and produced by Frank Pierson, Don Ingalls, Robert Sparks, and Julian Claman. There were 225 episodes of the TV series, 24 written by Gene Roddenberry. Other contributors included Bruce Geller, Harry Julian Fink, Don Brinkley and Irving Wallace. Andrew McLaglen directed 101 episodes and 19 were directed by series star Richard Boone.
Western | Action & Adventure
The Virginian 1962
The Virginian is an American Western television series starring James Drury and Doug McClure, which aired on NBC from 1962 to 1971 for a total of 249 episodes. It was a spin-off from a 1958 summer series called Decision. Filmed in color, The Virginian became television's first 90-minute western series. Immensely successful, it ran for nine seasons—television's third longest running western. It follows Bonanza at fourteen seasons and 430 episodes, and Gunsmoke at twenty seasons and 635 episodes.
The Big Valley 1965
The Big Valley is an American western television series which ran on ABC from September 15, 1965, to May 19, 1969. The show stars Barbara Stanwyck, as the widow of a wealthy nineteenth century California rancher. It was created by A.I. Bezzerides and Louis F. Edelman, and produced by Levy-Gardner-Laven for Four Star Television.
Deadwood 2004
The story of the early days of Deadwood, South Dakota; woven around actual historic events with most of the main characters based on real people. Deadwood starts as a gold mining camp and gradually turns from a lawless wild-west community into an organized wild-west civilized town. The story focuses on the real-life characters Seth Bullock and Al Swearengen.
Crime | Drama | Western
Yellowstone 2018
Follow the violent world of the Dutton family, who controls the largest contiguous ranch in the United States. Led by their patriarch John Dutton, the family defends their property against constant attack by land developers, an Indian reservation, and America’s first National Park.
Longmire 2012
A Wyoming sheriff rebuilds his life and career following the death of his wife. Based on the “Walt Longmire” series of mystery novels written by best-selling author Craig Johnson.
Dick Powell's Zane Grey Theater 1956
Dick Powell's Zane Grey Theatre, sometimes simply called Zane Grey Theatre, is an American Western anthology series which ran on CBS from 1956 to 1961.
The Rifleman 1958
The Rifleman is an American Western television program starring Chuck Connors as rancher Lucas McCain and Johnny Crawford as his son, Mark McCain. It was set in the 1880s in the town of North Fork, New Mexico Territory. The show was filmed in black-and-white, half-hour episodes. "The Rifleman" aired on ABC from September 30, 1958 to April 8, 1963 as a production of Four Star Television. It was one of the first prime time series to have a widowed parent raise a child.
Wanted: Dead or Alive 1958
Wanted: Dead or Alive is an American Western television series starring Steve McQueen as the bounty hunter Josh Randall. It aired on CBS for three seasons from 1958–61. The black-and-white program was a spin-off of a March 1958 episode of Trackdown, a 1957–59 western series starring Robert Culp. Both series were produced by Four Star Television in association with CBS Television. The series launched McQueen into becoming the first television star to cross over into comparable status on the big screen.
Dr. Quinn, Medicine Woman 1993
Dr. Michaela Quinn journeys to Colorado Springs to be the town's physician after her father's death in 1868.
Maverick 1957
Maverick is an American Western television series with comedic overtones created by Roy Huggins. The show ran from September 22, 1957 to July 8, 1962 on ABC and stars James Garner as Bret Maverick, an adroitly articulate cardsharp. Eight episodes into the first season, he was joined by Jack Kelly as his brother Bart, and from that point on, Garner and Kelly alternated leads from week to week, sometimes teaming up for the occasional two-brother episode. The Mavericks were poker players from Texas who traveled all over the American Old West and on Mississippi riverboats, constantly getting into and out of life-threatening trouble of one sort or another, usually involving money, women, or both. They would typically find themselves weighing a financial windfall against a moral dilemma. More often than not, their consciences trumped their wallets since both Mavericks were intensely ethical. When Garner left the series after the third season due to a legal dispute, Roger Moore was added to the cast as their cousin Beau Maverick. Robert Colbert appeared later in the fourth season as a third Maverick brother, Brent Maverick. No more than two of the series leads ever appeared together in the same episode, and usually only one.
Comedy | Western
Cheyenne 1955
Cheyenne is an American western television series of 108 black-and-white episodes broadcast on ABC from 1955 to 1963. The show was the first hour-long western, and in fact the first hour-long dramatic series of any kind, with continuing characters, to last more than one season. It was also the first series to be made by a major Hollywood film studio which did not derive from its established film properties, and the first of a long chain of Warner Brothers original series produced by William T. Orr.
Hell on Wheels 2011
Hell on Wheels tells the epic story of post-Civil War America, focusing on Cullen Bohannon, a Confederate soldier who sets out to exact revenge on the Union soldiers who killed his wife. His journey takes him west to Hell on Wheels, a dangerous, raucous, lawless melting pot of a town that travels with and services the construction of the first transcontinental railroad, an engineering feat unprecedented for its time.
Drama | Western | Action & Adventure
Laramie 1959
Laramie is an American Western television series that aired on NBC from 1959 to 1963. A Revue Studios production, the program originally starred John Smith as Slim Sherman, Robert Fuller as Jess Harper, Hoagy Carmichael as Jonesy and Robert L. Crawford, Jr., as Andy Sherman.
Bonanza 1959
The High-Sierra adventures of Ben Cartwright and his sons as they run and defend their ranch while helping the surrounding community.
Godless 2017
A ruthless outlaw terrorizes the West in search of a former member of his gang, who’s found a new life in a quiet town populated only by women.
The Wild Wild West 1965
The Wild Wild West is an American television series Developed at a time when the television western was losing ground to the spy genre, this show was conceived by its creator, Michael Garrison, as "James Bond on horseback." Set during the administration of President Ulysses Grant, the series followed Secret Service agents James West and Artemus Gordon as they solved crimes, protected the President, and foiled the plans of megalomaniacal villains to take over all or part of the United States. The show also featured a number of fantasy elements, such as the technologically advanced devices used by the agents and their adversaries. The combination of the Victorian era time-frame and the use of Verne-esque style technology have inspired some to give the show credit for the origins of the steam punk subculture.
Comedy | Drama | Western | Action & Adventure
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Questioning Sales
Automotive sales have been slowing in the U.S. for nearly a year.
Brett C. Smith
Sr. Research Associate , OSAT
Automotive sales have been slowing in the U.S. for nearly a year. Yet the extent of the downturn is still very much in doubt.
It is interesting and worthwhile to look at how this downturn has played out so far. The 2001 model year data (through May), correlates well with the start of the downturn last fall. The 5.5% drop in total light vehicle sales is an average: There are many losers, and a few winners. Early in the downturn, much was made about this being a Big Three sales drop, with Honda, Toyota and European luxury brands seeing growth. That is still true to an extent, but few have escaped entirely unscathed.
It has been a tough year for the Big Three on the passenger car side. The Chrysler Group was down over 20% through May, while Ford wasn’t much better at just over 17% down. And GM leads the pack with an 8% decrease—which happens to be better than the 9.3% decrease reported by the Toyota car division.
On the car side of the business, Toyota is having some difficulties. The Lexus IS300 and the LS430, both new, are the only cars that are showing any sign of growth in their car line-up. Sales for the company’s two volume cars—Camry and Corolla—are down, though the new Camry should change things. Interestingly, the Toyota truck division is carrying the company. With two new products (Highlander and Sequoia) and one redesigned product, Toyota trucks appear to be the sales success story of the year.
Honda was doing better through the first eight months of the model year (up nearly 3%), but it, too, was showing some signs of weakness. While the Accord continues to go strong, the new Civic has had some trouble keeping pace with the previous model. The Acura car division, in a market that has remained hot for luxury models, was down over 4%. In contrast to the performance of Toyota, the Honda ‘trucks’ (CRV, Odyssey, and Passport) have been down this year, while the Acura-branded MDX has boosted the company’s overall truck volume by almost 6%.
Many of the consumer forces that drove the Big Three profit machine of the mid- and late-90s may be changing.
Certainly it was little surprise that the new Explorer was down from previous model year figures. Given the previous version’s tire problems, and the excruciatingly slow launch, sales were bound to be down. Yet what is somewhat surprising is the speed at which Ford placed incentives on the hood of a high-profile vehicle.
GM has been a bit more restrained with the incentives on its midsize SUVs (Bravada, Trailblazer and Envoy). Yet it has had a slow launch to limit volume, doesn’t have the capacity (or history of sales leadership) that Ford does with the Explorer, and they were launched into an environment that is vastly different from just a year ago. They have competition not only from each other, but also from a multitude of highly versatile, more fuel-efficient cross utility vehicles (CUVs). Add to this an increased awareness by the press and some consumers of the safety trade-offs of truck-based SUVs, and the future is much less clear.
The CUVs—part car, part truck and yes, even part minivan are likely to continue to make inroads over the next several years. The question is: Will this growth come from SUVs or cars? So far, the car segment appears to be holding up slightly better than the SUV segment in this context.
It appears that the only way to make it in 2001 is to have new, uniquely positioned product, or a whole lot of cash on the hood. And that leads to more questions: Like how long can the manufacturers continue to support the incentives, and concomitantly, by offering big rebates, are they pulling sales ahead and merely exacerbating the crash when it comes? Finally, which of the emerging segments will be the goldmine of the future, and at the cost of which segments?
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Chris Brown Arrested in West Palm Beach, Will His Concert in Tampa Tonight Still Happen?
Collin Sherwin
Singer Chris Brown was arrested last night in West Palm Beach following his performance at the Coral Sky Amphitheatre.
His concert in Tampa at the MIDFLORIDA Credit Union Amphitheatre scheduled for tonight, July 6th, is expected to go on as planned.
Brown was arrested on a warrant from an incident at AJA Channelside in Tampa last August, where he is alleged to have punched a photographer being paid to document the singer's afterparty appearance. The warrant was served on behalf of the Tampa Police Department, and Brown was released in Palm Beach on $2,000 bond.
It's certainly not Brown's first run-in with the law, including a domestic violence settlement with Rihanna in 2009, a nightclub incident with Drake, Spurs point guard Tony Parker and their entourages in New York City in 2002, a guilty plea to assault outside a Washington D.C. hotel in 2013, and a restraining order from model Karrueche Tran just last year. Rihanna still has a restraining order against him as well.
Photo of Palm Beach County Sheriff's Office
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About a-n
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DSG Features
degree-show
Dear Shareholder
Solo Show at THE RYDER project
19a Herald St, London E2 6JT
THE RYDER Projects
The stock market, an endless pool of changing values. A constant movement of data circulation that stands behind the curtains of our everyday life. Its mechanical wheels turn slowly in the back stage’s of international corporations, translated into mathematical equations that determine their influence and power.
In the great hall of NYC stock exchange stand tall round pillars, covered by dozens of flickering screens. Green numbers and letters run up and down these custom monitors. To the untrained eye they are nothing more than a visual spectacle. Deciphering it is like trying to find meaning in the shapes clouds form in the sky. It is only the brokers, priests of the market, who can produce meaning by gazing at the sky of figures appearing before them. Only they can predict the economic rise and fall of kingdoms, the collapse of empires, or the birth of a new star. The delicate task of buying and selling is performed in part in screams, shouts and gestures in front of the screen. They are the prophets, practicing the divine art of money making –the knowledge of value and profit.
Occasionally (as in any astronomical system), something happens. A solar eclipse, a sudden but drastic change of climate…
The RYDER is proud to present the work of Fabio Lattanzi Antinori, which celebrates the fragile existence of mass data archives. Drawing from daily-trading figures, financial flash-crash algorithm records, news-websites, search engines results, dark pools operations and E-bay cheapest sales descriptions, Antinori manipulates these into stories of collapsed financial empires. Like the narrator of a Greek tragedy, his hand flickering on an imaginary harp, he plays the soundtrack of the predetermined collapse, transforming stock values and data entries into angelic voices who sing the chorus of inevitable catastrophe.
Fabio Lattanzi Antinori, born in Rome, earned his MFA in Arts and Computational Technologies from Goldsmiths, London, in 2013. Antinori was selected for the PS1 Summer School, New York, in 2012 to study with Marina Abramović; he recently had a solo exhibition at the MoCA Shanghai Pavilion and was also part of the Triennial of Fiber Art in Hangzhou (2016). Recent exhibitions include a duo show with Jeremy Everett at Kristin Hjellegjerde gallery, London (2016), Brun Fine Art (2016), East London Printmakers, London (2015), and Dream Home, Arebyte Gallery, London (2015). Group exhibitions include the Kaunas Biennial, Lithuania (2015), Heaven Is A Place Where Nothing Ever Happens, Pi Artworks, London (2015), NYU, New York (2015), Museum of Contemporary Cuts (2015), Production Methods, Watermans Arts Centre, London (2015), the Victoria & Albert Museum, London (2014), and the Museum für angewandte Kunst, Vienna (2013). He was awarded the Connections Through Culture bursary from the British Council (2016), the A-N Travel Bursary for extraordinary and inspirational research (2016), the Artist International Development Fund from the Arts Council (2016); he was selected for Guest Projects (2015), the Florence Trust residency (2014) and the Open Data Institute collection (2012). Public collections include the Villa Lagarina Civic Museum, Rovereto and the Crespina Civic Museum, Pisa and the V&A, London.
Bar Yerushalmi is of French-Israeli descent. His body of work has been based throughout and has worked in London, Paris, Melbourne and Tel Aviv, where he serves as an independent curator and art consultant. He received his BA in Fine Arts from École Nationale Supérieure des Beaux-Arts, Paris and MFA in Curating from Goldsmiths, University of London. His experience includes a wide range of curatorial work, in small to medium size gallery spaces. Bar currently represents Fehily Contemporary Gallery in London, and serving as associate-curator of ‘Into The Wild’, an artist development programme at the Chisenhale studios in London. His recent projects include EmbassyHACK (2016), a co-curated group exhibition at the Government Art Collection, London. Assistant to the curatorial team of Agnes Martin (2015) retrospective at Tate Modern, London, Panacea (2015), a group exhibition at 43 Inverness Street Gallery, London; MEIL (2015), a co-curated group exhibition at Chisenhale Studios, London; Partial Presence (2015), a co-curated group exhibition at the Zabludowicz Collection, London; CONFLUX (2015), a co-curated group exhibition at the Electrician’s Shop, London; BADLAND (2014), a group exhibition at Fehily Contemporary Gallery, Melbourne; and Chaiers (2013), a solo exhibition at ENSBA Gallery, Paris.
Fabio Lattanzi Antinori
My practice encompasses sculpture, print, sound, poetry and interactive installations and it attempts to provide an understanding of the process by which notions of belief and the perception of reality are being shaped and shared between the world of corporate systems and the individual. More recently, my artistic research has focused on the world and language of the International Finance, as after all, as Neil MacGregor once defined it, the whole financial system depends on voluntary acts of faith. It is precisely this fictional aspect of money, the co-operational act of agreeing on its value and its consequent moral obligations that derive from such a shared view of reality that drives my interest and artistic production. I incorporate elements of the invisible yet pervasive domain of digital technology and responsive materials in my works, in order to manifest that which is otherwise intangible; coded surfaces and data informed structured so become a tool of investigation of the constant act of negotiation that goes behind the system of information we call tangible reality. My process is often collaborative and research based. From collaborating with RCA graduates in developing an innovative sensor based technology, to working with English and Chinese opera singers to create interactive artworks with a strong choral vocal component, to commissioning data analysts, scientists and a financial astrologer to forecast the value of International Finance markets, to working with an economist and explore ways to re-imagine the market driven society through language and poetry. Selected solo shows comprehend the MoCA Shanghai (2016), Ryder Projects (London, 2016), Museum für angewandte Kunst, (Vienna 2013); selected group shows comprehend the National Museum of Science and Technology (Milan, 2017), the Holon Museum (2017), the Galerie Für Gegenwartskunst (Freiburg 2017), the Odessa Biennale (August 2017), the participation in the Hangzhou Triennial of Fiber Art (Hangzhou, September 2016), the Kaunas Biennale, (2015), PiArtworks Gallery (London 2015), the Guest Projects (London, 2015), New York University (2015), the Museum of Contemporary Cuts (on-line, 2015), the Watermans Arts Centre (London, 2015 and 2014), the V&A London (London, 2014), the Contemporary Art Terminal (Shenzen, 2013) the Open Data Institute (London, 2012). Public collections that have acquired my work include the V&A (London), the Villa Lagarina Civic Museum (Rovereto) and the Crespina Civic Museum (Pisa); private collections include the Open Data Institute (London) and various private collections in Trento, Milan, London and Rome.
© a-n The Artists Information Co
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Southern Music is American Music
By Tom Daniel on Dec 14, 2018
Why do Southerners continue to fall into that trap where we only talk about the years1861-1865? There are almost 400 years of Southern culture to talk about, yet we keep limiting ourselves to just four of them. And it doesn’t matter how much of an expert someone becomes about Fredericksburg, Yankees will always have that same ace-in-the-hole comeback, “You lost.” But music is different. Music is a decisive cultural venue where Yankees simply don’t stand a chance.
It would be notable enough if the South contributed maybe four or five significant genres of American music – but we contributed almost ALL of them! American music has a Southern accent, because practically all of American music is Southern in both origin and identity. Any identifiable American musical sound that’s known around the world is actually a Southern sound, and whenever people talk about American music, they’re actually talking about Southern music.
Creating a list of genres of American music that comes from the South is basically the same thing as creating a list of American music. Blues, ragtime, boogie-woogie, Dixieland,jazz, swing, country, honky-tonk, outlaw, rhythm & blues, rockabilly, rock‘n roll, bluegrass, western swing, coal mining, Appalachian, sacred harp, spiritual,gospel, barbershop, soul, funk, Gullah, Carolina shag, swamp rock, southern rock, Chicano rock, death metal, dirty south, parrot head, Tejano, creole,Cajun, zydeco, etc. All of those genres are unique to the South, and were created using authentic Southern ingredients. They didn’t “pass through”Dixie. They were all born in Dixie. Additionally, those genres literally couldn’t have come from anyplace else.
Southern music is like a big bowl of gumbo. Dixieland is a mixture of creole and Southern African-American music. Rock ‘n roll is a mixture of country and rhythm & blues. Soul is a mixture of rock ‘n roll and gospel. Western swing is a mixture of country and jazz. So, not only are the genres uniquely Southern, the very ingredients from which they are compiled are also uniquely Southern.
A Progressive might scan the list of Southern musical genres and object to its accuracy because examples of so-called “black music” and “white music” were included together. However, instead of seeing it only as a black vs white thing, Southerners recognize it as “Southern,”and not black or white. The same problem arises when a non-Southerners sees a plate of black-eyed peas and cornbread,and calls it, “soul food.” Southerners know that a plate of food like that is correctly called “Southern food,” not“soul food.” Therefore, in the South,the historically and culturally correct label for the music is “Southern music,”and not black or white music.
Southern music may very well be the undiscovered mother lode that we’ve all been seeking to help explain Southern culture to the non-Southerners. It might just be our elusive magic bullet. Southern music allows you to build relationships with people who are long gone, but still communicating.
Music has a magical ability to transport the listener directly into the mental state of the musicians, both performers and composers. You don’t just learn what they know, but you get to feel what they feel. Literature can’t exactly do that,because the writer is going to be necessarily literate. High-quality music frequently comes from the illiterate, the uneducated, and the unsophisticated. Also, music is a performance art, and is able to communicate more effectively than painting or literature. Every time a piece of music is performed,it’s rewritten, re-edited, and reinterpreted, and that becomes a HUGE advantage for Southern culture. Through ongoing performances of Southern music, people all over the world get to build contemporary relationships with our ancestors, and not just the selected,celebrated, historically important ancestors, but ALL of them. This includes the aforementioned illiterate, uneducated, unsophisticated, good, evil, profound,profane, black, and white Southern musician.
Southern music is a direct backdoor entrance to raw, authentic Southern culture without having to go through any filtered Yankee nonsense. “Come on in, y’all, thedoor’s open. Help yourself. This is what it’s like to be born and raised on a farm in Alabama. And this is what it’s like to work in a coal mine in Kentucky. And this is what it’s like to be so lonesome I could cry.”
I believe that the most significant difference between the South and the rest of the country is that in the South, although groups of people may not get along with each other and may clash and have their differences, frequently the people within the groups get along fine. They know each other, they work together, go to church together, and they’re neighbors. They have built relationships with each other, and they see eye-to-eye on a lot of face-to-face issues, and they are rightfully happy with that arrangement. However, outside the South, that situation is exactly reversed. Although groups of people may be technically cooperative, the individuals within the groups don’t have anything to do with each other. I like our way better.
Relationships are some of the most important things created in life, and that is the key to understanding Southern music. Southern music was not created by committee, or by decree, or by a government. It was created by individual people building relationships with each other, cooperating and collaborating with each other,learning from each other, and having a good time. Ultimately, that is also the key to understanding all of Southern culture.
Tom Daniel
About Tom Daniel
Tom Daniel holds a Ph.D in Music Education from Auburn University. He is a husband, father of four cats and a dog, and a college band director who lives back in the woods of Alabama with a cotton field right outside his bedroom window. His grandfather once told him he was "Scotch-Irish," and Tom has been trying to live up to those lofty Southern standards ever since. More from Tom Daniel
An Okie From Muskogee
By Timothy A. Duskin
As someone who grew up during the decade of the 1960’s, I am paying attention when I hear those on the Left talking of the events which took place 50 years ago. I was born… »
Timothy A. Duskin
Conan the Southerner?
By Joel T. Leggett
“Between the time when the oceans drank Atlantis, and the rise of the sons of Aryas, there was an age undreamed of. And unto this, Conan, destined to bear the jeweled crown of Aquilonia upon… »
Joel T. Leggett
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Afternoons Tonight! With James Valentine
Sunday, March 4, 2018 to Tuesday, December 31, 2019
Direct from sold out seasons including Sydney Opera House, James Valentine tours his wildly funny stage show across regional NSW between March-May 2018.
Experience all the hilarity of James Valentine’s Afternoon radio program from ABC Radio Sydney
but after dark! And in a theatre.
Expect live versions of such legendary segments as This Is What I Live With, Ex, The New Normal
and Petty Crime Stoppers…they’ll all be there. Who knows, maybe he’ll even attempt…Nothing.
You’ll laugh, you’ll crack up and you’ll have something to talk about all weekend!
No one looks at the world quite like James Valentine, and just when you think it can’t get any better, it does. Afternoons Tonight! is a fantastically funny and interactive night at the theatre and a great insight into how this radio show really works!
James Valentine is one of Australia’s most loved radio presenters and in a long and eclectic career has worked as a journalist, author, television host and musician. A saxophonist, he has performed with many acclaimed acts including: Jo Jo Zep, Models and Absent Friends. James also hosts the ABC Podcast Head Room which expands on musings and questions posed during James’ Afternoons radio show on ABC Radio Sydney.
NEW SHOWS ANNOUNCED SOON.
All the regular segments, and other stuff, will randomly emerge… as will the first full-length conversation between Richard Glover and James Valentine. If you saw last year’s show and loved it, if you listen to the radio version, or you just like to laugh, then don’t miss this all new live show.
Afternoons Tonight!is a fantastically funny and interactive night at the theatre and a great insight into how talk radio really works.
Book Tickets:https://theconcourse.com.au/james-valentine-w-special-guest-richard-glover/
Event Details: TBA
PLUS MORE SHOWS TO BE ANNOUNCED
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By The Topps Company
Introduction by Art Spiegelman
Afterword by John Pound
Imprint: Abrams ComicArts
Illustrations: 206 illustrations
Garbage Pail Kids—a series of collectible stickers produced by Topps in the 1980s—combined spectacular artwork and over-the-top satire. The result was an inspired collaboration between avant-garde cartoonists and humorists including Art Spiegelman, Mark Newgarden, John Pound, Tom Bunk, and Jay Lynch. A new generation of fans continues to embrace this pop-culture phenomenon as Garbage Pail Kids stickers are still being published. Now, for the first time, all 206 rare and hard-to-find images from Series 1 through 5 are collected in an innovative package, along with a special set of four limited-edition, previously unreleased bonus stickers. This exciting follow up to Wacky Packages is guaranteed to appeal to die-hard collectors as well as a new generation of fans.
Praise for Garbage Pail Kids:
"If you ask me, reliving my time with Bad Breath Seth and Potty Scotty is worth the cover price alone." —USAToday.com<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />
"I worried that [the Garbage Pail Kids] might seem too time-bound for their own good; but if anything, 27 years later, they’re more poignant. Maybe it’s because I’m a worried, concerned adult, but more likely it’s because nothing is ever as funny as it is when you’re ten years old—and everything is a lot scarier." —CapitalNewYork.com
"The book is a wonderfully designed tribute to these shit-disturbing cards in all their graphic, full-color glory." —ComicsBeat.com
"There's a lot of interesting stuff in Spiegel man's intro, and in the afterward by John Pound, the artist who originated and drew the bulk of the Kids. But the real reason to buy this book is for the graphic brilliance of the art itself…" —Boston Phoenix
The Topps Company, Inc., founded in 1938, is the preeminent creator and brand marketer of sports cards, entertainment products, and distinctive confectionery. Art Spiegelman is an American comics writer, artist, and editor best known for his Pulitzer Prize–winning graphic novel memoir, Maus.
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Home Attractions The Tower Bridge Exhibition Review
The Tower Bridge Exhibition Review
Reviewed by Emma Rogers
The famous Tower Bridge in London was built in 1894 to aid the crossing across the Thames when there were too many people using London Bridge. The Tower Bridge Exhibition hasn’t been open as long as the bridge has, but the structure was built with the East and West walkway and hollow towers which make up the interior of the exhibition. You’re taken to the top of the North Tower by lift where the museum tour starts, giving details of the background to why there was a need for a new bridge in the late Victorian era, then details the different designs that were submitted. Unusually, the original design and the finished product aren’t that dissimilar. There’s also one side of the walkway, 40+m above the road, which displays different famous bridges around the world. Half way along each walkway, the floor becomes a glass floor where most people take selfies of themselves above the London traffic!
After the walkways, the stairs lead down to an interesting art gallery exhibition from the resident artist, then the ground floor has an animation of how the bridge was built and life stories of those who worked there. The bridge was originally powered by coal, but in 1976 this all changed to electric, but the engines are still there to view, and still working! The Engine Rooms are slightly down the road on the South side of the river, so after a little walk, the tour begins and you see how it all worked. This area was not as interesting as the life stories, nor did it go into detail about how the engines worked apart from a few diagrams, but you do at least get to see the engine working.
The whole exhibition takes around 2 hours, although I wouldn’t say this was for very young children because of the height and the fact that you have to read all of the boards yourself – there’s no guided tour and not much interactive stuff. The engine room might be interesting to older children who are interested in mechanics but otherwise, it’s just walking through. There is a good gift shop at the end, although no cafe on site.
Perhaps fit this one in around going to the Tower of London or as part of a longer day out.
Tickets cost:
Adult £9.80 / Child (5-15 years) £4.20 / Family tickets from £15.30
Book online for disctounts (£8.70/£3.80)
For more information or to book tickets online visit www.towerbridge.org.uk.
Tower Bridge Exhibition, Tower Bridge Road, London, SE1 2UP
Previous articleJack the Ripper Tour Review
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Arundel Castle & Gardens Review
National Forest Adventure Farm Review
Windsor Castle Review
LaplandUK Christmas Experience Review
Shrek the Musical at the Palace Theatre, Manchester Review
Jesus Christ Superstar at the Liverpool Empire Review
Dance ‘Til Dawn at the Milton Keynes Theatre Review
Drayton Manor (June 2012) Review
Winchester Science Centre and Planetarium Review
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iRON a project of AGCI
The Interactive Roaring Fork Observation Network (iRON) is an AGCI project to collect and share data on climate and environmental conditions in the Roaring Fork Valley. The website features live and archived data from AGCI’s network of soil moisture sensors. The site also includes links to further information about the field stations, links for other environmental data from the Roaring Fork Valley, and a blog on weather and soil observations in the valley.
iRon History
The data collected by the iRON offers a glimpse of a few of the factors at play in our local ecosystems. The conditions we see today are part of the much larger overlapping systems that shape life in the Roaring Fork Valley, and many of these cycles are connected to geologic, biologic, or even anthropogenic trends of the past. Explore the history sections below for examples of some of the trends that have shaped life in this watershed and the data that helps researchers today to envision them.
Early Human Arrivals
(10,000 years ago-7,000 years ago)
There are many mysteries surrounding the first humans to reach the Rocky Mountains. Little evidence remains to tell us about how or where they lived. These early people were likely hunter-gatherers, and remains of an ancient man found in White River National Forest suggest that people may have been crossing, or even living on, the high slopes of the Roaring Fork Valley as early as 8,000 years ago.
Climate Change in the Prehistoric Era
150,000 to 100,000 years Before Present
When many people picture the Rocky Mountains, they picture pine-covered ridges or elk herds grazing winter meadows. Add in some growing towns, ranches, or the snaking trails of ski slopes, and you have a fairly accurate mental image of certain parts of the modern Roaring Fork Valley. But the valley didn't always look this way. How did the changes occur that took us from being the stomping grounds of mastodons to the ecological communities of today? Hidden evidence, ranging from pollen in local lake beds to ice cores taken from the arctic poles, can help to reconstruct what this region looked like in ancient times and provide clues as to the global trends that shaped it.
Miners and the Cycles of Boom and Bust
1800's through mid 1900's
Cycles of boom and bust are common both in the natural world and in the economic one. Prospectors flooded the Roaring Fork Valley after the discovery of silver in the area, bringing with them changes to the landscape. Although the high flying silver market did not last, the impacts of the settlers who arrived as a consequence of it still remain.
Geography and Ute History
Climate, geology, and large natural disturbances were the most significant generators of trends in this area for millions of years. As human populations grew and developed new tools, transportation, hunting, and farming techniques, this species joined the ranks of the most powerful drivers of change. Necessity, culture, and economics all became powerful forces in shaping who and what lives in the Roaring Fork Valley.
Potatoes to Ski Slopes: The Power of Outside Economics
1880s to Present
From mining to agriculture or from skiing to hiking, the economy of the Roaring Fork Valley has always been closely tied to the region’s geology. The success of marketing these resources however, is linked heavily with the economic, social, and political trends of geographically distant regions.
Climate Change and the Modern Era
2000's and beyond
The ecosystems of the Roaring Fork Valley shape everything from our economy to our recreation, but these ecosystems may be changing within the lifetime of today’s generations. Some of these changes are the consequence of natural successions, others may be caused by human development and local populations growth, and some will be a combination of both. Climate change will likely be one of the most powerful drivers of these ecological shifts.
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Nassau (NAS)
/fotos/nas-aeropuerto.jpg
Lynden Pindling International Airport, opened on January, 1940, is the main air terminal in the Bahamas and serves the capital of the country. It operates with flights to Caribbean islands, Central America, Canada and the United States.
Official Website: nassaulpia.com
Number of Terminals - 3 - Terminals A (international and domestic departures), B (international and U.S. arrivals) and C (U.S. departures). Open between 3:30 am and 0:00 am and located within walking distance of each other.
Annual passenger traffic: 3.3 million passengers went through it in 2017.
Tel: +1 242 702 1010. E-mail: [email protected] There are information desks in the International Arrivals Hall and the U.S. Departures area.
The airport is located 16 km (10 miles) to the west of Nassau.
There are car rental desks from the following companies:
Avis (Tel +1 242 377 7121 - 7:30 am to 8:30 pm)
Budget (Tel +1 242 377 9000 - Monday to Saturday from 7:00 am to 8:00 pm, Sunday from 8:00 am to 8:00 pm)
Dollar/Thrifty (Tel +1 242 377 0326)
Hertz (Tel +1 242 377 8684 - 7:30 am to 7:30 pm)
Vip Lounges and airport facilities
Accommodation near Nassau airport (NAS)
The closest accommodations include: Coral Harbour Beach House & Villas (Tel +1 242 362 2875), Orange Hill Beach Inn (Tel +1 242 327 7157), Marley Resort & Spa (Tel +1 407 545 6384), BELL At The Airport (Tel +1 242 676 7029), A Stone's Throw Away (Tel +1 242 327 7030), Compass Point Beach Resort (Tel +1 242 327 4500), Golden Palm Bed & Breakfast (Tel +1 242 327 7129), Ocean West Boutique Hotel (Tel +1 242 698 6744), Sun Fun Resort (Tel +1 242 327 8827), The Island House (Tel +1 242 698 6300).
Bus - Companies Bahamas Experience Tours (Tel +1 242 397 5000), Dan Knowles Tours (Tel +1 242 393 2220), Leisure Travel & Tours (Tel +1 242 325 6848) and Majestic Tours (Tel +1 242 322 2606 / 677 2600) offer private or shared transport from the airport. The service must be booked in advance.
Taxi - Ranks are located outside the three terminals. Fares are established by zone. The cost of the trip to downtown Nassau is USD32.00 and takes around 30 minutes.
Parking services at Nassau airport (NAS)
There are two parking areas in front of the terminals, with special discounts for frequent users. More information: Tel +1 242 702 1072. Rates
Short Term Parking - Reserved for short stays.
Long Term Parking - Lot for long periods.
Facilities include access ramps, lifts, escalators, adapted toilets and reserved parking spaces. To request wheelchairs, contact your airline prior to your arrival.
Latest updates: October 04, 2018
Airports in The Bahamas
Rome Fiumicino airport
Paris Charles de Gaulle airport
You are in United Kingdom
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Countrywide plans corporate expansion Mortgage lender grows workforce
Extends footprint into Florida
Inman News
After years of steady growth in its workforce, home loan lender Countrywide is planning a corporate expansion into Florida, the company said Thursday, with the purchase of two buildings in Tampa.
The financial services giant added nearly 20 percent to its workforce in 2004 and has continued at that pace this year, bringing its total headcount to about 50,000. Countrywide also plans to nearly double its employees over the next five years.
"In alignment with Countrywide's ambitious strategies for continued rapid growth through this decade, we have initiated searches for new office locations in business-friendly states, and we are particularly excited to make Florida our newest corporate facility home," said Patrick Benton, the company's managing director of corporate real estate administration.
The company, through its primary subsidiary Countrywide Homes Loans, has purchased two buildings totaling more than 231,000 square feet situated on 15.2 acres of land near the Tampa International Airport. The buildings are located at 4909 and 4951 Savarese Circle in the Tampa West Industrial Park.
State and local tax incentives, including approval of the project by the Governor's Office of Tourism, Trade and Economic Development for a Qualified Targeted Industry Tax Refund and the Hillsborough County Commission, were vital to Countrywide's decision to purchase and open its first central office campus in the state, the company said.
"In addition to the government support of targeted business development in Florida, we were attracted to the proximity of these buildings to the airport, allowing for the convenient handling of documents that will come to this location from Countrywide offices around the country," said Benton.
Countrywide expects to make a capital investment of $20 million to $25 million, including the purchase of the building "shells" and property for more than $15.9 million, plus additional costs to complete and equip the interiors.
Approximately 75 percent of the space will be dedicated to office uses, with the remaining space dedicated to records storage, an employee cafeteria, a fitness room and other functions.
Countrywide anticipates it will begin to occupy the campus in the first quarter of 2006, ultimately housing 900 to 1,000 members of its local workforce involved in its expanding mortgage origination, servicing and technology operations in the two buildings.
Countrywide is headquartered in Calabasas, Calif., and heavily invested in corporate office space in Southern California. For the past three years, however, the company has focused the expansion of its central office facilities in other states, citing California's high-cost business climate as a major reason for looking elsewhere.
During that time, the company has announced significant acquisitions and developments in Texas, Arizona and now Florida.
While the Tampa location marks the company's first purchase of a central office facility in Florida, Countrywide already leases more than 100 smaller Florida locations for mortgage production branches, related support operations and other financial services divisions. The company currently has more than 2,500 in its workforce throughout the state.
Copyright 2005 Inman News
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<p>Printed from American National Biography. Under the terms of the licence agreement, an individual user may print out a single article for personal use (for details see <a href="https://global.oup.com/privacy" target="_blank">Privacy Policy</a> and <a href="/page/legal-notice" target="_blank">Legal Notice</a>).</p><p>date: 17 July 2019</p>
(1579–27 December 1656)
J. A. Leo Lemay
https://doi.org/10.1093/anb/9780198606697.article.0801641
White, Andrew (1579–27 December 1656), Jesuit missionary and promotion writer, was born in London, England. The names and occupations of his parents are unknown. He matriculated at Douai College, France, in April 1593. After studying at other Catholic colleges, he returned to Douai, arriving on 4 June 1604, where he took vows as a priest in 1605. He then went to England, where, since the Gunpowder Plot had just been discovered, Catholic priests were being persecuted. Promptly arrested and imprisoned, White was banished from England on penalty of death. On 1 February 1607 he was admitted as a novitiate at Jesuit college of St. John’s, Louvain, Belgium. In 1612 White returned to London as a Jesuit missionary. From then until 1633, he alternated between various teaching positions on the Continent and missionary posts in England....
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AT&T LG G2 review
The Optimus tag has been replaced with cutting-edge hardware and a bold button layout
Jerry Hildenbrand
LG has been on a tear as of late, releasing phones that tick all the marks for hardware aficionados, while paring back their user interface slowly but surely. The G2 is the culmination of these efforts. It's currently the hardware king with the Snapdragon S800 CPU (though that will be changing soon enough) combined with a big screen and everything else Internet phone fans have a hankering for. But we've seen enough to know that it takes more than hardware to make a great phone.
The software is equally important. This is an area where LG has historically struggled, often adding too much of the wrong stuff to Android and delivering a product that nobody ever asked for. While we admire any company who thinks outside the box, everyone here has been waiting for LG to get it just right. A perfect phone is surely something that can never be, but the G2 comes close. Read on and see where the G2 excels, where it fails, and why the former outweighs the latter.
Inside this review: Hardware | Software | Cameras | Bottom line | G2 forums
It's quite the piece of phonery. As soon as you turn it on, you'll notice two things — the buttons, of course, and the screen. You may or may not be digging the buttons, but I think you'll like what you see when you look into the face of the G2.
Of course, there's more to the G2 than buttons and the screen.
If you're in the camp that says hardware is all that matters, you've found your dream phone. It's well built for the most part, has deliciously thin bezels astride the 5.2-inch screen, and will run most anything you throw at it with nary a flinch or stutter. It's stylish and thin, has a great curved shape, and ergonomically it feels very nice in your hand. It manages the size as well as the user can expect, and operation with one hand is certainly possible with minor adjustments.
The display is what we spend all of our time looking at, and is the most important spec to get right
What we didn't like (you knew this was coming) is the extra-glossy materials the G2 is built out of. It suffers from the same problem Samsung's Galaxy S4 does — it looks like it's cheaply made. Clearly it's not, and using it for more than a few minutes will affirm this. It's a solid device. But it looks like a cheap mass-market product. We understand that smartphones are a mass-market product, but we've seen devices use plastic in ways that look and feel good and wish LG would follow suit. If you were expecting a textured, premium feel as we've seen some from of LG's past products like the Optimus 2X, you'll be disappointed.
Don't let this stop you from buying or enjoying the G2. Slap a case on it if it bothers you as much as it does me. I'm not a case user usually, but the G2 is one of those phones that would force me to use one.
What's on the outside
We have to start with the display. It's a gorgeous 5.2-inch "Tru-HD" IPS LCD, checking in with a 1080 x 1920 resolution that gives us approximately 442 pixels displayed per inch. The quality, clarity and color reproduction rivals the celebrated HTC One display in every use case. The viewing angles are excellent, and you will appreciate the time and money LG has put into their LCD technology every time you watch a video or look at a picture. The display is what we spend all of our time looking at, and to me is the most important spec to get right. LG has done more than get it right, and you really need to see it to understand just how damn good it is.
Sharing the front of the phone with the gorgeous screen are the usual array of sensors, a 2.1MP camera, the earpiece speaker and a multi-color notification LED. While not nearly as thin as the side bezels, the top and bottom bezels are small and symmetrical. At the very bottom of the face of the phone you'll find an LG logo that we wish had been left out for appearances sake.
The sides of the phone house none of the standard controls as those are around the back — and we'll be talking about that, shortly — but there are a few things to take notice of. At the top of the phone you'll find one of the microphones, on the left side you'll find the micro SIM card tray, and on the bottom there rests a headphone jack (the 3.5mm standard), a microUSB charging and data port, and symmetrical speaker grills. Under those grills, there is a loudspeaker on the right and the main microphone on the left. The edges are all gently curved, which makes for a nice, seamless feel while holding and using the G2.
You will either love the buttons or hate them, but either way you will be able to adjust
Now we get to the back. Likely as a way to keep the bezels so impossibly thin, LG has moved the volume controls and the power button to the rear of the device. You will either love this or hate it, but either way you will be able to adjust to them unless you have very short fingers. On the AT&T version, the controls are nice and wide, and having the power switch made from a different material than the volume rocker allows you to operate everything by feel rather than turning the phone around to look where your fingers are. The controls work exactly as expected, they are just placed on the rear rather than on the sides where normal, sane people expect them to be. Surrounding the power button is a flashing ring that you would think acts as a notification light, but I'm not seeing this behavior. It does flash when the screen is turned on or off, though.
Also around back, and equally important, is the excellent 13MP camera and LED flash. We'll talk more about these further down the page.
What's on the inside
The features can be used without affecting the performance in ways that make you want to turn them off
Under the great screen is where the beast lives. Of course, I'm talking about the Qualcomm Snapdragon S800 power plant. Consisting of a quad-core array of Krait 400 cores, an Adreno 330 GPU, an extra fast 2MB L2 cache on a 28nm die means it's simply the best ARMv7 system-on-chip available. The version in the G2 is clocked at 2.26Ghz, and it chews through even poorly-coded software with ease. While I'm sure LG spent time optimizing their code to run as best as it can on the G2, the UI is heavy and full of features. With them all enabled, there is nary a stutter or complaint when using the phone. This is impressive, as things like Q-Slide apps, motion gestures and LG's Slide Aside features are heavy and processor intensive. You may or may not find these features useful, but it's nice to know they can be used without affecting the performance of the device in ways that makes you want to turn them off.
I think we have finally reached the point where the hardware is so damn good that we can throw any software on it and get great results. This makes me excited for the future, because a slim, less feature-rich (but highly optimized) operating system running on similar hardware should blow our hair back. I'll put it bluntly — the G2 is as fast and lag free, while running software that's feature-rich and heavy, as the Nexus 4 or Nexus 7 is running bare-bones Android. That's something we haven't been able to say before, and we're glad to see it.
The full specs
Linux Kernel 3.4.0
LG Optimus UI version D80010d
5.2-inch IPS LCD
1080 x 1920 resolution (424 ppi)
Multi-touch, 16M colors
Qualcomm MSM8974 Snapdragon 800
quad-core Krait 400 at 2.26GHz
32GB internal storage (25GB available)
Front: 2.1MP with 1080p/30 video recording
Rear: 13MP autofocus
Simultaneous video and image recording
Geo-tagging, face detection
Optical image stabilization, HDR
3000mAh Lithium Polymer
non-removeable
LTE 900 / 1800 / 2100 / 2600 / 850
802.11 a/b/g/n/ac dual-band Wifi, Wifi Direct
DLNA, Miracast
Forget the LG Android phones that ran the Optimus UI from 2012. If you've used one of LG's newer phones, you know they have been hard at work to deliver a better user experience than we've seen in the past. If you're looking for Google's Android, you'll want to look elsewhere, but LG has built their software into something they should be proud of, and it offers plenty of features and eye-candy for those who want the features and eye-candy.
I'll admit that out of the box the software wasn't to my liking. But I know two very important things (and so do you) about any device with Android roots:
You can customize almost anything
Not every phone should deliver the "Nexus experience"
With that in mind, I sat down and spent a few minutes getting rid of the things I didn't want to see, and adding software from Google Play. I'm left with something that's completely usable and productive. While I'd rather have a slim and utilitarian feel, chances are you'll find the way that works for you as well.
LG's user experience
There is a lot to digest here. In fact, it's more than you'll be able to grasp from a written review, no matter how many words are spent. LG has touched everything, so if this is your first foray into a custom manufacturer build of Android, you're in for an awakening. It's not bad, I won't lie to you. It's certainly not going to fit everyone's tastes, but as I mentioned above the good news is that you can "adjust" a lot of things.
In general, things are very colorful and every line item in the settings is full of options. You can change the font style and size, or enable face-tracking ability under the Display setting. You can set things like looping through your home screens or disable rotation under the Home screen setting. One-handed operation allows you to shift the location of on-screen elements like the keyboard or dial pad. A really cool and unique feature is Guest Mode, where you can display only a few apps of your choosing on a single screen when others are using your device.
All these settings and features seem to work well, though I found it to be a bit of an overload. Thankfully, most of them can be deactivated easily and other than having the line-item in the device settings they remain invisible to the user.
The good news is that the button layout is customizable, the bad news is that all the options still sort of suck
Most of these features are self explanatory when you use them, such as having multiple home screens and lots of LG widgets. Some need more explanation, like the Q-Slide apps and Slide Aside feature. And some are just plain cool and deserve a bit of playing with, like Knock-on. We'll touch on some of the highlights, but be sure to carry yourself into the G2 forums and read what other people using the phones have to say. Often, the best information comes from users just like yourself and not from reviewers who have to juggle around multiple devices and might have missed a nuance because of it.
One of the first things you'll notice is the on-screen button layout. The good news is that it's customizable, the bad news is that all the options still sort of suck. You have a choice which buttons to use — back, home, menu, QuickMemo, and a notification panel pull down. You're given no option for a multi-tasking button, nor an option to remove the menu button. Multi-tasking and app switching is done by long pressing the home button.
You can theme the button interface with different colors and turn transparency on and off. We understand the addition of a notification panel pull-down button, as the G2 is one of those phones where people may find it difficult to reach the very top of the screen when using it in one hand. The menu button is part of Android's legacy, and while it doesn't create any issues, it does buck the unified application design guidelines and standards put forth by Google. If we ever want apps to have the same navigation features, these menu buttons and the apps that need them have to go. On the plus side, there is no Appleesque physical clicky home button to wear out.
LG also offers a complete backup service, where all your apps and their data, personal data, system settings and media are bundled and saved to a compressed file on the device itself. These can be scheduled, and there is even an option to restore data from one device to another. If you're prudent — and you should be — you can then move this file or files to your computer or into the cloud for safe-keeping. LG includes a nifty utility that acts as a wireless gateway to copy files to and from your device from any computer with a web browser, but we've had trouble getting it to work as advertised.
All things considered, we think LG did a pretty good job here. We're ready to stop the ubiquitous eye-rolling that happens when we talk about LG's custom UI, and they are now on par with HTC or Samsung. That's a good thing. Android benefits from the changes and additions manufacturers make to the open-source code that is Android, and we've seen plenty of occasion where they do it better.
Bundled apps
I'm not suggesting you automatically disable all the AT&T bundled apps, but if you do I understand completely
The G2 is a phone that LG built for AT&T. We always need to remember that the carriers are the customers of the folks making most of our Android phones, and that means they will fill them with applications that they want you to try. I'm sure they know that those of us who are in to smartphones will do whatever we can do to delete, fold, spindle and mutilate these apps, but that's OK. They don't have these phones built for the enthusiasts, no matter how vocal we are.
The good news is that since the G2 runs Jelly Bean, you can just disable most of them. I'm not suggesting you automatically go into the settings and disable all the AT&T bundled apps without trying them first, but if you do I'll understand completely. Trust me, I understand completely.
Here's your list of what's included.
AT&T Address Book — particularly invasive, as it tries to preempt your Android contacts.
AT&T Code Scanner
AT&T Drive Mode
AT&T Family Map
AT&T Hot Spots
AT&T Locker
AT&T Messages
AT&T Navigator
AT&T Ready2Go
AT&T Smart Wifi
Carrier IQ
City ID
Wild Tangent Games
myAT&T
YPMobile
Of course, LG has a full compliment of apps built into the OS that you may not find useful, too. Flashlights, Task Managers, Several Notepad apps, those and more are there at the ready. Luckily, most of these can be disabled as well if you find you would rather not have two video editors or four messaging clients. You know the drill here.
The Camera
Just like the hardware section, there is plenty to get excited about here. The G2 offers one of the best smartphone cameras available today. Outdoor shots in bright conditions are good, just as you would expect, but the results from less than perfect conditions are also top-notch and consistent. There are various shooting modes — which we'll look at shortly — but what impressed me the most was the great automatic mode. I played around with all the settings and different options, but ended up favoring the 10MP setting (it uses a native 16:9 aspect ratio that I've grown accustomed to) with White balance, ISO, Focus and Brightness at the defaults while shooting in "Normal" (automatic) mode. I was pleased with the results. Any camera can take good pictures if you fiddle with the settings and take care to set things up just right, but how it performs in automatic mode, where you can pull it out of your pocket and take a quick picture, is important. While if your serious about taking photos you'll use a camera, the G2 delivers quality shots.
We can't ignore the other camera modes and settings, though. From photo sphere-like VR panorama mode, to Time catch mode, which captures ghosted images of moving objects, LG has almost every gimmick you can think of in the camera settings. I played with them, and you will, too, but to be honest their something so niche and subjective that there's no way I can decide what you should think of them. Don't let them be the deciding factor in your purchase, but do give them a try when you're playing with your new phone if you pick up a G2.
The test photos, all under normal and automatic settings, are below. Some were in good light, some were in not-so-good light, and one was under a hokey fake electric gaslight that glowed orange at one of those eateries that think hokey orange fake gaslights are good ambiance. The last example is of course the front-facing camera, which is also excellent — it's bright, clear, and a treat for video chatting.
The video cameras — both front and rear — are pretty awesome, too. The front camera will shoot in 1080p at 30 fps, and its 2.1MP sensor is nice and bright. It's perfect for video conferencing, or making short intro videos, on anything else where you would want a clear and well exposed video of your face.
The rear camera takes some great video as well. The focus is fast, the colors are accurate, and the image stabilization helps even a middle aged man who drinks too much coffee take videos that don't look like the Great San Francisco Quake. Here's not just a sample, but one of the videos I made with it for a couple of very special friends who happen to be junior fish nerds in training. You will use this video camera and share short clips more than you do now, because it's so easy to make videos that look good. And your friends and family will thank you for it.
How it all works together
There was a lot I really liked about the G2 on AT&T. Conversely, there were things I could do without as well. Most phones are going to be like that. In general, the G2 is a fine phone, and does the things it needs to do rather well. Call quality was acceptable on both ends, though I've used phones that were clearer sounding. Wifi signal was good, both on 2.4GHz and 5GHz, and the 802.11 ac channel works as advertised, reaching intranet (read: not internet) speeds of over 200Mb/s download — though I'm not sure that's necessary on a phone and still think the benefit of ac Wifi is the extended range in the 5GHz spectrum. On the cellular side of things, I have to say I'm really stoked with what AT&T is doing with their network. LTE is good where you can get it, but their HSPA 3G "4G" network is vast and fast in my area. And it keeps getting better. This makes for an almost seamless handoff when you leave an LTE area. I routinely bitch and moan about the evil that carriers do, so when they do something good I need to praise them. Nice work on your network, AT&T.
The phone lasts from the time I wake up until the time I go to bed, no matter what I ask it to do during those hours
Battery life was good. The G2 easily lasted me a full day without disabling anything, and would even stretch things out into part of the second day if I needed it to. I wasn't blown away by the battery life, however. Maybe it was my expectations, or maybe it was the fact that there's a 3000mAh battery under the hood, but I thought it would be better. I've done a lot of thinking and trying to make sense of it all and I've come to a conclusion — while the screen is on, and you're working the G2 hard, the battery life is much better than any phone I have here to compare it to. A 90-minute movie or a long session of playing a game drains a lot of juice, but far less than we're used to. I think that's the S800 at work. But (and there's always a but) while idling the G2 uses more battery than phones without all the stuff going on in the background. If my theory is right (and a few other people with the G2 are seeing similar results) that means if you do stop the things you might not want — like auto sync of weather info, or turning Bluetooth off, or using Wifi when you can — it will probably be much better. Folks using the G2 long-term will soon have a game plan, like they do with every other phone.
Just know that while using all the tools available on the phone, and gobbling up AT&T's data on their included SIM, the phone lasts from the time I wake up until the time I go to bed, no matter what I ask it to do during those hours. That's really all I can ask for.
Everything else works as advertised, too. Using Bluetooth for both audio and calls went without a hitch, as did the LE module when used with a Pebble. GPS was spot on, and you'll be pleased with the fact that navigation uses less battery than the phone you have now. There is nothing here that doesn't work just like it should. That's refreshing.
Of course, the subjective things — button placement, physical size, glossy materials and the like — can't be measured as working or not working. These are things you'll only know once you hold the phone itself. I could deal with them if I had bought a G2.
Should you buy this thing?
$600 is a lot of money. Whether you pay for it all at once, use AT&T's Next program, or take the subsidy and overpay for the privilege of only having $200 in up-front costs. That's why many of you are here reading this, and other, reviews. You want to find out as much as you can before you dust off the wallet.
It's fast
It's the most future-proof phone available today
It has an excellent camera
The screen is amazing
All the gimmicks / features actually work
It's a little big
Your OCD side will be constantly wiping the fingerprints off the back unless it's in a case
There's a lot of bloatware from AT&T
The rear buttons are less than optimal
Carrier models usually lag behind when it comes to critical security updates
The G2 is a fine phone, and does the things it needs to do rather well
I'll be blunt, because that's what I'm good at. In my opinion, at this very moment, the G2 is the best Android phone on AT&T if you want a phone filled with features. It doesn't look as good as the HTC One. It doesn't have the Samsung name behind it like the Galaxy S4. But it does have the best hardware available if you're into specs, and it's the only Android phone I've used that allows you to actually use all these features without affecting the performance. Other reviewers go on and on about fonts, or keyboards, but those things are all changeable. Maybe they should have spent more time changing them than complaining if they bothered them that much — I did. The buttons on the rear take some serious adjustment, and the odd on-screen button configurations can be infuriating, but as a complete package I think anyone interested should just bite the bullet and do it.
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Welsh government to abolish Right to Buy
The Right to Buy for social housing tenants is to be scrapped in Wales following a vote in the Welsh Assembly. A draft bill was introduced in March, as the Welsh government was concerned that the policy was leading to a decline in the available social housing stock. The vote in the assembly means it can now go forward for Royal Assent and pass into law.
Housing and regeneration minister Rebecca Evans responded by stating that ending the Right to Buy “ensures we safeguard the investment made in social housing over many generations, for Welsh families now and in the future”.
Furthermore, she said the move will give local authorities and housing associations the confidence to invest in new developments that help “meet the need for quality affordable housing in Wales”.
The Welsh government went on to state that the Right to Buy has resulted in the loss of a “significant number” of homes in recent decades, with more than 139,000 being lost between 1981 and 2016.
While it acknowledged that social housing sales have slowed down in the last few years, it stressed that stock is still being lost “at a time of considerable housing supply pressure”.
This, it stated, has led to many people in housing need waiting longer to access a home they can afford.
The bill allows at least a year after Royal Assent before the Right to Buy on existing properties is abolished.
However, the Right to Buy will end after two months for new social housing stock that currently has no existing tenants.
The Welsh government believes this will help to encourage investment in new homes.
For further information on any of the points raised in this article please contact Andrew Murray in our Social Housing Team.
View Profile | View all of Andrew's posts
View How to have a settlement discussion when there is no employment dispute or the employee is unaware there is an employment problem
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Mysticons - Season 1 Episode 11
IMDb 5 30 min / episode
Mysticons is an upcoming animated action television series which tell about four girls. They are summoned to become the legendary heroes known as the Mysticons. They will undertake a quest to find the..
Mysticons is an upcoming animated action television series which tell about four girls. They are summoned to become the legendary heroes known as the Mysticons. They will undertake a quest to find the Codex.
Adventure, Animation
Evany Rosen, lyson Court, Nicki Burke
Sean Jara
Marvel's Agents of S.H.I.E.L.D. - Season 6
Big Hero 6 The Series - Season 2
Travel Man: 48 Hours in... - Season 9
Urban Myths - Season 3
The Tick - Season 2
Deadliest Catch - Season 15
Knightfall - Season 2
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Simmons and 76ers to play in China
By RAW
China will get a first-hand look at Ben Simmons' prodigious talent when the Philadelphia 76ers play two NBA pre-season games there against the Dallas Mavericks.
The teams have announced they will play pre-season games on October 5 in Shanghai, then October 8 in Shenzhen.
Philadelphia and Dallas will be the 16th and 17th teams to compete in the "NBA China Games" since the league first began playing in China in 2004.
"Getting a chance to play all over the world has always been a dream of mine and I'm excited to play in China in October," Simmons said in a statement issued by the team.
"I know the fans there are passionate about basketball and I'm really looking forward to the trip to Shanghai and Shenzhen."
NBA rookie of the year favourite Simmons has played a big role in getting the 76ers into the playoffs this year for the first time since 2012.
The Mavericks, meanwhile, failed to qualify for the postseason for the second year in a row after a run of 15 playoff appearances in 16 years.
©RAW2018
More NBA news
Ben Simmons a top 10 NBA jersey seller
Simmons, Embiid power 76ers to NBA victory
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Musical Period
Classical, Modern, Romantic
1940 in Budapest, Hungary
Disbanded
Georges Janzer Paul Szabo Sandor Végh Sandor Zoldy
Végh Quartet
Biography by Robert Cummings
The Végh Quartet was not only one of the finest string quartets from mid-twentieth century Europe, but its style was never subjected to radical change over the years from personnel changes because the…
Artist Biography by Robert Cummings
The Végh Quartet was not only one of the finest string quartets from mid-twentieth century Europe, but its style was never subjected to radical change over the years from personnel changes because the four original players remained members for 38 of the 40 years of the ensemble's existence. Its style evolved in subtle ways, of course, but its essential character endured until 1978: the quartet was Central European in its sound, with a bit more prominence given to the cello in order to build tonal qualities from the bottom upward. The Végh Quartet was best known for its cycles -- two each -- of the Beethoven and Bartók quartets. It also performed and recorded many of the Haydn quartets, as well as numerous other staples of the repertory by Mozart, Schumann, Brahms, and Debussy. For a group that disbanded in 1980, its recordings are still quite popular, with major efforts available in varied reissues from Music & Arts, Archipel, Naïve, and Orfeo.
The Végh Quartet was founded in 1940 by its eponymic first violinist Sándor Végh. The other original members were Sándor Zöldy (second violin), Georges Janzer (viola), and Paul Szabó (cello). The war years were hardly productive for the group, but in 1946 the Végh players settled in France and launched their international career. Soon they were making regular concert tours across the globe with great critical acclaim, and their first major recordings appeared in the early '50s: six quartets by Mozart (K. 387, 421, 458, 464, 575, and 590) in 1951-1952 on the André Charlin label and the complete Beethoven quartets in 1952 on the Les Discophiles Français label. The complete Bartók quartets came in 1954 on EMI and met with the same critical success.
The ensemble's reputation flourished in the 1960s and '70s, even though Sándor Végh had developed a parallel conducting career and had always been active as a music teacher, first in Switzerland, then in Germany and Austria. The group continued making international tours and issued numerous successful recordings during this period, including remakes of the Beethoven quartets (1972-1974, on Auvidis/Valois) and the Bartók six (1972, on Astrée). In 1978 Zöldy and Janzer left the group and were replaced by violinist Philipp Naegele and violist Bruno Giuranna. Végh himself took up a conducting post that same year in Salzburg with the Salzburg Camerata Academica. The group disbanded two years later.
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WO2006121991A2 - Compositions and methods for detection, prognosis and treatment of breast cancer - Google Patents
Compositions and methods for detection, prognosis and treatment of breast cancer Download PDF
WO2006121991A2
WO2006121991A2 PCT/US2006/017653 US2006017653W WO2006121991A2 WO 2006121991 A2 WO2006121991 A2 WO 2006121991A2 US 2006017653 W US2006017653 W US 2006017653W WO 2006121991 A2 WO2006121991 A2 WO 2006121991A2
WIPO (PCT)
acid molecule
polypeptide
PCT/US2006/017653
WO2006121991A3 (en
Roberto A. Macina
Diadexus, Inc.
2006-05-08 Application filed by Diadexus, Inc. filed Critical Diadexus, Inc.
2006-11-16 Publication of WO2006121991A2 publication Critical patent/WO2006121991A2/en
C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
C12Q2600/00—Oligonucleotides characterized by their use
C12Q2600/112—Disease subtyping, staging or classification
C12Q2600/118—Prognosis of disease development
The present invention relates to methods of detection, prognosis and treatment of breast cancer using a plurality genes or gene products present in normal and neoplastic cells, tissues and bodily fluids. Gene products relate to compositions comprising the nucleic acids, polypeptides, antibodies, post translational modifications (PTMs), variants, derivatives, agonists and antagonists of the invention and methods for the use of these compositions. Additional uses include identifying, monitoring, staging, imaging and treating cancer and non-cancerous disease states in breast as well as determining the effectiveness of therapies alone or in combination for an individual. Therapies include gene therapy, therapeutic molecules including but not limited to antibodies, small molecules and antisense molecules.
Compositions and Methods for Detection, Prognosis and Treatment of Breast Cancer
This patent application claims the benefit of priority from U.S. Provisional Application Serial No. 60/749,287, filed December 9, 2005, U.S. Provisional Application Serial No. 60/696,164, filed June 29, 2005, and U.S. Provisional Application Serial No. 60/681,536, filed May 6, 2005, teachings of each of which are herein incorporated by reference in their entirety.
FIELD OF THE INVENTION The present invention relates to methods of detection, prognosis and treatment of breast cancer using a plurality genes or gene products present in normal and neoplastic cells, tissues and bodily fluids. Gene products relate to compositions comprising the nucleic acids, polypeptides, antibodies, post translational modifications (PTMs), variants, derivatives, agonists and antagonists of the invention and methods for the use of these compositions. Additional uses include identifying, monitoring, staging, imaging and treating cancer and non-cancerous disease states in breast as well as determining the effectiveness of therapies alone or in combination for an individual. Therapies include gene therapy, therapeutic molecules including but not limited to antibodies, small molecules and antisense molecules.
BACKGROUND OF THE INVENTION Breast Cancer
Breast cancer, also referred to as mammary cancer, is the second most common cancer among women, accounting for a third of the cancers diagnosed in the United States. One in nine women will develop breast cancer in her lifetime and about 192,000 new cases of breast cancer are diagnosed annually with about 42,000 deaths. Bevers, Primary Prevention of Breast Cancer, in Breast Cancer, 20-54 (Kelly K Hunt et ah, ed., 2001); Kochanek et ah, 49 Nat 'I. Vital Statistics Reports 1, 14 (2001). Breast cancer is rare in women younger than 20 and uncommon in women under 30. The incidence of breast cancer rises with age and becomes significant by age 50. White non-Hispanic women have the highest incidence rate for breast cancer and Korean women have the lowest. Increased prevalence of the genetic mutations BRCAl and BRC A2 that promote breast and other cancers are found in Ashkenazi Jews. African American women have the highest mortality rate for breast cancer among these same groups (31 per 100,000), while Chinese women have the lowest at 11 per 100,000. Although men can get breast cancer, this is rare. In the United States it is estimated there will be 214,640 new cases of breast cancer and 41,430 deaths due to breast cancer in 2006. (American Cancer Society Website: cancer with the extension .org of the world wide web). With the exception of those cases with associated genetic factors, precise causes of breast cancer are not known. In the treatment of breast cancer, there is considerable emphasis on detection and risk assessment because early and accurate staging of breast cancer has a significant impact on survival. For example, breast cancer detected at an early stage (stage TO, discussed below) has a five-year survival rate of 92%. Conversely, if the cancer is not detected until a late stage (i.e., stage T4 (IV)), the five-year survival rate is reduced to 13%. AJCC Cancer Staging Handbook pp. 164-65 (Irvin D. Fleming et al. eds., 5th ed. 1998).
Current methods for predicting or detecting breast cancer risk are not optimal. One method for predicting the relative risk of breast cancer is by examining a patient's risk factors and pursuing aggressive diagnostic and treatment regiments for high risk patients. A patient's risk of breast cancer has been positively associated with increasing age, nulliparity, family history of breast cancer, personal history of breast cancer, early menarche, late menopause, late age of first full term pregnancy, prior proliferative breast disease, irradiation of the breast at an early age and a personal history of malignancy. Lifestyle factors such as fat consumption, alcohol consumption, education, and socioeconomic status have also been associated with an increased incidence of breast cancer although a direct cause and effect relationship has not been established. While these risk factors are statistically significant, their weak association with breast cancer limits their usefulness. Most women who develop breast cancer have none of the risk factors listed above, other than the risk that comes with growing older. NIH Publication No. 00-1556 (2000).
Current screening methods for detecting cancer, such as breast self exam, ultrasound, and mammography have drawbacks that reduce their effectiveness or prevent their widespread adoption. Breast self exams, while useful, are unreliable for the detection of breast cancer in the initial stages where the tumor is small and difficult to detect by palpation. Ultrasound measurements require skilled operators at an increased expense. Mammography, while sensitive, is subject to over diagnosis in the detection of lesions that have questionable malignant potential. There is also the fear of the radiation used in mammography because prior chest radiation is a factor associated with an increased incidence of breast cancer.
At this time, current methods of breast cancer prevention are highly problematic. Specifically, these methods of breast cancer prevention involve either prophylactic mastectomy (mastectomy performed before cancer diagnosis) or chemoprevention
(chemotherapy before cancer diagnosis), drastic measures that limit their adoption even among women with increased risk of breast cancer. Bevers, supra.
A number of markers have been associated with breast cancer. Examples of these markers include carcinoembryonic antigen (CEA) (Mughal et al, JAMA 249:1881 (1983)), MUC-I (Frische and Liu, J. Clin. Ligand 22:320 (2000)), HER-2/neu (Haris et al, Proc.Am.Soc.Clin.Oncology 15:A96 (1996)), uPA, PAI-I, LPA, LPC, RAK and BRCA (Esteva and Fritsche, Serum and Tissue Markers for Breast Cancer, in Breast Cancer, 286-308 (2001)). These markers have problems with limited sensitivity, low correlation, and false negatives which limit their use for initial diagnosis. For example, while the BRCAl gene mutation is useful as an indicator of an increased risk for breast cancer, it has limited use in cancer diagnosis because only 6.2 % of breast cancers are BRCAl positive. Malone et al, JAMA 279:922 (1998). See also, Mewman et al., JAMA 279:915 (1998) (correlation of only 3.3%). Another breast cancer marker is mammaglobin which has been reported in serum. Fanger et al, Tumor Biol. 23: 212-221 (2002). There are four primary classifications of breast cancer varying by the site of origin and the extent of disease development.
I. Ductal carcinoma in situ (DCIS): Malignant transformation of ductal epithelial cells that remain in their normal position. By definition, DCIS is a localized disease, incapable of metastasis. II. Invasive ductal carcinoma (IDC): Malignancy of the ductal epithelial cells breaking through the basal membrane and into the supporting tissue of the breast.
IDC may eventually spread elsewhere in the body.
III. Lobular carcinoma in situ (LCIS): Malignancy arising in a single lobule of the breast that fails to extend through the lobule wall, it generally remains localized.
IV. Infiltrating lobular carcinoma (ILC): Malignancy arising in a single lobule of the breast and invading directly through the lobule wall into adjacent tissues. By virtue of its invasion beyond the lobule wall, ILC may penetrate lymphatics and blood vessels and spread to distant sites.
For purposes of determining prognosis and treatment, these four breast cancer types have been staged according to the size of the primary tumor (T), the involvement of lymph nodes (N), and the presence of metastasis (M). Although DCIS by definition represents localized stage I disease, the other forms of breast cancer may range from stage II to stage IV. There are additional prognostic factors that further serve to guide surgical and medical intervention. The most common ones are total number of lymph nodes involved, ER (estrogen receptor) status, PR (progesterone receptor) status, Her2/neu receptor status and histologic grades.
Recently, researchers have reported a number of additional molecular markers and their association with breast cancer. Esteva et al,. Seminars in Radiation Oncology 12(4): 319-322, (2002) reported molecular factors for breast cancer metastasis and survival. Specifically, they describe established markers, ER, PR, Ki-67, HER-2, and investigational markers, pS2, PCNA, Mitosin, EGFR, IGF, P53, BCL-2, Cyclins, uPA, PAI, VEGF, PD-ECGF, FGF. Haffy, Seminars in Radiation Oncology 12(4): 329-340 (2002), reviewed molecular factors relevant for breast cancer management including ER, PR, HER-2/neu, P53, Ki-67, thymidine kinase (TK), IGF, IGFR, cFMS proto-oncogene, cyclin D, VEGF, and germline mutations of BRCAl, BRCA2, p53, PTEN, and ATM. Chang et al, PNAS 102: 3738-3743 (2005), reported that patients with tumors expressing a wound response gene signature have a worse prognosis for survival and increased likelihood of metastasis. Other workers have reported chemokine receptors are implicated in metastasis, e.g., Wang et al, Cancer Research 64:1861-1866 (2004), CCR6 and CCR7, for carcinoma of the head and neck., Muller et a., Nature 410:50-56 (2001) with CXCR4 and CCR7 for breast cancer.
Other researchers have reported the use of gene expression as predictor of breast cancer outcomes. For example, Van de Vijver et al, N. Engl. J. Med. 347(25): 1999-2009 (2002) disclose the use of complementary DNA (cDNA) microarray to establish signatures associated with either a good or a poor prognosis. Van't Veer et al, Nature 415:530-536 (2002) describe a 70 gene profile associated with metastasis in young patients with lymph-node negative breast cancer. See also, US Patent Appn. 2003/0224374 (Dai et al.), the contents of which are hereby incorporated by reference. Specifically, Dai et al describe in Table 2 (genes that can be used as surrogates for ER status), Table 4 (genes that distinguish BRCA-I tumors from non-germline tumors), Table 6 (preferred prognosis markers).
Zehentner et al.,Clin. Chem. 48(8): 1225-1231 (2002) report a multigene PCR panel to detect breast cancer cells in lymph nodes. Specifically, they describe a panel of the following genes: mammaglobin (U33147.1), B305D, B726P (AL357148.22 GL30348856) which appears to be an isoform of NY-BR-I (NM_052997.1 GL16506284), GABA(A) receptor pi subunit (U95367.1 GL2197000).
Traditionally, breast cancers are diagnosed based on pathologic staging recognizing that different treatments are more effective for different stages of cancer. Stage TX indicates that primary tumor cannot be assessed (i. e. , tumor was removed or breast tissue was removed). Stage TO is characterized by abnormalities such as hyperplasia but with no evidence of primary tumor. Stage Tis is characterized by carcinoma in situ, intraductal carcinoma, lobular carcinoma in situ, or Paget' s disease of the nipple with no tumor. Stage Tl (I) is characterized as having a tumor of 2 cm or less in the greatest dimension. Within stage Tl, Tmic indicates microinvasion of 0.1 cm or less, TIa indicates a tumor of between 0.1 to 0.5 cm, TIb indicates a tumor of between 0.5 to 1 cm, and Tie indicates tumors of between 1 cm to 2 cm. Stage T2 (II) is characterized by tumors from 2 cm to 5 cm in the greatest dimension. Tumors greater than 5 cm in size are classified as stage T3 (III). Stage T4 (IV) indicates a tumor of any size with extension to the chest wall or skin. Within stage T4, T4a indicates extension of the tumor to the chess wall, T4b indicates edema or ulceration of the skin of the breast or satellite skin nodules confined to the same breast, T4c indicates a combination of T4a and T4b, and T4d indicates inflammatory carcinoma. AJCC Cancer Staging Handbook pp. 159-70 (Irvin D. Fleming et al. eds., 5th ed. 1998). In addition to standard staging, as described above, breast tumors may be classified according to their estrogen receptor and progesterone receptor protein status. Fisher et al., Breast Cancer Research and Treatment l:\Al (1986). Additional pathological status, such as HER2/neu status may also be useful. Thor et al, J.Nat'l.Cancer Inst. 90:1346 (1998); Paik et al, J. Natl Cancer Inst. 90:1361 (1998); Hutchins et al., Proc.Am.Soc.Clin.Oncology 17:A2 (1998); and Simpson et al, J.Clin.Oncology 18:2059 (2000).
In addition to the staging of the primary tumor, breast cancer metastases to regional lymph nodes may be staged. Stage NX indicates that the lymph nodes cannot be assessed (e.g., previously removed). Stage NO indicates no regional lymph node metastasis. Stage Nl indicates metastasis to movable ipsilateral axillary lymph nodes. Stage N2 indicates metastasis to ipsilateral axillary lymph nodes fixed to one another or to other structures. Stage N3 indicates metastasis to ipsilateral internal mammary lymph nodes. Id. Stage determination has potential prognostic value and provides criteria for designing optimal therapy. Simpson et al, J. Clin. Oncology 18:2059 (2000). Generally, pathological staging of breast cancer is preferable to clinical staging because the former gives a more accurate prognosis. However, quality clinical staging would be advantageous if it were as accurate as pathological staging because it does not depend on invasive procedures to obtain tissue for pathological evaluation. Staging of breast cancer would be greatly improved by use of specific molecular markers in cells, tissues, or bodily fluids which could differentiate between different stages of invasion. Progress in this field will allow for more rapid and reliable methods for treating breast cancer patients.
Treatment of breast cancer is generally decided after an accurate staging of the primary tumor. Primary treatment options include breast conserving therapy
(lumpectomy, breast irradiation, and surgical staging of the axilla), and modified radical mastectomy. Additional treatments include chemotherapy, regional irradiation, and, in extreme cases, terminating estrogen production by ovarian ablation.
Until recently, the customary treatment for all breast cancer was mastectomy. Fonseca et al, Annals of Internal Medicine 127:1013 (1997). However, recent data indicate that less radical procedures maybe equally effective, in terms of survival, for early stage breast cancer. Fisher et al, J. of Clinical Oncology 16:441 (1998). Fisher et al. have reported the use of tamoxifen and chemotherapy for patients with node negative, estrogen receptor positive breast cancer. Fisher et al, N. Engl. J. Med. 320:479-484 (1989); Fisher et al, Lancet 364:858-868 (2004); Fisher et al, J. Natl Cancer Inst. 89: 1673-1682 (1997). The treatment options for a patient with early stage breast cancer (i.e., stage Tis) may be breast-sparing surgery followed by localized radiation therapy at the breast. Alternatively, mastectomy optionally coupled with radiation or breast reconstruction may be employed. These treatment methods are equally effective in the early stages of breast cancer.
Patients with Stage I and Stage II breast cancer require surgery with chemotherapy and/or hormonal therapy. Surgery is of limited use in Stage III and Stage IV patients. Thus, these patients are better candidates for chemotherapy and radiation therapy with surgery limited to biopsy to permit initial staging or subsequent restaging because cancer is rarely curative at this stage of the disease. AJCC Cancer Staging; Handbook 84, 164-65 0-rvin D. Fleming et al. eds., 5th ed.1998).
In an effort to provide more treatment options to patients, efforts are underway to define an earlier stage of breast cancer with low recurrence which could be treated with lumpectomy without postoperative radiation treatment. While a number of attempts have been made to classify early stage breast cancer, no consensus recommendation on postoperative radiation treatment has been obtained from these studies. Page et al, Cancer 75:1219 (1995); Fisher et al, Cancer 75:1223 (1995); Silverstein et al, Cancer 77:2267 (1996). Recently, Paik et al, N. Engl. J. Med. 351(27):2817-2826 (2004) reported that a 21 gene panel could be used to predict breast cancer recurrence in tamoxifen treated, node negative women. Specifically, Paik et al. describe the use of proliferation genes (Ki67, STK15, Survivin, CCNBl (cyclin Bl), MYBL2), invasion genes (MMPIl (stromolysin 3), CTSL2 (cathepsin Ul)), estrogen receptor genes (ER, PGR, BCL2, SCUBE2), HER2, GRB7, GSTMl, CD68 and BAGl in an algorithm for recurrence. They used the following genes as reference genes: ACTB (b-actin), GAPDH, RPLPO, GUS and TFRC. See also, Cronin et al, Amer. J. Path. 164(l):35-42 (2004) and WO 2004/065583 (Genomic Health) the contents of which are hereby incorporated by reference, particularly Table 1 (for invasive carcinoma), Table 2 (for ER (+) outcomes), Table 3 (for ER (-) outcomes), Table 4 (multivariate analysis), Tables 5 A and 5B (for PCR amplicons), Tables 6A-6F (for PCR primers and probes).
Angio genesis in Cancer
Growth and metastasis of solid tumors are also dependent on angiogenesis. Folkman, J., Cancer Research, 46: 467-473 (1986); Folkman, J., Journal of the National Cancer Institute, 82: 4-6 (1989). It has been shown, for example, that tumors which enlarge to greater than 2 mm must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as liver, lung or bone. Weidner, N., et al, The New England Journal of Medicine, 324(1): 1-8 (1991).
Angiogenesis, defined as the growth or sprouting of new blood vessels from existing vessels, is a complex process that primarily occurs during embryonic development. The process is distinct from vasculogenesis, in that the new endothelial cells lining the vessel arise from proliferation of existing cells, rather than differentiating from stem cells. The process is invasive and dependent upon proteolysis of the extracellular matrix (ECM), migration of new endothelial cells, and synthesis of new matrix components. Angiogenesis occurs during embryogenic development of the circulatory system; however, in adult humans, angiogenesis only occurs as a response to a pathological condition (except during the reproductive cycle in women).
Under normal physiological conditions in adults, angiogenesis takes place only in very restricted situations such as hair growth and wounding healing. Auerbach, W. and Auerbach, ^Pharmacol Titer. 63(3):265-3 11 (1994); Ribatti et al., Haematologica 76(4):3 11-20 (1991); Risau, Nature 386(6626):67 1-4 (1997). Angiogenesis progresses by a stimulus which results in the formation of a migrating column of endothelial cells. Proteolytic activity is focused at the advancing tip of this "vascular sprout", which breaks down the ECM sufficiently to permit the column of cells to infiltrate and migrate. Behind the advancing front, the endothelial cells differentiate and begin to adhere to each other, thus forming a new basement membrane. The cells then cease proliferation and finally define a lumen for the new arteriole or capillary.
Unregulated angiogenesis has gradually been recognized to be responsible for a wide range of disorders, including, but not limited to, cancer, cardiovascular disease, rheumatoid arthritis, psoriasis and diabetic retinopathy. Folkman, Nat. Med. 1(1):27-31 (1995); Isner, Circulation 99(13): 1653-5 (1999); Koch, Arthritis Rheum. 41(6):951-62
(1998); Walsh, Rheumatology (Oxford) 38(2):103-12 (1999); Ware and Simons, Nat. Med. 3(2): 158-64 (1997).
Of particular interest is the observation that angiogenesis is required by solid tumors for their growth and metastases. Folkman, 1986 supra; Folkman, J. Natl. Cancer Inst, 82(1) 4-6 (1990); Folkman, Semin. Cancer Biol. 3(2):65-71 (1992); Zetter, Annu. Rev. Med. 49:407-24 (1998). A tumor usually begins as a single aberrant cell which can proliferate only to a size of a few cubic millimeters due to the distance from available capillary beds, and it can stay 'dormant" without further growth and dissemination for a long period of time. Some tumor cells then switch to the angiogenic phenotype to activate endothelial cells, which proliferate and mature into new capillary blood vessels. These newly formed blood vessels not only allow for continued growth of the primary tumor, but also for the dissemination and recolonization of metastatic tumor cells. The precise mechanisms that control the angiogenic switch is not well understood, but it is believed that neovascularization of tumor mass results from the net balance of a multitude of angiogenesis stimulators and inhibitors. Folkman, 1995, supra.
A potent angiogenesis inhibitor is endostatin identified by O'Reilly and Folkman. O'Reilly et al, Cell 88(2):277-85 (1997); O'Reilly et al, Cell 79(2):3 15-28 (1994). Its discovery was based on the phenomenon that certain primary tumors can inhibit the growth of distant metastases. O'Reilly and Folkman hypothesized that a primary tumor initiates angiogenesis by generating angiogenic stimulators in excess of inhibitors. However, angiogenic inhibitors, by virtue of their longer half life in the circulation, reach the site of a secondary tumor in excess of the stimulators. The net result is the growth of primary tumor and inhibition of secondary tumor. Endostatin is one of a growing list of such angiogenesis inhibitors produced by primary tumors. It is a proteolytic fragment of a larger protein: endostatin is a 20 IdDa fragment of collagen XVIII (amino acid Hl 132- K1315 in murine collagen XVIII). Endostatin has been shown to specifically inhibit endothelial cell proliferation in vitro and block angiogenesis in vivo. More importantly, administration of endostatin to tumor-bearing mice leads to significant tumor regression, and no toxicity or drug resistance has been observed even after multiple treatment cycles. Boehm et al, Nature 390(6658):404-407 (1997). The fact that endostatin targets genetically stable endothelial cells and inhibits a variety of solid tumors makes it a very attractive candidate for anticancer therapy. Fidler and Ellis, Cell 79(2): 185-8 (1994); Gastl et al, Oncology 54(3):177-84 (1997); Hinsbergh et al, Ann. Oncol. 10 Suppl. 4:60-3 (1999). In addition, angiogenesis inhibitors have been shown to be more effective when combined with radiation and chemotherapeutic agents. Klement, J. Clin. Invest., 105(8) Rl 5-24 (2000). Browder, Cancer Res. 6-(T) 1878-86 (2000) ; Arap et al, Science 279(5349):377-80 (1998); Mauceri et al, Nature 394(6690):287-91 (1998).
In one aspect, the invention concerns a method for determining the prognosis for an individual having breast cancer where the expression level of a plurality of gene products in Table 2a is determined, and where the differential expression of a plurality of gene products relative to a control is indicative of the individual's prognosis. In a particular embodiment, the expression level of a plurality of gene products of the genes in Table 2b is also determined, and the differential expression of a plurality of gene products relative to a control is indicative of the individual's prognosis. In another particular embodiment, the plurality of gene products comprises at least two, or at least four, or at least six, or at least eight gene products.
Li another embodiment, the plurality of gene products are selected from the group comprising RAD54L, CYR61, ECT2, CCR8, BXMAS2-10, ESRl, CXCR6, B7-H4, TERT, CDHl and CTSD. hi a further embodiment, the gene products are selected from the group comprising RAD54L, CCR8, BXMAS2-10, CXCR6, CYR61, CDHl and B7- H4. hi another embodiment, the over-expression of CYR61, ECT2, CCR8, ESRl, B7-H4, TERT, and CDHl gene products are indicative of a poor prognosis. In a further specific embodiment, the over-expression of RAD54L, CCR8, BXMAS2-10, CXCR6, CYR61, CDHl and B7-H4 gene products are indicative of a poor prognosis, hi another specific embodiment, the under-expression of ER and CTSD gene products are indicative of a poor prognosis. hi another embodiment, the over-expression of some gene products from Table 2a or the under-expression of some gene products from Table 2a are indicative of a good prognosis, hi a different embodiment, the over-expression of some gene products from Table 2a or the under-expression of some gene products from Table 2a are indicative of a poor prognosis. hi a particular embodiment, the gene product is RNA. hi a further embodiment, the gene product expression level is determined by quantitative PCR. hi another particular embodiment, the gene product is a polypeptide, hi a further embodiment, the gene product expression level is determined by an assay comprising one or more antibodies. hi another particular embodiment, the sample of gene products is selected from the group consisting of tissues, cells and bodily fluids, hi a further embodiment, the sample of gene products is selected where the tissues or cells are from a fixed, waxed, embedded specimen from said individual. hi another aspect, the invention provides a method for improving the prognosis for an individual comprising modulating levels of a plurality of gene products of Table 2a. hi a particular embodiment, the plurality of gene products comprises at least two, or at least four, or at least six, or at least eight gene products. hi another embodiment, modulating levels of gene products comprises increasing levels of gene products whose over-expression is associated with a good prognosis, hi a further embodiment, the method includes increasing levels of gene products whose over- expression is associated with a good prognosis where the gene products are selected from the group comprising the gene products of Table 2a.
In another embodiment, modulating levels of gene products comprises decreasing levels of gene products whose under-expression is associated with a good prognosis. In a further embodiment, the method includes decreasing levels of gene products whose under- expression is associated with a good prognosis where the gene products are selected from the group comprising the gene products of Table 2a.
In another embodiment, modulating levels of gene products comprises decreasing levels of gene products whose over-expression is associated with a poor prognosis. In another embodiment, modulating levels of gene products comprises increasing levels of gene products whose under-expression is associated with a poor prognosis.
In another embodiment, the individual is administered an appropriate agonist or antagonist for a gene product of Table 2a which will improve the prognosis of the individual. The invention further concerns an isolated nucleic acid molecule comprising (a) a nucleic acid molecule consisting essentially of a nucleic acid sequence that encodes an amino acid sequence of the gene products in Table 7; (b) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a); or (c) a nucleic acid molecule having at least 95% sequence identity to the nucleic acid molecule of (a). In a particular embodiment, the nucleic acid molecule is cDNA, genomic DNA,
RNA, a mammalian nucleic acid molecule, or a human nucleic acid molecule.
The invention further concerns a set of three isolated nucleic acid molecules wherein: (a) each nucleic acid molecule consists essentially of a nucleic acid sequence encoding a portion of gene product described in Table 2a or Table 2b and (i)the first nucleic acid molecule is a forward primer 15 to 30 base pairs in length; (ii) the second nucleic acid molecule is reverse primer 15 to 30 base pairs in length; (iii) the third nucleic acid molecule is a probe 15-30 base pairs in length; such that the forward primer and reverse primer produce an amplicon detectable by the probe wherein the amplicon bridges two exons and is 60 to 100 base pairs in length; (b) a nucleic acid molecule that selectively hybridizes to one of the three nucleic acid molecules of (a); or (c) a nucleic acid molecule having at least 95% sequence identity to one of the three nucleic acid molecules of (a). In another aspect, the invention concerns a method for determining the presence of a gene product of Table 2a in a sample, comprising the steps of: (a) contacting the sample with the nucleic acid molecule of Table 7 under conditions in which the nucleic acid molecule will selectively hybridize to a gene product of Table 2a; and (b) detecting hybridization of the nucleic acid molecule to a gene product of Table 2a in the sample, wherein the detection of the hybridization indicates the presence of a gene product of Table 2a in the sample.
In another aspect, the invention concerns a method for determining the presence of cancer specific protein in a sample, comprising the steps of: (a) contacting the sample with a suitable reagent under conditions in which the reagent will selectively interact with the cancer specific protein comprising an amino acid sequence with at least 95% sequence identity to the polypeptide encoded by a gene product in Table 2a; and (b) detecting the interaction of the reagent with a cancer specific protein in the sample, wherein the detection of the binding indicates the presence of a cancer specific protein in the sample. Another aspect of the invention concerns a method for diagnosing or monitoring the presence and metastases of breast cancer in an individual, comprising the steps of: (a) determining an amount of (i) a nucleic acid molecule consisting essentially of a nucleic acid sequence that encodes an amino acid sequence of a gene product in Table 2a; (ii) a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product in Table 2a; (iii) a nucleic acid molecule consisting essentially of a nucleic acid sequence of Table 7; (iv) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (i), (ii) or (iii); (v) a nucleic acid molecule having at least 95% sequence identity to the nucleic acid molecule of (i), (ii) or (iii); (vi) a polypeptide comprising an amino acid sequence with at least 95% sequence identity to the polypeptide encoded by a gene product in Table 2; or (vii) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule having at least 95% sequence identity to a nucleic acid molecule comprising a nucleic acid sequence of a gene product of Table 2a; and (b) comparing the amount of the determined nucleic acid molecule or the polypeptide in the sample of the individual to the amount of the cancer specific marker in a normal control; wherein a difference in the amount of the nucleic acid molecule or the polypeptide in the sample compared to the amount of the nucleic acid molecule or the polypeptide in the normal control is associated with the presence of breast cancer. In another aspect, the invention concerns a kit for detecting a risk of cancer or presence of cancer in a individual, where it is a kit comprising a means for determining the presence of: (a) a nucleic acid molecule consisting essentially of a nucleic acid sequence that encodes an amino acid sequence of the polypeptide encoded by a gene product in Table 2a; (b) a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product in Table 2a; (c) a nucleic acid molecule consisting essentially of a nucleic acid sequence of Table 7; (d) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a), (b) or (c); or (e) a nucleic acid molecule having at least 95% sequence identity to the nuclei acid molecule of (a), (b) or (c); or (f) a polypeptide comprising an amino acid sequence with at least 95% sequence identity to the polypeptide encoded by a gene product in Table 2a; or (g) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule having at least 95% sequence identity to a nucleic acid molecule comprising a nucleic acid sequence of a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product of Table 2a. In another aspect, the invention concerns a method of treating an individual with breast cancer, comprising the step of administering a composition consisting of: (a) a nucleic acid molecule consisting essentially of a nucleic acid sequence that encodes an amino acid sequence of the polypeptide encoded by a gene product in Table 2a; (b) a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product in Table 2a; (c) a nucleic acid molecule consisting essentially of a nucleic acid sequence of Table 7; (d) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a), (b) or (c); or (e) a nucleic acid molecule having at least 95% sequence identity to the nucleic acid molecule of (a), (b) or (c); or (f) a polypeptide comprising an amino acid sequence with at least 95% sequence identity to the polypeptide encoded by a gene product in Table 2a; or (g) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule having at least 95% sequence identity to a nucleic acid molecule comprising a nucleic acid sequence of a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product of Table 2a; (h) an appropriate agonist or antagonist for a gene product of Table 2a; to an individual in need thereof, wherein said administration induces an immune response against the breast cancer cell expressing the nucleic acid molecule or polypeptide. DETAILED DESCRIPTION OF THE INVENTION Definitions and General Techniques
Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well known and commonly used in the art. The methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press (1989) and Sambrook et al, Molecular Cloning: A Laboratory Manual, 3d ed., Cold Spring Harbor Press (2001); Ausubel et al, Current Protocols in Molecular Biology, Greene Publishing Associates (1992, and Supplements to 2000); Ausubel et al, Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology - 4th Ed., Wiley & Sons (1999); Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1990); and Harlow and Lane, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1999).
Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery and/or treatment of patients.
The following terms, unless otherwise indicated, shall be understood to have the following meanings:
A "nucleic acid molecule" of this invention refers to a polymeric form of nucleotides and includes both sense and antisense strands of RNA (e.g. mRNA, siRNA), cDNA, genomic DNA, and synthetic forms and mixed polymers of the above. A nucleotide refers to a ribonucleotide, deoxynucleotide or a modified form of either type of nucleotide. A "nucleic acid molecule" as used herein is synonymous with "nucleic acid" and "polynucleotide." The term "nucleic acid molecule" usually refers to a molecule of at least 10 bases in length, unless otherwise specified. The term includes single and double stranded forms of DNA. hi addition, a polynucleotide may include either or both naturally occurring and modified nucleotides linked together by naturally occurring and/or non-naturally occurring nucleotide linkages.
Nucleotides are represented by single letter symbols in nucleic acid molecule sequences. The following table lists symbols identifying nucleotides or groups of nucleotides which may occupy the symbol position on a nucleic acid molecule. See Nomenclature Committee of the International Union of Biochemistry (NC-IUB), Nomenclature for incompletely specified bases in nucleic acid sequences, Recommendations 1984., Eur J B 'iochem. 150(l):l-5 (1985).
The nucleic acid molecules may be modified chemically or biochemically or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those of skill in the art. Such modifications include, for example, labels, methylation, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as uncharged linkages {e.g., methyl phosphonates, phosphotriesters, phosphoramidates, carbamates, etc.), charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), pendent moieties (e.g., polypeptides), intercalators (e.g., acridine, psoralen, etc.), chelators, alkylators, and modified linkages (e.g., alpha anomeric nucleic acids, etc.) The term "nucleic acid molecule" also includes any topological conformation, including single-stranded, double-stranded, partially duplexed, triplexed, hairpinned, circular and padlocked conformations. Also included are synthetic molecules that mimic polynucleotides in their ability to bind to a designated sequence via hydrogen bonding and other chemical interactions. Such molecules are known in the art and include, for example, those in which peptide linkages substitute for phosphate linkages in the backbone of the molecule. A "gene" is defined as a nucleic acid molecule that comprises a nucleic acid sequence that encodes an RNA molecule and the expression control sequences that surround the nucleic acid sequence that encodes the RNA molecule. The encoded RNA molecule may a functional RNA (e.g. tRNA, rRNA), regulatory RNA (e.g. siRNA, miRNA, tncRNA, smRNA, snRNA) or messenger RNA (mRNA). Messenger RNA molecules may be transcribed into polypeptides which are also considered as being encoded for by the gene. For instance, a gene may comprise a promoter, one or more enhancers, a nucleic acid sequence that encodes an RNA molecule, downstream regulatory sequences and, possibly, other nucleic acid sequences involved in regulation of the expression of an RNA. As is well known in the art, eukaryotic genes usually contain both exons and introns. The term "exon" refers to a nucleic acid sequence found in genomic DNA that is bioinformatically predicted and/or experimentally confirmed to contribute contiguous sequence to a mature RNA transcript. The term "intron" refers to a nucleic acid sequence found in genomic DNA that is predicted and/or confirmed to not contribute to a mature RNA transcript, but rather to be "spliced out" during processing of the transcript.
A "gene product" is defined as a molecule expressed or encoded directly or indirectly by a gene. For example, gene products include pre-mRNA, mature mRNA, tRNA, rRNA, srJRNA, ulRNA, siRNA, miRNA, tncRNA, smRNA, pre-polypeptides, pro- polypeptides, mature polypeptides, post translationally modified polypeptides, processed polypeptides, functionally active polypeptides, functionally inactive polypeptides, and complexed polypeptides. A single gene product may have several molecular functions and different gene products may share a single or similar molecular function. The term "level(s) of gene product" is defined as a quantifiable measurement of the gene product. The measurement may be an assay to determine the amount or mass of the product in a sample, the amount of chemically or enzymatically active product in a sample, or the amount of biologically functional product in a sample. Examples of these assays include determining relative and total RNA expression, gene copies, pre-mRNA and mature mRNA levels, knockdown levels, regulatory or surrogate marker levels, ISH, FISH, immunoassays, IHC, proteomic assays and other assays described below.
A nucleic acid molecule or polypeptide is "derived" from a particular species if the nucleic acid molecule or polypeptide has been isolated from the particular species, or if the nucleic acid molecule or polypeptide is homologous to a nucleic acid molecule or polypeptide isolated from a particular species.
An "isolated" or "substantially pure" nucleic acid or polynucleotide (e.g., an RNA, DNA or a mixed polymer) is one which is substantially separated from other cellular components that naturally accompany the native polynucleotide in its natural host cell, e.g., ribosomes, polymerases, or genomic sequences with which it is naturally associated. The term embraces a nucleic acid or polynucleotide that (1) has been removed from its naturally occurring environment, (2) is not associated with all or a portion of a polynucleotide in which the "isolated polynucleotide" is found in nature, (3) is operatively linked to a polynucleotide which it is not linked to in nature, (4) does not occur in nature as part of a larger sequence or (5) includes nucleotides or internucleoside bonds that are not found in nature. The term "isolated" or "substantially pure" also can be used in reference to recombinant or cloned DNA isolates, chemically synthesized polynucleotide analogs, or polynucleotide analogs that are biologically synthesized by heterologous systems. The term "isolated nucleic acid molecule" includes nucleic acid molecules that are integrated into a host cell chromosome at a heterologous site, recombinant fusions of a native fragment to a heterologous sequence, recombinant vectors present as episomes or as integrated into a host cell chromosome.
A "part" of a nucleic acid molecule refers to a nucleic acid molecule that comprises a partial contiguous sequence of at least 10 bases of the reference nucleic acid molecule and can range in length from at least 10 bases up to the full length reference nucleic acid sequence minus one nucleotide base. Thus, for example, when the full length reference nucleic acid molecule contains 1000 nucleotide bases, the part may contain from at least 10 up to 999 nucleotide bases of that reference nucleic acid molecule. Preferably, apart comprises at least 15- 20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80 or 90-100 bases of a reference nucleic acid molecule. In theory, a nucleic acid sequence of 17 nucleotides is of sufficient length to occur at random less frequently than once in the three gigabase human genome, and thus to provide a nucleic acid probe that can uniquely identify the reference sequence in a nucleic acid mixture of genomic complexity. A preferred part is thus one which comprises at least 17 nucleotides and provides a nucleic acid probe specific for a reference nucleic acid molecule of the present invention. A further preferred part is one which comprises at least 17 nucleotides and spans an exon-exon junction of a mature RNA molecule. Another preferred part is one comprising a nucleic acid sequence, the expression of which is indicative of breast cancer. Another preferred part is one that comprises a nucleic acid sequence that can encode at least 6 contiguous amino acid sequences (fragments of at least 18 nucleotides) because they are useful in directing the expression or synthesis of peptides that are useful in mapping the epitopes of the polypeptide encoded by the reference nucleic acid. See, e.g., Geysen et ah, Proc. Natl. Acad. Sd. USA 81:3998-4002 (1984); and U.S. Patent Nos. 4,708,871 and 5,595,915, the disclosures of which are incorporated herein by reference in their entireties. Preferably the 6 contiguous amino acids comprise a contiguous region of amino acids identical to a portion of a CaSP of the present invention. A part may also comprise at least 25, 30, 35 or 40 nucleotides of a reference nucleic acid molecule, or at least 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400 or 500 nucleotides of a reference nucleic acid molecule. A part of a nucleic acid molecule may comprise no other nucleic acid sequences. Alternatively, a part of a nucleic acid may comprise other nucleic acid sequences from other nucleic acid molecules.
The term "oligonucleotide" refers to a nucleic acid molecule generally comprising a length of 200 bases or fewer. A nucleoside, as known by those skilled in the art, is a base-sugar combination. The base portion of a nucleoside is typically a heterocyclic base, the two most common classes of which are purines and the pyrimidines. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to the 2', 3' or 5' hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. In some embodiments, the respective ends of this linear polymeric structure can be further joined to form a circular structure. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside backbone of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3' to 5' phosphodiester linkage. The term "oligonucleotide" often refers to single-stranded deoxyribonucleotides, but it can refer as well to single-or double-stranded ribonucleotides, RNA:DNA hybrids and double-stranded DNAs, among others.
Preferably, oligonucleotides are 10 to 60 bases in length and most preferably 12, 13, 14, 15, 16, 17, 18, 19 or 20 bases in length. Other preferred oligonucleotides are 25, 30, 35, 40, 45, 50, 55 or 60 bases in length. Oligonucleotides may be single-stranded, e.g. for use as probes or primers, or may be double-stranded, e.g. for use in the construction of a mutant gene. Oligonucleotides of the invention can be either sense or antisense oligonucleotides. An oligonucleotide can be derivatized or modified as discussed herein for nucleic acid molecules.
Thus, in the context of the present invention, the term "oligonucleotide" refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent internucleoside (backbone) linkages as well as oligonucleotides having non-naturally-occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for a reference nucleic acid molecule and increased stability in the presence of nucleases.
Oligonucleotides, such as single-stranded DNA probe oligonucleotides, often are synthesized by chemical methods, such as those implemented on automated oligonucleotide synthesizers. However, oligonucleotides can be made by a variety of other methods, including in vitro recombinant DNA-mediated techniques and by expression of DNAs in cells and organisms. Initially, chemically synthesized DNAs typically are obtained without a 5' phosphate. The 5' ends of such oligonucleotides are not substrates for phosphodiester bond formation by ligation reactions that employ DNA ligases typically used to form recombinant DNA molecules. Where ligation of such oligonucleotides is desired, a phosphate can be added by standard techniques, such as those that employ a kinase and ATP. The 3' end of a chemically synthesized oligonucleotide generally has a free hydroxyl group and, in the presence of a ligase, such as T4 DNA ligase, readily will form a phosphodiester bond with a 5' phosphate of another polynucleotide, such as another oligonucleotide. As is well known, this reaction can be prevented selectively, where desired, by removing the 5' phosphates of the other polynucleotide(s) prior to ligation.
Oligonucleotides of the present invention may further include ribozymes, external guide sequence (EGS), oligozymes, and other short catalytic RNAs or catalytic oligonucleotides which hybridize to the reference nucleic acid molecules.
The term "naturally occurring nucleotide" referred to herein includes naturally occurring deoxyribonucleotides and ribonucleotides. The term "modified nucleotides" referred to herein includes nucleotides with modified or substituted sugar groups and the like. The term "nucleotide linkages" referred to herein includes nucleotides linkages such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate, phosphoroamidate, and the like. See e.g., LaPlanche et al, Nucl. Acids Res. 14:9081-9093 (1986); Stein et al, Nucl. Acids Res. 16:3209-3221 (1988); Zon et al, Anti-Cancer Drug Design 6:539-568 (1991); Zon et al, in Eckstein (ed.) Oligonucleotides and Analogues: A Practical Approach, pp. 87-108,
Oxford University Press (1991); Uhlmann and Peyman, Chemical Reviews 90:543 (1990), and U.S. Patent No. 5,151,510, the disclosure of which is hereby incorporated by reference in its entirety.
Unless specified otherwise, the left hand end of a polynucleotide sequence in sense orientation is the 5' end and the right hand end of the sequence is the 3' end. In addition, the left hand direction of a polynucleotide sequence in sense orientation is referred to as the 5' direction, while the right hand direction of the polynucleotide sequence is referred to as the 3' direction. Further, unless otherwise indicated, each nucleotide sequence is set forth herein as a sequence of deoxyribonucleotides. It is intended, however, that the given sequence be interpreted as would be appropriate to the polynucleotide composition: for example, if the isolated nucleic acid is composed of RNA, the given sequence intends ribonucleotides, with uridine substituted for thymidine.
The term "allelic variant" refers to one of two or more alternative naturally occurring forms of a gene, wherein each gene possesses a unique nucleotide sequence. In a preferred embodiment, different alleles of a given gene have similar or identical biological properties.
The term "percent sequence identity" in the context of nucleic acid sequences refers to the residues in two sequences which are the same when aligned for maximum correspondence. The length of sequence identity comparison may be over a stretch of at least about nine nucleotides, usually at least about 20 nucleotides, more usually at least about 24 nucleotides, typically at least about 28 nucleotides, more typically at least about 32 nucleotides, and preferably at least about 36 or more nucleotides. There are a number of different algorithms known in the art which can be used to measure nucleotide sequence identity. For instance, polynucleotide sequences can be compared using FASTA, Gap or Bestfit, which are programs in Wisconsin Package Version 10.0, Genetics Computer Group (GCG), Madison, Wisconsin. FASTA, which includes, e.g., the programs FASTA2 and FASTA3, provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson, Methods Enzymol. 183: 63-98 (1990); Pearson, Methods MoI. Biol. 132: 185-219 (2000); Pearson, Methods Enzymol. 266: 227-258 (1996); Pearson, J. MoI. Biol. 276: 71-84 (1998)). Unless otherwise specified, default parameters for a particular program or algorithm are used. For instance, percent sequence identity between nucleic acid sequences can be determined using FASTA with its default parameters (a word size of 6 and the NOPAM factor for the scoring matrix) or using Gap with its default parameters as provided in GCG Version 6.1.
A reference to a nucleic acid sequence encompasses its complement unless otherwise specified. Thus, a reference to a nucleic acid molecule having a particular sequence should be understood to encompass its complementary strand, with its complementary sequence. The complementary strand is also useful, e.g., for antisense therapy, double stranded RNA (dsRNA) inhibition (RNAi), combination of triplex and antisense, hybridization probes and PCR primers.
In the molecular biology art, researchers use the terms "percent sequence identity", "percent sequence similarity" and "percent sequence homology" interchangeably. In this application, these terms shall have the same meaning with respect to nucleic acid sequences only.
The term "substantial similarity" or "substantial sequence similarity," when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 50%, more preferably 60% of the nucleotide bases, usually at least about 70%, more usually at least about 80%, preferably at least about 90%, more preferably at least about 95-99%, and most preferably at least about 99.5-99.9% of the nucleotide bases, as measured by any well known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed above.
Alternatively, substantial similarity exists between a first and second nucleic acid sequence when the first nucleic acid sequence or fragment thereof hybridizes to an antisense strand of the second nucleic acid, under selective hybridization conditions. Typically, selective hybridization will occur between the first nucleic acid sequence and an antisense strand of the second nucleic acid sequence when there is at least about 55% sequence identity between the first and second nucleic acid sequences — preferably at least about 65%, more preferably at least about 75%, more preferably at least about 90%, even more preferably at least about 95%, further preferably at least about 98%, and most preferably at least about 99%, 99.5%, 99.8% or 99.9% — over a stretch of at least about 14 nucleotides, more preferably at least 17 nucleotides, even more preferably at least 20, 25, 30, 35, 40, 50, 60, 70, 80, 90 or 100 nucleotides, and most preferably at least 200, 300, 400, 500 or 1000 or greater nucleotides. Alternatively, substantial similarity exists between a first and second nucleic acid sequence when the second nucleic acid sequence or fragment thereof hybridizes to an antisense strand of the first nucleic acid. Preferably, there is at least about 70% sequence identity between the first and second nucleic acid sequences — more preferably at least about 80%, more preferably at least about 90%, even more preferably at least about 95%, further preferably at least about 98%, and most preferably at least about 99%, 99.5%, 99.8% or 99.9% sequence identity — over the entire length of the second nucleic acid.
Nucleic acid hybridization will be affected by such conditions as salt concentration, temperature, solvents, the base composition of the hybridizing species, length of the complementary regions, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art. "Stringent hybridization conditions" and "stringent wash conditions" in the context of nucleic acid hybridization experiments depend upon a number of different physical parameters. The most important parameters include temperature of hybridization, base composition of the nucleic acids, salt concentration and length of the nucleic acid. One having ordinary skill in the art knows how to vary these parameters to achieve a particular stringency of hybridization. In general, "stringent hybridization" is performed at about 25°C below the thermal melting point (Tm) for the specific DNA hybrid under a particular set of conditions. "Stringent washing" is performed at temperatures about 50C lower than the Tm for the specific DNA hybrid under a particular set of conditions. The Tm is the temperature at which 50% of the target sequence hybridizes to a perfectly matched probe. See Sambrook (1989), supra, p. 9.51.
The Tm for a particular DNA-DNA hybrid can be estimated by the formula: Tm = 81.5°C + 16.6 (1Og10[Na+]) + 0.41 (fraction G + C) -
0.63 (% formamide) - (600/1) where 1 is the length of the hybrid in base pairs.
The Tm for a particular RNA-RNA hybrid can be estimated by the formula:
Tm = 79.80C + 18.5 (1Og10[Na+]) + 0.58 (fraction G + C) +
11.8 (fraction G + C)2 - 0.35 (% formamide) - (820/1). The Tm for a particular RNA-DNA hybrid can be estimated by the formula:
Tm = 79.80C + 18.5(1OgI0[Na+]) + 0.58 (fraction G + C) +
11.8 (fraction G + C)2 - 0.50 (% formamide) - (820/1).
In general, the Tm decreases by 1-1.50C for each 1% of mismatch between two nucleic acid sequences. Thus, one having ordinary skill in the art can alter hybridization and/or washing conditions to obtain sequences that have higher or lower degrees of sequence identity to the target nucleic acid. For instance, to obtain hybridizing nucleic acids that contain up to 10% mismatch from the target nucleic acid sequence, 10-150C would be subtracted from the calculated Tm of a perfectly matched hybrid, and then the hybridization and washing temperatures adjusted accordingly. Probe sequences may also hybridize specifically to duplex DNA under certain conditions to form triplex or other higher order DNA complexes. The preparation of such probes and suitable hybridization conditions are well known in the art.
An example of stringent hybridization conditions for hybridization of complementary nucleic acid sequences having more than 100 complementary residues on a filter in a Southern or Northern blot or for screening a library is 50% formamide/6X SSC at 42°C for at least ten hours and preferably overnight (approximately 16 hours). Another example of stringent hybridization conditions is 6X SSC at 68°C without formamide for at least ten hours and preferably overnight. An example of moderate stringency hybridization conditions is 6X SSC at 55°C without formamide for at least ten hours and preferably overnight. An example of low stringency hybridization conditions for hybridization of complementary nucleic acid sequences having more than 100 complementary residues on a filter in a Southern or northern blot or for screening a library is 6X SSC at 42°C for at least ten hours. Hybridization conditions to identify nucleic acid sequences that are similar but not identical can be identified by experimentally changing the hybridization temperature from 68°C to 42°C while keeping the salt concentration constant (6X SSC), or keeping the hybridization temperature and salt concentration constant (e.g. 420C and 6X SSC) and varying the formamide concentration from 50% to 0%. Hybridization buffers may also include blocking agents to lower background. These agents are well known in the art. See Sambrook et al. (1989), supra, pages 8.46 and 9.46- 9.58. See also Ausubel (1992), supra, Ausubel (1999), supra, and Sambrook (2001), supra.
Wash conditions can also be altered to change stringency conditions. An example of stringent wash conditions is a 0.2x SSC wash at 65°C for 15 minutes (see Sambrook (1989), supra, for SSC buffer). Often the high stringency wash is preceded by a low stringency wash to remove excess probe. An exemplary medium stringency wash for duplex DNA of more than 100 base pairs is Ix SSC at 45°C for 15 minutes. An exemplary low stringency wash for such a duplex is 4x SSC at 40°C for 15 minutes. In general, signal-to-noise ratio of 2x or higher than that observed for an unrelated probe in the particular hybridization assay indicates detection of a specific hybridization.
As defined herein, nucleic acids that do not hybridize to each other under stringent conditions are still substantially similar to one another if they encode polypeptides that are substantially identical to each other. This occurs, for example, when a nucleic acid is created synthetically or recombinantly using a high codon degeneracy as permitted by the redundancy of the genetic code.
Hybridization conditions for nucleic acid molecules that are shorter than 100 nucleotides in length (e.g., for oligonucleotide probes) may be calculated by the formula: Tm = 81.5°C + 16.6(1Og10[Na+]) + 0.41(fraction G+C) -(600/N), wherein N is change length and the [Na+] is 1 M or less. See Sambrook (1989), supra, p. 11.46. For hybridization of probes shorter than 100 nucleotides, hybridization is usually performed under stringent conditions (5-10°C below the Tm) using high concentrations (0.1-1.0 pmol/ml) of probe. Id. at p. 11.45. Determination of hybridization using mismatched probes, pools of degenerate probes or "guessmers," as well as hybridization solutions and methods for empirically determining hybridization conditions are well known in the art. See, e.g., Ausubel (1999), supra; Sambrook (1989), supra, pp. 11.45-11.57.
The term "digestion" or "digestion of DNA" refers to catalytic cleavage of the DNA with a restriction enzyme that acts only at certain sequences in the DNA. The various restriction enzymes referred to herein are commercially available and their reaction conditions, cofactors and other requirements for use are known and routine to the skilled artisan. For analytical purposes, typically, 1 μg of plasmid or DNA fragment is digested with about 2 units of enzyme in about 20 μl of reaction buffer. For the purpose of isolating DNA fragments for plasmid construction, typically 5 to 50 μg of DNA are digested with 20 to 250 units of enzyme in proportionately larger volumes. Appropriate buffers and substrate amounts for particular restriction enzymes are described in standard laboratory manuals, such as those referenced below, and are specified by commercial suppliers. Incubation times of about 1 hour at 370C are ordinarily used, but conditions may vary in accordance with standard procedures, the supplier's instructions and the particulars of the reaction. After digestion, reactions may be analyzed, and fragments may be purified by electrophoresis through an agarose or polyacrylamide gel, using well known methods that are routine for those skilled in the art.
The term "ligation" refers to the process of forming phosphodiester bonds between two or more polynucleotides, which most often are double-stranded DNAs. Techniques for ligation are well known to the art and protocols for ligation are described in standard laboratory manuals and references, such as, e.g., Sambrook (1989), supra.
Genome-derived "single exon probes," are probes that comprise at least part of an exon ("reference exon") and can hybridize detectably under high stringency conditions to transcript-derived nucleic acids that include the reference exon but do not hybridize detectably under high stringency conditions to nucleic acids that lack the reference exon. Single exon probes typically further comprise, contiguous to a first end of the exon portion, a first intronic and/or intergenic sequence that is identically contiguous to the exon in the genome, and may contain a second intronic and/or intergenic sequence that is identically contiguous to the exon in the genome. The minimum length of genome- derived single exon probes is defined by the requirement that the exonic portion be of sufficient length to hybridize under high stringency conditions to transcript-derived nucleic acids, as discussed above. The maximum length of genome-derived single exon probes is defined by the requirement that the probes contain portions of no more than one exon. The single exon probes may contain priming sequences not found in contiguity with the rest of the probe sequence in the genome, which priming sequences are useful for PCR and other amplification-based technologies, hi another aspect, the invention is directed to single exon probes based on the CaSNAs disclosed herein. In one embodiment, the term "microarray" refers to a "nucleic acid microarray" having a substrate-bound plurality of nucleic acids, hybridization to each of the plurality of bound nucleic acids being separately detectable. The substrate can be solid or porous, planar or non-planar, unitary or distributed. Nucleic acid microarrays include all the devices so called in Schena (ed.), DNA Microarrays: A Practical Approach (Practical Approach Series),, Oxford University Press (1999); Nature Genet. 21(l)(suppl.):l - 60 (1999); Schena (ed.), Microarray Biochip: Tools and Technology, Eaton Publishing Company/BioTechniques Books Division (2000). Additionally, these nucleic acid microarrays include substrate-bound plurality of nucleic acids in which the plurality of nucleic acids are disposed on a plurality of beads, rather than on a unitary planar substrate, as is described, inter alia, in Brenner et al, Proa Natl. Acad. ScL USA 97(4):1665-1670 (2000). Examples of nucleic acid microarrays may be found in U.S. Patent Nos. 6,391,623, 6,383,754, 6,383,749, 6,380,377, 6,379,897, 6,376,191, 6,372,431, 6,351,712 6,344,316, 6,316,193, 6,312,906, 6,309,828, 6,309,824, 6,306,643, 6,300,063, 6,287,850, 6,284,497, 6,284,465, 6,280,954, 6,262,216, 6,251,601, 6,245,518, 6,263,287, 6,251,601, 6,238,866, 6,228,575, 6,214,587, 6,203,989, 6,171,797, 6,103,474, 6,083,726, 6,054,274, 6,040,138, 6,083,726, 6,004,755, 6,001,309, 5,958,342, 5,952,180, 5,936,731, 5,843,655, 5,814,454, 5,837,196, 5,436,327, 5,412,087, 5,405,783, the disclosures of which are incorporated herein by reference in their entireties. In an alternative embodiment, a "microarray" may also refer to a "peptide microarray" or "protein microarray" having a substrate-bound collection of plurality of polypeptides, the binding to each of the plurality of bound polypeptides being separately detectable. Alternatively, the peptide microarray may have a plurality of binders, including but not limited to monoclonal antibodies, polyclonal antibodies, phage display binders, yeast 2 hybrid binders, aptamers, which can specifically detect the binding of the polypeptides of this invention. The array may be based on autoantibody detection to the polypeptides of this invention, see Robinson et al., Nature Medicine 8(3):295-301 (2002). Examples of peptide arrays may be found in WO 02/31463, WO 02/25288, WO 01/94946, WO 01/88162, WO 01/68671, WO 01/57259, WO 00/61806, WO 00/54046, WO 00/47774, WO 99/40434, WO 99/39210, WO 97/42507 and U.S. Patent Nos. 6,268,210, 5,766,960, 5,143,854, the disclosures of which are incorporated herein by reference in their entireties. In addition, determination of the levels of the CaSNA or CaSP may be made in a multiplex manner using techniques described in WO 02/29109, WO 02/24959, WO 01/83502, WO01/73113, WO 01/59432, WO 01/57269, WO 99/67641, the disclosures of which are incorporated herein by reference in their entireties. The term "mutant", "mutated", or "mutation" when applied to nucleic acid sequences means that nucleotides in a nucleic acid sequence may be inserted, deleted or changed compared to a reference nucleic acid sequence. A single alteration may be made at a locus (a point mutation) or multiple nucleotides may be inserted, deleted or changed at a single locus. In addition, one or more alterations may be made at any number of loci within a nucleic acid sequence. In a preferred embodiment of the present invention, the nucleic acid sequence is the wild type nucleic acid sequence encoding a CaSP or is a CaSNA. The nucleic acid sequence may be mutated by any method known in the art including those mutagenesis techniques described infra.
The term "error-prone PCR" refers to a process for performing PCR under conditions where the copying fidelity of the DNA polymerase is low, such that a high rate of point mutations is obtained along the entire length of the PCR product. See, e.g., Leung et al, Technique 1: 11-15 (1989) and Caldwell et al, PCR Methods Applic. 2: 28-33 (1992).
The term "oligonucleotide-directed mutagenesis" refers to a process which enables the generation of site-specific mutations in any cloned DNA segment of interest. See, e.g. , Reidhaar-Olson et al, Science 241: 53-57 (1988).
The term "assembly PCR" refers to a process which involves the assembly of a PCR product from a mixture of small DNA fragments. A large number of different PCR reactions occur in parallel in the same vial, with the products of one reaction priming the products of another reaction.
The term "sexual PCR mutagenesis" or "DNA shuffling" refers to a method of error-prone PCR coupled with forced homologous recombination between DNA molecules of different but highly related DNA sequence in vitro, caused by random fragmentation of the DNA molecule based on sequence similarity, followed by fixation of the crossover by primer extension in an error-prone PCR reaction. See, e.g. , Stemmer, Proc. Natl. Acad. Sd. U.S.A. 91: 10747-10751 (1994). DNA shuffling can be carried out between several related genes ("Family shuffling"). The term "in vivo mutagenesis" refers to a process of generating random mutations in any cloned DNA of interest which involves the propagation of the DNA in a strain of bacteria such as E. coli that carries mutations in one or more of the DNA repair pathways. These "mutator" strains have a higher random mutation rate than that of a wild-type parent. Propagating the DNA in a mutator strain will eventually generate random mutations within the DNA.
The term "cassette mutagenesis" refers to any process for replacing a small region of a double-stranded DNA molecule with a synthetic oligonucleotide "cassette" that differs from the native sequence. The oligonucleotide often contains completely and/or partially randomized native sequence.
The term "recursive ensemble mutagenesis" refers to an algorithm for protein engineering (protein mutagenesis) developed to produce diverse populations of phenotypically related mutants whose members differ in amino acid sequence. This method uses a feedback mechanism to control successive rounds of combinatorial cassette mutagenesis. See, e.g., Arkin et al., Proc. Nail. Acad. Sd. U.S.A. 89: 7811-7815 (1992). The term "exponential ensemble mutagenesis" refers to a process for generating combinatorial libraries with a high percentage of unique and functional mutants, wherein small groups of residues are randomized in parallel to identify, at each altered position, amino acids which lead to functional proteins. See, e.g., Delegrave et al, Biotechnology Research 11 : 1548-1552 (1993); Arnold, Current Opinion in Biotechnology 4: 450-455 (1993).
"Operatively linked" expression control sequences refers to a linkage in which the expression control sequence is either contiguous with the gene of interest to control the gene of interest, or acts in trans or at a distance to control the gene of interest. The term "expression control sequence" as used herein refers to polynucleotide sequences which are necessary to affect the expression of coding sequences to which they are operatively linked. Expression control sequences are sequences which control the transcription, post-transcriptional events and translation of nucleic acid sequences. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency {e.g., ribosome binding sites); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include promoter, ribosomal binding site, and transcription termination sequence. The term "control sequences" is intended to include, at a minimum, all components whose presence is essential for expression, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.
The term "vector," as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Other vectors include cosmids, bacterial artificial chromosomes (BAC) and yeast artificial chromosomes (YAC). Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Viral vectors that infect bacterial cells are referred to as bacteriophages. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication). Other vectors can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors"). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" may be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include other forms of expression vectors that serve equivalent functions. The term "recombinant host cell" (or simply "host cell"), as used herein, is intended to refer to a cell into which a recombinant expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term "host cell" as used herein.
As used herein, the phrase "open reading frame" and the equivalent acronym "ORF" refers to that portion of a transcript-derived nucleic acid that can be translated in its entirety into a sequence of contiguous amino acids. As so defined, an ORF has length, measured in nucleotides, exactly divisible by 3. As so defined, an ORF need not encode the entirety of a natural protein.
As used herein, the phrase "ORF-encoded peptide" refers to the predicted or actual translation of an ORF.
As used herein, the phrase "degenerate variant" of a reference nucleic acid sequence is meant to be inclusive of all nucleic acid sequences that can be directly translated, using the standard genetic code, to provide an amino acid sequence identical to that translated from the reference nucleic acid sequence. The term "polypeptide" encompasses both naturally occurring and non-naturally occurring proteins and polypeptides, as well as polypeptide fragments and polypeptide mutants, derivatives and analogs thereof. A polypeptide may be monomeric or polymeric. Further, a polypeptide may comprise a number of different modules within a single polypeptide each of which has one or more distinct activities. A preferred polypeptide in accordance with the invention comprises a CaSP encoded by a nucleic acid molecule of the instant invention, or a fragment, mutant, analog, isoform, allelic variant and derivative thereof.
The term "isolated protein" or "isolated polypeptide" is a protein or polypeptide that by virtue of its origin or source of derivation (1) is not associated with naturally associated components that accompany it in its native state, (2) is free of other proteins from the same species, (3) is expressed by a cell from a different species, or (4) does not occur in nature. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cell from which it naturally originates will be "isolated" from its naturally associated components. A polypeptide or protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well known in the art.
A protein or polypeptide is "substantially pure," "substantially homogeneous" or "substantially purified" when at least about 60% to 75% of a sample exhibits a single species of polypeptide. The polypeptide or protein may be monomeric or multimeric. A substantially pure polypeptide or protein will typically comprise about 50%, 60%, 70%, 80% or 90% WAV of a protein sample, more usually about 95%, and preferably will be over 99% pure. Protein purity or homogeneity may be determined by a number of means well known in the art, such as polyacrylamide gel electrophoresis of a protein sample, followed by visualizing a single polypeptide band upon staining the gel with a stain well known in the art. For certain purposes, higher resolution may be provided by using HPLC or other means well known in the art for purification.
The term "fragment" when used herein with respect to polypeptides of the present invention refers to a polypeptide that has an amino-terminal and/or carboxy-terminal deletion compared to a full-length CaSP. hi a preferred embodiment, the fragment is a contiguous sequence in which the amino acid sequence of the fragment is identical to the corresponding positions in the naturally occurring polypeptide. Fragments typically are at least 5, 6, 7, 8, 9 or 10 amino acids long, preferably at least 12, 14, 16 or 18 amino acids long, more preferably at least 20 amino acids long, more preferably at least 25, 30, 35, 40 or 45, amino acids, even more preferably at least 50 or 60 amino acids long, and even more preferably at least 70 amino acids long.
A "derivative" when used herein with respect to polypeptides of the present invention refers to a polypeptide which is substantially similar in primary structural sequence to a CaSP but which include, e.g., in vivo or in vitro chemical and biochemical modifications that are not found in the CaSP. Such modifications include, for example, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. Other modifications include, e.g., labeling with radionuclides, and various enzymatic modifications, as will be readily appreciated by those skilled in the art. A variety of methods for labeling polypeptides and of substituents or labels useful for such purposes are well known in the art, and include radioactive isotopes such as 1251, 32P, 35S, 14C and H, ligands which bind to labeled antiligands (e.g., antibodies), fluorophores, chemiluminescent agents, enzymes, and antiligands which can serve as specific binding pair members for a labeled ligand. The choice of label depends on the sensitivity required, ease of conjugation with the primer, stability requirements, and available instrumentation. Methods for labeling polypeptides are well known in the art. See Ausubel (1992), supra; Ausubel (1999), supra.
The term "fusion protein" refers to polypeptides of the present invention coupled to heterologous amino acid sequences. Fusion proteins are useful because they can be constructed to contain two or more desired functional elements from two or more different proteins. A fusion protein comprises at least 10 contiguous amino acids from a polypeptide of interest, more preferably at least 20 or 30 amino acids, even more preferably at least 40, 50 or 60 amino acids, yet more preferably at least 75, 100 or 125 amino acids. Fusion proteins can be produced recombinantly by constructing a nucleic acid sequence that encodes the polypeptide or a fragment thereof in frame with a nucleic acid sequence encoding a different protein or peptide and then expressing the fusion protein. Alternatively, a fusion protein can be produced chemically by crosslinking the polypeptide or a fragment thereof to another protein.
The term "analog" refers to both polypeptide analogs and non-peptide analogs. The term "polypeptide analog" as used herein refers to a polypeptide that is comprised of a segment of at least 25 amino acids that has substantial identity to a portion of an amino acid sequence but which contains non-natural amino acids or non-natural inter-residue bonds. In a preferred embodiment, the analog has the same or similar biological activity as the native polypeptide. Typically, polypeptide analogs comprise a conservative amino acid substitution (or insertion or deletion) with respect to the naturally occurring sequence. Analogs typically are at least 20 amino acids long, preferably at least 50 amino acids long or longer, and can often be as long as a full-length naturally occurring polypeptide.
The term "non-peptide analog" refers to a compound with properties that are analogous to those of a reference polypeptide. A non-peptide compound may also be termed a "peptide mimetic" or a "peptidomimetic." Such compounds are often developed with the aid of computerized molecular modeling. Peptide mimetics that are structurally similar to useful peptides may be used to produce an equivalent effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide {i.e., a polypeptide that has a desired biochemical property or pharmacological activity), but have one or more peptide linkages optionally replaced by a linkage selected from the group consisting of: -CH2NH-, -CH2S-, -CH2-CH2-, -CH=CH~(cis and trans), -COCH2-, -CH(OH)CH2-, and -CH2SO-, by methods well known in the art. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) may also be used to generate more stable peptides. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo et al, Ann. Rev. Biochem. 61:387-418 (1992)). For example, one may add internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide.
The term "mutant" or "mutein" when referring to a polypeptide of the present invention relates to an amino acid sequence containing substitutions, insertions or deletions of one or more amino acids compared to the amino acid sequence of a CaSP. A mutein may have one or more amino acid point substitutions, in which a single amino acid at a position has been changed to another amino acid, one or more insertions and/or deletions, in which one or more amino acids are inserted or deleted, respectively, in the sequence of the naturally occurring protein, and/or truncations of the amino acid sequence at either or both the amino or carboxy termini. Further, a mutein may have the same or different biological activity as the naturally occurring protein. For instance, a mutein may have an increased or decreased biological activity. A mutein has at least 50% sequence similarity to the wild type protein, preferred is 60% sequence similarity, more preferred is 70% sequence similarity. Even more preferred are muteins having 80%, 85% or 90% sequence similarity to a CaSP. In an even more preferred embodiment, a mutein exhibits 95% sequence identity, even more preferably 97%, even more preferably 98% and even more preferably 99%. Sequence similarity may be measured by any common sequence analysis algorithm, such as GAP or BESTFIT or other variation Smith- Waterman alignment. See, T. F. Smith and M. S. Waterman, J. MoI. Biol. 147:195-197 (1981) and W.R. Pearson, Genomics 11 :635-650 (1991).
Preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinity or enzymatic activity, and (5) confer or modify other physicochemical or functional properties of such analogs. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally occurring sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts. In a preferred embodiment, the amino acid substitutions are moderately conservative substitutions or conservative substitutions. In a more preferred embodiment, the amino acid substitutions are conservative substitutions. A conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to disrupt a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Creighton (ed.), Proteins, Structures and Molecular Principles, W. H. Freeman and Company (1984); Branden et al. (ed.), Introduction to Protein Structure, Garland Publishing (1991); Thornton et al, Nature 354:105-106 (1991). As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. See Golub et al. (eds.), Immunology - A Synthesis 2nd Ed., Sinauer Associates (1991). Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as α-, α-disubstituted amino acids, N-alkyl amino acids, and other unconventional amino acids may also be suitable components for polypeptides of the present invention. Examples of unconventional amino acids include:
4-hydroxyproline, γ-carboxyglutamate, ε-N,N,N-trimethylrysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, s-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the lefthand direction is the amino terminal direction and the right hand direction is the carboxy-terminal direction, in accordance with standard usage and convention.
By "homology" or "homologous" when referring to a polypeptide of the present invention, it is meant polypeptides from different organisms with a similar sequence to the encoded amino acid sequence of a CaSP and a similar biological activity or function. Although two polypeptides are said to be "homologous," this does not imply that there is necessarily an evolutionary relationship between the polypeptides. Instead, the term "homologous" is defined to mean that the two polypeptides have similar amino acid sequences and similar biological activities or functions. In a preferred embodiment, a homologous polypeptide is one that exhibits 50% sequence similarity to CaSP, preferred is 60% sequence similarity, more preferred is 70% sequence similarity. Even more preferred are homologous polypeptides that exhibit 80%, 85% or 90% sequence similarity to a CaSP. Li a yet more preferred embodiment, a homologous polypeptide exhibits 95%, 97%, 98% or 99% sequence similarity. When "sequence similarity" is used in reference to polypeptides, it is recognized that residue positions that are not identical often differ by conservative amino acid substitutions. In a preferred embodiment, a polypeptide that has "sequence similarity" comprises conservative or moderately conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art. See, e.g., Pearson, Methods MoI. Biol. 24: 307-31 (1994).
For instance, the following six groups each contain amino acids that are conservative substitutions for one another:
1) Serine (S), Threonine (T);
2) Aspartic Acid (D), Glutamic Acid (E);
3) Asparagine (N), Glutamine (Q);
4) Arginine (R), Lysine (K); 5) Isoleucine (T), Leucine (L), Methionine (M), Alanine (A), Valine (V), and
6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).
Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et ah, Science 256: 1443-45 (1992). A "moderately conservative" replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.
Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG contains programs such as "Gap" and "Bestfit" which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Other programs include FASTA, discussed supra.
A preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially blastp or tblastn. See, e.g., Altschul et al, J. MoI. Biol. 215: 403-410 (1990); Altschul et al, Nucleic Acids Res. 25:3389-402 (1997). Preferred parameters for blastp are:
Expectation value: 10 (default)
Filter: seg (default) Cost to open a gap: 11 (default)
Cost to extend a gap: 1 (default)
Max. alignments: 100 (default)
Word size: 11 (default)
No. of descriptions: 100 (default) Penalty Matrix: BLOSUM62
The length of polypeptide sequences compared for homology will generally be at least about 16 amino acid residues, usually at least about 20 residues, more usually at least about 24 residues, typically at least about 28 residues, and preferably more than about 35 residues. When searching a database containing sequences from a large number of different organisms, it is preferable to compare amino acid sequences.
Algorithms other than blastp for database searching using amino acid sequences are known in the art. For instance, polypeptide sequences can be compared using FASTA, a program in GCG Version 6.1. FASTA {e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (1990), supra; Pearson (2000), supra). For example, percent sequence identity between amino acid sequences can be determined using FASTA with its default or recommended parameters (a word size of 2 and the PAM250 scoring matrix), as provided in GCG Version 6.1.
An "antibody" refers to an intact immunoglobulin, or to an antigen-binding portion thereof that competes with the intact antibody for specific binding to a molecular species, e.g., a polypeptide of the instant invention. Antigen-binding portions may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Antigen-binding portions include, inter alia, Fab, Fab', F(ab')2, Fv, dAb, and complementarity determining region (CDR) fragments, single-chain antibodies (scFv), chimeric antibodies, diabodies and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide. A Fab fragment is a monovalent fragment consisting of the VL, VH, CL and CHl domains; a F(ab')2 fragment is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consists of the VH and CHl domains; a Fv fragment consists of the VL and VH domains of a single arm of an antibody; and a dAb fragment consists of a VH domain. See, e.g., Ward et ah, Nature 341: 544-546 (1989).
By "bind specifically" and "specific binding" as used herein it is meant the ability of the antibody to bind to a first molecular species in preference to binding to other molecular species with which the antibody and first molecular species are admixed. An antibody is said specifically to "recognize" a first molecular species when it can bind specifically to that first molecular species.
A single-chain antibody (scFv) is an antibody in which VL and VH regions are paired to form a monovalent molecule via a synthetic linker that enables them to be made as a single protein chain. See, e.g., Bird et al., Science 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sd. USA 85: 5879-5883 (1988). Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites. See e.g., Holliger et al., Proc. Natl. Acad. ScL USA 90: 6444-6448 (1993); Poljak et al, Structure 2: 1121-1123 (1994). One or more CDRs may be incorporated into a molecule either covalently or noncovalently to make it an immunoadhesin. An immunoadhesin may incorporate the CDR(s) as part of a larger polypeptide chain, may covalently link the CDR(s) to another polypeptide chain, or may incorporate the CDR(s) noncovalently. The CDRs permit the immunoadhesin to specifically bind to a particular antigen of interest. A chimeric antibody is an antibody that contains one or more regions from one antibody and one or more regions from one or more other antibodies. An antibody may have one or more binding sites. If there is more than one binding site, the binding sites may be identical to one another or may be different. For instance, a naturally occurring immunoglobulin has two identical binding sites, a single-chain antibody or Fab fragment has one binding site, while a "bispecific" or "bifunctional" antibody has two different binding sites.
An "isolated antibody" is an antibody that (1) is not associated with naturally- associated components, including other naturally-associated antibodies, that accompany it in its native state, (2) is free of other proteins from the same species, (3) is expressed by a cell from a different species, or (4) does not occur in nature. It is known that purified proteins, including purified antibodies, may be stabilized with non-naturally-associated components. The non-naturally-associated component may be a protein, such as albumin (e.g., BSA) or a chemical such as polyethylene glycol (PEG). A "neutralizing antibody" or "an inhibitory antibody" is an antibody that inhibits the activity of a polypeptide or blocks the binding of a polypeptide to a ligand that normally binds to it. An "activating antibody" is an antibody that increases the activity of a polypeptide.
The term "epitope" includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. An antibody is said to specifically bind an antigen when the dissociation constant is less thanl μM, preferably less thanlOO nM and most preferably less than 1O nM.
The terms "patient" and "individual" includes human and veterinary subjects. Throughout this specification and claims, the word "comprise," or variations such as "comprises" or "comprising," will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. The term "cancer specific" refers to a nucleic acid molecule or polypeptide that is differentially expressed predominantly in the breast cancer as compared to other tissues in the body. In a preferred embodiment, a "cancer specific" nucleic acid molecule or polypeptide is detected at a level that is 1.5-fold higher than any other tissue in the body. In a more preferred embodiment, the "cancer specific" nucleic acid molecule or polypeptide is detected at a level that is 1.8-fold higher than any other tissue in the body, more preferably 2-fold higher, still more preferably at least 2.5-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold or 100-fold higher than any other tissue in the body. In another preferred embodiment, a "cancer specific" nucleic acid molecule or polypeptide is detected at a level that is 1.5-fold lower than any other tissue in the body. In a more preferred embodiment, the "cancer specific" nucleic acid molecule or polypeptide is detected at a level that is 1.8-fold lower than any other tissue in the body, more preferably 2-fold lower, still more preferably at least 2.5-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold or 100-fold lower than any other tissue in the body. Nucleic acid molecule levels may be measured by nucleic acid hybridization, such as Northern blot hybridization, microarray analysis or quantitative PCR. Polypeptide levels may be measured by any method known to accurately quantitate protein levels, such as Western blot analysis, ELISA, IHC, protein chip array, mass-spec and flow cytometry. The term "prognosis" defines a forecast as to the probable outcome of a disease, the prospect as to recovery from a disease, or the potential recurrence of a disease as indicated by the nature and symptoms of the case. In general, prognosis is defined as "good" when there is a probable favorable outcome of a disease, recovery from a disease or low potential for disease recurrence. A "poor" prognosis is generally defined as a non- favorable outcome of a disease, non-recovery from a disease, or greater potential for disease recurrence. Prognosis may be determined using clinical factors, pathological evaluation, genotypic or phenotypic molecular profiling.
Nucleic Acid Molecules, Regulatory Sequences, Vectors, Host Cells and Recombinant Methods of Making Polypeptides Nucleic Acid Molecules
One aspect of the invention provides isolated nucleic acid molecules that are specific to cancer or to caner cells or tissue or that are derived from such nucleic acid molecules. These isolated cancer specific nucleic acids (CaSNAs) may comprise cDNA genomic DNA, RNA, or a combination thereof, a fragment of one of these nucleic acids, or may be a non-naturally occurring nucleic acid molecule. A CaSNA may be derived from an animal. In a preferred embodiment, the CaSNA is derived from a human or other mammal. In a more preferred embodiment, the CaSNA is derived from a human or other primate. In an even more preferred embodiment, the CaSNA is derived from a human, hi a preferred embodiment, the nucleic acid molecule encodes a polypeptide that is specific to cancer, a cancer-specific polypeptide (CaSP). In a more preferred embodiment, the nucleic acid molecule encodes a polypeptide that comprises an amino acid sequence of the gene products of Table 2a or Table 2b. In another highly preferred embodiment, the nucleic acid molecule comprises a nucleic acid sequence of the gene products of Table 2a, Table 2b or Table 7. Nucleotide sequences of the instantly- described nucleic acid molecules were determined by assembling several DNA molecules from either public or proprietary databases. Some of the underlying DNA sequences are the result, directly or indirectly, of at least one enzymatic polymerization reaction (e.g., reverse transcription and/or polymerase chain reaction) using an automated sequencer (such as the MegaBACE™ 1000, Amersham Biosciences, Sunnyvale, CA, USA).
Nucleic acid molecules of the present invention may also comprise sequences that selectively hybridizes to a nucleic acid molecule encoding a CaSNA or a complement or antisense thereof. The hybridizing nucleic acid molecule may or may not encode a polypeptide or may or may not encode a CaSP. However, in a preferred embodiment, the hybridizing nucleic acid molecule encodes a CaSP. hi a more preferred embodiment, the invention provides a nucleic acid molecule that selectively hybridizes to a nucleic acid molecule or the antisense sequence of a nucleic acid molecule that encodes a polypeptide comprising an amino acid sequence of the gene products of Table 2a or Table 2b. hi an even more preferred embodiment, the invention provides a nucleic acid molecule that selectively hybridizes to a nucleic acid molecule comprising the nucleic acid sequence of the gene products of Table 2a, Table 2b or Table 7 or the antisense sequence thereof. Preferably, the nucleic acid molecule selectively hybridizes to a nucleic acid molecule or the antisense sequence of a nucleic acid molecule encoding a CaSP under low stringency conditions. More preferably, the nucleic acid molecule selectively hybridizes to a nucleic acid molecule or the antisense sequence of a nucleic acid molecule encoding a CaSP under moderate stringency conditions. Most preferably, the nucleic acid molecule selectively hybridizes to a nucleic acid molecule or the antisense sequence of a nucleic acid molecule encoding a CaSP under high stringency conditions. In a preferred embodiment, the nucleic acid molecule hybridizes under low, moderate or high stringency conditions to a nucleic acid molecule or the antisense sequence of a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence of the gene products of Table 2a or Table 2b. hi a more preferred embodiment, the nucleic acid molecule hybridizes under low, moderate or high stringency conditions to a nucleic acid molecule or the antisense sequence of a nucleic acid molecule comprising a nucleic acid sequence selected from the gene products of Table2a, Table 2b or Table 7. Nucleic acid molecules of the present invention may also comprise nucleic acid sequences that exhibit substantial sequence similarity to a nucleic acid encoding a CaSP or a complement of the encoding nucleic acid molecule. In this embodiment, it is preferred that the nucleic acid molecule exhibit substantial sequence similarity to a nucleic acid molecule encoding human CaSP. More preferred is a nucleic acid molecule exhibiting substantial sequence similarity to a nucleic acid molecule encoding a polypeptide having an amino acid sequence of the gene products of Table 2a or Table 2b. By substantial sequence similarity it is meant a nucleic acid molecule having at least 60% sequence identity with a nucleic acid molecule encoding a CaSP, such as a polypeptide having an amino acid sequence of the gene products of Table 2a or Table 2b, more preferably at least 70%, even more preferably at least 80% and even more preferably at least 85%. In a more preferred embodiment, the similar nucleic acid molecule is one that has at least 90% sequence identity with a nucleic acid molecule encoding a CaSP, more preferably at least 95%, more preferably at least 97%, even more preferably at least 98%, and still more preferably at least 99%. Most preferred in this embodiment is a nucleic acid molecule that has at least 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity with a nucleic acid molecule encoding a CaSP.
The nucleic acid molecules of the present invention are also inclusive of those exhibiting substantial sequence similarity to a CaSNA or its complement. In this embodiment, it is preferred that the nucleic acid molecule exhibit substantial sequence similarity to a nucleic acid molecule having a nucleic acid sequence of the gene products of Table 2a, Table 2b or Table 7. By substantial sequence similarity it is meant a nucleic acid molecule that has at least 60% sequence identity with a CaSNA, such as one having a nucleic acid sequence of the gene products of Table 2a, Table 2b or Table 7, more preferably at least 70%, even more preferably at least 80% and even more preferably at least 85%. More preferred is a nucleic acid molecule that has at least 90% sequence identity with a CaSNA, more preferably at least 95%, more preferably at least 97%, even more preferably at least 98%, and still more preferably at least 99%. Most preferred is a nucleic acid molecule that has at least 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity with a CaSNA.
Nucleic acid molecules that exhibit substantial sequence similarity are inclusive of sequences that exhibit sequence identity over their entire length to a CaSNA or to a nucleic acid molecule encoding a CaSP, as well as sequences that are similar over only a part of its length. In this case, the part is at least 50 nucleotides of the CaSNA or the nucleic acid molecule encoding a CaSP, preferably at least 100 nucleotides, more preferably at least 150 or 200 nucleotides, even more preferably at least 250 or 300 nucleotides, still more preferably at least 400 or 500 nucleotides. The substantially similar nucleic acid molecule may be a naturally occurring one that is derived from another species, especially one derived from another primate, wherein the similar nucleic acid molecule encodes an amino acid sequence that exhibits significant sequence identity to that of the gene products of Table 2a or Table 2b or demonstrates significant sequence identity to the nucleotide sequence of the gene products of Table 2a, Table 2b or Table 7. The similar nucleic acid molecule may also be a naturally occurring nucleic acid molecule from a human, when the CaSNA is a member of a gene family. The similar nucleic acid molecule may also be a naturally occurring nucleic acid molecule derived from a non-primate, mammalian species, including without limitation, domesticated species, e.g., dog, cat, mouse, rat, rabbit, hamster, cow, horse and pig; and wild animals, e.g., monkey, fox, lions, tigers, bears, giraffes, zebras, etc. The substantially similar nucleic acid molecule may also be a naturally occurring nucleic acid molecule derived from a non-mammalian species, such as birds or reptiles. The naturally occurring substantially similar nucleic acid molecule may be isolated directly from humans or other species. In another embodiment, the substantially similar nucleic acid molecule may be one that is experimentally produced by random mutation of a nucleic acid molecule. In another embodiment, the substantially similar nucleic acid molecule may be one that is experimentally produced by directed mutation of a CaSNA. hi a preferred embodiment, the substantially similar nucleic acid molecule is an CaSNA.
The nucleic acid molecules of the present invention are also inclusive of allelic variants of a CaSNA or a nucleic acid encoding a CaSP. For example, single nucleotide polymorphisms (SNPs) occur frequently in eukaryotic genomes and the sequence determined from one individual of a species may differ from other allelic forms present within the population. More than 1.4 million SNPs have already identified in the human genome, International Human Genome Sequencing Consortium, Nature 409: 860-921 (2001). Variants with small deletions and insertions of more than a single nucleotide are also found in the general population, and often do not alter the function of the protein. In addition, amino acid substitutions occur frequently among natural allelic variants, and often do not substantially change protein function. In a preferred embodiment, the allelic variant is a variant of a gene, wherein the gene is transcribed into an RNA molecule. In a more preferred embodiment, the RNA molecule is an mRNA that encodes a CaSP. Ih a more preferred embodiment, the gene is transcribed into an mRNA that encodes a CaSP comprising an amino acid sequence of the gene products of Table 2a or Table 2b. In another preferred embodiment, the allelic variant is a variant of a gene, wherein the gene is transcribed into an mRNA that is a CaSNA. In a more preferred embodiment, the gene is transcribed into an mRNA that comprises the nucleic acid sequence of the gene products of Table 2a, Table 2b or Table 7. Also preferred is that the allelic variant is a naturally occurring allelic variant in the species of interest, particularly human.
Nucleic acid molecules of the present invention are also inclusive of nucleic acid sequences comprising a part of a nucleic acid sequence of the instant invention. The part may or may not encode a polypeptide, and may or may not encode a polypeptide that is a CaSP. m a preferred embodiment, the part encodes a CaSP. In one embodiment, the nucleic acid molecule comprises a part of a CaSNA. In another embodiment, the nucleic acid molecule comprises a part of a nucleic acid molecule that hybridizes or exhibits substantial sequence similarity to a CaSNA. In another embodiment, the nucleic acid molecule comprises a part of a nucleic acid molecule that is an allelic variant of a CaSNA. In another embodiment, the nucleic acid molecule comprises a part of a nucleic acid molecule that bridges an exon-exon junction of a CaSNA. In yet another embodiment, the nucleic acid molecule comprises a part of a nucleic acid molecule that encodes a CaSP. A part comprises at least 10 nucleotides, more preferably at least 15, 17, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400 or 500 nucleotides. The maximum size of a nucleic acid part is one nucleotide shorter than the sequence of the nucleic acid molecule encoding the full-length protein.
Nucleic acid molecules of the present invention are also inclusive of nucleic acid sequences that encode fusion proteins, homologous proteins, polypeptide fragments, muteins and polypeptide analogs, as described infra.
Nucleic acid molecules of the present invention are also inclusive of nucleic acid sequences containing modifications of the native nucleic acid molecule. Examples of such modifications include, but are not limited to, normative internucleoside bonds, postsynthetic modifications or altered nucleotide analogues. One having ordinary skill in the art would recognize that the type of modification that may be made will depend upon the intended use of the nucleic acid molecule. For instance, when the nucleic acid molecule is used as a hybridization probe, the range of such modifications will be limited to those that permit sequence-discriminating base pairing of the resulting nucleic acid. When used to direct expression of RNA or protein in vitro or in vivo, the range of such modifications will be limited to those that permit the nucleic acid to function properly as a polymerization substrate. When the isolated nucleic acid is used as a therapeutic agent, the modifications will be limited to those that do not confer toxicity upon the isolated nucleic acid.
Accordingly, in one embodiment, a nucleic acid molecule may include nucleotide analogues that incorporate labels that are directly detectable, such as radiolabels or fluorophores, or nucleotide analogues that incorporate labels that can be visualized in a subsequent reaction, such as biotin or various haptens. The labeled nucleic acid molecules are particularly useful as hybridization probes.
Common radiolabeled analogues include those labeled with 33P, 32P, and 35S, such as α-32P-dATP, α-32P-dCTP, α-32P-dGTP, α-32P-dTTP, α-32P-3 'dATP, α-32P-ATP, α-32P- CTP, α-32P-GTP, CX-32P-UTP, α-35S-dATP, γ-35S-GTP, γ-33P-dATP, and the like.
Commercially available fluorescent nucleotide analogues readily incorporated into the nucleic acids of the present invention include Cy3-dCTP, Cy3-dUTP, Cy5-dCTP, Cy3- dUTP (Amersham Biosciences, Piscataway, New Jersey, USA), fluorescein- 12-dUTP, tetramethylrhodamine-6-dUTP, Texas Red®-5-dUTP, Cascade Blue®-7-dUTP, BODIPY® FL-14-dUTP, BODIPY® TMR-14-dUTP, BODIPY® TR-14-dUTP, Rhodamine Green™-5-dUTP, Oregon Green® 488-5-dUTP, Texas Red®-12-dUTP, BODIPY® 630/650-14-dUTP, BODIPY® 650/665-14-dUTP, Alexa Fluor® 488-5-dUTP, Alexa Fluor® 532-5-dUTP, Alexa Fluor® 568-5-dUTP, Alexa Fluor® 594-5-dUTP, Alexa Fluor® 546- 14-dUTP, fluorescein- 12-UTP, tetramethylrhodamine-6-UTP, Texas Red®-5-UTP, Cascade Blue®-7-UTP, BODIPY® FL-14-UTP, BODIPY® TMR-14-UTP, BODIPY® TR-14-UTP, Rhodamine Green™-5-UTP, Alexa Fluor® 488-5-UTP, Alexa Fluor® 546-14-UTP (Molecular Probes, Inc. Eugene, OR, USA). One may also custom synthesize nucleotides having other fluorophores. See Henegariu et ah, Nature Biotechnol. 18: 345-348 (2000).
Haptens that are commonly conjugated to nucleotides for subsequent labeling include biotin (biotin- 11-dUTP, Molecular Probes, Inc., Eugene, OR, USA; biotin-21-UTP, biotin-21-dUTP, Clontech Laboratories, Inc., Palo Alto, CA, USA), digoxigenin (DIG-11-dUTP, alkali labile, DIG-Il-UTP, Roche Diagnostics Corp., Indianapolis, IN, USA), and dinitrophenyl (dinitrophenyl-11-dUTP, Molecular Probes, Inc., Eugene, OR, USA).
Nucleic acid molecules of the present invention can be labeled by incorporation of labeled nucleotide analogues into the nucleic acid. Such analogues can be incorporated by enzymatic polymerization, such as by nick translation, random priming, polymerase chain reaction (PCR), terminal transferase tailing, and end-filling of overhangs, for DNA molecules, and in vitro transcription driven, e.g., from phage promoters, such as T7, T3, and SP6, for RNA molecules. Commercial kits are readily available for each such labeling approach. Analogues can also be incorporated during automated solid phase chemical synthesis. Labels can also be incorporated after nucleic acid synthesis, with the 5' phosphate and 3' hydroxyl providing convenient sites for post-synthetic covalent attachment of detectable labels.
Other post-synthetic approaches also permit internal labeling of nucleic acids. For example, fluorophores can be attached using a cisplatin reagent that reacts with the N7 of guanine residues (and, to a lesser extent, adenine bases) in DNA, RNA, and Peptide Nucleic Acids (PNA) to provide a stable coordination complex between the nucleic acid and fluorophore label (Universal Linkage System) (available from Molecular Probes, Inc., Eugene, OR, USA and Amersham Pharmacia Biotech, Piscataway, NJ, USA); see Alers et al, Genes, Chromosomes & Cancer 25: 301- 305 (1999); Jelsma et al, J. NIH Res. 5: 82 (1994); Van Belkum et al, BioTechniques 16: 148-153 (1994). Alternatively, nucleic acids can be labeled using a disulfide-containing linker (FastTag™ Reagent, Vector Laboratories, Inc., Burlingame, CA, USA) that is photo- or thermally coupled to the target nucleic acid using aryl azide chemistry; after reduction, a free thiol is available for coupling to a hapten, fluorophore, sugar, affinity ligand, or other marker.
One or more independent or interacting labels can be incorporated into the nucleic acid molecules of the present invention. For example, both a fluorophore and a moiety that in proximity thereto acts to quench fluorescence can be included to report specific hybridization through release of fluorescence quenching or to report exonucleotidic excision. See, e.g., Tyagi et al., Nature Biotechnol. 14: 303-308 (1996); Tyagi et al, Nature Biotechnol 16: 49-53 (1998); Sokol et al, Proc. Natl Acad. Sd. USA 95: 11538-11543 (1998); Kostrikis et al, Science 279: 1228-1229 (1998); Marras et al, Genet. Anal. 14: 151-156 (1999); Holland et al, Proc. Natl. Acad. Sd. USA 88: 7276-7280 (1991); Heid et al, Genome Res. 6(10): 986-94 (1996); Kuimelis et al, Nucleic Acids Symp. Ser. (37): 255-6 (1997); and U.S. Patent Nos. 5,846,726, 5,925,517, 5,925,517, 5,723,591 and 5,538,848, the disclosures of which are incorporated herein by reference in their entireties. Nucleic acid molecules of the present invention may also be modified by altering one or more native phosphodiester internucleoside bonds to more nuclease-resistant, internucleoside bonds. See Hartmann et al (eds.), Manual of Antisense Methodology: Perspectives in Antisense Science. Kluwer Law International (1999); Stein et al. (eds.), Applied Antisense Oligonucleotide Technology, Wiley-Liss (1998); Chadwick et al. (eds.), Oligonucleotides as Therapeutic Agents - Symposium No. 209, John Wiley & Son Ltd (1997). Such altered internucleoside bonds are often desired for techniques or for targeted gene correction, Gamper et al, Nucl. Acids Res. 28(21): 4332-4339 (2000). For double stranded RNA inhibition which may utilize either natural ds RNA or ds RNA modified in its, sugar, phosphate or base, see Harmon, Nature 418(11): 244-251 (2002); Fire et al. in WO 99/32619; Tuschl et al. in US2002/0086356; Kruetzer et al. in WO
00/44895, the disclosures of which are incorporated herein by reference in their entirety. For circular antisense, see Kool in U.S. Patent No. 5,426,180, the disclosure of which is incorporated herein by reference in its entirety.
Modified oligonucleotide backbones include, without limitation, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3 '-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. Representative U.S. Patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Patent Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050, the disclosures of which are incorporated herein by reference in their entireties. In a preferred embodiment, the modified internucleoside linkages may be used for antisense techniques. Other modified oligonucleotide backbones do not include a phosphorus atom, but have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH2 component parts. Representative U.S. patents that teach the preparation of the above backbones include, but are not limited to, U.S. Patent Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437 and 5,677,439; the disclosures of which are incorporated herein by reference in their entireties.
In other preferred nucleic acid molecules, both the sugar and the internucleoside linkage are replaced with novel groups, such as peptide nucleic acids (PNA). In PNA compounds, the phosphodiester backbone of the nucleic acid is replaced with an amide- containing backbone, in particular by repeating N-(2-aminoethyl) glycine units linked by amide bonds. Nucleobases are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone, typically by methylene carbonyl linkages. PNA can be synthesized using a modified peptide synthesis protocol. PNA oligomers can be synthesized by both Fmoc and tBoc methods. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Patent Nos.
5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference in its entirety. Automated PNA synthesis is readily achievable on commercial synthesizers {see, e.g., "PNA User's Guide," Rev. 2, February 1998, Perseptive Biosystems Part No. 60138, Applied Biosystems, Inc., Foster City, CA). PNA molecules are advantageous for a number of reasons. First, because the PNA backbone is uncharged, PNA/DNA and PNA/RNA duplexes have a higher thermal stability than is found in DNA/DNA and DNA/RNA duplexes. The Tm of a PNA/DNA or PNA/RNA duplex is generally 1°C higher per base pair than the Tm of the corresponding DNA/DNA or DNA/RNA duplex (in 100 niM NaCl). Second, PNA molecules can also form stable PNA/DNA complexes at low ionic strength, under conditions in which DNA/DNA duplex formation does not occur. Third, PNA also demonstrates greater specificity in binding to complementary DNA because a PNA/DNA mismatch is more destabilizing than DNA/DNA mismatch. A single mismatch in mixed a PNA/DNA 15-mer lowers the Tm by 8-20°C (15°C on average). In the corresponding DNA/DNA duplexes, a single mismatch lowers the Tm by 4-160C (11°C on average). Because PNA probes can be significantly shorter than DNA probes, their specificity is greater. Fourth, PNA oligomers are resistant to degradation by enzymes, and the lifetime of these compounds is extended both in vivo and in vitro because nucleases and proteases do not recognize the PNA polyamide backbone with nucleobase sidechains. See, e.g., Ray et al, FASEB J. 14(9): 1041-60 (2000); Nielsen et al, Pharmacol Toxicol. 86(1): 3-7 (2000); Larsen et al, Biochim Biophys Acta. 1489(1): 159-66 (1999); Nielsen, Curr. Opin. Struct. Biol. 9(3): 353-7 (1999), and Nielsen, Curr. Opin. Biotechnol. 10(1): 71-5 (1999). Nucleic acid molecules may be modified compared to their native structure throughout the length of the nucleic acid molecule or can be localized to discrete portions thereof. As an example of the latter, chimeric nucleic acids can be synthesized that have discrete DNA and RNA domains and that can be used for targeted gene repair and modified PCR reactions, as further described in, Misra et al, Biochem. 37: 1917-1925 (1998); and Finn et al, Nucl. Acids Res. 24: 3357-3363 (1996), and U.S. Patent Nos.
5,760,012 and 5,731,181, the disclosures of which are incorporated herein by reference in their entireties.
Unless otherwise specified, nucleic acid molecules of the present invention can include any topological conformation appropriate to the desired use; the term thus explicitly comprehends, among others, single-stranded, double-stranded, triplexed, quadruplexed, partially double-stranded, partially- triplexed, partially-quadruplexed, branched, hairpinned, circular, and padlocked conformations. Padlock conformations and their utilities are further described in Baner et al, Curr. Opin. Biotechnol. 12: 11-15 (2001); Escude et al, Proc. Natl Acad. ScL USA 14: 96(19):10603-7 (1999); and Nilsson et al, Science 265(5181): 2085-8 (1994). Triplex and quadruplex conformations, and their utilities, are reviewed in Praseuth et al, Biochim. Biophys. Acta. 1489(1): 181-206 (1999); Fox, Curr. Med. Chem. 7(1): 17-37 (2000); Kochetkova et al, Methods MoI Biol. 130: 189-201 (2000); Chan et al, J. MoL Med. 75(4): 267-82 (1997); Rowley et al, MoI Med 5(10): 693-700 (1999); Kool, Annu Rev Biophys Biomol Struct. 25: 1-28 (1996).
SNP Polymorphisms
Commonly, sequence differences between individuals involve differences in single nucleotide positions. SNPs may account for 90% of human DNA polymorphism. Collins et al, 8 Genome Res. 1229-31 (1998). SNPs include single base pair positions in genomic DNA at which different sequence alternatives (alleles) exist in a population. In addition, the least frequent allele generally must occur at a frequency of 1% or greater. DNA sequence variants with a reasonably high population frequency are observed approximately every 1,000 nucleotide across the genome, with estimates as high as 1 SNP per 350 base pairs. Wang et al, 280 Science 1077-82 (1998); Harding et al, 60 Am. J. Human Genet. 772-89 (1997); Taillon-Miller et al, Genome Res. 8 :748-54 (1998); Cargill et al, Nat. Genet. 22:231-38 (1999); and Semple et al, Bioinform. Disc. Note 16:735-38 (2000). The frequency of SNPs varies with the type and location of the change. In base substitutions, two-thirds of the substitutions involve the C-T and G-A type. This variation in frequency can be related to 5-methylcytosine deamination reactions that occur frequently, particularly at CpG dinucleotides. Regarding location, SNPs occur at a much higher frequency in non-coding regions than in coding regions. Information on over one million variable sequences is already publicly available via the Internet and more such markers are available from commercial providers of genetic information. Kwok and Gu, Med. Today 5:538-53 (1999).
Several definitions of SNPs exist. See, e.g., Brooks, 235 Gene 177-86 (1999). As used herein, the term "single nucleotide polymorphism" or "SNP" includes all single base variants, thus including nucleotide insertions and deletions in addition to single nucleotide substitutions. There are two types of nucleotide substitutions. A transition is the replacement of one purine by another purine or one pyrimidine by another pyrimidine. A transversion is the replacement of a purine for a pyrimidine, or vice versa.
Numerous methods exist for detecting SNPs within a nucleotide sequence. A review of many of these methods can be found in Landegren et al, 8 Genome Res. 769-76 (1998). For example, a SNP in a genomic sample can be detected by preparing a Reduced Complexity Genome (RCG) from the genomic sample, then analyzing the RCG for the presence or absence of a SNP. See, e.g., WO 00/18960. Multiple SNPs in a population of target polynucleotides in parallel can be detected using, for example, the methods of WO 00/50869. Other SNP detection methods include the methods of U.S. Pat. Nos. 6,297,018 and 6,322,980. Furthermore, SNPs can be detected by restriction fragment length polymorphism (RFLP) analysis. See, e.g., U.S. Pat. Nos. 5,324,631; 5,645,995. RFLP analysis of SNPs, however, is limited to cases where the SNP either creates or destroys a restriction enzyme cleavage site. SNPs can also be detected by direct sequencing of the nucleotide sequence of interest. In addition, numerous assays based on hybridization have also been developed to detect SNPs and mismatch distinction by polymerases and ligases. Several web sites provide information about SNPs including Ensembl (ensembl with the extension .org of the world wide web), Sanger Institute (sanger with the extension .ac.uk/genetics/exon/ of the world wide web), National Center for Biotechnology
Information (NCBI) (ncbi with the extension .nlm.nih.gov/SNP/ of the world wide web), The SNP Consortium Ltd. (snp with the extension .cshl.org/ of the world wide web). The chromosomal locations for the compositions disclosed herein are provided below. In addition, one of ordinary skill in the art could perform a search against the genome or any of the databases cited above using BLAST to find the chromosomal location or locations of SNPs. Another preferred method to find the genomic coordinates and associated SNPs would be to use the BLAT tool (genome.ucsc.edu, Kent et al. 2001, The Human Genome Browser at UCSC, Genome Research 996-1006 or Kent 2002 BLAT, The BLAST -Like Alignment Tool Genome Research, 1-9). AU web sites above were accessed December 3, 2003.
RNA interference
RNA interference refers to the process of sequence-specific transcriptional or post transcriptional gene silencing in animals mediated by various RNAi species including short interfering RNAs (siRNA), microRNAs (miRNA), tiny non-coding RNAs (tncRNA) and small modulatory RNA (smRNA). Fire et al. , Nature 391 : 806 (1998)and Novina et al., Nature 430:161-164(2004). The corresponding process in plants is commonly referred to as post transcriptional gene silencing or RNA silencing and is also referred to as quelling in fungi. The process of post transcriptional gene silencing is thought to be an evolutionarily conserved cellular defense mechanism used to prevent the expression of foreign genes which is commonly shared by diverse flora and phyla. Fire et al, Trends Genet. 15: 358 (1999). Such protection from foreign gene expression may have evolved in response to the production of double stranded RNAs (dsRNA) derived from viral infection or the random integration of transposon elements into a host genome via a cellular response that specifically destroys homologous single stranded RNA or viral genomic RNA. The presence of dsRNA in cells triggers the RNAi response though a mechanism that has yet to be fully characterized. This mechanism appears to be different from the interferon response that results from dsRNA mediated activation of protein kinase PKR and 2',5'-oligoadenylate synthetase resulting in non-specific cleavage of mRNA by ribonuclease L.
The presence of long dsRNAs in cells stimulates the activity of a ribonuclease III enzyme referred to as dicer. Dicer is involved in the processing of the dsRNA into short pieces of dsRNA known as short interfering RNAs (siRNA). Berstein et al, Nature 409: 363 (2001). Short interfering RNAs derived from dicer activity are typically about 21-23 nucleotides in length and comprise about 19 base pair duplexes. Dicer has also been implicated in the excision of 21 and 22 nucleotide small temporal RNAs (stRNA) from precursor RNA of conserved structure that are implicated in translational control. Hutvagner et al, Science 293: 834 (2001). The RNAi response also features an endonuclease complex containing a siRNA, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single stranded RNA having sequence complementary to the antisense strand of the siRNA duplex. Cleavage of the target RNA takes place in the middle of the region complementary to the antisense strand of the siRNA duplex. Elbashir et al, Genes Dev. 15: 188 (2001); Novina, 2004 supra. Short interfering RNA mediated RNAi has been studied in a variety of systems.
Fire et al, Nature, 391 : 806 (1998),were the first to observe RNAi in C. Elegans. Wianny and Goetz, Nature Cell Biol. 2: 70 (1999), describe RNAi mediated by dsRNA in mouse embryos. Hammond et al, Nature 404: 293 (2000), describe RNAi in Drosophila cells transfected with dsRNA. Elbashir et al, Nature 411 : 494 (2001), describe RNAi induced by introduction of duplexes of synthetic 21-nucleotide RNAs in cultured mammalian cells including human embryonic kidney and HeLa cells. Recent work in Drosophila embryonic lysates (Elbashir et al, EMBO J. 20: 6877 (2001) has revealed certain requirements for siRNA length, structure, chemical composition, and sequence that are essential to mediate efficient RNAi activity. These studies have shown that 21 nucleotide siRNA duplexes are most active when containing two nucleotide 3'-overhangs. Furthermore, complete substitution of one or both siRNA strands with 2'-deoxy (2'-H) or 2'-O-methyl nucleotides abolishes RNAi activity, whereas substitution of the 3'-terminal siRNA overhang nucleotides with deoxy nucleotides (2'-H) was shown to be tolerated. Single mismatch sequences in the center of the siRNA duplex were also shown to abolish RNAi activity. In addition, these studies also indicate that the position of the cleavage site in the target RNA is defined by the 5'-end of the siRNA guide sequence rather than the 3'-end. Elbashir et ah, EMBO J. 20:6877 (2001). Other studies have indicated that a 5'-phosphate on the target-complementary strand of a siRNA duplex is required for siRNA activity and that ATP is utilized to maintain the 5 '-phosphate moiety on the siRNA. Nykanen et at, Cell 107: 309 (2001).
Studies have shown that replacing the 3 '-overhanging segments of a 21-mer siRNA duplex having 2 nucleotide 3' overhangs with deoxyribonucleotides does not have an adverse effect on RNAi activity. Replacing up to 4 nucleotides on each end of the siRNA with deoxyribonucleotides has been reported to be well tolerated whereas complete substitution with deoxyribonucleotides results in no RNAi activity. Elbashir et al, EMBO J. 20: 6877 (2001). In addition, Elbashir et ah, supra, also report that substitution of siRNA with 2'-O-methyl nucleotides completely abolishes RNAi activity. Li et ah, WO 00/44914, and Beach et ah, WO 01/68836 both suggest that siRNA "may include modifications to either the phosphate-sugar back bone or the nucleoside to include at least one of a nitrogen or sulfur heteroatom", however neither application teaches to what extent these modifications are tolerated in siRNA molecules nor provide any examples of such modified siRNA. Kreutzer and Limmer, Canadian Patent Application No. 2,359,180, also describe certain chemical modifications for use in dsRNA constructs in order to counteract activation of double stranded-RNA-dependent protein kinase PKR, specifically 2'-amino or 2'-O-methyl nucleotides, and nucleotides containing a 2'-0 or 4'-C methylene bridge. However, Kreutzer and Limmer similarly fail to show to what extent these modifications are tolerated in siRNA molecules nor do they provide any examples of such modified siRNA.
Parrish et ah, Molecular Cell 6:1977-1087 (2000), tested certain chemical modifications targeting the unc-22 gene in C. elegans using long (>25 nt) siRNA transcripts. The authors describe the introduction of thiophosphate residues into these siRNA transcripts by incorporating thiophosphate nucleotide analogs with T7 and T3 RNA polymerase and observed that "RNAs with two [phosphorothioate] modified bases also had substantial decreases in effectiveness as RNAi triggers; [phosphorothioate] modification of more than two residues greatly destabilized the RNAs in vitro and we were not able to assay interference activities." Id. at 1081. The authors also tested certain modifications at the 2'-position of the nucleotide sugar in the long siRNA transcripts and observed that substituting deoxynucleotides for ribonucleotides "produced a substantial decrease in interference activity", especially in the case of Undine to Thymidine and/or Cytidine to deoxy-Cytidine substitutions. Id. hi addition, the authors tested certain base modifications, including substituting 4-thiouracil, 5-bromouracil, 5-iodouracil, 3-
(aminoallyl)uracil for uracil, and inosine for guanosine in sense and antisense strands of the siRNA, and found that whereas 4-thiouracil and 5-bromouracil were all well tolerated, inosine "produced a substantial decrease in interference activity" when incorporated in either strand. Incorporation of 5-iodouracil and 3-(aminoallyl)uracil in the antisense strand resulted in substantial decrease in RNAi activity as well.
Beach et al, WO 01/68836, describes specific methods for attenuating gene expression using endogenously derived dsRNA. Tuschl et al, WO 01/75164, describes a Drosophila in vitro RNAi system and the use of specific siRNA molecules for certain functional genomic and certain therapeutic applications; although Tuschl, Chem. Biochem. 2:239-245 (2001), doubts that RNAi can be used to cure genetic diseases or viral infection due "to the danger of activating interferon response". Li et al, WO 00/44914, describes the use of specific dsRNAs for use in attenuating the expression of certain target genes. Zernicka-Goetz et al, WO 01/36646, describes certain methods for inhibiting the expression of particular genes in mammalian cells using certain dsRNA molecules. Fire et al, WO 99/32619, U.S. Patent No. 6,506,559, the contents of which are hereby incorporated by reference, describes particular methods for introducing certain dsRNA molecules into cells for use in inhibiting gene expression. Plaetinck et al, WO 00/01846, describes certain methods for identifying specific genes responsible for conferring a particular phenotype in a cell using specific dsRNA molecules. Mello et al, WO 01/29058, describes the identification of specific genes involved in dsRNA mediated RNAi. Deschamps Depaillette et al, International PCT Publication No. WO 99/07409, describes specific compositions consisting of particular dsRNA molecules combined with certain anti-viral agents. Driscoll et al, International PCT Publication No. WO 01/49844, describes specific DNA constructs for use in facilitating gene silencing in targeted organisms. Parrish et al, Molecular Cell 6: 1977-1087 (2000), describes specific chemically modified siRNA constructs targeting the unc-22 gene of C. elegans. Tuschl et al, International PCT Publication No. WO 02/44321, describe certain synthetic siRNA constructs. Methods for Using Nucleic Acid Molecules as Probes and Primers The isolated nucleic acid molecules of the present invention can be used as hybridization probes to detect, characterize, and quantify hybridizing nucleic acids in, and isolate hybridizing nucleic acids from, both genomic and transcript-derived nucleic acid samples. When free in solution, such probes are typically, but not invariably, detectably labeled; bound to a substrate, as in a microarray, such probes are typically, but not invariably unlabeled.
In one embodiment, the isolated nucleic acid molecules of the present invention can be used as probes to detect and characterize gross alterations in the gene of a CaSNA, such as deletions, insertions, translocations, and duplications of the CaSNA genomic locus through fluorescence in situ hybridization (FISH) to chromosome spreads. See, e.g., Andreeff et al. (eds.), Introduction to Fluorescence In Situ Hybridization: Principles and Clinical Applications, John Wiley & Sons (1999). The isolated nucleic acid molecules of the present invention can be used as probes to assess smaller genomic alterations using, e.g., Southern blot detection of restriction fragment length polymorphisms. The isolated nucleic acid molecules of the present invention can be used as probes to isolate genomic clones that include a nucleic acid molecule of the present invention, which thereafter can be restriction mapped and sequenced to identify deletions, insertions, translocations, and substitutions (single nucleotide polymorphisms, SNPs) at the sequence level. Alternatively, detection techniques such as molecular beacons may be used, see Kostrikis et άl,. Science 279:1228-1229 (1998).
The isolated nucleic acid molecules of the present invention can be also be used as probes to detect, characterize, and quantify CaSNA in, and isolate CaSNA from, transcript-derived nucleic acid samples. In one embodiment, the isolated nucleic acid molecules of the present invention can be used as hybridization probes to detect, characterize by length, and quantify mRNA by Northern blot of total or poly- A - selected RNA samples. In another embodiment, the isolated nucleic acid molecules of the present invention can be used as hybridization probes to detect, characterize by location, and quantify mRNA by in situ hybridization to tissue sections. See, e.g., Schwarchzacher et al, In Situ Hybridization, Springer- Verlag New York (2000). In another preferred embodiment, the isolated nucleic acid molecules of the present invention can be used as hybridization probes to measure the representation of clones in a cDNA library or to isolate hybridizing nucleic acid molecules acids from cDNA libraries, permitting sequence level characterization of mRNAs that hybridize to CaSNAs, including, without limitations, identification of deletions, insertions, substitutions, truncations, alternatively spliced forms and single nucleotide polymorphisms. In yet another preferred embodiment, the nucleic acid molecules of the instant invention may be used in microarrays. AU of the aforementioned probe techniques are well within the skill in the art, and are described at greater length in standard texts such as Sambrook (2001), supra; Ausubel (1999), supra; and Walker et al. (eds.), The Nucleic Acids Protocols Handbook, Humana Press (2000).
In another embodiment, a nucleic acid molecule of the invention may be used as a probe or primer to identify and/or amplify a second nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of the invention. In this embodiment, it is preferred that the probe or primer be derived from a nucleic acid molecule encoding a CaSP. More preferably, the probe or primer is derived from a nucleic acid molecule encoding a polypeptide having an amino acid sequence of the gene products of Table 2a or Table 2b. Also preferred are probes or primers derived from a CaSNA. More preferred are probes or primers derived from a nucleic acid molecule having a nucleotide sequence of the gene products of Table 2a, Table 2b or Table 7. hi general, a probe or primer is at least 10 nucleotides in length, more preferably at least 12, more preferably at least 14 and even more preferably at least 16 or 17 nucleotides in length. In an even more preferred embodiment, the probe or primer is at least 18 nucleotides in length, even more preferably at least 20 nucleotides and even more preferably at least 22 nucleotides in length. Primers and probes may also be longer in length. For instance, a probe or primer may be 25 nucleotides in length, or may be 30, 40 or 50 nucleotides in length. Methods of performing nucleic acid hybridization using oligonucleotide probes are well known in the art. See, e.g., Sambrook et at, 1989, supra, Chapter 11 and pp. 11.31-11.32 and 11.40-11.44, which describes radiolabeling of short probes, and pp. 11.45-11.53, which describe hybridization conditions for oligonucleotide probes, including specific conditions for probe hybridization (pp. 11.50-11.51).
Methods of performing primer-directed amplification are also well known in the art. Methods for performing the polymerase chain reaction (PCR) are compiled, inter alia, in McPherson, PCR Basics: From Background to Bench. Springer Verlag (2000); hinis et al. (eds.), PCR Applications: Protocols for Functional Genomics, Academic Press (1999); Gelfand et al. (eds.), PCR Strategies. Academic Press (1998); Newton et al, PCR. Springer- Verlag New York (1997); Burke (ed.), PCR: Essential Techniques, John Wiley & Son Ltd (1996); White (ed.), PCR Cloning Protocols: From Molecular Cloning to Genetic Engineering, Vol. 67, Humana Press (1996); and McPherson et al. (eds.), PCR 2: A Practical Approach, Oxford University Press, Inc. (1995). Methods for performing RT- PCR are collected, e.g., in Siebert et al. (eds.), Gene Cloning and Analysis by RT-PCR, Eaton Publishing Company/Bio Techniques Books Division, 1998; and Siebert (ed.), PCR Technique:RT-PCR, Eaton Publishing Company/ BioTechniques Books (1995).
PCR and hybridization methods may be used to identify and/or isolate nucleic acid molecules of the present invention including allelic variants, homologous nucleic acid molecules and fragments. PCR and hybridization methods may also be used to identify, amplify and/or isolate nucleic acid molecules of the present invention that encode homologous proteins, analogs, fusion protein or muteins of the invention. Nucleic acid primers as described herein can be used to prime amplification of nucleic acid molecules of the invention, using transcript-derived or genomic DNA as template. These nucleic acid primers can also be used, for example, to prime single base extension (SBE) for SNP detection {See, e.g., U.S. Pat. No. 6,004,744, the disclosure of which is incorporated herein by reference in its entirety).
Isothermal amplification approaches, such as rolling circle amplification, are also now well-described. See, e.g., Schweitzer et al, Curr. Opin. Biotechnol. 12(1): 21-7 (2001); international patent publications WO 97/19193 and WO 00/15779, and U.S. Patent Nos. 5,854,033 and 5,714,320, the disclosures of which are incorporated herein by reference in their entireties. Rolling circle amplification can be combined with other techniques to facilitate SNP detection. See, e.g., Lizardi et al, Nature Genet. 19(3): 225-32 (1998). Nucleic acid molecules of the present invention may be bound to a substrate either covalently or noncovalently. The substrate can be porous or solid, planar or non-planar, unitary or distributed. The bound nucleic acid molecules may be used as hybridization probes, and may be labeled or unlabeled. In a preferred embodiment, the bound nucleic acid molecules are unlabeled. In one embodiment, the nucleic acid molecule of the present invention is bound to a porous substrate, e.g., a membrane, typically comprising nitrocellulose, nylon, or positively charged derivatized nylon. The nucleic acid molecule of the present invention can be used to detect a hybridizing nucleic acid molecule that is present within a labeled nucleic acid sample, e.g., a sample of transcript-derived nucleic acids. In another embodiment, the nucleic acid molecule is bound to a solid substrate, including, without limitation, glass, amorphous silicon, crystalline silicon or plastics. Examples of plastics include, without limitation, polymethylacrylic, polyethylene, polypropylene, polyacrylate, polymethylmethacrylate, polyvinylchloride, polytetrafluoroethylene, polystyrene, polycarbonate, polyacetal, polysulfone, celluloseacetate, cellulosenitrate, nitrocellulose, or mixtures thereof. The solid substrate may be any shape, including rectangular, disk-like and spherical. In a preferred embodiment, the solid substrate is a microscope slide or slide-shaped substrate. The nucleic acid molecule of the present invention can be attached covalently to a surface of the support substrate or applied to a derivatized surface in a chao tropic agent that facilitates denaturation and adherence by presumed noncovalent interactions, or some combination thereof. The nucleic acid molecule of the present invention can be bound to a substrate to which a plurality of other nucleic acids are concurrently bound, hybridization to each of the plurality of bound nucleic acids being separately detectable. At low density, e.g. on a porous membrane, these substrate-bound collections are typically denominated macroarrays; at higher density, typically on a solid support, such as glass, these substrate bound collections of plural nucleic acids are colloquially termed microarrays. As used herein, the term microarray includes arrays of all densities. It is, therefore, another aspect of the invention to provide microarrays that comprise one or more of the nucleic acid molecules of the present invention.
In yet another embodiment, the invention is directed to single exon probes based on the CaSNAs disclosed herein.
Expression Vectors, Host Cells and Recombinant Methods of Producing Polypeptides
Another aspect of the present invention provides vectors that comprise one or more of the isolated nucleic acid molecules of the present invention, and host cells in which such vectors have been introduced.
The vectors can be used, inter alia, for propagating the nucleic acid molecules of the present invention in host cells (cloning vectors), for shuttling the nucleic acid molecules of the present invention between host cells derived from disparate organisms (shuttle vectors), for inserting the nucleic acid molecules of the present invention into host cell chromosomes (insertion vectors), for expressing sense or antisense RNA transcripts of the nucleic acid molecules of the present invention in vitro or within a host cell, and for expressing polypeptides encoded by the nucleic acid molecules of the present invention, alone or as fusion proteins with heterologous polypeptides (expression vectors). Vectors are by now well known in the art, and are described, inter alia, in Jones et al. (eds.), Vectors: Cloning Applications: Essential Techniques (Essential Techniques Series), John Wiley & Son Ltd. (1998); Jones et al. (eds.), Vectors: Expression Systems: Essential Techniques (Essential Techniques Series), John Wiley & Son Ltd. (1998); Gacesa et al, Vectors: Essential Data. John Wiley & Sons Ltd. (1995); Cid-Arregui (eds.), Viral Vectors: Basic Science and Gene Therapy, Eaton Publishing Co. (2000); Sambrook (2001), supra; Ausubel (1999), supra. Furthermore, a variety of vectors are available commercially. Use of existing vectors and modifications thereof are well within the skill in the art. Thus, only basic features need be described here.
Nucleic acid sequences may be expressed by operatively linking them to an expression control sequence in an appropriate expression vector and employing that expression vector to transform an appropriate unicellular host. Expression control sequences are sequences that control the transcription, post-transcriptional events and translation of nucleic acid sequences. Such operative linking of a nucleic sequence of this invention to an expression control sequence, of course, includes, if not already part of the nucleic acid sequence, the provision of a translation initiation codon, ATG or GTG, in the correct reading frame upstream of the nucleic acid sequence.
A wide variety of host/expression vector combinations may be employed in expressing the nucleic acid sequences of this invention. Useful expression vectors, for example, may consist of segments of chromosomal, non-chromosomal and synthetic nucleic acid sequences. In one embodiment, prokaryotic cells may be used with an appropriate vector.
Prokaryotic host cells are often used for cloning and expression. In a preferred embodiment, prokaryotic host cells include E. coli, Pseudomonas, Bacillus and Streptomyces . In a preferred embodiment, bacterial host cells are used to express the nucleic acid molecules of the instant invention. Useful expression vectors for bacterial hosts include bacterial plasmids, such as those from E. coli, Bacillus or Streptomyces, including pBluescript, ρGEX-2T, pUC vectors, col El, pCRl, pBR322, pMB9 and their derivatives, wider host range plasmids, such as RP4, phage DNAs, e.g., the numerous derivatives of phage lambda, e.g., NM989, λGTIO and λGTll, and other phages, e.g., M13 and filamentous single stranded phage DNA. Where E. coli is used as host, selectable markers are, analogously, chosen for selectivity in gram negative bacteria: e.g., typical markers confer resistance to antibiotics, such as ampicillin, tetracycline, chloramphenicol, kanamycin, streptomycin and zeocin; auxotrophic markers can also be used.
In other embodiments, eukaryotic host cells, such as yeast, insect, mammalian or plant cells, may be used. Yeast cells, typically S. cerevisiae, are useful for eukaryotic genetic studies, due to the ease of targeting genetic changes by homologous recombination and the ability to easily complement genetic defects using recombinantly expressed proteins. Yeast cells are useful for identifying interacting protein components, e.g. through use of a two-hybrid system. In a preferred embodiment, yeast cells are useful for protein expression. Vectors of the present invention for use in yeast will typically, but not invariably, contain an origin of replication suitable for use in yeast and a selectable marker that is functional in yeast. Yeast vectors include Yeast Integrating plasmids (e.g., YIp5) and Yeast Replicating plasmids (the YRp and YEp series plasmids), Yeast Centromere plasmids (the YCp series plasmids), Yeast Artificial Chromosomes (YACs) which are based on yeast linear plasmids, denoted YLp, pGPD-2, 2μ plasmids and derivatives thereof, and improved shuttle vectors such as those described in Gietz et ah, Gene, 74: 527-34 (1988) (YIplac, YΕplac and YCplac). Selectable markers in yeast vectors include a variety of auxotrophic markers, the most common of which are (in Saccharomyces cerevisiae) URA3, HIS3, LΕU2, TRPl and LYS2, which complement specific auxotrophic mutations, such as ura3-52, his3-Dl, Ieu2-Dl, trpl-Dl and lys2-201.
Insect cells may be chosen for high efficiency protein expression. Where the host cells are from Spodoptera frugiperda, e.g., Sf9 and Sf21 cell lines, and expresSF™ cells (Protein Sciences Corp., Meriden, CT, USA), the vector replicative strategy is typically based upon the baculovirus life cycle. Typically, baculovirus transfer vectors are used to replace the wild-type AcMNPV polyhedrin gene with a heterologous gene of interest. Sequences that flank the polyhedrin gene in the wild-type genome are positioned 5' and 3' of the expression cassette on the transfer vectors. Following co-transfection with AcMNPV DNA, a homologous recombination event occurs between these sequences resulting in a recombinant virus carrying the gene of interest and the polyhedrin or plO promoter. Selection can be based upon visual screening for lacZ fusion activity. The host cells may also be mammalian cells, which are particularly useful for expression of proteins intended as pharmaceutical agents, and for screening of potential agonists and antagonists of a protein or a physiological pathway. Mammalian vectors intended for autonomous extrachromosomal replication will typically include a viral origin, such as the S V40 origin (for replication in cell lines expressing the large T-antigen, such as COSl and C0S7 cells), the papillomavirus origin, or the EBV origin for long term episomal replication (for use, e.g., in 293 -EBNA cells, which constitutively express the EBV EBNA-I gene product and adenovirus ElA). Vectors intended for integration, and thus replication as part of the mammalian chromosome, can, but need not, include an origin of replication functional in mammalian cells, such as the SV40 origin. Vectors based upon viruses, such as adenovirus, adeno-associated virus, vaccinia virus, and various mammalian retroviruses, will typically replicate according to the viral replicative strategy. Selectable markers for use in mammalian cells include, include but are not limited to, resistance to neomycin (G418), blasticidin, hygromycin and zeocin, and selection based upon the purine salvage pathway using HAT medium.
Expression in mammalian cells can be achieved using a variety of plasmids, including pSV2, pBC12BI, and p91023, as well as lytic virus vectors (e.g., vaccinia virus, adeno virus, and baculovirus), episomal virus vectors (e.g., bovine papillomavirus), and retroviral vectors (e.g., murine retroviruses). Useful vectors for insect cells include baculoviral vectors and pVL 941.
Plant cells can also be used for expression, with the vector replicon typically derived from a plant virus (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) and selectable markers chosen for suitability in plants.
It is known that codon usage of different host cells may be different. For example, a plant cell and a human cell may exhibit a difference in codon preference for encoding a particular amino acid. As a result, human mRNA may not be efficiently translated in a plant, bacteria or insect host cell. Therefore, another embodiment of this invention is directed to codon optimization. The codons of the nucleic acid molecules of the invention may be modified to resemble, as much as possible, genes naturally contained within the host cell without altering the amino acid sequence encoded by the nucleic acid molecule.
Any of a wide variety of expression control sequences may be used in these vectors to express the nucleic acid molecules of this invention. Such useful expression control sequences include the expression control sequences associated with structural genes of the foregoing expression vectors. Expression control sequences that control transcription include, e.g., promoters, enhancers and transcription termination sites. Expression control sequences in eukaryotic cells that control post-transcriptional events include splice donor and acceptor sites and sequences that modify the half-life of the transcribed RNA, e.g., sequences that direct poly(A) addition or binding sites for RNA- binding proteins. Expression control sequences that control translation include ribosome binding sites, sequences which direct targeted expression of the polypeptide to or within particular cellular compartments, and sequences in the 5' and 3' untranslated regions that modify the rate or efficiency of translation. Examples of useful expression control sequences for a prokaryote, e.g., E. coli, will include a promoter, often a phage promoter, such as phage lambda pL promoter, the trc promoter, a hybrid derived from the trp and lac promoters, the bacteriophage T7 promoter (in E. coli cells engineered to express the T7 polymerase), the TAC or TRC system, the major operator and promoter regions of phage lambda, the control regions of fd coat protein, and the araBAD operon. Prokaryotic expression vectors may further include transcription terminators, such as the asp A terminator, and elements that facilitate translation, such as a consensus ribosome binding site and translation termination codon, Schomer et al, Proc. Natl. Acad. ScL USA 83: 8506-8510 (1986).
Expression control sequences for yeast cells, typically S. cerevisiae, will include a yeast promoter, such as the CYCl promoter, the GALl promoter, the GALlO promoter, ADHl promoter, the promoters of the yeast α-mating system, or the GPD promoter, and will typically have elements that facilitate transcription termination, such as the transcription termination signals from the CYCl or ADHl gene.
Expression vectors useful for expressing proteins in mammalian cells will include a promoter active in mammalian cells. These promoters include, but are not limited to, those derived from mammalian viruses, such as the enhancer-promoter sequences from the immediate early gene of the human cytomegalovirus (CMV), the enhancer-promoter sequences from the Rous sarcoma virus long terminal repeat (RSV LTR), the enhancer- promoter from SV40 and the early and late promoters of adenovirus. Other expression control sequences include the promoter for 3-phosphoglycerate kinase or other glycolytic enzymes, the promoters of acid phosphatase. Other expression control sequences include those from the gene comprising the CaSNA of interest. Often, expression is enhanced by incorporation of polyadenylation sites, such as the late SV40 polyadenylation site and the polyadenylation signal and transcription termination sequences from the bovine growth hormone (BGH) gene, and ribosome binding sites. Furthermore, vectors can include introns, such as intron II of rabbit β-globin gene and the SV40 splice elements.
Preferred nucleic acid vectors also include a selectable or amplifiable marker gene and means for amplifying the copy number of the gene of interest. Such marker genes are well known in the art. Nucleic acid vectors may also comprise stabilizing sequences (e.g., ori- or ARS-like sequences and telomere-like sequences), or may alternatively be designed to favor directed or non-directed integration into the host cell genome. In a preferred embodiment, nucleic acid sequences of this invention are inserted in frame into an expression vector that allows a high level expression of an RNA which encodes a protein comprising the encoded nucleic acid sequence of interest. Nucleic acid cloning and sequencing methods are well known to those of skill in the art and are described in an assortment of laboratory manuals, including Sambrook (1989), supra, Sambrook (2000), supra; and Ausubel (1992), supra, Ausubel (1999), supra. Product information from manufacturers of biological, chemical and immunological reagents also provide useful information.
Expression vectors may be either constitutive or inducible. Inducible vectors include either naturally inducible promoters, such as the trc promoter, which is regulated by the lac operon, and the pL promoter, which is regulated by tryptophan, the MMTV-LTR promoter, which is inducible by dexamethasone, or can contain synthetic promoters and/or additional elements that confer inducible control on adjacent promoters. Examples of inducible synthetic promoters are the hybrid Plac/ara-1 promoter and the PLtetO-1 promoter. The PLtetO-1 promoter takes advantage of the high expression levels from the PL promoter of phage lambda, but replaces the lambda repressor sites with two copies of operator 2 of the TnIO tetracycline resistance operon, causing this promoter to be tightly repressed by the Tet repressor protein and induced in response to tetracycline (Tc) and Tc derivatives such as anhydrotetracycline. Vectors may also be inducible because they contain hormone response elements, such as the glucocorticoid response element (GRE) and the estrogen response element (ERE), which can confer hormone inducibility where vectors are used for expression in cells having the respective hormone receptors. To reduce background levels of expression, elements responsive to ecdysone, an insect hormone, can be used instead, with coexpression of the ecdysone receptor. In one embodiment of the invention, expression vectors can be designed to fuse the expressed polypeptide to small protein tags that facilitate purification and/or visualization. Such tags include a polyhistidine tag that facilitates purification of the fusion protein by immobilized metal affinity chromatography, for example using NiNTA resin (Qiagen Inc., Valencia, CA, USA) or TALON™ resin (cobalt immobilized affinity chromatography medium, Clontech Labs, Palo Alto, CA, USA). The fusion protein can include a chitin- binding tag and self-excising intern, permitting chitin-based purification with self-removal of the fused tag (IMPACT™ system, New England Biolabs, Inc., Beverley, MA, USA). Alternatively, the fusion protein can include a calmodulin-binding peptide tag, permitting purification by calmodulin affinity resin (Stratagene, La Jolla, CA, USA), or a specifically excisable fragment of the biotin carboxylase carrier protein, permitting purification of in vivo biotinylated protein using an avidin resin and subsequent tag removal (Promega, Madison, WI, USA). As another useful alternative, the polypeptides of the present invention can be expressed as a fusion to glutathione-S-transferase, the affinity and specificity of binding to glutathione permitting purification using glutathione affinity resins, such as Glutathione-Superflow Resin (Clontech Laboratories, Palo Alto, CA, USA), with subsequent elution with free glutathione. Other tags include, for example, the Xpress epitope, detectable by anti-Xpress antibody (Invitrogen, Carlsbad, CA, USA), a myc tag, detectable by anti-myc tag antibody, the V5 epitope, detectable by anti-V5 antibody (Invitrogen, Carlsbad, CA, USA), FLAG® epitope, detectable by anti-FLAG® antibody (Stratagene, La Jolla, CA, USA), and the HA epitope, detectable by anti-HA antibody.
For secretion of expressed polypeptides, vectors can include appropriate sequences that encode secretion signals, such as leader peptides. For example, the pSecTag2 vectors (Invitrogen, Carlsbad, CA, USA) are 5.2 kb mammalian expression vectors that carry the secretion signal from the V-J2-C region of the mouse Ig kappa-chain for efficient secretion of recombinant proteins from a variety of mammalian cell lines.
Expression vectors can also be designed to fuse proteins encoded by the heterologous nucleic acid insert to polypeptides that are larger than purification and/or identification tags. Useful protein fusions include those that permit display of the encoded protein on the surface of a phage or cell, fusions to intrinsically fluorescent proteins, such as those that have a green fluorescent protein (GFP)-like chromophore, fusions to the IgG Fc region, and fusions for use in two hybrid systems. Vectors for phage display fuse the encoded polypeptide to, e.g., the gene III protein (pill) or gene VIII protein (p VIII) for display on the surface of filamentous phage, such as Ml 3. See Barbas et at, Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press (2001); Kay et at (eds.), Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, Inc., (1996); Abelson et at (eds.), Combinatorial Chemistry (Methods in Enzymology, Vol. 267) Academic Press (1996). Vectors for yeast display, e.g. the pYDl yeast display vector (Invitrogen, Carlsbad, CA, USA), use the α-agglutinin yeast adhesion receptor to display recombinant protein on the surface of & cerevisiae. Vectors for mammalian display, e.g., the pDisplay™ vector (Invitrogen, Carlsbad, CA, USA), target recombinant proteins using an N-terminal cell surface targeting signal and a C-terminal transmembrane anchoring domain of platelet derived growth factor receptor.
A wide variety of vectors now exist that fuse proteins encoded by heterologous nucleic acids to the chromophore of the substrate-independent, intrinsically fluorescent green fluorescent protein from Aequorea victoria ("GFP") and its variants. The GFP-like chromophore can be selected from GFP-like chromophores found in naturally occurring proteins, such as A. victoria GFP (GenBank accession number AAA27721), Renilla reniformis GFP, FP583 (GenBank accession no. AF168419) (DsRed), FP593 (AF272711), FP483 (AF168420), FP484 (AF168424), FP595 (AF246709), FP486 (AF168421), FP538 (AF168423), and FP506 (AF168422), and need include only so much of the native protein as is needed to retain the chromophore's intrinsic fluorescence. Methods for determining the minimal domain required for fluorescence are known in the art. See Li et at, J. Biol. Chem. 272: 28545-28549 (1997). Alternatively, the GFP-like chromophore can be selected from GFP-like chromophores modified from those found in nature. The methods for engineering such modified GFP-like chromophores and testing them for fluorescence activity, both alone and as part of protein fusions, are well known in the art. See Heim et at, Curr. Biol. 6: 178-182 (1996) and Palm et at, Methods Enzymot 302: 378-394 (1999). A variety of such modified chromophores are now commercially available and can readily be used in the fusion proteins of the present invention. These include EGFP ("enhanced GFP"), EBFP ("enhanced blue fluorescent protein"), BFP2, EYFP ("enhanced yellow fluorescent protein"), ECFP ("enhanced cyan fluorescent protein") or Citrine. EGFP {see, e.g, Cormack et at, Gene 173: 33-38 (1996); U.S. Patent Nos. 6,090,919 and 5,804,387, the disclosures of which are incorporated herein by reference in their entireties) is found on a variety of vectors, both plasmid and viral, which are available commercially (Clontech Labs, Palo Alto, CA, USA); EBFP is optimized for expression in mammalian cells whereas BFP2, which retains the original jellyfish codons, can be expressed in bacteria {see, e.g,. Heim et al, Curr. Biol. 6: 178-182 (1996) and Cormack et al, Gene 173: 33-38 (1996)). Vectors containing these blue-shifted variants are available from
Clontech Labs (Palo Alto, CA, USA). Vectors containing EYFP, ECFP {see, e.g., Heim et al, Curr. Biol. 6: 178-182 (1996); Miyawaki et al, Nature 388: 882-887 (1997)) and Citrine {see, e.g., Heikal et al., Proc. Natl. Acad. ScL USA 97: 11996-12001 (2000)) are also available from Clontech Labs. The GFP-like chromophore can also be drawn from other modified GFPs, including those described in U.S. Patent Nos. 6,124,128; 6,096,865; 6,090,919; 6,066,476; 6,054,321; 6,027,881; 5,968,750; 5,874,304; 5,804,387; 5,777,079; 5,741,668; and 5,625,048, the disclosures of which are incorporated herein by reference in their entireties. See also Conn (ed.), Green Fluorescent Protein (Methods in Enzymology, Vol. 302), Academic Press, Inc. (1999); Yang, et al, J Biol Chem, 273: 8212-6 (1998); Bevis et al., Nature Biotechnology, 20:83-7 (2002). The GFP-like chromophore of each of these GFP variants can usefully be included in the fusion proteins of the present invention.
Fusions to the IgG Fc region increase serum half-life of protein pharmaceutical products through interaction with the FcRn receptor (also denominated the FcRp receptor and the Brambell receptor, FcRb), further described in International Patent Application nos. WO 97/43316, WO 97/34631, WO 96/32478, WO 96/18412, the disclosures of which are incorporated herein by reference in their entireties.
For long-term, high-yield recombinant production of the polypeptides of the present invention, stable expression is preferred. Stable expression is readily achieved by integration into the host cell genome of vectors having selectable markers, followed by selection of these integrants. Vectors such as pUB6/V5-His A, B, and C (Invitrogen, Carlsbad, CA, USA) are designed for high-level stable expression of heterologous proteins in a wide range of mammalian tissue types and cell lines. pUB6/V5-His uses the promoter/enhancer sequence from the human ubiquitin C gene to drive expression of recombinant proteins: expression levels in 293, CHO, and NIH3T3 cells are comparable to levels from the CMV and human EF-Ia promoters. The bsd gene permits rapid selection of stably transfected mammalian cells with the potent antibiotic blasticidin. Replication incompetent retroviral vectors, typically derived from Moloney murine leukemia virus, also are useful for creating stable transfectants having integrated provirus. The highly efficient transduction machinery of retroviruses, coupled with the availability of a variety of packaging cell lines such as RetroPack™ PT 67, EcoPack2™-293, AmphoPack-293, and GP2-293 cell lines (all available from Clontech Laboratories, Palo Alto, CA, USA) allow a wide host range to be infected with high efficiency; varying the multiplicity of infection readily adjusts the copy number of the integrated provirus.
Of course, not all vectors and expression control sequences will function equally well to express the nucleic acid molecules of this invention. Neither will all hosts function equally well with the same expression system. However, one of skill in the art may make a selection among these vectors, expression control sequences and hosts without undue experimentation and without departing from the scope of this invention. For example, in selecting a vector, the host must be considered because the vector must be replicated in it. The vector's copy number, the ability to control that copy number, the ability to control integration, if any, and the expression of any other proteins encoded by the vector, such as antibiotic or other selection markers, should also be considered. The present invention further includes host cells comprising the vectors of the present invention, either present episomally within the cell or integrated, in whole or in part, into the host cell chromosome. Among other considerations, some of which are described above, a host cell strain may be chosen for its ability to process the expressed polypeptide in the desired fashion. Such post-translational modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation, and it is an aspect of the present invention to provide CaSPs with such post-translational modifications. In selecting an expression control sequence, a variety of factors should also be considered. These include, for example, the relative strength of the sequence, its controllability, and its compatibility with the nucleic acid molecules of this invention, particularly with regard to potential secondary structures. Unicellular hosts should be selected by consideration of their compatibility with the chosen vector, the toxicity of the product coded for by the nucleic acid sequences of this invention, their secretion characteristics, their ability to fold the polypeptide correctly, their fermentation or culture requirements, and the ease of purification from them of the products coded for by the nucleic acid molecules of this invention. The recombinant nucleic acid molecules and more particularly, the expression vectors of this invention may be used to express the polypeptides of this invention as recombinant polypeptides in a heterologous host cell. The polypeptides of this invention may be full-length or less than full-length polypeptide fragments recombinantly expressed from the nucleic acid molecules according to this invention. Such polypeptides include analogs, derivatives and muteins that may or may not have biological activity.
Vectors of the present invention will also often include elements that permit in vitro transcription of RNA from the inserted heterologous nucleic acid. Such vectors typically include a phage promoter, such as that from T7, T3, or SP6, flanking the nucleic acid insert. Often two different such promoters flank the inserted nucleic acid, permitting separate in vitro production of both sense and antisense strands.
Transformation and other methods of introducing nucleic acids into a host cell (e.g., conjugation, protoplast transformation or fusion, transfection, electroporation, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion) can be accomplished by a variety of methods which are well known in the art (See, for instance, Ausubel, supra, and Sambrook et ah, supra). Bacterial, yeast, plant or mammalian cells are transformed or transfected with an expression vector, such as a plasmid, a cosmid, or the like, wherein the expression vector comprises the nucleic acid of interest. Alternatively, the cells may be infected by a viral expression vector comprising the nucleic acid of interest. Depending upon the host cell, vector, and method of transformation used, transient or stable expression of the polypeptide will be constitutive or inducible. One having ordinary skill in the art will be able to decide whether to express a polypeptide transiently or stably, and whether to express the protein constitutively or inducibly. A wide variety of unicellular host cells are useful in expressing the DNA sequences of this invention. These hosts may include well known eukaryotic and prokaryotic hosts, such as strains of, fungi, yeast, insect cells such as Spodoptera frugiperda (SF9), animal cells such as CHO, as well as plant cells in tissue culture. Representative examples of appropriate host cells include, but are not limited to, bacterial cells, such as E. coli, Caulobacter crescentus, Streptomyces species, and Salmonella typhimurium; yeast cells, such as Saccharomyces cerevisiae, Schizosaccharomycespom.be, Pichiapastoris, Pichia methanolica; insect cell lines, such as those from Spodoptera frugiperda — e.g., Sf9 and Sf21 cell lines, and expresSF™ cells (Protein Sciences Corp., Meriden, CT, USA) — Drosophila S2 cells, and Trichoplusia ni High Five® Cells (Invitrogen, Carlsbad, CA, USA); and mammalian cells. Typical mammalian cells include BHK cells, BSC 1 cells, BSC 40 cells, BMT 10 cells, VERO cells, COSl cells, C0S7 cells, Chinese hamster ovary (CHO) cells, 3T3 cells, NIH 3T3 cells, 293 cells, HEPG2 cells, HeLa cells, L cells, MDCK cells, HEK293 cells, WI38 cells, murine ES cell lines (e.g., from strains 129/SV, C57/BL6, DBA-1, 129/SVJ), K562 cells, Jurkat cells, and BW5147 cells. Other mammalian cell lines are well known and readily available from the American Type Culture Collection (ATCC) (Manassas, VA, USA) and the National Institute of General Medical Sciences (NIGMS) Human Genetic Cell Repository at the Coriell Cell Repositories (Camden, NJ, USA). Cells or cell lines derived from breast, intestine, colon, lung, ovarian or prostate tissue are particularly preferred because they may provide a more native post-translational processing. Particularly preferred are human breast cells.
Particular details of the transfection, expression and purification of recombinant proteins are well documented and are understood by those of skill in the art. Further details on the various technical aspects of each of the steps used in recombinant production of foreign genes in bacterial cell expression systems can be found in a number of texts and laboratory manuals in the art. See, e.g., Ausubel (1992), supra, Ausubel (1999), supra, Sambrook (1989), supra, and Sambrook (2001), supra. Methods for introducing the vectors and nucleic acid molecules of the present invention into the host cells are well known in the art; the choice of technique will depend primarily upon the specific vector to be introduced and the host cell chosen.
Nucleic acid molecules and vectors may be introduced into prokaryotes, such as E. coli, in a number of ways. For instance, phage lambda vectors will typically be packaged using a packaging extract (e.g., Gigapack® packaging extract, Stratagene, La Jolla, CA, USA), and the packaged virus used to infect E. coli.
Plasmid vectors will typically be introduced into chemically competent or electrocompetent bacterial cells. E. coli cells can be rendered chemically competent by treatment, e.g., with CaCl2, or a solution OfMg2+, Mn2+, Ca2+, Rb+ or K+, dimethyl sulfoxide, dithiothreitol, and hexamine cobalt (III), Hanahan, J. MoI. Biol. 166(4):557-80 (1983), and vectors introduced by heat shock. A wide variety of chemically competent strains are also available commercially (e.g., Epicurian Coli® XLIO-Gold® Ultracompetent Cells (Stratagene, La Jolla, CA, USA); DH5α competent cells (Clontech Laboratories, Palo Alto, CA, USA); and TOPlO Chemically Competent E. coli Kit (Invitrogen, Carlsbad, CA, USA)). Bacterial cells can be rendered electrocompetent to take up exogenous DNA by electroporation by various pre-pulse treatments; vectors are introduced by electroporation followed by subsequent outgrowth in selected media. An extensive series of protocols is provided by BioRad (Richmond, CA, USA).
Vectors can be introduced into yeast cells by spheroplasting, treatment with lithium salts, electroporation, or protoplast fusion. Spheroplasts are prepared by the action of hydrolytic enzymes such as a snail-gut extract, usually denoted Glusulase or Zymolyase, or an enzyme from Arthrobacter luteus to remove portions of the cell wall in the presence of osmotic stabilizers, typically 1 M sorbitol. DNA is added to the spheroplasts, and the mixture is co-precipitated with a solution of polyethylene glycol (PEG) and Ca2+. Subsequently, the cells are resuspended in a solution of sorbitol, mixed with molten agar and then layered on the surface of a selective plate containing sorbitol. For lithium-mediated transformation, yeast cells are treated with lithium acetate to permeabilize the cell wall, DNA is added and the cells are co-precipitated with PEG. The cells are exposed to a brief heat shock, washed free of PEG and lithium acetate, and subsequently spread on plates containing ordinary selective medium. Increased frequencies of transformation are obtained by using specially-prepared single-stranded carrier DNA and certain organic solvents. Schiestl et ah, Curr. Genet. 16(5-6): 339-46 (1989).
For electroporation, freshly-grown yeast cultures are typically washed, suspended in an osmotic protectant, such as sorbitol, mixed with DNA, and the cell suspension pulsed in an electroporation device. Subsequently, the cells are spread on the surface of plates containing selective media. Becker et ah, Methods Enzymol. 194: 182-187 (1991). The efficiency of transformation by electroporation can be increased over 100-fold by using PEG, single-stranded carrier DNA and cells that are in late log-phase of growth. Larger constructs, such as YACs, can be introduced by protoplast fusion.
Mammalian and insect cells can be directly infected by packaged viral vectors, or transfected by chemical or electrical means. For chemical transfection, DNA can be coprecipitated with CaPO4 or introduced using liposomal and nonliposomal lipid-based agents. Commercial kits are available for CaPO4 transfection (CalPhos™ Mammalian Transfection Kit, Clontech Laboratories, Palo Alto, CA, USA), and lipid-mediated transfection can be practiced using commercial reagents, such as LIPOFECT AMINE™ 2000, LIPOFECTAMINE™ Reagent, CELLFECTIN® Reagent, and LIPOFECTIN® Reagent (Invitrogen, Carlsbad, CA, USA), DOTAP Liposomal Transfection Reagent, FuGENE 6, X-tremeGENE Q2, DOSPER, (Roche Molecular Biochemicals, Indianapolis, IN USA), Effectene™, PolyFect®, Superfect® (Qiagen, Inc., Valencia, CA, USA). Protocols for electroporating mammalian cells can be found in, for example, Norton et al (eds.), Gene Transfer Methods: Introducing DNA into Living Cells and Organisms, BioTechniques Books, Eaton Publishing Co. (2000). Other transfection techniques include transfection by particle bombardment and microinjection. See, e.g., Cheng et al, Proc. Natl. Acad. ScL USA 90(10): 4455-9 (1993); Yang et al, Proc. Natl Acad. Sd. USA 87(24): 9568-72 (1990).
Production of the recombinantly produced proteins of the present invention can optionally be followed by purification.
Purification of recombinantly expressed proteins is now well within the skill in the art and thus need not be detailed here. See, e.g., Thorner et al. (eds.), Applications of Chimeric Genes and Hybrid Proteins, Part A: Gene Expression and Protein Purification (Methods in Enzymology, Vol. 326), Academic Press (2000); Harbin (ed.), Cloning, Gene Expression and Protein Purification : Experimental Procedures and Process Rationale, Oxford Univ. Press (2001); Marshak et al, Strategies for Protein Purification and Characterization: A Laboratory Course Manual, Cold Spring Harbor Laboratory Press (1996); and Roe (ed.), Protein Purification Applications, Oxford University Press (2001). Briefly, however, if purification tags have been fused through use of an expression vector that appends such tag, purification can be effected, at least in part, by means appropriate to the tag, such as use of immobilized metal affinity chromatography for polyhistidine tags. Other techniques common in the art include ammonium sulfate fractionation, immunoprecipitation, fast protein liquid chromatography (FPLC), high performance liquid chromatography (HPLC), and preparative gel electrophoresis.
Polypeptides, including Fragments Muteins, Homologous Proteins, Allelic Variants, Analogs and Derivatives
Another aspect of the invention relates to polypeptides encoded by the nucleic acid molecules described herein. In a preferred embodiment, the polypeptide is a cancer specific polypeptide (CaSP). In an even more preferred embodiment, the polypeptide comprises an amino acid sequence of the gene products of Table 2a or Table 2b or is derived from a polypeptide having the amino acid sequence of the gene products of Table 2a or Table 2b. A polypeptide as defined herein may be produced recombinantly, as discussed supra, may be isolated from a cell that naturally expresses the protein, or may be chemically synthesized following the teachings of the specification and using methods well known to those having ordinary skill in the art. Polypeptides of the present invention may also comprise a part or fragment of a
CaSP. In a preferred embodiment, the fragment is derived from a polypeptide having an amino acid sequence selected from the group consisting of the gene products of Table 2a or Table 2b. Polypeptides of the present invention comprising a part or fragment of an entire CaSP may or may not be CaSPs. For example, a full-length polypeptide may be cancer-specific, while a fragment thereof may be found in normal breast, intestine, colon, lung, ovarian or prostate tissues as well as in breast, intestine, colon, lung, ovarian or prostate cancer. A polypeptide that is not a CaSP, whether it is a fragment, analog, mutein, homologous protein or derivative, is nevertheless useful, especially for immunizing animals to prepare anti-CaSP antibodies. In a preferred embodiment, the part or fragment is a CaSP. Methods of determining whether a polypeptide of the present invention is a CaSP are described infra.
Polypeptides of the present invention comprising fragments of at least 6 contiguous amino acids are also useful in mapping B cell and T cell epitopes of the reference protein. See, e.g., Geysen et al, Proc. Natl. Acad. ScL USA 81: 3998-4002 (1984) and U.S. Patent Nos. 4,708,871 and 5,595,915, the disclosures of which are incorporated herein by reference in their entireties. Because the fragment need not itself be immunogenic, part of an immunodominant epitope, nor even recognized by native antibody, to be useful in such epitope mapping, all fragments of at least 6 amino acids of a polypeptide of the present invention have utility in such a study. Polypeptides of the present invention comprising fragments of at least 8 contiguous amino acids, often at least 15 contiguous amino acids, are useful as immunogens for raising antibodies that recognize polypeptides of the present invention. See, e.g., Lerner, Nature 299: 592-596 (1982); Shinnick et al., Annu. Rev. Microbiol. 37: 425-46 (1983); Sutcliffe et al, Science 219: 660-6 (1983). As further described in the above-cited references, virtually all 8-mers, conjugated to a carrier, such as a protein, prove immunogenic and are capable of eliciting antibodies for the conjugated peptide; accordingly, all fragments of at least 8 amino acids of the polypeptides of the present invention have utility as immunogens. Polypeptides comprising fragments of at least 8, 9, 10 or 12 contiguous amino acids are also useful as competitive inhibitors of binding of the entire polypeptide, or a portion thereof, to antibodies (as in epitope mapping), and to natural binding partners, such as subunits in a multimeric complex or to receptors or ligands of the subject protein; this competitive inhibition permits identification and separation of molecules that bind specifically to the polypeptide of interest. See U.S. Patent Nos. 5,539,084 and 5,783,674, incorporated herein by reference in their entireties.
The polypeptide of the present invention thus preferably is at least 6 amino acids in length, typically at least 8, 9, 10 or 12 amino acids in length, and often at least 15 amino acids in length. Often, the polypeptide of the present invention is at least 20 amino acids in length, even 25 amino acids, 30 amino acids, 35 amino acids, or 50 amino acids or more in length. Of course, larger polypeptides having at least 75 amino acids, 100 amino acids, or even 150 amino acids are also useful, and at times preferred.
One having ordinary skill in the art can produce fragments by truncating the nucleic acid molecule, e.g., a CaSNA, encoding the polypeptide and then expressing it recombinantly. Alternatively, one can produce a fragment by chemically synthesizing a portion of the full-length polypeptide. One may also produce a fragment by enzymatically cleaving either a recombinant polypeptide or an isolated naturally occurring polypeptide. Methods of producing polypeptide fragments are well known in the art. See, e.g., Sambrook (1989), supra; Sambrook (2001), supra; Ausubel (1992), supra; and Ausubel (1999), supra. In one embodiment, a polypeptide comprising only a fragment, preferably a fragment of a CaSP, maybe produced by chemical or enzymatic cleavage of a CaSP polypeptide. In a preferred embodiment, a polypeptide fragment is produced by expressing a nucleic acid molecule of the present invention encoding a fragment, preferably of a CaSP, in a host cell.
Polypeptides of the present invention are also inclusive of mutants, fusion proteins, homologous proteins and allelic variants.
A mutant protein, or mutein, may have the same or different properties compared to a naturally occurring polypeptide and comprises at least one amino acid insertion, duplication, deletion, rearrangement or substitution compared to the amino acid sequence of a native polypeptide. Small deletions and insertions can often be found that do not alter the function of a protein. Muteins may or may not be cancer-specific. Preferably, the mutein is cancer-specific. More preferably the mutein is specific for breast cancer. Even more preferably the mutein is a polypeptide that comprises at least one amino acid insertion, duplication, deletion, rearrangement or substitution compared to the amino acid sequence of the gene products of Table 2a or Table 2b. Accordingly, in a preferred embodiment, the mutein is one that exhibits at least 50% sequence identity, more preferably at least 60% sequence identity, even more preferably at least 70%, yet more preferably at least 80% sequence identity to a CaSP comprising an amino acid sequence of the gene products of Table 2a or Table 2b. In a yet more preferred embodiment, the mutein exhibits at least 85%, more preferably 90%, even more preferably 95% or 96%, and yet more preferably at least 97%, 98%, 99% or 99.5% sequence identity to a CaSP comprising an amino acid sequence of the gene products of Table 2a or Table 2b.
A mutein may be produced by isolation from a naturally occurring mutant cell, tissue or organism. A mutein may be produced by isolation from a cell, tissue or organism that has been experimentally mutagenized. Alternatively, a mutein may be produced by chemical manipulation of a polypeptide, such as by altering the amino acid residue to another amino acid residue using synthetic or semi-synthetic chemical techniques. In a preferred embodiment, a mutein is produced from a host cell comprising a mutated nucleic acid molecule compared to the naturally occurring nucleic acid molecule. For instance, one may produce a mutein of a polypeptide by introducing one or more mutations into a nucleic acid molecule of the invention and then expressing it recombinantly. These mutations may be targeted, in which particular encoded amino acids are altered, or may be untargeted, in which random encoded amino acids within the polypeptide are altered. Muteins with random amino acid alterations can be screened for a particular biological activity or property, particularly whether the polypeptide is cancer-specific, as described below. Multiple random mutations can be introduced into the gene by methods well known to the art, e.g., by error-prone PCR, shuffling, oligonucleotide-directed mutagenesis, assembly PCR, sexual PCR mutagenesis, in vivo mutagenesis, cassette mutagenesis, recursive ensemble mutagenesis, exponential ensemble mutagenesis and site- specific mutagenesis. Methods of producing muteins with targeted or random amino acid alterations are well known in the art. See, e.g., Sambrook (1989), supra; Sambrook (2001), supra; Ausubel (1992), supra; and Ausubel (1999), as well as U.S. Patent No. 5,223,408, which is herein incorporated by reference in its entirety.
The invention also contemplates polypeptides that are homologous to a polypeptide of the invention, hi a preferred embodiment, the polypeptide is homologous to a CaSP. In an even more preferred embodiment, the polypeptide is homologous to a CaSP selected from the group having an amino acid sequence of the gene products of Table 2a or Table 2b. By homologous polypeptide it is means one that exhibits significant sequence identity to a CaSP, preferably a CaSP having an amino acid sequence of the gene products of Table 2a or Table 2b. By significant sequence identity it is meant that the homologous polypeptide exhibits at least 50% sequence identity, more preferably at least 60% sequence identity, even more preferably at least 70%, yet more preferably at least 80% sequence identity to a CaSP comprising an amino acid sequence of the gene products of Table 2a or Table 2b. More preferred are homologous polypeptides exhibiting at least 85%, more preferably 90%, even more preferably 95% or 96%, and yet more preferably at least 97% or 98% sequence identity to a CaSP comprising an amino acid sequence of the gene products of Table 2a or Table 2b. Most preferably, the homologous polypeptide exhibits at least 99%, more preferably 99.5%, even more preferably 99.6%, 99.7%, 99.8% or 99.9% sequence identity to a CaSP comprising an amino acid sequence of the gene products of Table 2a or Table 2b. In a preferred embodiment, the amino acid substitutions of the homologous polypeptide are conservative amino acid substitutions as discussed above.
Homologous polypeptides of the present invention also comprise polypeptide encoded by a nucleic acid molecule that selectively hybridizes to a CaSNA or an antisense sequence thereof. In this embodiment, it is preferred that the homologous polypeptide be encoded by a nucleic acid molecule that hybridizes to a CaSNA under low stringency, moderate stringency or high stringency conditions, as defined herein. More preferred is a homologous polypeptide encoded by a nucleic acid sequence which hybridizes to a CaSNA selected from the group consisting of the gene products of Table 2a, Table 2b or Table 7, or a homologous polypeptide encoded by a nucleic acid molecule that hybridizes to a nucleic acid molecule that encodes a CaSP, preferably an CaSP of the gene products of Table 2a or Table 2b under low stringency, moderate stringency or high stringency conditions, as defined herein.
Homologous polypeptides of the present invention may be naturally occurring and derived from another species, especially one derived from another primate, such as chimpanzee, gorilla, rhesus macaque, or baboon, wherein the homologous polypeptide comprises an amino acid sequence that exhibits significant sequence identity to that of the gene products of Table 2a or Table 2b. The homologous polypeptide may also be a naturally occurring polypeptide from a human, when the CaSP is a member of a family of polypeptides. The homologous polypeptide may also be a naturally occurring polypeptide derived from a non-primate, mammalian species, including without limitation, domesticated species, e.g., dog, cat, mouse, rat, rabbit, guinea pig, hamster, cow, horse, goat or pig. The homologous polypeptide may also be a naturally occurring polypeptide derived from a non-mammalian species, such as birds or reptiles. The naturally occurring homologous protein may be isolated directly from humans or other species. Alternatively, the nucleic acid molecule encoding the naturally occurring homologous polypeptide may be isolated and used to express the homologous polypeptide recombinantly. The homologous polypeptide may also be one that is experimentally produced by random mutation of a nucleic acid molecule and subsequent expression of the nucleic acid molecule. Alternatively, the homologous polypeptide may be one that is experimentally produced by directed mutation of one or more codons to alter the encoded amino acid of a CaSP. In a preferred embodiment, the homologous polypeptide encodes a polypeptide that is a CaSP.
Relatedness of proteins can also be characterized using a second functional test, the ability of a first protein competitively to inhibit the binding of a second protein to an antibody. It is, therefore, another aspect of the present invention to provide isolated polypeptide not only identical in sequence to those described with particularity herein, but also to provide isolated second polypeptide ("cross-reactive protein") that competitively inhibits the binding of antibodies to all or to a portion of various of the isolated polypeptides of the present invention. Such competitive inhibition can readily be determined using immunoassays well known in the art.
As discussed above, single nucleotide polymorphisms (SNPs) occur frequently in eukaryotic genomes, and the sequence determined from one individual of a species may differ from other allelic forms present within the population. Thus, polypeptides of the present invention are also inclusive of those encoded by an allelic variant of a nucleic acid molecule encoding a CaSP. In this embodiment, it is preferred that the polypeptide be encoded by an allelic variant of a gene that encodes a polypeptide having the amino acid sequence selected from the group consisting of the gene products of Table 2a or Table 2b. More preferred is that the polypeptide be encoded by an allelic variant of a gene that has the nucleic acid sequence selected from the group consisting of the gene products of Table 2a, Table 2b or Table 7. Polypeptides of the present invention are also inclusive of derivative polypeptides encoded by a nucleic acid molecule according to the instant invention. In this embodiment, it is preferred that the polypeptide be a CaSP. Also preferred are derivative polypeptides having an amino acid sequence selected from the group consisting of the gene products of Table 2a and Table 2b and which has been acetylated, carboxylated, phosphorylated, glycosylated, ubiquitinated or other PTMs. In another preferred embodiment, the derivative has been labeled with, e.g., radioactive isotopes such as I, 32P, 35S, and 3H. hi another preferred embodiment, the derivative has been labeled with fluorophores, chemiluminescent agents, enzymes, and antiligands that can serve as specific binding pair members for a labeled ligand.
Polypeptide modifications are well known to those of skill and have been described in great detail in the scientific literature. Several particularly common modifications, glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, for instance, are described in most basic texts, such as, for instance Creighton, Protein Structure and Molecular Properties, 2nd ed., W. H. Freeman and Company (1993). Many detailed reviews are available on this subject, such as, for example, those provided by Wold, in Johnson (ed.), Posttranslational Covalent Modification of Proteins, pgs. 1-12, Academic Press (1983); Seifter et al., Meth. Enzymol 182: 626-646 (1990) and Rattan et al., Ann. KY. Acad. Sd. 663: 48-62 (1992).
One may determine whether a polypeptide of the invention is likely to be post- translationally modified by analyzing the sequence of the polypeptide to determine if there are peptide motifs indicative of sites for post-translational modification. There are a number of computer programs that permit prediction of post-translational modifications. See, e.g., expasy with the extension .org of the world wide web (accessed November 11, 2002), which includes PSORT, for prediction of protein sorting signals and localization sites, SignalP, for prediction of signal peptide cleavage sites, MITOPROT and Predotar, for prediction of mitochondrial targeting sequences, NetOGlyc, for prediction of type O- glycosylation sites in mammalian proteins, big-PI Predictor and DGPI, for prediction of prenylation-anchor and cleavage sites, and NetPhos, for prediction of Ser, Thr and Tyr phosphorylation sites in eukaryotic proteins. Other computer programs, such as those included in GCG, also may be used to determine post-translational modification peptide motifs. General examples of types of post-translational modifications include, but are not limited to: (Z)-dehydrobutyrine; 1-chondroitin sulfate-L-aspartic acid ester; l'-glycosyl-L- tryptophan; l'-phospho-L-histidine; 1-thioglycine; 2'-(S-L-cysteinyl)-L-histidine; 2'-[3- carboxamido (trimethylammonio)propyl]-L-histidine; 2'-alpha-mannosyl-L-tryptophan; 2- methyl-L-glutamine; 2-oxobutanoic acid; 2-pyrrolidone carboxylic acid; 3'-(l'-L-histidyl)- L-tyrosine; 3'-(8alpha-FAD)-L-liistidine; 3'-(S-L-cysteinyl)-L-tyrosine; 3', 3",5'-triiodo-L- thyronine; 3'-4'-phospho-L-tyrosine; 3-hydroxy-L-proline; 3'-methyl-L-histidine; 3- methyl-L-lanthionine; 3'-phospho-L-histidine; 4'-(L-tryptophan)-L-tryptophyl quinone; 42 N-cysteinyl-glycosylphosphatidylinositolethanolamine; 43 -(T-L-histidyl)-L-tyrosine; 4- hydroxy-L-arginine; 4-hydroxy-L-lysine; 4-hydroxy-L-proline; 5'-(N6-L-lysine)-L- topaquinone; 5-hydroxy-L-lysine; 5-methyl-L-arginine; alpha-1-microglobulin-Ig alpha complex chromophore; bis-L-cysteinyl bis-L-histidino diiron disulfide; bis-L~cysteinyl-L- N3'-histidino-L-serinyI tetrairon' tetrasulfide; chondroitin sulfate D-glucuronyl-D- galactosyl-D-galactosyl-D-xylosyl-L-serine; D-alanine; D-allo-isoleucine; D-asparagine; dehydroalanine; dehydrotyrosine; dermatan 4-sulfate D-glucuronyl-D-galactosyl-D- galactosyl-D-xylosyl-L-serinej D-glucuronyl-N-glycine; dipyrrolylmethanemethyl-L- cysteine; D-leucine; D-methionine; D-phenylalanine; D-serine; D-tryptophan; glycine amide; glycine oxazolecarboxylic acid; glycine thiazolecarboxylic acid; heme P450-bis-L- cysteine-L-tyrosine; heme-bis-L-cysteine; hemediol-L-aspartyl ester-L-glutamyl ester; hemediol-L-aspartyl ester-L-glutamyl ester-L-methionine sulfonium; heme-L-cysteine; heme-L-histidine; heparan sulfate D-glucuronyl-D-galactosyl-D-galactosyl-D-xylosyl-L- serine; heme P450-bis-L-cysteine-L-lysine; hexakis-L-cysteinyl hexairon hexasulfide; keratan sulfate D-glucuronyl-D-galactosyl-D-galactosyl-D-xylosyl-L-threonine; L oxoalanine- lactic acid; L phenyllactic acid; l'-(8alpha-FAD)-L-histidme; L-2'.4',5'- topaquinone; L-3',4'-dihydroxyphenylalanine; L-3'.4'.5'-trihydroxyphenylalanine; L-4'- bromophenylalanine; L-6'-bromotryptophan; L-alanine amide; L-alanyl imidazolinone glycine; L-allysine; L-arginine amide; L-asparagine amide; L-aspartic 4-phosphoric anhydride; L-aspartic acid 1 -amide; L-beta-methylthioaspartic acid; L-bromobistidine; L- citrulline; L-cysteine amide; L-cysteine glutathione disulfide; L-cysteine methyl disulfide; L-cysteine methyl ester; L-cysteine oxazolecarboxylic acid; L-cysteine oxazolinecarboxylic acid; L-cysteine persulfide; L-cysteine sulfenic acid; L-cysteine sulfϊnic acid; L-cysteine thiazolecarboxylic acid; L-cysteinyl homocitryl molybdenum- heptairon-nonasulfide; L-cysteinyl imidazolinone glycine; L-cysteinyl molybdopterin; L- cysteinyl molybdopterin guanine dinucleotide; L-cystine; L-erythro-beta- hydroxyasparagine; L-erythro-beta-hydroxyaspartic acid; L-gamma-carboxyglutamic acid; L-glutamic acid 1 -amide; L-glutamic acid 5-methyl ester; L-glutamine amide; L- glutamyl 5-glycerylphosphorylethanolarnine; L-histidine amide; L-isoglutamyl-polyglutamic acid; L-isoglutamyl-polyglycine; L-isoleucine amide; L-lanthionine; L-leucine amide; L-lysine amide; L-lysine thiazolecarboxylic acid; L-lysinoalanine; L-methionine amide; L- methionine sulfone; L-phenyalanine thiazolecarboxylic acid; L-phenylalanine amide; L- proline amide; L-selenocysteine; L-selenocysteinyl molybdopterin guanine dinucleotide; L-serine amide; L-serine thiazolecarboxylic acid; L-seryl imidazolinone glycine; L-T- bromophenylalanine; L-T-bromophenylalanine; L-threonine amide; L-thyroxine; L- tryptophan amide; L-tryptophyl quinone; L-tyrosine amide; L-valine amide; meso- lanthionine; N-(L-glutamyl)-L-tyrosine; N-(L-isoaspartyl)-glycine; N-(L-isoaspartyl)-L- cysteine; N,N,N-trimethyl-L-alanine; N,N-dimethyl-L-proline; N2-acetyl-L-lysine; N2- succinyl-L-tryptophan; N4-(ADP-ribosyl)-L-asparagine; N4-glycosyl-L-asparagine; N4- hydroxymethyl-L-asparagine; N4-methyl-L-asparagine; N5-methyl-L-glutamine; N6- 1 - carboxyethyl-L-lysine; N6-(4-amino hydroxybutyl)-L-lysine; N6-(L-isoglutamyl)-L- lysine; N6-(phospho-5'-adenosine)-L-lysine; N6-(phospho-5'-guanosine)-L-lysme; N6,N6,N6-trimethyl-L-lysine; N6,N6-dimethyl-L-lysine; N6-acetyl-L-lysine; N6-biotinyl- L-lysine; N6-carboxy-L-lysine; N6-formyl-L-lysine; N6-glycyl-L-lysine; N6-lipoyl-L- lysine; N6-methyl-L-lysine; N6-methyl-N6-poly(N-methyl-propylamine)-L-lysine; N6- mureinyl-L-lysine; N6-myristoyl-L-lysine; N6-palmitoyl-L-lysine; N6-pyridoxal phosphate-L-lysine; N6-pyruvic acid 2-iminyl-L-lysine; N6-retinal-L-lysine; N- acetylglycine; N-acetyl-L-glutamine; N-acetyl-L-alanine; N-acetyl-L-aspartic acid; N- acetyl-L-cysteine; N-acetyl-L-glutamic acid; N-acetyl-L-isoleucine; N-acetyl-L- methionine; N-acetyl-L-proline; N-acetyl-L-serine; N-acetyl-L-threonine; N-acetyl-L- tyrosine; N-acetyl-L-valine; N-alanyl-glycosylphosphatidylinositolethanolamine; N- asparaginyl-glycosylphosphatidylinositolethanolarnine; N-aspartyl- glycosylphosphatidylinositolethanolamine; N-formylglycine; N-formyl-L-methionine; N- glycyl-glycosylphosphatidylinositolethanolamine; N-L-glutamyl-poly-L-glutamic acid; N- methylglycine; N-methyl-L-alanine; N-methyl-L-methionine; N-methyl-L-phenylalanine; N-myristoyl-glycine; N-palmitoyl-L-cysteine; N-pyruvic acid 2-iminyl-L-cysteine; N- pyruvic acid 2-iminyl-L-valine; N-seryl-glycosylphosphatidylinositolethanolamine; N- seryl-glycosyCaSPhingolipidinositolethanolamine; O-(ADP-ribosyl)-L-serine; O- (phospho-5'-adenosine)-L-threonine; O-(phospho-5'-DNA)-L-serine; O-(phospho-5'- DNA)-L-threonine; O-(phospho-5'rRNA)-L-serine; O-(phosphoribosyl dephospho- coenzyme A)-L-serine; O-(sn-l-glycerophosphoryl)-L-serine; O4'-(8alpha-F AD)-L- tyrosine; O4'-(phosplio-5'-adenosine)-L-tyrosine; O4'-(phospho-5'-DNA)-L-tyrosine; 04'- (ph.ospho-5'-RNA)-L-tyrosine; O4'-(phospho-5l-uridine)-L-tyiOsine; 04-glycosyl-L- hydroxyproline; O4'-glycosyl-L-tyrosine; O4'-sulfo-L-tyrosine; 05-glycosyl-L- hydroxylysine; O-glycosyl-L-serine; O-glycosyl-L-threonine; omega-N-(ADP-ribosyl)-L- arginine; omega-N-omega-N'-dimethyl-L-arginine; omega-N-methyl-L-arginine; omega- N-omega-N-dimethyl-L-arginine; omega-N-phospho-L-arginine; O'octanoyl-L-serine; O- palmitoyl-L-serine; O-palmitoyl-L-threonine; O-phospho-L-serine; O-phospho-L- threonine; O-phosphopantetheme-L-serinej phycoerythrobilin-bis-L-cysteine; phycourobilin-bis-L-cysteine; pyrroloquinoline quinone; pyruvic acid; S hydroxycinnamyl-L-cysteine; S-(2-aminovinyl) methyl-D-cysteine; S-(2-aminovinyl)-D- cysteine; S-(6-FW-L-cysteine; S-(8alpha-FAD)-L-cysteine; S-(ADP-ribosyl)-L-cysteine; S-(L-isoglutamyl)-L-cysteine; S-12-hydroxyfarnesyl-L-cysteine; S-acetyl-L-cysteine; S- diacylglycerol-L-cysteine; S-diphytanylglycerot diether-L-cysteine; S-farnesyl-L-cysteine; S-geranylgeranyl-L-cysteine; S-glycosyl-L-cysteine; S-glycyl-L-cysteine; S-methyl-L- cysteine; S-nitrosyl-L-cysteine; S-palmitoyl-L-cysteine; S-phospho-L-cysteine; S- phycobiliviolin-L-cysteine; S-phycocyanobilin-L-cysteine; S-phycoerythrobilin-L- cysteine; S-phytochromobilin-L-cysteine; S-selenyl-L-cysteine; S-sulfo-L-cysteine; tetrakis-L-cysteinyl diiron disulfide; tetrakis-L-cysteinyl iron; tetrakis-L-cysteinyl tetrairon tetrasulfide; trans-2,3-cis 4-dihydroxy-L-proline; tris-L-cysteinyl triiron tetrasulfide; tris-L-cysteinyl triiron trisulfide; tris-L-cysteinyl-L-aspartato tetrairon tetrasulfide; tris-L-cysteinyl-L-cysteine persulfido-bis-L-glutamato-L-histidino tetrairon disulfide trioxide; tris-L-cysteinyl-L-N3'-histidino tetrairon tetrasulfide; tris-L-cysteinyl- L-Nl'-liistidino tetrairon tetrasulfide; and tris-L-cysteinyl-L-serinyl tetrairon tetrasulfide. Additional examples of PTMs may be found in web sites such as the Delta Mass database based on Krishna, R. G. and F. Wold (1998). Posttranslational Modifications. Proteins - Analysis and Design. R. H. Angeletti. San Diego, Academic Press. 1: 121-206; Methods in Enzymology, 193, J.A. McClosky (ed) (1990), pages 647-660; Methods in Protein Sequence Analysis edited by Kazutomo Imahori and Fumio Sakiyama, Plenum Press, (1993) "Post-translational modifications of proteins" R.G. Krishna and F. Wold pages 167-172; "GlycoSuiteDB: a new curated relational database of glycoprotein glycan structures and their biological sources" Cooper et al. Nucleic Acids Res. 29; 332-335 (2001) "O-GLYCBASE version 4.0: a revised database of O-glycosylated proteins" Gupta et al. Nucleic Acids Research, 27: 370-372 (1999); and "PhosphoBase, a database of phosphorylation sites: release 2.O.", Kreegipuu et al.Nucleic Acids Res 27(l):237-239 (1999) see also,WO 02/21139A2, the disclosure of which is incorporated herein by reference in its entirety.
Tumorigenesis is often accompanied by alterations in the post-translational modifications of proteins. Thus, in another embodiment, the invention provides polypeptides from cancerous cells or tissues that have altered post-translational modifications compared to the post-translational modifications of polypeptides from normal cells or tissues. A number of altered post-translational modifications are known. One common alteration is a change in phosphorylation state, wherein the polypeptide from the cancerous cell or tissue is hyperphosphorylated or hypophosphorylated compared to the polypeptide from a normal tissue, or wherein the polypeptide is phosphorylated on different residues than the polypeptide from a normal cell. Another common alteration is a change in glycosylation state, wherein the polypeptide from the cancerous cell or tissue has more or less glycosylation than the polypeptide from a normal tissue, and/or wherein the polypeptide from the cancerous cell or tissue has a different type of glycosylation than the polypeptide from a noncancerous cell or tissue. Changes in glycosylation may be critical because carbohydrate-protein and carbohydrate-carbohydrate interactions are important in cancer cell progression, dissemination and invasion. See, e.g., Barchi, Curr. Pharm. Des. 6: 485-501 (2000), Verma, Cancer Biochem. Biophys. 14: 151-162 (1994) and Dennis et al., Bioessays 5: 412-421 (1999).
Another post-translational modification that may be altered in cancer cells is prenylation. Prenylation is the covalent attachment of a hydrophobic prenyl group (either farnesyl or geranylgeranyl) to a polypeptide. Prenylation is required for localizing a protein to a cell membrane and is often required for polypeptide function. For instance, the Ras superfamily of GTPase signaling proteins must be prenylated for function in a cell. See, e.g., Prendergast et al., Semin. Cancer Biol. 10: 443-452 (2000) and Khwaja et al., Lancet 355: 741-744 (2000).
Other post-translation modifications that may be altered in cancer cells include, without limitation, polypeptide methylation, acetylation, arginylation or racemization of amino acid residues. In these cases, the polypeptide from the cancerous cell may exhibit either increased or decreased amounts of the post-translational modification compared to the corresponding polypeptides from noncancerous cells.
Other polypeptide alterations in cancer cells include abnormal polypeptide cleavage of proteins and aberrant protein-protein interactions. Abnormal polypeptide cleavage may be cleavage of a polypeptide in a cancerous cell that does not usually occur in a normal cell, or a lack of cleavage in a cancerous cell, wherein the polypeptide is cleaved in a normal cell. Aberrant protein-protein interactions may be either covalent cross-linking or non-covalent binding between proteins that do not normally bind to each other. Alternatively, in a cancerous cell, a protein may fail to bind to another protein to which it is bound in a noncancerous cell. Alterations in cleavage or in protein-protein interactions may be due to over- or underproduction of a polypeptide in a cancerous cell compared to that in a normal cell, or may be due to alterations in post-translational modifications (see above) of one or more proteins in the cancerous cell. See, e.g., Henschen-Edman, Ann. KY. Acad. ScL 936: 580-593 (2001). Alterations in polypeptide post-translational modifications, as well as changes in polypeptide cleavage and protein-protein interactions, may be determined by any method known in the art. For instance, alterations in phosphorylation may be determined by using anti-phosphoserine, anti-phosphothreonine or anti-phosphotyrosine antibodies or by amino acid analysis. Glycosylation alterations may be determined using antibodies specific for different sugar residues, by carbohydrate sequencing, or by alterations in the size of the glycoprotein, which can be determined by, e.g., SDS polyacrylamide gel electrophoresis (PAGE). Other alterations of post-translational modifications, such as prenylation, racemization, methylation, acetylation and arginylation, may be determined by chemical analysis, protein sequencing, amino acid analysis, or by using antibodies specific for the particular post-translational modifications. Changes in protein-protein interactions and in polypeptide cleavage may be analyzed by any method known in the art including, without limitation, non-denaturing PAGE (for non-covalent protein-protein interactions), SDS PAGE (for covalent protein-protein interactions and protein cleavage), chemical cleavage, protein sequencing or immunoassays. hi another embodiment, the invention provides polypeptides that have been post- translationally modified, hi one embodiment, polypeptides may be modified enzymatically or chemically, by addition or removal of a post-translational modification. For example, a polypeptide may be glycosylated or deglycosylated enzymatically. Similarly, polypeptides may be phosphorylated using a purified kinase, such as a MAP kinase (e.g, p38, ERK, or JNK) or a tyrosine kinase (e.g., Src or erbB2). A polypeptide may also be modified through synthetic chemistry. Alternatively, one may isolate the polypeptide of interest from a cell or tissue that expresses the polypeptide with the desired post-translational modification. In another embodiment, a nucleic acid molecule encoding the polypeptide of interest is introduced into a host cell that is capable of post- translationally modifying the encoded polypeptide in the desired fashion. If the polypeptide does not contain a motif for a desired post-translational modification, one may alter the post-translational modification by mutating the nucleic acid sequence of a nucleic acid molecule encoding the polypeptide so that it contains a site for the desired post- translational modification. Amino acid sequences that may be post-translationally modified are known in the art. See, e.g., the programs described above on the website expasy with the extension .org of the world wide web. The nucleic acid molecule may also be introduced into a host cell that is capable of post-translationally modifying the encoded polypeptide. Similarly, one may delete sites that are post-translationally modified by either mutating the nucleic acid sequence so that the encoded polypeptide does not contain the post-translational modification motif, or by introducing the native nucleic acid molecule into a host cell that is not capable of post-translationally modifying the encoded polypeptide. It will be appreciated, as is well known and as noted above, that polypeptides are not always entirely linear. For instance, polypeptides may be branched as a result of ubiquitination, and they may be circular, with or without branching, generally as a result of posttranslation events, including natural processing event and events brought about by human manipulation which do not occur naturally. Circular, branched and branched circular polypeptides may be synthesized by non-translation natural process and by entirely synthetic methods, as well. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. In fact, blockage of the amino or carboxyl group in a polypeptide, or both, by a covalent modification, is common in naturally occurring and synthetic polypeptides and such modifications may be present in polypeptides of the present invention, as well. For instance, the amino terminal residue of polypeptides made in E. coli, prior to proteolytic processing, almost invariably will be N-formylmethionine. Useful post-synthetic (and post-translational) modifications include conjugation to detectable labels, such as fluorophores. A wide variety of amine-reactive and thiol- reactive fluorophore derivatives have been synthesized that react under nondenaturing conditions with N-terminal amino groups and epsilon amino groups of lysine residues, on the one hand, and with free thiol groups of cysteine residues, on the other.
Kits are available commercially that permit conjugation of proteins to a variety of amine-reactive or thiol-reactive fluorophores: Molecular Probes, Inc. (Eugene, OR, USA), e.g., offers kits for conjugating proteins to Alexa Fluor 350, Alexa Fluor 430, Fluorescein-EX, Alexa Fluor 488, Oregon Green 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, and Texas Red-X.
A wide variety of other amine-reactive and thiol-reactive fluorophores are available commercially (Molecular Probes, Inc., Eugene, OR, USA), including Alexa Fluor® 350, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 647 (monoclonal antibody labeling kits available from Molecular Probes, Inc., Eugene, OR, USA), BODIPY dyes, such as BODIPY 493/503, BODIPY FL, BODIPY R6G, BODPY 530/550, BODIPY TMR, BODIPY 558/568, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY TR, BODIPY 630/650, BODIPY 650/665, Cascade Blue, Cascade Yellow, Dansyl, lissamine rhodamine B, Marina Blue, Oregon Green 488, Oregon Green 514, Pacific Blue, rhodamine 6G, rhodamine green, rhodamine red, tetramethylrhodamine, Texas Red (available from Molecular Probes, Inc., Eugene, OR, USA).
The polypeptides of the present invention can also be conjugated to fluorophores, other proteins, and other macromolecules, using bifunctional linking reagents. Common homobifunctional reagents include, e.g., APG, AEDP, BASED, BMB, BMDB, BMH, BMOE, BM[PEO]3, BM[PE0]4, BS3, BSOCOES, DFDNB, DMA, DMP, DMS, DPDPB, DSG, DSP (Lomant's Reagent), DSS, DST, DTBP, DTME, DTSSP, EGS, HBVS, Sulfo-BSOCOES, Sulfo-DST, Sulfo-EGS (all available from Pierce, Rockford, IL, USA); common heterobifunctional cross-linkers include ABH, AMAS, ANB-NOS, APDP, ASBA, BMPA, BMPH, BMPS, EDC, EMCA, EMCH, EMCS, KMUA, KMUH, GMBS, LC-SMCC, LC-SPDP, MBS, M2C2H, MPBH, MSA, NHS-ASA, PDPH, PMPI, SADP, SAED, SAND, SANPAH, SASD, SATP, SBAP, SFAD, SIA, SIAB, SMCC, SMPB, SMPH, SMPT, SPDP, Sulfo-EMCS, Sulfo-GMBS, Sulfo-HSAB, Sulfo-KMUS, Sulfo-LC-SPDP, Sulfo-MBS, Sulfo-NHS-LC-ASA, Sulfo-SADP, Sulfo-SANPAH, Sulfo-SIAB, Sulfo-SMCC, Sulfo-SMPB, Sulfo-LC-SMPT, SVSB, TFCS (all available from Pierce, Rockford, IL, USA).
Polypeptides of the present invention, including full length polypeptides, fragments and fusion proteins, can be conjugated, using such cross-linking reagents, to fluorophores that are not amine- or thiol-reactive. Other labels that usefully can be conjugated to polypeptides of the present invention include radioactive labels, echosonographic contrast reagents, and MRI contrast agents.
Polypeptides of the present invention, including full length polypeptide, fragments and fusion proteins, can also usefully be conjugated using cross-linking agents to carrier proteins, such as KLH, bovine thyroglobulin, and even bovine serum albumin (BSA), to increase immunogenicity for raising anti-CaSP antibodies.
Polypeptides of the present invention, including full length polypeptide, fragments and fusion proteins, can also usefully be conjugated to polyethylene glycol (PEG); PEGylation increases the serum half life of proteins administered intravenously for replacement therapy. Delgado et al, Crit. Rev. Ther. Drug Carrier Syst. 9(3-4): 249-304 (1992); Scott et al, Curr. Pharm. Des. 4(6): 423-38 (1998); DeSantis et al, Curr. Opin. Biotechnol. 10(4): 324-30 (1999). PEG monomers can be attached to the protein directly or through a linker, with PEGylation using PEG monomers activated with tresyl chloride (2,2,2-trifluoroethanesulphonyl chloride) permitting direct attachment under mild conditions.
Polypeptides of the present invention are also inclusive of analogs of a polypeptide encoded by a nucleic acid molecule according to the instant invention. In a preferred embodiment, this polypeptide is a CaSP. hi a more preferred embodiment, this polypeptide is derived from a polypeptide having part or all of the amino acid sequence of the gene products of Table 2a or Table 2b. Also preferred is an analog polypeptide comprising one or more substitutions of non-natural amino acids or non-native inter- residue bonds compared to the naturally occurring polypeptide. In one embodiment, the analog is structurally similar to a CaSP, but one or more peptide linkages is replaced by a linkage selected from the group consisting of — CH2NH— , --CH2S--, --CH2-CH2— , -CH-CH~(cis and trans), -COCH2--, -CH(OH)CH2- and -CH2SO-. In another embodiment, the analog comprises substitution of one or more amino acids of a CaSP with a D-amino acid of the same type or other non-natural amino acid in order to generate more stable peptides. D-amino acids can readily be incorporated during chemical peptide synthesis: peptides assembled from D-amino acids are more resistant to proteolytic attack; incorporation of D-amino acids can also be used to confer specific three-dimensional conformations on the peptide. Other amino acid analogues commonly added during chemical synthesis include ornithine, norleucine, phosphorylated amino acids (typically phosphoserine, phosphothreonine, phosphotyrosine), L-malonyltyrosine, a non- hydrolyzable analog of phosphotyrosine {see, e.g., KoIe et ah, Biochem. Biophys. Res. Com. 209: 817-821 (1995)), and various halogenated phenylalanine derivatives.
Non-natural amino acids can be incorporated during solid phase chemical synthesis or by recombinant techniques, although the former is typically more common. Solid phase chemical synthesis of peptides is well established in the art. Procedures are described, inter alia, in Chan et al. (eds.), Fmoc Solid Phase Peptide Synthesis: A Practical Approach (Practical Approach Series), Oxford Univ. Press (March 2000); Jones, Amino Acid and Peptide Synthesis (Oxford Chemistry Primers, No 7), Oxford Univ. Press (1992); and Bodanszky, Principles of Peptide Synthesis (Springer Laboratory), Springer Verlag (1993).
Amino acid analogues having detectable labels are also usefully incorporated during synthesis to provide derivatives and analogs. Biotin, for example can be added using biotinoyl~(9-fluorenylmethoxycarbonyl)-L-lysine (FMOC biocytin) (Molecular Probes, Eugene, OR, USA). Biotin can also be added enzymatically by incorporation into a fusion protein of a E. coli BirA substrate peptide. The FMOC and tBOC derivatives of dabcyl-L-lysine (Molecular Probes, Inc., Eugene, OR, USA) can be used to incorporate the dabcyl chromophore at selected sites in the peptide sequence during synthesis. The aminonaphthalene derivative EDANS, the most common fluorophore for pairing with the dabcyl quencher in fluorescence resonance energy transfer (FRET) systems, can be introduced during automated synthesis of peptides by using EDANS— FMOC-L-glutamic acid or the corresponding tBOC derivative (both from Molecular Probes, Inc., Eugene, OR, USA). Tetramethylrhodamine fluorophores can be incorporated during automated FMOC synthesis of peptides using (FMOC)--TMR-L-lysine (Molecular Probes, Inc. Eugene, OR, USA).
Other useful amino acid analogues that can be incorporated during chemical synthesis include aspartic acid, glutamic acid, lysine, and tyrosine analogues having allyl side-chain protection (Applied Biosystems, Inc., Foster City, CA, USA); the allyl side chain permits synthesis of cyclic, branched-chain, sulfonated, glycosylated, and phosphorylated peptides.
A large number of other FMOC-protected non-natural amino acid analogues capable of incorporation during chemical synthesis are available commercially, including, e.g., Fmoc-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, Fmoc-3-endo- aminobicyclo[2.2.1]heptane-2-endo-carboxylic acid, Fmoc-3-exo- aminobicyclo[2.2. l]heptane-2-exo-carboxylic acid, Fmoc-3-endo-amino- bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid, Fmoc-3-exo-amino-bicyclo[2.2.1]hept- 5-ene-2-exo-carboxylic acid, Fmoc-cis-2-amino-l-cyclohexanecarboxylic acid, Fmoc- trans-2-amino- 1 -cyclohexanecarboxylic acid, Fmoc- 1 -amino- 1 -cyclopentanecarboxylic acid, Fmoc-cis-2-amino-l -cyclopentanecarboxylic acid, Fmoc- 1 -amino- 1- cyclopropanecarboxylic acid, Fmoc-D-2-amino-4-(ethylthio)butyric acid, Fmoc-L-2- amino-4-(ethylthio)butyric acid, Fmoc-L-buthionine, Fmoc-S-methyl-L-Cysteine, Fmoc- 2-aminobenzoic acid (anthranillic acid), Fmoc-3-aminobenzoic acid, Fmoc-4- aminobenzoic acid, Fmoc-2-aminobenzophenone-2'-carboxylic acid, Fmoc-N-(4- aminobenzoyl)-β-alanine, Fmoc-2-amino-4,5-dimethoxybenzoic acid, Fmoc-4- aminohippuric acid, Fmoc-2-amino-3-hydroxybenzoic acid, Fmoc-2-amino-5- hydroxybenzoic acid, Fmoc-3-amino-4-hydroxybenzoic acid, Fmoc-4-amino-3- hydroxybenzoic acid, Fmoc-4-amino-2-hydroxybenzoic acid, Fmoc-5-amino-2- hydroxybenzoic acid, Fmoc-2-amino-3-methoxybenzoic acid, Fmoc-4-amino-3- methoxybenzoic acid, Fmoc-2-amino-3-methylbenzoic acid, Fmoc-2-amino-5- methylbenzoic acid, Fmoc-2-amino-6-methylbenzoic acid, Fmoc-3-amino-2- methylbenzoic acid, Fmoc-3-amino-4-methylbenzoic acid, Fmoc-4-amino-3- methylbenzoic acid, Fmoc-3-amino-2-naphtoic acid, Fmoc-D,L-3-amino-3- phenylpropionic acid, Fmoc-L-Methyldopa, Fmoc-2-amino-4,6-dimethyl-3- pyridinecarboxylic acid, Fmoc-D,L-amino-2-thiophenacetic acid, Fmoc-4- (carboxymethyl)piperazine, Fmoc-4-carboxypiperazine, Fmoc-4- (carboxymethyl)homopiperazine, Fmoc-4-phenyl-4-piperidinecarboxylic acid, Fmoc-L- l,2,3,4-tetrahydronorharman-3-carboxylic acid, Fmoc-L-thiazolidine-4-carboxylic acid, all available from The Peptide Laboratory (Richmond, CA, USA).
Non-natural residues can also be added biosynthetically by engineering a suppressor tRNA, typically one that recognizes the UAG stop codon, by chemical aminoacylation with the desired unnatural amino acid. Conventional site-directed mutagenesis is used to introduce the chosen stop codon UAG at the site of interest in the protein gene. When the acylated suppressor tRNA and the mutant gene are combined in an in vitro transcription/translation system, the unnatural amino acid is incorporated in response to the UAG codon to give a protein containing that amino acid at the specified position. Liu et al, Proc. Natl Acad. ScL USA 96(9): 4780-5 (1999); Wang et al, Science 292(5516): 498-500 (2001).
Another aspect of the present invention relates to the fusion of a polypeptide of the present invention to heterologous polypeptides, hi a preferred embodiment, the polypeptide of the present invention is a CaSP. hi a more preferred embodiment, the polypeptide of the present invention that is fused to a heterologous polypeptide comprises part or all of the amino acid sequence of the gene products of Table 2a or Table 2b, or is a mutein, homologous polypeptide, analog or derivative thereof. In an even more preferred embodiment, the fusion protein is encoded by a nucleic acid molecule comprising all or part of the nucleic acid sequence of the gene products of Table 2a, Table 2b or Table 7, or comprises all or part of a nucleic acid sequence that selectively hybridizes or is homologous to a nucleic acid molecule comprising a nucleic acid sequence of the gene products of Table 2a, Table 2b or Table 7.
The fusion proteins of the present invention will include at least one fragment of a polypeptide of the present invention, which fragment is at least 6, typically at least 8, often at least 15, and usefully at least 16, 17, 18, 19, or 20 amino acids long. The fragment of the polypeptide of the present to be included in the fusion can usefully be at least 25 amino acids long, at least 50 amino acids long, and can be at least 75, 100, or even 150 amino acids long. Fusions that include the entirety of a polypeptide of the present invention have particular utility.
The heterologous polypeptide included within the fusion protein of the present invention is at least 6 amino acids in length, often at least 8 amino acids in length, and preferably at least 15, 20, or 25 amino acids in length. Fusions that include larger polypeptides, such as the IgG Fc region, and even entire proteins (such as GFP chromophore-containing proteins) are particularly useful.
As described above in the description of vectors and expression vectors of the present invention, which discussion is incorporated here by reference in its entirety, heterologous polypeptides to be included in the fusion proteins of the present invention can usefully include those designed to facilitate purification and/or visualization of recombinantly-expressed proteins. See, e.g., Ausubel, Chapter 16, (1992), supra. Although purification tags can also be incorporated into fusions that are chemically synthesized, chemical synthesis typically provides sufficient purity that further purification by HPLC suffices; however, visualization tags as above described retain their utility even when the protein is produced by chemical synthesis, and when so included render the fusion proteins of the present invention useful as directly detectable markers of the presence of a polypeptide of the invention.
As also discussed above, heterologous polypeptides to be included in the fusion proteins of the present invention can usefully include those that facilitate secretion of recombinantly expressed proteins into the periplasmic space or extracellular milieu for prokaryotic hosts or into the culture medium for eukaryotic cells through incorporation of secretion signals and/or leader sequences. For example, a His6 tagged protein can be purified on a Ni affinity column and a GST fusion protein can be purified on a glutathione affinity column. Similarly, a fusion protein comprising the Fc domain of IgG can be purified on a Protein A or Protein G column and a fusion protein comprising an epitope tag such as myc can be purified using an immunoaffmity column containing an anti-c-myc antibody. It is preferable that the epitope tag be separated from the protein encoded by the essential gene by an enzymatic cleavage site that can be cleaved after purification. See also the discussion of nucleic acid molecules encoding fusion proteins that may be expressed on the surface of a cell.
Other useful fusion proteins of the present invention include those that permit use of the polypeptide of the present invention as bait in a yeast two-hybrid system. See Bartel et al (eds.), The Yeast Two-Hybrid System, Oxford University Press (1997); Zhu et al , Yeast Hybrid Technologies. Eaton Publishing (2000); Fields et al , Trends Genet. 10(8): 286-92 (1994); Mendelsohn et al, Curr. Opin. Biotechnol. 5(5): 482-6 (1994); Luban et al., Curr. Opin. Biotechnol. 6(1): 59-64 (1995); Allen et al, Trends Biochem. ScL 20(12): 511-6 (1995); Drees, Curr. Opin. Chem. Biol. 3(1): 64-70 (1999); Topcu et al, Pharm. Res. 17(9): 1049-55 (2000); Fashena et al, Gene 250(1-2): 1-14 (2000); Colas et al, Nature 380, 548-550 (1996); Norman, T. et al, Science 285, 591-595 (1999); Fabbrizio et α/"., Oncogene 18, 4357-4363 (1999); Xu et al, Proc Natl Acad Sd USA. 94, 12473-12478 (1997); Yang, et al, Nuc. Acids Res. 23, 1152-1156 (1995); Kolonin et al, Proc Natl Acad Sd USA 95, 14266-14271 (1998); Cohen et al, Proc Natl Acad Sci U SA 95, 14272-14277 (1998); Uetz, et al. Nature 403, 623-627(2000); Ito, et al, Proc Natl Acad Sci USA 98, 4569-4574 (2001). Typically, such fusion is to either E. coli LexA or yeast GAL4 DNA binding domains. Related bait plasmids are available that express the bait fused to a nuclear localization signal. Other useful fusion proteins include those that permit display of the encoded polypeptide on the surface of a phage or cell, fusions to intrinsically fluorescent proteins, such as green fluorescent protein (GFP), and fusions to the IgG Fc region, as described above.
The polypeptides of the present invention can also usefully be fused to protein toxins, such as Pseudomonas exotoxin A, diphtheria toxin, shiga toxin A, anthrax toxin lethal factor, ricin, in order to effect ablation of cells that bind or take up the proteins of the present invention.
Fusion partners include, inter alia, myc, hemagglutinin (HA), GST, immunoglobulins, β-galactosidase, biotin trpE, protein A, β -lactamase, α-amylase, maltose binding protein, alcohol dehydrogenase, polyhistidine (for example, six histidine at the amino and/or carboxyl terminus of the polypeptide), lacZ, green fluorescent protein (GFP), yeast α mating factor, GAL4 transcription activation or DNA binding domain, luciferase, and serum proteins such as ovalbumin, albumin and the constant domain of IgG. See, e.g., Ausubel (1992), supra and Ausubel (1999), supra. Fusion proteins may also contain sites for specific enzymatic cleavage, such as a site that is recognized by enzymes such as Factor XIII, trypsin, pepsin, or any other enzyme known in the art. Fusion proteins will typically be made by either recombinant nucleic acid methods, as described above, chemically synthesized using techniques well known in the art {e.g., a Merrifield synthesis), or produced by chemical cross-linking. Another advantage of fusion proteins is that the epitope tag can be used to bind the fusion protein to a plate or column through an affinity linkage for screening binding proteins or other molecules that bind to the CaSP.
As further described below, the polypeptides of the present invention can readily be used as specific immunogens to raise antibodies that specifically recognize polypeptides of the present invention including CaSPs and their allelic variants and homologues. The antibodies, in turn, can be used, inter alia, specifically to assay for the polypeptides of the present invention, particularly CaSPs, e.g. by ELISA for detection of protein fluid samples, such as serum, by immunohistochemistry or laser scanning cytometry, for detection of protein in tissue samples, or by flow cytometry, for detection of intracellular protein in cell suspensions, for specific antibody-mediated isolation and/or purification of CaSPs, as for example by immunoprecipitation, and for use as specific agonists or antagonists of CaSPs. One may determine whether polypeptides of the present invention including
CaSPs, muteins, homologous proteins or allelic variants or fusion proteins of the present invention are functional by methods known in the art. For instance, residues that are tolerant of change while retaining function can be identified by altering the polypeptide at known residues using methods known in the art, such as alanine scanning mutagenesis, Cunningham et al, Science 244(4908): 1081-5 (1989); transposon linker scanning mutagenesis, Chen et al, Gene 263(1-2): 39-48 (2001); combinations of homolog- and alanine-scanning mutagenesis, Jin et al., J. MoI. Biol. 226(3): 851-65 (1992); combinatorial alanine scanning, Weiss et al, Proc. Natl. Acad. Sd USA 97(16): 8950-4 (2000), followed by functional assay. Transposon linker scanning kits are available commercially (New England Biolabs, Beverly, MA, USA, catalog, no. E7-102S; EZ::TN™ In-Frame Linker Insertion Kit, catalogue no. EZI04KN, (Epicentre Technologies Corporation, Madison, WI, USA)).
Purification of the polypeptides or fusion proteins of the present invention is well known and within the skill of one having ordinary skill in the art. See, e.g., Scopes, Protein Purification, 2d ed. (1987). Purification of recombinantly expressed polypeptides is described above. Purification of chemically-synthesized peptides can readily be effected, e.g., by HPLC.
Accordingly, it is an aspect of the present invention to provide the isolated polypeptides or fusion proteins of the present invention in pure or substantially pure form in the presence or absence of a stabilizing agent. Stabilizing agents include both proteinaceous and non-proteinaceous material and are well known in the art. Stabilizing agents, such as albumin and polyethylene glycol (PEG) are known and are commercially available.
Although high levels of purity are preferred when the isolated polypeptide or fusion protein of the present invention are used as therapeutic agents, such as in vaccines and replacement therapy, the isolated polypeptides of the present invention are also useful at lower purity. For example, partially purified polypeptides of the present invention can be used as immunogens to raise antibodies in laboratory animals. In a preferred embodiment, the purified and substantially purified polypeptides of the present invention are in compositions that lack detectable ampholytes, acrylamide monomers, bis-acrylamide monomers, and polyacrylamide.
The polypeptides or fusion proteins of the present invention can usefully be attached to a substrate. The substrate can be porous or solid, planar or non-planar; the bond can be covalent or noncovalent. For example, the peptides of the invention may be stabilized by covalent linkage to albumin. See, U.S. Patent No. 5,876,969, the contents of which are hereby incorporated in its entirety.
For example, the polypeptides or fusion proteins of the present invention can usefully be bound to a porous substrate, commonly a membrane, typically comprising nitrocellulose, polyvinylidene fluoride (PVDF), or cationically derivatized, hydrophilic PVDF; so bound, the polypeptides or fusion proteins of the present invention can be used to detect and quantify antibodies, e.g. in serum, that bind specifically to the immobilized polypeptide or fusion protein of the present invention. As another example, the polypeptides or fusion proteins of the present invention can usefully be bound to a substantially nonporous substrate, such as plastic, to detect and quantify antibodies, e.g. in serum, that bind specifically to the immobilized protein of the present invention. Such plastics include polymethylacrylic, polyethylene, polypropylene, polyacrylate, polymethylmethacrylate, polyvinylchloride, polytetrafluoroethylene, polystyrene, polycarbonate, polyacetal, polysulfone, celluloseacetate, cellulosenitrate, nitrocellulose, or mixtures thereof; when the assay is performed in a standard microtiter dish, the plastic is typically polystyrene.
The polypeptides and fusion proteins of the present invention can also be attached to a substrate suitable for use as a surface enhanced laser desorption ionization source; so attached, the polypeptide or fusion protein of the present invention is useful for binding and then detecting secondary proteins that bind with sufficient affinity or avidity to the surface-bound polypeptide or fusion protein to indicate biologic interaction there between. The polypeptides or fusion proteins of the present invention can also be attached to a substrate suitable for use in surface plasmon resonance detection; so attached, the polypeptide or fusion protein of the present invention is useful for binding and then detecting secondary proteins that bind with sufficient affinity or avidity to the surface- bound polypeptide or fusion protein to indicate biological interaction there between. Alternative Transcripts
In another aspect, the present invention provides splice variants of genes and proteins encoded thereby. The identification of a novel splice variant which encodes an amino acid sequence with a novel region can be targeted for the generation of reagents for use in detection and/or treatment of cancer. The novel amino acid sequence may lead to a unique protein structure, protein subcellular localization, biochemical processing or function of the splice variant. This information can be used to directly or indirectly facilitate the generation of additional or novel therapeutics or diagnostics. The nucleotide sequence in this novel splice variant can be used as a nucleic acid probe for the diagnosis and/or treatment of cancer.
Specifically, the newly identified sequences may enable the production of new antibodies or compounds directed against the novel region for use as a therapeutic or diagnostic. Alternatively, the newly identified sequences may alter the biochemical or biological properties of the encoded protein in such a way as to enable the generation of improved or different therapeutics targeting this protein.
In another aspect, the invention provides antibodies, including fragments and derivatives thereof, which bind specifically to polypeptides encoded by the nucleic acid molecules of the invention. In a preferred embodiment, the antibodies are specific for a polypeptide that is a CaSP, or a fragment, mutein, derivative, analog, isoform, allelic variant or fusion protein thereof. In a more preferred embodiment, the antibodies are specific for a polypeptide that comprises the gene products of Table 2a or Table 2b, or a fragment, mutein, derivative, analog, isoform, allelic variant or fusion protein thereof. The antibodies of the present invention can be specific for linear epitopes, discontinuous epitopes, or conformational epitopes of such proteins or protein fragments, either as present on the protein in its native conformation or, in some cases, as present on the proteins as denatured, as, e.g., by solubilization in SDS. New epitopes may be also due to a difference in post translational modifications (PTMs) in disease versus normal tissue. For example, a particular site on a CaSP may be glycosylated in cancerous cells, but not glycosylated in normal cells or vice versa, hi addition, alternative splice forms of a CaSP may be indicative of cancer. Differential degradation of the C or N-terminus of a CaSP may also be a marker or target for anticancer therapy. For example, an CaSP may be N-terminal degraded in cancer cells exposing new epitopes to which antibodies may selectively bind for diagnostic or therapeutic uses.
As is well known in the art, the degree to which an antibody can discriminate as among molecular species in a mixture will depend, in part, upon the conformational relatedness of the species in the mixture; typically, the antibodies of the present invention will discriminate over adventitious binding to non-CaSP polypeptides by at least two-fold, more typically by at least 5-fold, typically by more than 10-fold, 25-fold, 50-fold, 75-fold, and often by more than 100-fold, and on occasion by more than 500-fold or 1000-fold.
When used to detect the proteins or protein fragments of the present invention, the antibody of the present invention is sufficiently specific when it can be used to determine the presence of the polypeptide of the present invention in samples derived from bodily fluids and normal or cancerous human breast, lymph, intestine, colon, lung, ovarian or prostate tissue.
Typically, the affinity or avidity of an antibody (or antibody multimer, as in the case of an IgM pentamer) of the present invention for a protein or protein fragment of the present invention will be at least about 1 x 10"6 molar (M), typically at least about 5 x 10"7
M, 1 x 10"7 M, with affinities and avidities of at least 1 x 10"8 M, 5 x 10"9 M, 1 x 10'10 M and up to 1 X 10"13 M proving especially useful.
The antibodies of the present invention can be naturally occurring forms, such as IgG, IgM, IgD, IgE, IgY, and IgA, from any avian, reptilian, or mammalian species.
Human antibodies can, but will infrequently, be drawn directly from human donors or human cells. In such case, antibodies to the polypeptides of the present invention will typically have resulted from fortuitous immunization, such as autoimmune immunization, with the polypeptide of the present invention. Such antibodies will typically, but will not invariably, be polyclonal. In addition, individual polyclonal antibodies may be isolated and cloned to generate monoclonals.
Human antibodies are more frequently obtained using transgenic animals that express human immunoglobulin genes, which transgenic animals can be affirmatively immunized with the protein immunogen of the present invention. Human Ig-transgenic mice capable of producing human antibodies and methods of producing human antibodies therefrom upon specific immunization are described, inter alia, in U.S. Patent Nos.
6,162,963; 6,150,584; 6,114,598; 6,075,181; 5,939,598; 5,877,397; 5,874,299; 5,814,318;
5,789,650; 5,770,429; 5,661,016; 5,633,425; 5,625,126; 5,569,825; 5,545,807; 5,545,806, and 5,591,669, the disclosures of which are incorporated herein by reference in their entireties. Such antibodies are typically monoclonal, and are typically produced using techniques developed for production of murine antibodies.
Human antibodies are particularly useful, and often preferred, when the antibodies of the present invention are to be administered to human beings as in vivo diagnostic or therapeutic agents, since recipient immune response to the administered antibody will often be substantially less than that occasioned by administration of an antibody derived from another species, such as mouse.
IgG, IgM, IgD, IgE, IgY, and IgA antibodies of the present invention are also usefully obtained from other species, including mammals such as rodents (typically mouse, but also rat, guinea pig, and hamster), lagomorphs (typically rabbits), and also larger mammals, such as sheep, goats, cows, and horses; or egg laying birds or reptiles such as chickens or alligators, hi such cases, as with the transgenic human-antibody- producing non-human mammals, fortuitous immunization is not required, and the non- human mammal is typically affirmatively immunized, according to standard immunization protocols, with the polypeptide of the present invention. One form of avian antibodies may be generated using techniques described in WO 00/29444, published 25 May 2000.
As discussed above, virtually all fragments of 8 or more contiguous amino acids of a polypeptide of the present invention can be used effectively as immunogens when conjugated to a carrier, typically a protein such as bovine thyroglobulin, keyhole limpet hemocyanin, or bovine serum albumin, conveniently using a bifunctional linker such as those described elsewhere above, which discussion is incorporated by reference here.
Immunogenicity can also be conferred by fusion of the polypeptide of the present invention to other moieties. For example, polypeptides of the present invention can be produced by solid phase synthesis on a branched polylysine core matrix; these multiple antigenic peptides (MAPs) provide high purity, increased avidity, accurate chemical definition and improved safety in vaccine development. Tarn et al, Proc. Natl. Acad. Sd. USA 85: 5409-5413 (1988); Posnett et al., J. Biol. Chem. 263: 1719-1725 (1988). Protocols for immunizing non-human mammals or avian species are well- established in the art. See Harlow et al. (eds.), Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1998); Coligan et al. (eds.), Current Protocols in Immunology, John Wiley & Sons, Inc. (2001); Zola, Monoclonal Antibodies: Preparation and Use of Monoclonal Antibodies and Engineered Antibody Derivatives (Basics: From Background to Bench), Springer Verlag (2000); Gross M, Speck J.Dtsch. Tierarztl. Wochenschr. 103: 417-422 (1996). Immunization protocols often include multiple immunizations, either with or without adjuvants such as Freund's complete adjuvant and Freund's incomplete adjuvant, and may include naked DNA immunization (Moss, Semin. Immunol. 2: 317-327 (1990).
Antibodies from non-human mammals and avian species can be polyclonal or monoclonal, with polyclonal antibodies having certain advantages in immunohistochemical detection of the polypeptides of the present invention and monoclonal antibodies having advantages in identifying and distinguishing particular epitopes of the polypeptides of the present invention. Antibodies from avian species may have particular advantage in detection of the polypeptides of the present invention, in human serum or tissues (Vikinge et al., Biosens. Bioelectron. 13: 1257-1262 (1998). Following immunization, the antibodies of the present invention can be obtained using any art-accepted technique. Such techniques are well known in the art and are described in detail in references such as Coligan, supra; Zola, supra; Howard et al. (eds.), Basic
Methods in Antibody Production and Characterization, CRC Press (2000); Harlow, supra; Davis (ed.), Monoclonal Antibody Protocols, Vol. 45, Humana Press (1995); Delves (ed.), Antibody Production: Essential Techniques, John Wiley & Son Ltd (1997); and Kenney, Antibody Solution: An Antibody Methods Manual, Chapman & Hall (1997). Briefly, such techniques include, inter alia, production of monoclonal antibodies by hybridomas and expression of antibodies or fragments or derivatives thereof from host cells engineered to express immunoglobulin genes or fragments thereof. These two methods of production are not mutually exclusive: genes encoding antibodies specific for the polypeptides of the present invention can be cloned from hybridomas and thereafter expressed in other host cells. Nor need the two necessarily be performed together: e.g. , genes encoding antibodies specific for the polypeptides of the present invention can be cloned directly from B cells known to be specific for the desired protein, as further described in U.S. Patent No. 5,627,052, the disclosure of which is incorporated herein by reference in its entirety, or from antibody-displaying phage. Recombinant expression in host cells is particularly useful when fragments or derivatives of the antibodies of the present invention are desired.
Host cells for recombinant antibody production of whole antibodies, antibody fragments, or antibody derivatives can be prokaryotic or eukaryotic. Prokaryotic hosts are particularly useful for producing phage displayed antibodies of the present invention.
The technology of phage-displayed antibodies, in which antibody variable region fragments are fused, for example, to the gene III protein (pill) or gene VIII protein (p VIII) for display on the surface of filamentous phage, such as M 13, is by now well-established. See, e.g., Sidhu, Curr. Opin. Biotechnol. 11(6): 610-6 (2000); Griffiths et al, Curr. Opin. Biotechnol. 9(1): 102-8 (1998); Hoogenboom et al.Jmmunotechnology, 4(1): 1-20 (1998); Rader et ah, Current Opinion in Biotechnology 8: 503-508 (1997); Aujame et ah, Human Antibodies 8: 155-168 (1997); Hoogenboom, Trends in Biotechnol. 15: 62-70 (1997); de Kruif et ah, 17: 453-455 (1996); Barbas et ah, Trends in Biotechnol. 14: 230-234 (1996); Winter et ah, Ann. Rev. Immunol. 433-455 (1994). Techniques and protocols required to generate, propagate, screen (pan), and use the antibody fragments from such libraries have recently been compiled. See, e.g., Barbas (2001), supra; Kay, supra; and Abelson, supra. Typically, phage-displayed antibody fragments are scFv fragments or Fab fragments; when desired, full length antibodies can be produced by cloning the variable regions from the displaying phage into a complete antibody and expressing the full length antibody in a further prokaryotic or a eukaryotic host cell. Eukaryotic cells are also useful for expression of the antibodies, antibody fragments, and antibody derivatives of the present invention. For example, antibody fragments of the present invention can be produced in Pichia pastoris and in Saccharomyces cerevisiae. See, e.g., Takahashi et ah, Biosci. Biotechnol. Biochem. 64(10): 2138-44 (2000); Freyre et ah, J. Biotechnol. 76(2-3):l 57-63 (2000); Fischer et ah, Biotechnol. Apph Biochem. 30 (Pt 2): 117-20 (1999); Pennell et ah, Res. Immunol. 149(6): 599-603 (1998); Eldin et ah, J. Immunol. Methods. 201(1): 67-75 (1997);, Frenken et ah, Res. Immunol. 149(6): 589-99 (1998); and Shusta et ah, Nature Biotechnol. 16(8): 773-7 (1998).
Antibodies, including antibody fragments and derivatives, of the present invention can also be produced in insect cells. See, e.g., Li et ah, Protein Expr. Purif. 21(1): 121-8 (2001); Ailor et ah, Biotechnol. Bioeng. 58(2-3): 196-203 (1998); Hsu et ah, Biotechnol. Prog. 13(1): 96-104 (1997); Edelman et ah, Immunology 91(1): 13-9 (1997); andNesbit et ah, J. Immunol. Methods 151(1-2): 201-8 (1992).
Antibodies and fragments and derivatives thereof of the present invention can also be produced in plant cells, particularly maize or tobacco, Giddings et ah, Nature Biotechnol. 18(11): 1151-5 (2000); Gavilondo et ah, Biotechniques 29(1): 128-38 (2000); Fischer et al, J. Biol. Regul. Homeost. Agents 14(2): 83-92 (2000); Fischer et al, Biotechnol. Appl. Biochem. 30 (Pt 2): 113-6 (1999); Fischer et al, Biol. Chem. 380(7-8): 825-39 (1999); Russell, Curr. Top. Microbiol. Immunol. 240: 119-38 (1999); and Ma et al, Plant Physiol. 109(2): 341-6 (1995). Antibodies, including antibody fragments and derivatives, of the present invention can also be produced in transgenic, non-human, mammalian milk. See, e.g. Pollock et al., J. Immunol Methods. 231: 147-57 (1999); Young et al., Res. Immunol. 149: 609-10 (1998); and Limonta et al., Immunotechnology 1: 107-13 (1995).
Mammalian cells useful for recombinant expression of antibodies, antibody fragments, and antibody derivatives of the present invention include CHO cells, COS cells, 293 cells, and myeloma cells. Verma et al, J. Immunol. Methods 216(1-2):165-81 (1998) review and compare bacterial, yeast, insect and mammalian expression systems for expression of antibodies. Antibodies of the present invention can also be prepared by cell free translation, as further described in Merk et al, J. Biochem. (Tokyo) 125(2): 328-33 (1999) and Ryabova et al, Nature Biotechnol. 15(1): 79-84 (1997), and in the milk of transgenic animals, as further described in Pollock et al, J. Immunol Methods 231(1-2): 147-57 (1999).
The invention further provides antibody fragments that bind specifically to one or more of the polypeptides of the present invention, to one or more of the polypeptides encoded by the isolated nucleic acid molecules of the present invention, or the binding of which can be competitively inhibited by one or more of the polypeptides of the present invention or one or more of the polypeptides encoded by the isolated nucleic acid molecules of the present invention. Among such useful fragments are Fab, Fab', Fv, F(ab)'2, and single chain Fv (scFv) fragments. Other useful fragments are described in Hudson, Curr. Opin. Biotechnol 9(4): 395-402 (1998).
The present invention also relates to antibody derivatives that bind specifically to one or more of the polypeptides of the present invention, to one or more of the polypeptides encoded by the isolated nucleic acid molecules of the present invention, or the binding of which can be competitively inhibited by one or more of the polypeptides of the present invention or one or more of the polypeptides encoded by the isolated nucleic acid molecules of the present invention.
Among such useful derivatives are chimeric, primatized, and humanized antibodies; such derivatives are less immunogenic in human beings, and thus are more suitable for in vivo administration, than are unmodified antibodies from non-human mammalian species. Another useful method is PEGylation to increase the serum half life of the antibodies.
Chimeric antibodies typically include heavy and/or light chain variable regions (including both CDR and framework residues) of immunoglobulins of one species, typically mouse, fused to constant regions of another species, typically human. See, e.g., Morrison et al, Proc. Natl. Acad. Sd USAM(IY): 6851-5 (1984); Sharon et al, Nature 309(5966): 364-7 (1984); Takeda et al, Nature 314(6010): 452-4 (1985); and U.S. Patent No. 5,807,715 the disclosure of which is incorporated herein by reference in its entirety. Primatized and humanized antibodies typically include heavy and/or light chain CDRs from a murine antibody grafted into a non-human primate or human antibody V region framework, usually further comprising a human constant region, Riechmann et al, Nature 332(6162): 323-7 (1988); Co et al, Nature 351(6326): 501-2 (1991); and U.S. Patent Nos. 6,054,297; 5,821,337; 5,770,196; 5,766,886; 5,821,123; 5,869,619; 6,180,377; 6,013,256; 5,693,761; and 6,180,370, the disclosures of which are incorporated herein by reference in their entireties. Other useful antibody derivatives of the invention include heteromeric antibody complexes and antibody fusions, such as diabodies (bispecific antibodies), single-chain diabodies, and intrabodies.
It is contemplated that the nucleic acids encoding the antibodies of the present invention can be operably joined to other nucleic acids forming a recombinant vector for cloning or for expression of the antibodies of the invention. Accordingly, the present invention includes any recombinant vector containing the coding sequences, or part thereof, whether for eukaryotic transduction, transfection or gene therapy. Such vectors may be prepared using conventional molecular biology techniques, known to those with skill in the art, and would comprise DNA encoding sequences for the immunoglobulin V- regions including framework and CDRs or parts thereof, and a suitable promoter either with or without a signal sequence for intracellular transport. Such vectors may be transduced or transfected into eukaryotic cells or used for gene therapy (Marasco et al., Proc. Natl. Acad. Sd. (USA) 90: 7889-7893 (1993); Duan et al., Proc. Natl. Acad. Sd. (USA) 91 : 5075-5079 (1994), by conventional techniques, known to those with skill in the art.
The antibodies of the present invention, including fragments and derivatives thereof, can usefully be labeled. It is, therefore, another aspect of the present invention to provide labeled antibodies that bind specifically to one or more of the polypeptides of the present invention, to one or more of the polypeptides encoded by the isolated nucleic acid molecules of the present invention, or the binding of which can be competitively inhibited by one or more of the polypeptides of the present invention or one or more of the polypeptides encoded by the isolated nucleic acid molecules of the present invention. The choice of label depends, in part, upon the desired use.
For example, when the antibodies of the present invention are used for immunohistochemical staining of tissue samples, the label can usefully be an enzyme that catalyzes production and local deposition of a detectable product. Enzymes typically conjugated to antibodies to permit their immunohistochemical visualization are well known, and include alkaline phosphatase, β-galactosidase, glucose oxidase, horseradish peroxidase (HRP), and urease. Typical substrates for production and deposition of visually detectable products include o-nitrophenyl-beta-D-galactopyranoside (ONPG); o-phenylenediamine dihydrochloride (OPD); p-nitrophenyl phosphate (PNPP); p- nitrophenyl-beta-D-galactopyranoside (PNPG); 3',3'-diaminobenzidine (DAB); 3-amino- 9-ethylcarbazole (AEC); 4-chloro-l-naphthol (CN);
5-bromo-4-chloro-3-indolyl-phosphate (BCIP); ABTS®; BluoGal; iodonitrotetrazolium (INT); nitroblue tetrazolium chloride (NBT); phenazine methosulfate (PMS); phenolphthalein monophosphate (PMP); tetramethyl benzidine (TMB); tetranitroblue tetrazolium (TNBT); X-GaI; X-Gluc; and X-Glucoside.
Other substrates can be used to produce products for local deposition that are luminescent. For example, in the presence of hydrogen peroxide (H2O2), horseradish peroxidase (HRP) can catalyze the oxidation of cyclic diacylhydrazides, such as luminol. Immediately following the oxidation, the luminol is in an excited state (intermediate reaction product), which decays to the ground state by emitting light. Strong enhancement of the light emission is produced by enhancers, such as phenolic compounds. Advantages include high sensitivity, high resolution, and rapid detection without radioactivity and requiring only small amounts of antibody. See, e.g., Thorpe et al, Methods Enzymol. 133: 331-53 (1986); Kricka et al, J. Immunoassay 17(1): 67-83 (1996); and Lundqvist et al, J. Biolumin. Chemilumin. 10(6): 353-9 (1995). Kits for such enhanced chemiluminescent detection (ECL) are available commercially. The antibodies can also be labeled using colloidal gold. As another example, when the antibodies of the present invention are used, e.g., for flow cytometric detection, for scanning laser cytometric detection, or for fluorescent immunoassay, they can usefully be labeled with fluorophores. There are a wide variety of fluorophore labels that can usefully be attached to the antibodies of the present invention. For flow cytometric applications, both for extracellular detection and for intracellular detection, common useful fluorophores can be fluorescein isothiocyanate (FITC), allophycocyanin (APC), R-phycoerythrin (PE), peridinin chlorophyll protein (PerCP), Texas Red, Cy3, Cy5, fluorescence resonance energy tandem fluorophores such as PerCP- Cy5.5, PE-Cy5, PE-Cy5.5, PE-Cy7, PE-Texas Red, and APC-Cy7. Other fluorophores include, inter alia, Alexa Fluor® 350, Alexa Fluor® 488,
Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 647 (monoclonal antibody labeling kits available from Molecular Probes, Inc., Eugene, OR, USA), BODIPY dyes, such as BODIPY 493/503, BODIPY FL, BODIPY R6G, BODIPY 530/550, BODIPY TMR, BODIPY 558/568, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY TR, BODIPY 630/650, BODIPY 650/665, Cascade Blue, Cascade Yellow, Dansyl, lissamine rhodamine B, Marina Blue, Oregon Green 488, Oregon Green 514, Pacific Blue, rhodamine 6G, rhodamine green, rhodamine red, tetramethylrhodamine, Texas Red (available from Molecular Probes, Inc., Eugene, OR, USA), and Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, all of which are also useful for fluorescently labeling the antibodies of the present invention. For secondary detection using labeled avidin, streptavidin, captavidin or neutravidin, the antibodies of the present invention can usefully be labeled with biotin.
When the antibodies of the present invention are used, e.g., for western blotting applications, they can usefully be labeled with radioisotopes, such as 33P, 32P, 35S, 3H, and
11^ I. As another example, when the antibodies of the present invention are used for radioimmunotherapy, the label can usefully be 228Th, 227Ac, 225Ac, 223Ra, 213Bi, 212Pb, 212Bi5 211At, 203Pb, 194Os, 188Re, 186Re, 153Sm, 149Tb, 1311, 1251, 111In, 105Rh, 99mTc, 97Ru, 90Y, 90Sr5 88Y5 72Se5 67Cu5 Or 47Sc.
As another example, when the antibodies of the present invention are to be used for in vivo diagnostic use, they can be rendered detectable by conjugation to MRI contrast agents, such as gadolinium diethylenetriaminepentaacetic acid (DTPA), Lauffer et ah, Radiology 207(2): 529-38 (1998), or by radioisotopic labeling. As would be understood, use of the labels described above is not restricted to the application as for which they were mentioned.
The antibodies of the present invention, including fragments and derivatives thereof, can also be conjugated to toxins, in order to target the toxin's ablative action to cells that display and/or express the polypeptides of the present invention. Commonly, the antibody in such immunotoxins is conjugated to Pseudomonas exotoxin A, diphtheria toxin, shiga toxin A, anthrax toxin lethal factor, or ricin. See Hall (ed.), Immunotoxin Methods and Protocols (Methods in Molecular Biology, vol. 166), Humana Press (2000); and Frankel et al. (eds.), Clinical Applications of Immunotoxins, Springer- Verlag (1998). The antibodies of the present invention can usefully be attached to a substrate, and it is, therefore, another aspect of the invention to provide antibodies that bind specifically to one or more of the polypeptides of the present invention, to one or more of the polypeptides encoded by the isolated nucleic acid molecules of the present invention, or the binding of which can be competitively inhibited by one or more of the polypeptides of the present invention or one or more of the polypeptides encoded by the isolated nucleic acid molecules of the present invention, attached to a substrate. Substrates can be porous or nonporous, planar or nonplanar. For example, the antibodies of the present invention can usefully be conjugated to filtration media, such as NHS-activated Sepharose or CNBr- activated Sepharose for purposes of immunoaffinity chromatography. For example, the antibodies of the present invention can usefully be attached to paramagnetic microspheres, typically by biotin-streptavidin interaction, which microsphere can then be used for isolation of cells that express or display the polypeptides of the present invention. As another example, the antibodies of the present invention can usefully be attached to the surface of a microtiter plate for ELISA. As noted above, the antibodies of the present invention can be produced in prokaryotic and eukaryotic cells. It is, therefore, another aspect of the present invention to provide cells that express the antibodies of the present invention, including hybridoma cells, B cells, plasma cells, and host cells recombinantly modified to express the antibodies of the present invention. hi yet a further aspect, the present invention provides aptamers evolved to bind specifically to one or more of the CaSPs of the present invention or to polypeptides encoded by the CaSNAs of the invention. In sum, one of skill in the art, provided with the teachings of this invention, has available a variety of methods which may be used to alter the biological properties of the antibodies of this invention including methods which would increase or decrease the stability or half-life, immunogenicity, toxicity, affinity or yield of a given antibody molecule, or to alter it in any other way that may render it more suitable for a particular application.
Transgenic Animals and Cells
In another aspect, the invention provides transgenic cells and non-human organisms comprising nucleic acid molecules of the invention. In a preferred embodiment, the transgenic cells and non-human organisms comprise a nucleic acid molecule encoding a CaSP. In a preferred embodiment, the CaSP comprises an amino acid sequence selected from the gene products of Table 2a or Table 2b, or a fragment, mutein, homologous protein or allelic variant thereof. In another preferred embodiment, the transgenic cells and non-human organism comprise a CaSNA of the invention, preferably a CaSNA comprising a nucleotide sequence selected from the group consisting of the gene products of Table 2a, Table 2b or Table 7, or a part, substantially similar nucleic acid molecule, allelic variant or hybridizing nucleic acid molecule thereof.
In another embodiment, the transgenic cells and non-human organisms have a targeted disruption or replacement of the endogenous orthologue of the human CaSG. The transgenic cells can be embryonic stem cells or somatic cells. The transgenic non-human organisms can be chimeric, nonchimeric heterozygotes, and nonchimeric homozygotes. Methods of producing transgenic animals are well known in the art. See, e.g., Hogan et al, Manipulating the Mouse Embryo; A Laboratory Manual, 2d ed., Cold Spring Harbor Press (1999); Jackson et al, Mouse Genetics and Transgenics: A Practical Approach, Oxford University Press (2000); and Pinkert, Transgenic Animal Technology: A Laboratory Handbook, Academic Press (1999).
Any technique known in the art may be used to introduce a nucleic acid molecule of the invention into an animal to produce the founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection, {see, e.g., Paterson et al, Appl. Microbiol. Biotechnol 40: 691-698 (1994); Carver et al, Biotechnology 11: 1263-1270 (1993); Wright et al, Biotechnology 9: 830-834 (1991); and U.S. Patent No. 4,873,191, herein incorporated by reference in its entirety); retrovirus-mediated gene transfer into germ lines, blastocysts or embryos {see, e.g., Van der Putten et al, Proc. Natl. Acad. ScL, USA 82: 6148-6152 (1985)); gene targeting in embryonic stem cells {see, e.g., Thompson et al, Cell 56: 313-321 (1989)); electroporation of cells or embryos (see, e.g., Lo, 1983, MoI. Cell. Biol. 3: 1803-1814 (1983)); introduction using a gene gun (see, e.g., Ulmer et al, Science 259: 1745-49 (1993); introducing nucleic acid constructs into embryonic pleuripotent stem cells and transferring the stem cells back into the blastocyst; and sperm-mediated gene transfer (see, e.g., Lavitrano et al, Cell 57: 717-723 (1989)).
Other techniques include, for example, nuclear transfer into enucleated oocytes of nuclei from cultured embryonic, fetal, or adult cells induced to quiescence (see, e.g., Campell et al, Nature 380: 64-66 (1996); Wilmut et al, Nature 385: 810-813 (1997)). The present invention provides for transgenic animals that carry the trans gene (i.e., a nucleic acid molecule of the invention) in all their cells, as well as animals which carry the transgene in some, but not all their cells, i.e., mosaic animals or chimeric animals.
The transgene may be integrated as a single transgene or as multiple copies, such as in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, e.g., the teaching of Lasko et al et al, Proc. Natl. Acad. Sd. USA 89: 6232- 6236 (1992). The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.
Once transgenic animals have been generated, the expression of the recombinant gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to verify that integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and reverse transcriptase-PCR (RT-PCR). Samples of transgenic gene-expressing tissue may also be evaluated immunocytochemically or immunohistochemically using antibodies specific for the transgene product.
Once the founder animals are produced, they may be bred, inbred, outbred, or crossbred to produce colonies of the particular animal. Examples of such breeding strategies include, but are not limited to: outbreeding of founder animals with more than one integration site in order to establish separate lines; inbreeding of separate lines in order to produce compound transgenics that express the transgene at higher levels because of the effects of additive expression of each transgene; crossing of heterozygous transgenic animals to produce animals homozygous for a given integration site in order to both augment expression and eliminate the need for screening of animals by DNA analysis; crossing of separate homozygous lines to produce compound heterozygous or homozygous lines; and breeding to place the transgene on a distinct background that is appropriate for an experimental model of interest.
Transgenic animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.
Methods for creating a transgenic animal with a disruption of a targeted gene are also well known in the art. In general, a vector is designed to comprise some nucleotide sequences homologous to the endogenous targeted gene. The vector is introduced into a cell so that it may integrate, via homologous recombination with chromosomal sequences, into the endogenous gene, thereby disrupting the function of the endogenous gene. The transgene may also be selectively introduced into a particular cell type, thus inactivating the endogenous gene in only that cell type. See, e.g., Gu et al, Science 265: 103-106 (1994). The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art. See, e.g., Smithies et al, Nature 317: 230-234 (1985); Thomas et al, Cell 51: 503- 512 (1987); Thompson et al, Cell 5: 313-321 (1989).
In one embodiment, a mutant, non-functional nucleic acid molecule of the invention (or a completely unrelated DNA sequence) flanked by DNA homologous to the endogenous nucleic acid sequence (either the coding regions or regulatory regions of the gene) can be used, with or without a selectable marker and/or a negative selectable marker, to transfect cells that express polypeptides of the invention in vivo. In another embodiment, techniques known in the art are used to generate knockouts in cells that contain, but do not express the gene of interest. Insertion of the DNA construct, via targeted homologous recombination, results in inactivation of the targeted gene. Such approaches are particularly suited in research and agricultural fields where modifications to embryonic stem cells can be used to generate animal offspring with an inactive targeted gene. See, e.g., Thomas, supra and Thompson, supra. However this approach can be routinely adapted for use in humans provided the recombinant DNA constructs are directly administered or targeted to the required site in vivo using appropriate viral vectors that will be apparent to those of skill in the art.
In further embodiments of the invention, cells that are genetically engineered to express the polypeptides of the invention, or alternatively, that are genetically engineered not to express the polypeptides of the invention (e.g., knockouts) are administered to a patient in vivo. Such cells may be obtained from an animal or patient or an MHC compatible donor and can include, but are not limited to fibroblasts, bone marrow cells, blood cells (e.g., lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cells are genetically engineered in vitro using recombinant DNA techniques to introduce the coding sequence of polypeptides of the invention into the cells, or alternatively, to disrupt the coding sequence and/or endogenous regulatory sequence associated with the polypeptides of the invention, e.g., by transduction (using viral vectors, and preferably vectors that integrate the transgene into the cell genome) or transfection procedures, including, but not limited to, the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc.
The coding sequence of the polypeptides of the invention can be placed under the control of a strong constitutive or inducible promoter or promoter/enhancer to achieve expression, and preferably secretion, of the polypeptides of the invention. The engineered cells which express and preferably secrete the polypeptides of the invention can be introduced into the patient systemically, e.g., in the circulation, or intraperitoneally.
Alternatively, the cells can be incorporated into a matrix and implanted in the body, e.g., genetically engineered fibroblasts can be implanted as part of a skin graft; genetically engineered endothelial cells can be implanted as part of a lymphatic or vascular graft. See, e.g., U.S. Patent Nos. 5,399,349 and 5,460,959, each of which is incorporated by reference herein in its entirety.
When the cells to be administered are non-autologous or non-MHC compatible cells, they can be administered using well known techniques which prevent the development of a host immune response against the introduced cells. For example, the cells may be introduced in an encapsulated form which, while allowing for an exchange of components with the immediate extracellular environment, does not allow the introduced cells to be recognized by the host immune system. Transgenic and "knock-out" animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.
Computer Readable Means
A further aspect of the invention is a computer readable means for storing the nucleic acid and amino acid sequences of the instant invention. In a preferred embodiment, the invention provides a computer readable means for storing the gene products of Table 2a and Table 2b and the gene products of Table 2a, Table 2b or Table 7 as described herein, as the complete set of sequences or in any combination. The records of the computer readable means can be accessed for reading and display and for interface with a computer system for the application of programs allowing for the location of data upon a query for data meeting certain criteria, the comparison of sequences, the alignment or ordering of sequences meeting a set of criteria, and the like.
The nucleic acid and amino acid sequences of the invention are particularly useful as components in databases useful for search analyses as well as in sequence analysis algorithms. As used herein, the terms "nucleic acid sequences of the invention" and "amino acid sequences of the invention" mean any detectable chemical or physical characteristic of a polynucleotide or polypeptide of the invention that is or may be reduced to or stored in a computer readable form. These include, without limitation, chromatographic scan data or peak data, photographic data or scan data therefrom, and mass spectrographic data.
This invention provides computer readable media having stored thereon sequences of the invention. A computer readable medium may comprise one or more of the following: a nucleic acid sequence comprising a sequence of a nucleic acid sequence of the invention; an amino acid sequence comprising an amino acid sequence of the invention; a set of nucleic acid sequences wherein at least one of said sequences comprises the sequence of a nucleic acid sequence of the invention; a set of amino acid sequences wherein at least one of said sequences comprises the sequence of an amino acid sequence of the invention; a data set representing a nucleic acid sequence comprising the sequence of one or more nucleic acid sequences of the invention; a data set representing a nucleic acid sequence encoding an amino acid sequence comprising the sequence of an amino acid sequence of the invention; a set of nucleic acid sequences wherein at least one of said sequences comprises the sequence of a nucleic acid sequence of the invention; a set of amino acid sequences wherein at least one of said sequences comprises the sequence of an amino acid sequence of the invention; a data set representing a nucleic acid sequence comprising the sequence of a nucleic acid sequence of the invention; a data set representing a nucleic acid sequence encoding an amino acid sequence comprising the sequence of an amino acid sequence of the invention. The computer readable medium can be any composition of matter used to store information or data, including, for example, commercially available floppy disks, tapes, hard drives, compact disks, and video disks. Also provided by the invention are methods for the analysis of character sequences, particularly genetic sequences. Preferred methods of sequence analysis include, for example, methods of sequence homology analysis, such as identity and similarity analysis, RNA structure analysis, sequence assembly, cladistic analysis, sequence motif analysis, open reading frame determination, nucleic acid base calling, and sequencing chromatogram peak analysis.
A computer-based method is provided for performing nucleic acid sequence identity or similarity identification. This method comprises the steps of providing a nucleic acid sequence comprising the sequence of a nucleic acid of the invention in a computer readable medium; and comparing said nucleic acid sequence to at least one nucleic acid or amino acid sequence to identify sequence identity or similarity.
A computer-based method is also provided for performing amino acid homology identification, said method comprising the steps of: providing an amino acid sequence comprising the sequence of an amino acid of the invention in a computer readable medium; and comparing said amino acid sequence to at least one nucleic acid or an amino acid sequence to identify homology.
A computer-based method is still further provided for assembly of overlapping nucleic acid sequences into a single nucleic acid sequence, said method comprising the steps of: providing a first nucleic acid sequence comprising the sequence of a nucleic acid of the invention in a computer readable medium; and screening for at least one overlapping region between said first nucleic acid sequence and a second nucleic acid sequence, hi addition, the invention includes a method of using patterns of expression associated with either the nucleic acids or proteins in a computer-based method to diagnose disease. Diagnostic Methods for Breast Cancer
The present invention also relates to quantitative and qualitative diagnostic assays and methods for detecting, diagnosing, monitoring, staging and predicting cancers by comparing the expression of a CaSNA or a CaSP in a human patient that has or may have breast cancer, or who is at risk of developing breast cancer, with the expression of a CaSNA or a CaSP in a normal human control. For purposes of the present invention, "expression of a CaSNA" or "CaSNA expression" means the quantity of CaSNA mRNA that can be measured by any method known in the art or the level of transcription that can be measured by any method known in the art in a cell, tissue, bodily fluid, organ or whole patient. Similarly, the term "expression of a CaSP" or "CaSP expression" means the amount of CaSP that can be measured by any method known in the art or the level of translation of a CaSNA that can be measured by any method known in the art.
The present invention provides methods for diagnosing breast cancer in a patient, by analyzing for changes in levels of CaSNA or CaSP in cells, tissues, organs or bodily fluids compared with levels of CaSNA or CaSP in cells, tissues, organs or bodily fluids of preferably the same type from a control, wherein an increase, or decrease in certain cases, in levels of a CaSNA or CaSP in the patient versus the control is associated with the presence of breast cancer or with a predilection to the disease. In a preferred embodiment the control is a normal human control or recombinant standard control. In another preferred embodiment, the present invention provides methods for diagnosing breast cancer in a patient by analyzing changes in the structure of the mRNA of a CaSG compared to the mRNA from a normal control. These changes include, without limitation, aberrant splicing, alterations in polyadenylation and/or alterations in 5' nucleotide capping. In yet another preferred embodiment, the present invention provides methods for diagnosing breast cancer in a patient by analyzing changes in a CaSP compared to a CaSP from a normal patient. These changes include, e.g., alterations, including post translational modifications such as glycosylation and/or phosphorylation of the CaSP or changes in the subcellular CaSP localization.
For purposes of the present invention, diagnosing means that CaSNA or CaSP levels are used to determine the presence, absence, recurrence, metastases or prognosis of disease in a patient. As will be understood by those of skill in the art, measurement of other diagnostic parameters may be required for definitive diagnosis, prognosis or determination of the appropriate treatment for the disease. The determination may be made by a clinician, a doctor, a testing laboratory, or a patient using an over the counter test. The patient may have symptoms of disease or may be asymptomatic. In addition, the CaSNA or CaSP levels of the present invention may be used as screening marker to determine whether further tests or biopsies are warranted. In addition, the CaSNA or CaSP levels may be used to determine the vulnerability or susceptibility to disease.
In a preferred embodiment, the expression of a CaSNA is measured by determining the amount of a mRNA that encodes an amino acid sequence selected from the gene products of Table 2a and Table 2b, a homo log, an allelic variant, or a fragment thereof, hi a more preferred embodiment, the CaSNA expression that is measured is the level of expression of a CaSNA mRNA selected from the gene products of Table 2a, Table 2b or Table 7, or a hybridizing nucleic acid, homologous nucleic acid or allelic variant thereof, or a part of any of these nucleic acid molecules. CaSNA expression may be measured by any method known in the art, such as those described supra, including measuring mRNA expression by Northern blot, quantitative or qualitative reverse transcriptase PCR (RT-PCR), microarray, dot or slot blots or in situ hybridization. See, e.g., Ausubel (1992), supra; Ausubel (1999), supra; Sambrook (1989), supra; and Sambrook (2001), supra. CaSNA transcription may be measured by any method known in the art including using a reporter gene hooked up to the promoter of a CaSG of interest or doing nuclear run-off assays. Alterations in mRNA structure, e.g., aberrant splicing variants, may be determined by any method known in the art, including, RT-PCR followed by sequencing or restriction analysis. As necessary, CaSNA expression may be compared to a known control, such as a normal breast nucleic acid, to detect a change in expression. hi another preferred embodiment, the expression of a CaSP is measured by determining the level of a CaSP having an amino acid sequence selected from the group consisting of the gene products of Table 2a and Table 2b, a homolog, an allelic variant, or a fragment thereof. Such levels are preferably determined in at least one of cells, tissues, organs and/or bodily fluids, including determination of normal and abnormal levels. Thus, for instance, a diagnostic assay in accordance with the invention for diagnosing over- or underexpression of a CaSNA or CaSP compared to normal control bodily fluids, cells, tissue samples or recombinant standards may be used to diagnose the presence of breast cancer. The expression level of a CaSP may be determined by any method known in the art, such as those described supra, hi a preferred embodiment, the CaSP expression level may be determined by radioimmunoassays, competitive-binding assays, ELISA, Western blot, FACS, immunohistochemistry, immunoprecipitation, proteomic approaches: two-dimensional gel electrophoresis (2D electrophoresis) and non-gel-based approaches such as mass spectrometry or protein interaction profiling. See, e.g, Harlow (1999), supra; Ausubel (1992), supra; and Ausubel (1999), supra. Alterations in the CaSP structure may be determined by any method known in the art, including, e.g., using antibodies that specifically recognize phosphoserine, phosphothreonine or phosphotyrosine residues, two- dimensional polyacrylamide gel electrophoresis (2D PAGE) and/or chemical analysis of amino acid residues of the protein. Id.
In a preferred embodiment, a radioimmunoassay (RIA) or an ELISA is used. An antibody specific to a CaSP is prepared if one is not already available. In a preferred embodiment, the antibody is a monoclonal antibody. The anti-CaSP antibody is bound to a solid support and any free protein binding sites on the solid support are blocked with a protein such as bovine serum albumin. A sample of interest is incubated with the antibody on the solid support under conditions in which the CaSP will bind to the anti-CaSP antibody. The sample is removed, the solid support is washed to remove unbound material, and an anti-CaSP antibody that is linked to a detectable reagent (a radioactive substance for RIA and an enzyme for ELISA) is added to the solid support and incubated under conditions in which binding of the CaSP to the labeled antibody will occur. After binding, the unbound labeled antibody is removed by washing. For an ELISA, one or more substrates are added to produce a colored reaction product that is based upon the amount of an CaSP in the sample. For an RIA, the solid support is counted for radioactive decay signals by any method known in the art. Quantitative results for both RIA and ELISA typically are obtained by reference to a standard curve.
Other methods to measure CaSP levels are known in the art. For instance, a competition assay may be employed wherein an anti-CaSP antibody is attached to a solid support and an allocated amount of a labeled CaSP and a sample of interest are incubated with the solid support. The amount of labeled CaSP attached to the solid support can be correlated to the quantity of a CaSP in the sample.
Of the proteomic approaches, 2D PAGE is a well known technique. Isolation of individual proteins from a sample such as serum is accomplished using sequential separation of proteins by isoelectric point and molecular weight. Typically, polypeptides are first separated by isoelectric point (the first dimension) and then separated by size using an electric current (the second dimension). In general, the second dimension is perpendicular to the first dimension. Because no two proteins with different sequences are identical on the basis of both size and charge, the result of 2D PAGE is a roughly square gel in which each protein occupies a unique spot. Analysis of the spots with chemical or antibody probes, or subsequent protein microsequencing can reveal the relative abundance of a given protein and the identity of the proteins in the sample.
Expression levels of a CaSNA can be determined by any method known in the art, including PCR and other nucleic acid methods, such as ligase chain reaction (LCR) and nucleic acid sequence based amplification (NASBA), can be used to detect malignant cells for diagnosis and monitoring of various malignancies. For example, reverse-transcriptase PCR (RT-PCR) is a powerful technique which can be used to detect the presence of a specific mRNA population in a complex mixture of thousands of other mRNA species. In RT-PCR, an mRNA species is first reverse transcribed to complementary DNA (cDNA) with use of the enzyme reverse transcriptase; the cDNA is then amplified as in a standard PCR reaction. Hybridization to specific DNA molecules (e.g., oligonucleotides) arrayed on a solid support can be used to both detect the expression of and quantitate the level of expression of one or more CaSNAs of interest. In this approach, all or a portion of one or more CaSNAs is fixed to a substrate. A sample of interest, which may comprise RNA, e.g., total RNA or polyA-selected mRNA, or a complementary DNA (cDNA) copy of the RNA is incubated with the solid support under conditions in which hybridization will occur between the DNA on the solid support and the nucleic acid molecules in the sample of interest. Hybridization between the substrate-bound DNA and the nucleic acid molecules in the sample can be detected and quantitated by several means, including, without limitation, radioactive labeling or fluorescent labeling of the nucleic acid molecule or a secondary molecule designed to detect the hybrid.
The above tests can be carried out on samples derived from a variety of cells, bodily fluids and/or tissue extracts such as homogenates or solubilized tissue obtained from a patient. Tissue extracts are obtained routinely from tissue biopsy and autopsy material. Bodily fluids useful in the present invention include blood, urine, saliva, peritoneal wash, lymphatic fluid, nipple aspirate, breast milk, mammary gland secretions or any other bodily secretion or derivative thereof. As used herein "blood" includes whole blood, plasma, serum, circulating epithelial cells, constituents, or any derivative of blood. In addition to detection in bodily fluids, the proteins and nucleic acids of the invention are suitable to detection by cell capture technology. Whole cells may be captured by a variety methods for example magnetic separation, U.S. Patent. Nos. 5,200,084; 5,186,827; 5,108,933; 4,925,788, the disclosures of which are incorporated herein by reference in their entireties. Epithelial cells may be captured using such products as Dynabeads® or CELLection™ (Dynal Biotech, Oslo, Norway). Alternatively, fractions of blood may be captured, e.g., the buffy coat fraction (50mm cells isolated from 5ml of blood) containing epithelial cells, hi addition, cancer cells may be captured using the techniques described in WO 00/47998, the disclosure of which is incorporated herein by reference in its entirety. Once the cells are captured or concentrated, the proteins or nucleic acids are detected by the means described in the subject application. Alternatively, nucleic acids may be captured directly from blood samples, see U.S. Patent Nos. 6,156,504, 5,501,963; or WO 01/42504, the disclosures of which are incorporated herein by reference in their entireties. hi a preferred embodiment, the specimen tested for expression of CaSNA or CaSP includes without limitation normal or cancerous breast, intestine, colon, lung, ovarian, prostate, lymph or bone marrow tissue; normal or cancerous breast, intestine, colon, lung, ovarian, prostate, lymph or bone marrow cells grown in cell culture; blood, serum, lymph node tissue, fecal samples, colonocytes, BAL, sputum and lymphatic fluid, hi another preferred embodiment, especially when metastasis of a primary breast cancer is known or suspected, specimens include, without limitation, tissues from brain, bone, bone marrow, liver, lungs, lymphatic system, colon, and adrenal glands. In general, the tissues may be sampled by biopsy, including, without limitation, needle biopsy, e.g., transthoracic needle aspiration, cervical mediatinoscopy, endoscopic lymph node biopsy, video-assisted thoracoscopy, exploratory thoracotomy, bone marrow biopsy and bone marrow aspiration.
All the methods of the present invention may optionally include determining the expression levels of one or more other cancer markers in addition to determining the expression level of a CaSNA or CaSP. hi many cases, the use of another cancer marker will decrease the likelihood of false positives or false negatives. In one embodiment, the one or more other cancer markers include other CaSNA or CaSPs as disclosed herein. Other cancer markers useful in the present invention will depend on the cancer being tested and are known to those of skill in the art. hi a preferred embodiment, at least one other cancer marker in addition to a particular CaSNA or CaSP is measured, hi a more preferred embodiment, at least two other additional cancer markers are used. In an even more preferred embodiment, at least three, more preferably at least five, even more preferably at least ten additional cancer markers are used.
Colonocytes represent an important source of the CaSP or CaSNAs because they provide a picture of the immediate past metabolic history of the GI tract of a subject. In addition, such cells are representative of the cell population from a statistically large sampling frame reflecting the state of the colonic mucosa along the entire length of the colon in a non-invasive manner, in contrast to a limited sampling by colonic biopsy using an invasive procedure involving endoscopy. Specific examples of patents describing the isolation of colonocytes include U.S. Patent Nos. 6,335,193; 6,020,137 5,741,650; 6,258,541; US 2001 0026925 Al; WO 00/63358 Al, the disclosures of which are incorporated herein by reference in their entireties.
For metastases of breast cancer in the prostate, the progress of therapy can be assessed by routine methods, usually by measuring serum PSA (prostate specific antigen) levels; the higher the level of PSA in the blood, the more extensive the cancer.
Commercial assays for detecting PSA are available, e.g, Hybitech Tandem-E and Tandem-R PSA assay kits, the Yang ProsCheck polyclonal assay (Yang Labs, Bellevue, WA), Abbott Imx (Abbott Labs, Abbott Park, IL), etc. Metastasis can be determined by staging tests and by bone scan and tests for calcium levels and other enzymes to determine spread to the bone, CT scans can also be done to look for spread to the pelvis and lymph nodes in the area. Chest X-rays and measurement of liver enzyme levels by known methods are used to look for metastasis to the lungs and liver, respectively. Other routine methods for monitoring the disease include transrectal ultrasonography (TRUS) and transrectal needle biopsy (TRNB). For bladder cancer, which is a more localized cancer, methods to determine progress of disease include urinary cytologic evaluation by cystoscopy, monitoring for presence of blood in the urine, visualization of the urothelial tract by sonography or an intravenous pyelogram, computed tomography (CT) and magnetic resonance imaging (MRI). The presence of distant metastases can be assessed by CT of the abdomen, chest x- rays, or radionuclide imaging of the skeleton.
Diagnosing
In one aspect, the invention provides a method for determining the expression levels and/or structural alterations of one or more CaSNA and/or CaSP in a sample from a patient suspected of having breast cancer. In general, the method comprises the steps of obtaining the sample from the patient, determining the expression level or structural alterations of a CaSNA and/or CaSP and then ascertaining whether the patient has breast cancer from the expression level of the CaSNA or CaSP. In general, if high expression relative to a control of a CaSNA or CaSP is indicative of breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times higher, and more preferably are at least two times higher, still more preferably five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. In contrast, if low expression relative to a control of a CaSNA or CaSP is indicative of breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times lower, and more preferably are at least two times lower, still more preferably five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. The normal human control may be from a different patient or from uninvolved tissue of the same patient.
In another aspect, the present invention provides a method of determining the expression levels and/or structural alteration of a plurality of CaSNAs and/or CaSPs in a sample from a patient suspected of having breast cancer. In general, the method comprises the steps of obtaining the sample from the patient, determining the expression level or structural alterations of the CaSNAs and/or CaSPs and then ascertaining whether the patient has breast cancer from the expression level of the CaSNAs or CaSPs. In general, if high expression relative to a control of a CaSNA or CaSP is indicative of breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times higher, and more preferably are at least two times higher, still more preferably five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. In contrast, if low expression relative to a control of a CaSNA or CaSP is indicative of breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times lower, and more preferably are at least two times lower, still more preferably five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. The normal human control may be from a different patient or from uninvolved tissue of the same patient.
The present invention also provides a method of determining whether breast cancer has metastasized in a patient. One may identify whether the breast cancer has metastasized by measuring the expression levels and/or structural alterations of one or more CaSNAs and/or CaSPs in a variety of tissues. The presence of a CaSNA or CaSP in a certain tissue at levels higher than that of corresponding noncancerous tissue (e.g., the same tissue from another individual) is indicative of metastasis if high level expression of a CaSNA or CaSP is associated with breast cancer. Similarly, the presence of a CaSNA or CaSP in a tissue at levels lower than that of corresponding noncancerous tissue is indicative of metastasis if low level expression of a CaSNA or CaSP is associated with breast cancer. Further, the presence of a structurally altered CaSNA or CaSP that is associated with breast cancer is also indicative of metastasis.
In general, if high expression relative to a control of a CaSNA or CaSP is indicative of metastasis, an assay for metastasis is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times higher, and more preferably are at least two times higher, still more preferably five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control. In contrast, if low expression relative to a control of a CaSNA or CaSP is indicative of metastasis, an assay for metastasis is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times lower, and more preferably are at least two times lower, still more preferably five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human control. Li another aspect, the present invention provides a method of determining whether breast cancer has metastasized in a patient based on the expression levels and/or structural alteration of a plurality of CaSNAs and/or CaSPs in a sample from the patient. In general, the method comprises the steps of obtaining the sample from the patient, determining the expression level or structural alterations of a CaSNAs and/or CaSPs and then ascertaining whether the patient has metastatic breast cancer from the expression level of the CaSNAs or CaSPs. hi general, if high expression relative to a control of a CaSNA or CaSP is indicative of metastatic breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times higher, and more preferably are at least two times higher, still more preferably five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. In contrast, if low expression relative to a control of a CaSNA or CaSP is indicative of metastatic breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times lower, and more preferably are at least two times lower, still more preferably five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. The normal human control may be from a different patient or from uninvolved tissue of the same patient. Staging
The invention also provides a method of staging breast cancer in a human patient. The method comprises identifying a human patient having breast cancer and analyzing cells, tissues or bodily fluids from such human patient for expression levels and/or structural alterations of one or more CaSNAs or CaSPs. First, one or more tumors from a variety of patients are staged according to procedures well known in the art, and the expression levels of one or more CaSNAs or CaSPs is determined for each stage to obtain a standard expression level for each CaSNA and CaSP. Then, the CaSNA or CaSP expression levels of the CaSNA or CaSP are determined in a biological sample from a patient whose stage of cancer is not known. The CaSNA or CaSP expression levels from the patient are then compared to the standard expression level. By comparing the expression level of the CaSNAs and CaSPs from the patient to the standard expression levels, one may determine the stage of the tumor. The same procedure may be followed using structural alterations of a CaSNA or CaSP to determine the stage of abreast cancer. In another aspect, the present invention provides a method of staging breast cancer in a patient based on the expression levels and/or structural alteration of a plurality of
CaSNAs and/or CaSPs in a sample from the patient. In general, the method comprises the steps of obtaining the sample from the patient, determining the expression level or structural alterations of a CaSNAs and/or CaSPs and then ascertaining the stage of the breast cancer from the expression level of the CaSNA or CaSP. In general, if high expression relative to a control of a CaSNA or CaSP is useful for staging breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times higher, and more preferably are at least two times higher, still more preferably five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. In contrast, if low expression relative to a control of a CaSNA or CaSP is useful for staging breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times lower, and more preferably are at least two times lower, still more preferably five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. The normal human control may be from a different patient or from uninvolved tissue of the same patient.
Monitoring Further provided is a method of monitoring breast cancer in a human patient. One may monitor a human patient to determine whether there has been metastasis and, if there has been, when metastasis began to occur. One may also monitor a human patient to determine whether a preneoplastic lesion has become cancerous. One may also monitor a human patient to determine whether a therapy, e.g., chemotherapy, radiotherapy or surgery, has decreased or eliminated the breast cancer. The monitoring may determine if there has been a reoccurrence and, if so, determine its nature. The method comprises identifying a human patient that one wants to monitor for breast cancer, periodically analyzing cells, tissues or bodily fluids from such human patient for expression levels of one or more CaSNAs or CaSPs, and comparing the CaSNA or CaSP levels over time to those CaSNA or CaSP expression levels obtained previously. Patients may also be monitored by measuring one or more structural alterations in a CaSNA or CaSP that are associated with breast cancer.
If increased expression of a CaSNA or CaSP is associated with metastasis, treatment failure, or conversion of a preneoplastic lesion to a cancerous lesion, then detecting an increase in the expression level of a CaSNA or CaSP indicates that the tumor is metastasizing, that treatment has failed or that the lesion is cancerous, respectively. One having ordinary skill in the art would recognize that if this were the case, then a decreased expression level would be indicative of no metastasis, effective therapy or failure to progress to a neoplastic lesion. If decreased expression of a CaSNA or CaSP is associated with metastasis, treatment failure, or conversion of a preneoplastic lesion to a cancerous lesion, then detecting a decrease in the expression level of a CaSNA or CaSP indicates that the tumor is metastasizing, that treatment has failed or that the lesion is cancerous, respectively. In a preferred embodiment, the levels of CaSNAs or CaSPs are determined from the same cell type, tissue or bodily fluid as prior patient samples. Monitoring a patient for onset of breast cancer metastasis is periodic and preferably is done on a quarterly basis, but may be done more or less frequently.
In another aspect, the present invention provides a method of monitoring breast cancer in a patient based on the expression levels and/or structural alteration of a plurality of CaSNAs and/or CaSPs in a sample from the patient. In general, the method comprises the steps of obtaining the sample from the patient, determining the expression level or structural alterations of a CaSNAs and/or CaSPs and then monitoring the breast cancer from the expression level of the CaSNA or CaSP. In general, if high expression relative to a control of a CaSNA or CaSP is useful for monitoring breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times higher, and more preferably are at least two times higher, still more preferably five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. In contrast, if low expression relative to a control of a CaSNA or CaSP is useful for monitoring breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times lower, and more preferably are at least two times lower, still more preferably five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. The normal human control may be from a different patient or from uninvolved tissue of the same patient.
The methods described herein can further be utilized as prognostic assays to identify subjects having or at risk of developing a disease or disorder associated with increased or decreased expression levels of a CaSNA and/or CaSP. The present invention provides a method in which a test sample is obtained from a human patient and one or more CaSNAs and/or CaSPs are detected. The presence of higher (or lower) CaSNA or CaSP levels as compared to normal human controls is diagnostic for the human patient being at risk for developing cancer, particularly breast cancer. The effectiveness of therapeutic agents to decrease (or increase) expression or activity of one or more CaSNAs and/or CaSPs of the invention can also be monitored by analyzing levels of expression of the CaSNAs and/or CaSPs in a human patient in clinical trials or in in vitro screening assays such as in human cells. In this way, the gene product expression pattern can serve as a marker, indicative of the physiological response of the human patient or cells, as the case may be, to the agent being tested.
Detection of Genetic Lesions or Mutations
The methods of the present invention can also be used to detect genetic lesions or mutations in a CaSG, thereby determining if a human with the genetic lesion is susceptible to developing breast cancer or to determine what genetic lesions are responsible, or are partly responsible, for a person's existing breast cancer. Genetic lesions can be detected, for example, by ascertaining the existence of a deletion, insertion and/or substitution of one or more nucleotides from the CaSGs of this invention, a chromosomal rearrangement of a CaSG, an aberrant modification of a CaSG (such as of the methylation pattern of the genomic DNA), or allelic loss of a CaSG. Methods to detect such lesions in the CaSG of this invention are known to those having ordinary skill in the art following the teachings of the specification.
Methods of Detecting Noncancerous Breast Diseases The present invention also provides methods for determining the expression levels and/or structural alterations of one or more CaSNAs and/or CaSPs in a sample from a patient suspected of having or known to have a noncancerous breast disease. In general, the method comprises the steps of obtaining a sample from the patient, determining the expression level or structural alterations of a CaSNA and/or CaSP, comparing the expression level or structural alteration of the CaSNA or CaSP to a normal breast control, and then ascertaining whether the patient has a noncancerous breast disease. In general, if high expression relative to a control of a CaSNA or CaSP is indicative of a particular noncancerous breast disease, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least two times higher, and more preferably are at least five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control, hi contrast, if low expression relative to a control of a CaSNA or CaSP is indicative of a noncancerous breast disease, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least two times lower, more preferably are at least five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human control. The normal human control may be from a different patient or from uninvolved tissue of the same patient. In another aspect, the present invention provides a method of detecting noncancerous breast diseases in a patient based on the expression levels and/or structural alteration of a plurality of CaSNAs and/or CaSPs in a sample from the patient. In general, the method comprises the steps of obtaining the sample from the patient, determining the expression level or structural alterations of a CaSNAs and/or CaSPs and then ascertaining whether the patient has a non-cancerous breast disease from the expression level of the CaSNA or CaSP. In general, if high expression relative to a control of a CaSNA or CaSP is useful for staging breast cancer, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times higher, and more preferably are at least two times higher, still more preferably five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. In contrast, if low expression relative to a control of a CaSNA or CaSP is useful for ascertaining whether the patient has a noncancerous breast disease, a diagnostic assay is considered positive if the level of expression of the CaSNA or CaSP is at least one and a half times lower, and more preferably are at least two times lower, still more preferably five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human or standard control. The normal human control may be from a different patient or from uninvolved tissue of the same patient. One having ordinary skill in the art may determine whether a CaSNA and/or CaSP is associated with a particular noncancerous breast disease by obtaining breast tissue from a patient having a noncancerous breast disease of interest and determining which CaSNAs and/or CaSPs are expressed in the tissue at either a higher or a lower level than in normal breast tissue. In another embodiment, one may determine whether a CaSNA or CaSP exhibits structural alterations in a particular noncancerous breast disease state by obtaining breast tissue from a patient having a noncancerous breast disease of interest and determining the structural alterations in one or more CaSNAs and/or CaSPs relative to normal breast tissue.
Methods for Identifying Breast Tissue In another aspect, the invention provides methods for identifying breast tissue.
These methods are particularly useful in, e.g., forensic science, breast cell differentiation and development, and in tissue engineering. In one embodiment, the invention provides a method for determining whether a sample is breast tissue or has breast tissue-like characteristics. The method comprises the steps of providing a sample suspected of comprising breast tissue or having breast tissue- like characteristics, determining whether the sample expresses one or more CaSNAs and/or CaSPs, and, if the sample expresses one or more CaSNAs and/or CaSPs, concluding that the sample comprises breast tissue. In a preferred embodiment, the CaSNA encodes a polypeptide having an amino acid sequence selected from the gene products of Table 2a and Table 2b, or a homolog, allelic variant or fragment thereof. In a more preferred embodiment, the CaSNA has a nucleotide sequence selected from the gene products of Table 2a, Table 2b or Table 7, or a hybridizing nucleic acid, an allelic variant or a part thereof. Determining whether a sample expresses a CaSNA can be accomplished by any method known in the art. Preferred methods include hybridization to microarrays, Northern blot hybridization, and quantitative or qualitative RT-PCR. In another preferred embodiment, the method can be practiced by determining whether a CaSP is expressed. Determining whether a sample expresses a CaSP can be accomplished by any method known in the art. Preferred methods include Western blot, ELISA, RIA and 2D PAGE. In one embodiment, the CaSP has an amino acid sequence selected from the gene products of Table 2a and Table 2b, or a homolog, allelic variant or fragment thereof. In another preferred embodiment, the expression of at least two CaSNAs and/or CaSPs is determined. m a more preferred embodiment, the expression of at least three, more preferably four and even more preferably five CaSNAs and/or CaSPs are determined.
In one embodiment, the method can be used to determine whether an unknown tissue is breast tissue. This is particularly useful in forensic science, in which small, damaged pieces of tissues that are not identifiable by microscopic or other means are recovered from a crime or accident scene. In another embodiment, the method can be used to determine whether a tissue is differentiating or developing into breast tissue. This is important in monitoring the effects of the addition of various agents to cell or tissue culture, e.g., in producing new breast tissue by tissue engineering. These agents include, e.g., growth and differentiation factors, extracellular matrix proteins and culture medium. Other factors that may be measured for effects on tissue development and differentiation include gene transfer into the cells or tissues, alterations inpH, aqueous: air interface and various other culture conditions. Methods for Producing and Modifying Breast Tissue
In another aspect, the invention provides methods for producing engineered breast tissue or cells. In one embodiment, the method comprises the steps of providing cells, introducing a CaSNA or a CaSG into the cells, and growing the cells under conditions in which they exhibit one or more properties of breast tissue cells. In a preferred embodiment, the cells are pleuripotent. As is well known in the art, normal breast tissue comprises a large number of different cell types. Thus, in one embodiment, the engineered breast tissue or cells comprises one of these cell types. In another embodiment, the engineered breast tissue or cells comprises more than one breast cell type. Further, the culture conditions of the cells or tissue may require manipulation in order to achieve full differentiation and development of the breast cell tissue. Methods for manipulating culture conditions are well known in the art.
Nucleic acid molecules encoding one or more CaSPs are introduced into cells, preferably pleuripotent cells. In a preferred embodiment, the nucleic acid molecules encode CaSPs having amino acid sequences selected from the gene products of Table 2a and Table 2b, or homologous proteins, analogs, allelic variants or fragments thereof. In a more preferred embodiment, the nucleic acid molecules have a nucleotide sequence selected from the gene products of Table 2a, Table 2b or Table 7, or hybridizing nucleic acids, allelic variants or parts thereof. In another highly preferred embodiment, a CaSG is introduced into the cells. Expression vectors and methods of introducing nucleic acid molecules into cells are well known in the art and are described in detail, supra.
Artificial breast tissue may be used to treat patients who have lost some or all of their breast function.
Pharmaceutical Compositions In another aspect, the invention provides pharmaceutical compositions comprising the nucleic acid molecules, polypeptides, fusion proteins, antibodies, antibody derivatives, antibody fragments, agonists, antagonists, or inhibitors of the present invention. In a preferred embodiment, the pharmaceutical composition comprises a CaSNA or part thereof. In a preferred embodiment, the pharmaceutical composition comprises a plurality of CaSNAs or parts thereof. In a more preferred embodiment, the CaSNA has a nucleotide sequence selected from the group consisting of the gene products of Table 2a, Table 2b or Table 7, a nucleic acid that hybridizes thereto, an allelic variant thereof, or a nucleic acid that has substantial sequence identity thereto. In another preferred embodiment, the pharmaceutical composition comprises a CaSP or fragment thereof. In a preferred embodiment, the pharmaceutical composition comprises a plurality of CaSPs or fragments thereof. In a more preferred embodiment, the pharmaceutical composition comprises a CaSP having an amino acid sequence that is selected from the group consisting of the gene products of Table 2a and Table 2b, a polypeptide that is homologous thereto, a fusion protein comprising all or a portion of the polypeptide, or an analog or derivative thereof. In another preferred embodiment, the pharmaceutical composition comprises an anti-CaSP antibody, preferably an antibody that specifically binds to a CaSP having an amino acid sequence that is selected from the group consisting of the gene products of Table 2a and Table 2b, or an antibody that binds to a polypeptide that is homologous thereto, a fusion protein comprising all or a portion of the polypeptide, or an analog, isoform, allelic variant or derivative thereof. In another preferred embodiment, the pharmaceutical composition comprises a plurality of anti-CaSP antibodies, preferably antibodies that specifically bind to a CaSPs having an amino acid sequences that are selected from the group consisting of the gene products of Table 2a and Table 2b, or antibodies that bind to polypeptides that are homologous thereto, fusion proteins comprising all or a portion of the polypeptides, or analogs, iso forms, allelic variants or derivatives thereof. . hi another preferred embodiment, the pharmaceutical composition comprises a plurality of CaSP agonist molecules, preferably agonist molecules that are agonistic to CaSPs having an amino acid sequences that are selected from the group consisting of the gene products of Table 2a and Table 2b, or agonists that are agonistic to polypeptides that are homologous thereto, fusion proteins comprising all or a portion of the polypeptides, or analogs, isoforms, allelic variants or derivatives thereof. . In another preferred embodiment, the pharmaceutical composition comprises a plurality of CaSP antagonist molecules, preferably antagonist molecules that are antagonistic to CaSPs having an amino acid sequences that are selected from the group consisting of the gene products of Table 2a and Table 2b, or antagonists that are antagonistic to polypeptides that are homologous thereto, fusion proteins comprising all or a portion of the polypeptides, or analogs, isoforms, allelic variants or derivatives thereof. In another preferred embodiment, the pharmaceutical composition comprises a plurality of CaSP antagonist and agonist molecules, preferably antagonist and agonist molecules that are antagonistic and agonistic to CaSPs having an amino acid sequences that are selected from the group consisting of the gene products of Table 2a and Table 2b, or antagonists and agonists that are antagonistic or agonistic to polypeptides that are homologous thereto, fusion proteins comprising all or a portion of the polypeptides, or analogs, isoforms, allelic variants or derivatives thereof. Due to the association of angiogenesis with cancer vascularization there is great need of new markers and methods for diagnosing angiogenesis activity to identify developing tumors and angiogenesis related diseases. Furthermore, great need is also present for new molecular targets useful in the treatment of angiogenesis and angiogenesis related diseases such as cancer. In addition known modulators of angiogenesis such as endostatin or vascular endothelial growth factor (VEGF). Use of the methods and compositions disclosed herein in combination with anti-angiogenesis drugs, drugs that block the matrix breakdown (such as BMS-275291, Dalteparin (Fragmin®), Suramin), drugs that inhibit endothelial cells (2-methoxyestradiol (2-ME), CC-5013 (Thalidomide Analog), Combretastatin A4 Phosphate, LY317615 (Protein Kinase C Beta Inhibitor), Soy Isoflavone (Genistein; Soy Protein Isolate), Thalidomide), drugs that block activators of angiogenesis (AE-941 (Neovastat™; GW786034), Anti-VEGF Antibody (Bevacizumab; Avastin™), Interferon-alpha, PTK787/ZK 222584, VEGF-Trap, ZD6474), drugs that inhibit endothelial-specific integrin/survival signaling (EMD 12191 A, Anti-Anb3 Megrin Antibody (Medi-522; Vitaxin™)). Such a composition typically contains from about 0.1 to 90% by weight of a therapeutic agent of the invention formulated in and/or with a pharmaceutically acceptable carrier or excipient.
Pharmaceutical formulation is a well-established art that is further described in Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th ed., Lippincott, Williams & Wilkins (2000); Ansel et al, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippincott Williams & Wilkins (1999); and Kibbe (ed.), Handbook of Pharmaceutical Excipients American Pharmaceutical Association, 3rd ed. (2000) and thus need not be described in detail herein.
Briefly, formulation of the pharmaceutical compositions of the present invention will depend upon the route chosen for administration. The pharmaceutical compositions utilized in this invention can be administered by various routes including both enteral and parenteral routes, including oral, intravenous, intramuscular, subcutaneous, inhalation, topical, sublingual, rectal, intra-arterial, intramedullary, intrathecal, intraventricular, transmucosal, transdermal, intranasal, intraperitoneal, intrapulmonary, and intrauterine.
Oral dosage forms can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient. Solid formulations of the compositions for oral administration can contain suitable carriers or excipients, such as carbohydrate or protein fillers; sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose, such as methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or microcrystalline cellulose; gums including arabic and tragacanth; proteins such as gelatin and collagen; inorganics, such as kaolin, calcium carbonate, dicalcium phosphate, sodium chloride; and other agents such as acacia and alginic acid.
Agents that facilitate disintegration and/or solubilization can be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate, microcrystalline cellulose, cornstarch, sodium starch glycolate, and alginic acid.
Tablet binders that can be used include acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone™), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.
Lubricants that can be used include magnesium stearates, stearic acid, silicone fluid, talc, waxes, oils, and colloidal silica.
Fillers, agents that facilitate disintegration and/or solubilization, tablet binders and lubricants, including the aforementioned, can be used singly or in combination.
Solid oral dosage forms need not be uniform throughout. For example, dragee cores can be used in conjunction with suitable coatings, such as concentrated sugar solutions, which can also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
Oral dosage forms of the present invention include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating, such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with a filler or binders, such as lactose or starches, lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid, or liquid polyethylene glycol with or without stabilizers.
Additionally, dyestuffs or pigments can be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound, i.e., dosage. Liquid formulations of the pharmaceutical compositions for oral (enteral) administration are prepared in water or other aqueous vehicles and can contain various suspending agents such as methylcellulose, alginates, tragacanth, pectin, kelgin, carrageenan, acacia, polyvinylpyrrolidone, and polyvinyl alcohol. The liquid formulations can also include solutions, emulsions, syrups and elixirs containing, together with the active compound(s), wetting agents, sweeteners, and coloring and flavoring agents.
The pharmaceutical compositions of the present invention can also be formulated for parenteral administration. Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions.
For intravenous injection, water soluble versions of the compounds of the present invention are formulated in, or if provided as a lyophilate, mixed with, a physiologically acceptable fluid vehicle, such as 5% dextrose ("D5"), physiologically buffered saline, 0.9% saline, Hanks' solution, or Ringer's solution. Intravenous formulations may include carriers, excipients or stabilizers including, without limitation, calcium, human serum albumin, citrate, acetate, calcium chloride, carbonate, and other salts. Intramuscular preparations, e.g. a sterile formulation of a suitable soluble salt form of the compounds of the present invention, can be dissolved and administered in a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5% glucose solution. Alternatively, a suitable insoluble form of the compound can be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, such as an ester of a long chain fatty acid {e.g., ethyl oleate), fatty oils such as sesame oil, triglycerides, or liposomes.
Parenteral formulations of the compositions can contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like).
Aqueous injection suspensions can also contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Non-lipid polycationic amino polymers can also be used for delivery. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Pharmaceutical compositions of the present invention can also be formulated to permit injectable, long-term, deposition. Injectable depot forms may be made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in microemulsions that are compatible with body tissues.
The pharmaceutical compositions of the present invention can be administered topically. For topical use the compounds of the present invention can also be prepared in suitable forms to be applied to the skin, or mucus membranes of the nose and throat, and can take the form of lotions, creams, ointments, liquid sprays or inhalants, drops, tinctures, lozenges, or throat paints. Such topical formulations further can include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient. In other transdermal formulations, typically in patch-delivered formulations, the pharmaceutically active compound is formulated with one or more skin penetrants, such as 2-N-methyl-pyrrolidone (NMP) or Azone. A topical semi-solid ointment formulation typically contains a concentration of the active ingredient from about 1 to 20%, e.g., 5 to 10%, in a carrier such as a pharmaceutical cream base.
For application to the eyes or ears, the compounds of the present invention can be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders. For rectal administration the compounds of the present invention can be administered in the form of suppositories admixed with conventional carriers such as cocoa butter, wax or other glyceride.
Inhalation formulations can also readily be formulated. For inhalation, various powder and liquid formulations can be prepared. For aerosol preparations, a sterile formulation of the compound or salt form of the compound may be used in inhalers, such as metered dose inhalers, and nebulizers. Aerosolized forms may be especially useful for treating respiratory disorders. Alternatively, the compounds of the present invention can be in powder form for reconstitution in the appropriate pharmaceutically acceptable carrier at the time of delivery.
The pharmaceutically active compound in the pharmaceutical compositions of the present invention can be provided as the salt of a variety of acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, and succinic acid. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
After pharmaceutical compositions have been prepared, they are packaged in an appropriate container and labeled for treatment of an indicated condition.
The active compound will be present in an amount effective to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.
A "therapeutically effective dose" refers to that amount of active ingredient, for example CaSP polypeptide, fusion protein, or fragments thereof, antibodies specific for CaSP, agonists, antagonists or inhibitors of CaSP, which ameliorates the signs or symptoms of the disease or prevent progression thereof; as would be understood in the medical arts, cure, although desired, is not required.
The therapeutically effective dose of the pharmaceutical agents of the present invention can be estimated initially by in vitro tests, such as cell culture assays, followed by assay in model animals, usually mice, rats, rabbits, dogs, or pigs. The animal model can also be used to determine an initial preferred concentration range and route of administration.
For example, the ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population) can be determined in one or more cell culture of animal model systems. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred.
The data obtained from cell culture assays and animal studies are used in formulating an initial dosage range for human use, and preferably provide a range of circulating concentrations that includes the ED50 with little or no toxicity. After administration, or between successive administrations, the circulating concentration of active agent varies within this range depending upon pharmacokinetic factors well known in the art, such as the dosage form employed, sensitivity of the patient, and the route of administration.
The exact dosage will be determined by the practitioner, in light of factors specific to the subject requiring treatment. Factors that can be taken into account by the practitioner include the severity of the disease state, general health of the subject, age, weight, gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. Normal dosage amounts may vary from 0.1 to 100,000 micrograms, up to a total dose of about 1 g, depending upon the route of administration. Where the therapeutic agent is a protein or antibody of the present invention, the therapeutic protein or antibody agent typically is administered at a daily dosage of 0.01 mg to 30 mg/kg of body weight of the patient (e.g., lmg/kg to 5 mg/kg). The pharmaceutical formulation can be administered in multiple doses per day, if desired, to achieve the total desired daily dose.
Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art. Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.
Conventional methods, known to those of ordinary skill in the art of medicine, can be used to administer the pharmaceutical formulation(s) of the present invention to the patient. The pharmaceutical compositions of the present invention can be administered alone, or in combination with other therapeutic agents or interventions. Therapeutic Methods
The present invention further provides methods of treating subjects having defects in a gene of the invention, e.g., in expression, activity, distribution, localization, and/or solubility, which can manifest as a disorder of breast function. As used herein, "treating" includes all medically-acceptable types of therapeutic intervention, including palliation and prophylaxis (prevention) of disease. The term "treating" encompasses any improvement of a disease, including minor improvements. These methods are discussed below. Gene Therapy and Vaccines
The isolated nucleic acids of the present invention can also be used to drive in vivo expression of the polypeptides of the present invention. In vivo expression can be driven from a vector, typically a viral vector, often a vector based upon a replication incompetent retrovirus, an adenovirus, or an adeno-associated virus (AAV), for the purpose of gene therapy. In vivo expression can also be driven from signals endogenous to the nucleic acid or from a vector, often a plasmid vector, such as pVAXl (fnvitrogen, Carlsbad, CA, USA), for purpose of "naked" nucleic acid vaccination, as further described in U.S. Patent Nos. 5,589,466; 5,679,647; 5,804,566; 5,830,877; 5,843,913; 5,880,104; 5,958,891; 5,985,847; 6,017,897; 6,110,898; 6,204,250, the disclosures of which are incorporated herein by reference in their entireties. For cancer therapy, it is preferred that the vector also be tumor-selective. See, e.g., Doronin et al, J. Virol. 75: 3314-24 (2001).
In another embodiment of the therapeutic methods of the present invention, a therapeutically effective amount of a pharmaceutical composition comprising a nucleic acid molecule of the present invention is administered. The nucleic acid molecule can be delivered in a vector that drives expression of a CaSP, fusion protein, or fragment thereof, or without such vector. Nucleic acid compositions that can drive expression of a CaSP are administered, for example, to complement a deficiency in the native CaSP, or as DNA vaccines. Expression vectors derived from virus, replication deficient retroviruses, adenovirus, adeno-associated (AAV) virus, herpes virus, or vaccinia virus can be used as plasmids. See, e.g., Cid-Arregui, supra. In a preferred embodiment, the nucleic acid molecule encodes a CaSP having the amino acid sequence of the gene products of Table 2a and Table 2b, or a fragment, fusion protein, allelic variant or homolog thereof, hi still other therapeutic methods of the present invention, pharmaceutical compositions comprising host cells that express a CaSP, fusions, or fragments thereof can be administered, hi such cases, the cells are typically autologous, so as to circumvent xenogeneic or allotypic rejection, and are administered to complement defects in CaSP production or activity. In a preferred embodiment, the nucleic acid molecules in the cells encode a CaSP having the amino acid sequence of the gene products of Table 2a and Table 2b, or a fragment, fusion protein, allelic variant or homolog thereof. Antisense Administration
Antisense nucleic acid compositions, or vectors that drive expression of a CaSG antisense nucleic acid, are administered to downregulate transcription and/or translation of a CaSG in circumstances in which excessive production, or production of aberrant protein, is the pathophysiologic basis of disease.
Antisense compositions useful in therapy can have a sequence that is complementary to coding or to noncoding regions of a CaSG. For example, oligonucleotides derived from the transcription initiation site, e.g., between positions -10 and +10 from the start site, are preferred. Catalytic antisense compositions, such as ribozymes, that are capable of sequence-specific hybridization to CaSG transcripts, are also useful in therapy. See, e.g., Phylactou, Adv. DrugDeliv. Rev. 44(2-3): 97-108 (2000); Phylactou et al, Hum. MoI. Genet. 7(10): 1649-53 (1998); Rossi, Ciba Found. Symp. 209: 195-204 (1997); and Sigurdsson et al, Trends Biotechnol. 13(8): 286-9 (1995). Other nucleic acids useful in the therapeutic methods of the present invention are those that are capable of triplex helix formation in or near the CaSG genomic locus. Such triplexing oligonucleotides are able to inhibit transcription. See, e.g., Intody et al, Nucleic Acids Res. 28(21): 4283-90 (2000); and McGuffie et α/., Cancer Res. 60(14): 3790-9 (2000). Pharmaceutical compositions comprising such triplex forming oligos (TFOs) are administered in circumstances in which excessive production, or production of aberrant protein, is a pathophysiologic basis of disease.
In a preferred embodiment, the antisense molecule is derived from a nucleic acid molecule encoding a CaSP, preferably a CaSP comprising an amino acid sequence of the gene products of Table 2a and Table 2b, or a fragment, allelic variant or homolog thereof. In a more preferred embodiment, the antisense molecule is derived from a nucleic acid molecule having a nucleotide sequence of the gene products of Table 2a, Table 2b or Table 7, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.
Polypeptide Administration
In one embodiment of the therapeutic methods of the present invention, a therapeutically effective amount of a pharmaceutical composition comprising a CaSP, a fusion protein, fragment, analog or derivative thereof is administered to a subject with a clinically-significant CaSP defect. Protein compositions are administered, for example, to complement a deficiency in native CaSP. In other embodiments, protein compositions are administered as a vaccine to elicit a humoral and/or cellular immune response to CaSP. The immune response can be used to modulate activity of CaSP or, depending on the immunogen, to immunize against aberrant or aberrantly expressed forms, such as mutant or inappropriately expressed isoforms. In yet other embodiments, protein fusions having a toxic moiety are administered to ablate cells that aberrantly accumulate CaSP. hi a preferred embodiment, the polypeptide administered is a CaSP comprising an amino acid sequence of the gene products of Table 2a and Table 2b, or a fusion protein, allelic variant, homo log, analog or derivative thereof. In a more preferred embodiment, the polypeptide is encoded by a nucleic acid molecule having a nucleotide sequence of the gene products of Table 2a, Table 2b or Table 7, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.
Antibody, Agonist and Antagonist Administration hi another embodiment of the therapeutic methods of the present invention, a therapeutically effective amount of a pharmaceutical composition comprising an antibody (including a fragment or derivative thereof) of the present invention is administered. As is well known, antibody compositions are administered, for example, to antagonize activity of CaSP, or to target therapeutic agents to sites of CaSP presence and/or accumulation. In a preferred embodiment, the antibody specifically binds to a CaSP comprising an amino acid sequence of the gene products of Table 2a and Table 2b, or a fusion protein, allelic variant, homolog, analog or derivative thereof, hi a more preferred embodiment, the antibody specifically binds to a CaSP encoded by a nucleic acid molecule having a nucleotide sequence of the gene products of Table 2a, Table 2b or Table 7, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.
The present invention also provides methods for identifying modulators which bind to a CaSP or have a modulatory effect on the expression or activity of a CaSP. Modulators which decrease the expression or activity of CaSP (antagonists) are believed to be useful in treating breast cancer. Such screening assays are known to those of skill in the art and include, without limitation, cell-based assays and cell-free assays. Small molecules predicted via computer imaging to specifically bind to regions of a CaSP can also be designed, synthesized and tested for use in the imaging and treatment of breast cancer. Further, libraries of molecules can be screened for potential anticancer agents by assessing the ability of the molecule to bind to the CaSPs identified herein. Molecules identified in the library as being capable of binding to a CaSP are key candidates for further evaluation for use in the treatment of breast cancer. In a preferred embodiment, these molecules will downregulate expression and/or activity of a CaSP in cells. In another embodiment of the therapeutic methods of the present invention, a pharmaceutical composition comprising a non-antibody antagonist of CaSP is administered. Antagonists of CaSP can be produced using methods generally known in the art. In particular, purified CaSP can be used to screen libraries of pharmaceutical agents, often combinatorial libraries of small molecules, to identify those that specifically bind and antagonize at least one activity of a CaSP.
In other embodiments a pharmaceutical composition comprising an agonist of a CaSP is administered. Agonists can be identified using methods analogous to those used to identify antagonists.
In a preferred embodiment, the antagonist or agonist specifically binds to and antagonizes or agonizes, respectively, a CaSP comprising an amino acid sequence of the gene products of Table 2a and Table 2b, or a fusion protein, allelic variant, homolog, analog or derivative thereof. In a more preferred embodiment, the antagonist or agonist specifically binds to and antagonizes or agonizes, respectively, a CaSP encoded by a nucleic acid molecule having a nucleotide sequence of the gene products of Table 2a, Table 2b or Table 7, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.
Targeting Breast Tissue
The invention also provides a method in which a polypeptide of the invention, or an antibody thereto, is linked to a therapeutic agent such that it can be delivered to the breast, intestine, colon, lung, ovarian or prostate; or to specific cells in the breast, colon, lung, ovarian or prostate; or metastatic breast cancer cells in lymphatic tissues, bone and bone marrow. In a preferred embodiment, an anti-CaSP antibody is linked to a therapeutic agent and is administered to a patient in need of such therapeutic agent. The therapeutic agent may be a toxin, if breast tissue needs to be selectively destroyed. This is useful for targeting and killing local or metastatic breast cancer cells. In another embodiment, the therapeutic agent may be a growth or differentiation factor, which is useful for promoting breast cell function. In another embodiment, an anti-CaSP antibody may be linked to an imaging agent that can be detected using, e.g., magnetic resonance imaging, CT or PET. This would be useful for determining and monitoring breast function, identifying local and metastasized breast cancer tumors, and identifying non-cancerous breast diseases.
Example Ia: Differentially Expressed Gene Products in Breast Cancer
For the detection of cancer or stratification of individuals into groups predicted to have different disease outcomes, the expression levels of gene products were determined. Genes were selected based on individual expression profiles and functional relevance of the encoded protein as described by gene ontology and the literature. Genes within the functionally relevant groups below are likely to be useful for (1) detection of cancer, (2) stratification of individuals into groups predicted to have different disease outcomes; (3) selection of individuals for a particular therapeutic intervention; or (4) identification of individuals responding to a therapeutic regimen. Table 1
Cell adhesion
Estrogen receptor signaling pathway
Regulation of transcription
Ubiquitination
DNA repair
Estrogen metabolism
Chemotaxis
G-protein couple receptor
Cell recognition
Anti-apoptosis
A gene product associated with one or more of the functional categories above will be particularly useful if it has one or more of the following properties: structural and/or physical, chemical or enzymatic, regulatory, signal transduction, or ligand, receptor or substrate binding, hi addition, genes or gene products directly involved in the sequential and organ specific development of cancer are of interest.
Based on the criteria above, we identified a set of genes and associated gene products. Table 2a and Table 2b below provide a summary of these genes including: the GenBank Accessions (ncbi with the extension .nhn.nih.gov of the world wide web), the abbreviated common name for the genes, internal identifiers, functional association(s) for the gene product and annotation of the gene from public databases (e.g. GenBank).
In addition, Table 3 below contains the GenBank Accession, the chromosomal location of the gene (with amplification or loss of homology annotation), Gene Ontology (GO) ID / classifications including: Cellular Component Ontology, Molecular Function Ontology and Biological Process Ontology. Also included is a description of gene product function derived from the literature. References supporting GO and functional annotations of the GenBank Accession in Table 3 are available in public databases such as GenBank and Swissprot.
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Genes within a region know to be amplified in cancer are indicated by (Amp) next to the chromosomal location;
Genes within a region know to have loss of heterozygosity (LOH) in cancer are indicated by (LOH) next to the chromosomal location;
NA = not available
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In addition, 13 genes were selected for use as endogenous controls. Endogenous control candidates were selected from among those well-known in the literature as commonly constitutively expressed gene products across a wide range of tissues and biological conditions. See Kok, JB et at, Lab Invest. 2005 Jan;85(l): 154-9 ; and Janssens, N., et ah, MoI. Diagn. 2004;8(2): 107-13 which are hereby incorporated by reference in their entirety. Table 4: Endogenous controls.
The ATP6 CDS is located at nucleotides [7941..8621] of D38112.1 "Homo sapiens mitochondrial DNA, complete sequence"
Individuals and Sample Sets
Expression of gene products may be evaluated in primary tissues and/or lymph nodes; and alternatively in primary tissue and/or bone marrow samples. Additionally, expressions of gene products are evaluated in blood samples. In addition, primary tissues, lymph nodes, bone marrow and blood may be used in combination.
Samples were collect retrospectively for individuals with primary or metastatic breast cancer. Gene product expression profiles were evaluated on archival paraffin- preserved primary tissue from individuals who had metastatic breast cancer. As a control, primary tissues from individuals with no metastasis were evaluated.
In the studies above, both positive and negative groups of individuals have a minimum of 5-10 years follow-up information to evaluate the relation of gene product expression to disease outcome. Both groups have a representation of individuals with good outcome (no disease progression) 5-8 years after surgery, and poor outcome with disease progression (either metastatic disease or local recurrence) within 5 years of surgery. Clinical information for all individuals is reported in an extensive Case Report Form (CRF) containing at least the following clinical information summarized in Tables 5 and 6 below: Individual ID; Demographics (Age and Menopausal Status); Lymph Node status; Estrogen Receptor status; Progesterone Receptor status; HER2 status; DNA ploidy; Clinical TNM Staging based on the modified AJCC/UICC TNM classification per CAP protocol (revision Jan 2004); Histopathological Type; Pathological and/or Nuclear Grade (Modified Bloom Richardson score); Pathological staging, pT size (Pathologic tumor size, size of the invasive component) based on the modified AJCC/UICC TNM classification per CAP protocol (revision Jan 2004); Treatment summary (date and type of surgery, chemotherapy received, radiotherapy received) and Clinical Outcome (date of evaluation, vitality at date of evaluation, disease progression status, months of disease free survival at date of evaluation and disease progression information). Additionally, the percentage of cells that are cancerous (Turn %) in the sample used for diagnosis and subsequent analysis is included.
Furthermore, when applicable, clinical information includes the percentage of cancerous cells per sample used for analysis.
NA= information not available
Age is at time of diagnosis
For Ploidy: D= Diploid, T = Tetraploid, A = Aneuploid
For Histopathological Type: Inv = Invasive, IS = In Situ
For Pathological Grade: GX = Cannot be graded, G1 = Score 3-5, G2 = Score 6-7, G3 = Score 8-9
NA= information not available.
For Type of Surgery: S = Simple Mastectomy with axillary clearance, L = Lumpectomy with axillary clearance, M = Modified radical mastectomy, O = Other (specify in comment). For Neo-adjuvant Chemotherapy (ChemoRx NA): C = cyclophosphamide, A = Adriamycin (doxorubicin), F = 5FU, E = epirubicin, M = methotrexate, D = docetaxel, P = paclitaxel, H = Herceptin (trastuzumab), G = gemcitabine, X = Xeloda (capecitabline), O = Others (specify in comment), Y = received treatment but regimen unknown, N = did not receive treatment. For Adjuvant Chemotherapy (ChemoRx Adj): C = cyclophosphamide, A = Adriamycin (doxorubicin), F = 5FU, E = epirubicin, M = methotrexate, D = docetaxel, P = paclitaxel, H = Herceptin (trastuzumab), G = gemcitabine, X = Xeloda (capecitabline), O = Others (specify in comment), Y = received treatment but regimen unknown, N = did not receive treatment. For Metastatic Chemotherapy (ChemoRx Met): C = cyclophosphamide, A = Adriamycin (doxorubicin), F = 5FU, E = epirubicin, M = methotrexate, D = docetaxel, P = paclitaxel, H = Herceptin (trastuzumab), G = gemcitabine, X = Xeloda (capecitabine), Ci=Cisplatin, O = Others (specify in comment), Y = received treatment but regimen unknown, NM = Not meaningful, N= Did not receive treatment. For Hormone Therapy (ChemoRx HT): HT+ = Received treatment, HT- = Did not receive treatment.
For Neo-adjuvant Radiotherapy (RadioRx NA): RT+ = received treatment, RT- = did not receive treatment. For Adjuvant Radiotherapy (RadioRx Adj): RT+ = received treatment, RT- = did not receive treatment.
For Clinical Outcome (as of date of assessment): DF = Disease-free, PD = Progressive disease Disease Free Survival (DFS) in months (at date of assessment): NM = Not meaningful (in event of disease progression), NK = Information not available.
For Progression Details (Progression, Desc): LR = Local recurrence, CLD = Contra-lateral disease, DM = Distant metastasis, O = Others, NM = Not meaningful (no Disease Progression). For Time to Progression in months (Progression, TTP) Relevant only in case of disease progression: NM = Not meaningful.
Differential expression of gene products from Tables 2a and 2b above identifies individuals with good outcome (disease free survival, DF, as no disease progression) and poor outcome with disease progression (progressive disease, PD, as either metastatic disease or local recurrence).
Example Ib: Prognosis Based on Gene Product Expression in Primary Tissue
Primary Tissue Samples
As described above, the prognosis of individuals with breast cancer was determined based on gene product expression. Primary tissues from 45 individuals were evaluated for determining good or poor prognosis based on differential gene expression. The 20 individuals evaluated are ID numbers: 34, 50, 81, 173, 238, 277, 556, 952, 983, 1009, 1105, 1109, 1221, 1222, 1265, 1275, 1277, 1279, 1280, 1281, 1282, 1283, 1286, 1298, 1319, 1321, 1322, 1325, 1376, 1377, 1379, 1386, 1399, 1464, 1469, 1475, 1499, 1502, 1504, 1561, 1642, 1683, 1846, 1904 and 1905 which are characterized in tables 5 and 6 above. The results of the differential gene product expression analysis from the samples from these individuals are described below.
Example 2: Relative Quantitation of Gene Expression
Blood or Formalin Fixed Paraffin Embedded (FFPE) histological samples from the individuals described above were analyzed for gene expression by QPCR methodologies known to those of skill in the art, as exemplified below. FFPE Samples
Specifically, one FFPE block from a primary tumor resection from each individual was selected based on maximal tumor content. A narrow tumor content range was used to minimize the effects of the presence of non-cancer cells on the expression profile. Tumor content range is expected to be between 60 to 80 % of cancer cells based on the characteristics of the samples in the sample bank.
Total RNA was extracted from two whole 20 micron sections from each FFPE block or from macro-dissected material. A total of 3-4 RNA samples from breast tissue from normal individuals and 3-4 total RNA samples from normal adjacent tissues (NAT) from pathologically normal breast tissues adjacent to a tumor from an individual with breast cancer were tested to obtain a baseline level of expression for each of the gene products tested. Prior to RNA extraction, paraffin was removed from samples by a deparaffinization step consisting of a xylene extraction followed by an ethanol wash. Kits for the extraction of RNA from FFPE samples such as the Optimun™ FFPE RNA Isolation Kit (Catalog # 47000) from Ambion® Diagnostics (Austin, TX) are commercially available. Additionally, methodologies for processing FFPE samples are known to those of skill in the art, see Cronin et al. American Journal of Pathology, January 2004, Vol. 164, No. 1, pages 35-42. AU measurements of gene products were normalized against endogenous controls.
TaqMan™ Gene Expression Profiling;
Removal of contaminating genomic DNA, quantitation of total RNA, measurements of residual genomic DNA contamination and preparation of cDNA by reverse transcription was performed prior to TaqMan™ gene expression profiling. TaqMan™ gene expression was performed on targets selected from Table 2 above.
Real-Time quantitative PCR with fluorescent Taqman® probes is a quantitation detection system utilizing the 5'- 3' nuclease activity of Taq DNA polymerase. The method uses an internal fluorescent oligonucleotide probe (Taqman®) labeled with a 5' reporter dye and a downstream, 3' quencher dye. During PCR, the 5'-3' nuclease activity of Taq DNA polymerase releases the reporter, whose fluorescence can then be detected by the laser detector of a Realtime Quantitative PCR machine such as the Model 7000, 7700 or 7900 Sequence Detection System from PE Applied Biosystems (Foster City, CA, USA). Amplification of an endogenous control(s) is used to standardize the amount of sample RNA added to the reaction and normalize for Reverse Transcriptase (RT) efficiency. Gene products from Table 4 above were used as endogenous control(s).
To calculate relative quantitation between all the samples studied, the target RNA levels for one sample can be used as the basis for comparative results (calibrator). Quantitation relative to the "calibrator" can be obtained using the comparative method (User Bulletin #2: ABI PRISM 7700 Sequence Detection System).
The tissue distribution and the level of the target gene are evaluated for every sample in normal and cancer tissues. Total RNA is extracted from normal tissues, cancer tissues, and from cancers and the corresponding matched adjacent tissues. Subsequently, first strand cDNA is prepared with reverse transcriptase and the polymerase chain reaction is done using primers and Taqman® probes specific to each target gene. The results are analyzed using the ABI PRISM 7700 Sequence Detector. The absolute numbers are relative levels of expression of the target gene in a particular tissue compared to the calibrator tissue.
One of ordinary skill can design appropriate primers using commercially available software such as Primer Express® 2.0 from Applied Biosystems (Foster City, CA) or Oligo® version 5 or 6 from Molecular Biology Insights, Inc (Cascade, CO). Criteria for designing primers are known to those of skill in the art, see Cronin et al. American Journal of Pathology, January 2004, Vol. 164, No. 1, pages 35-42.
The relative levels of expression of the gene in normal tissues versus other cancer tissues can then be determined. All the values are compared to the calibrator. Normal RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals. The expression of each gene was normalized against one or more endogenous controls as described above.
Alternatively, to compare expression profiles between specimens, normalization based on endogenous controls is used to correct for differences arising from variability in RNA quality and total quantity of RNA in each assay. A reference CT (threshold cycle) for each tested specimen is defined as the average measured CT of the endogenous controls. In an approach similar to what has been described by others, endogenous controls are selected for use from among several candidate reference genes tested in this assay. See Vandesompele J, et al, Genome Biol 2002, 3: RESEARCH0034. The endogenous controls selected for the final analysis show the lowest levels of expression variability among the individual specimens tested. An average of multiple gene products is used to minimize the risk of normalization bias that can result from variation in expression of any single reference gene. See Suzuki T, et al, Biotechniques 29:332-337 (2000). Relative mRNA level of a test gene within a tissue specimen is defined as 2ACT +10.0, where ΔCT = CT (test gene) - CT (mean of endogenous controls). Unless indicated otherwise, normalized expression is represented on a scale in which the average expression of the endogenous controls is 10, corresponding to a mean CT of 30.7.
Table 7 below lists the components of each QPCR experiment performed on the genes described above. In some cases, multiple experiments have been designed for a single gene. The table includes the GenBank Accession for each gene, the SEQ ID NO and DDXS Accession for the amplified and detected portion of the gene, the DDXS nomenclature for the amplicon, the SEQ ID NO and DDXS Accession for the QPCR forward primer, the SEQ ID NO and DDXS Accession for the QPCR reverse primer and SEQ ID NO and DDXS Accession for the QPCR probe. Experiments are grouped by accession. For example, in a QPCR experiment for GenBank accession NM_##### the amplified and detected sequence is annotated as accession DEX0595_XXX.nt.l, the forward primer is DEX0595_XXX.nt.2, the reverse primer is DEX0595_XXX.nt.3 and the probe is DEX0595_XXX.nt.4.
Expression Results
Expression results for several gene products measured by QPCR in samples from 20 individuals are listed in Table 8 below. Data is presented as relative expression using a Human Reference sample as a calibrator, which is assigned a value of one (1) for all other samples to be calibrated against. All expression data is normalized using the geometric mean of 2 endogenous controls (HPRTl and RPL13A).
The results in Table 8 show that the over-expression levels of the gene products RAD54L, CYR61, ECT2, CCR8, BXMAS2-10, ESRl3 CXCR6, B7-H4, TERT5 CDHl and CTSD above of a particular threshold are indicative of poor outcome and recurrence of disease within 5 years of surgery. More particularly gene products RAD54L, CCR8, BXMAS2-10, CXCR6, CYR61, CDHl and B7-H4 (borderline significance) under a particular threshold were indicative of poor outcome and recurrence of disease within 5 years of surgery. Statistical analysis was based on a student t-test. Additionally, the results in Table 8 indicate that combinations of two or more of the gene products listed in Table 2 or Table 7 can be used to determine likelihood of long-term survival and therapy response for an individual.
Example 3: Statistical Analyses
Normalized gene product expression values from the experiments described above are used to study the existence of correlation of each individual gene product with overall outcome. Gene products identified as relevant for the prediction of outcome are evaluated in a multivariate model as predictors of prognosis. Analyses include: Principal
Component Analysis, supervised principal component analysis, support vector machines, classification algorithms; calculation of survival rates at 5 years by prognosis signature (independently by gene and by combination of genes); Kaplan-Meier analysis for survival or events at 5 years by prognosis signature (independently by gene and by combination of genes) including p-values; univariate Cox or logistic regressions for survival or events at 5 years by prognosis signature (independently by gene and by combination of genes) ■ including p-values; and multivariate Cox or logistic regressions for survival or events at 5 years by prognosis signature using individual genes (selected from Survival Analysis 3) or gene combination and incorporating significant clinical variables. References and additional statistical methodologies can be found in Van De Vijver, et ah, NEJM, Vol. 347, No. 25 December 19, 2002.
Univariate Testing
For comparison of individual gene product expression between disease free (DF) and progressive disease (PD) individuals two-sample Wilcoxon test, t-test and Wlech tests analyses are used. The Wilcoxon test is a non-parametric alternative to the two sample t- test which does not make any underlying distributional assumptions. Using these tests sets of genes from Table 2a, Table 2b or Table 7 showing the strongest gene product up- regulation in the PD population are identified. These gene sets preferably comprise 2, 3, 4, 5, 6, 7, 8, 9 or 10 genes. Most preferably these gene sets comprise 2, 3, 4, or 5 genes. Up-regulation or down-regulation of gene products from a gene set may be indicative of an individual falling in the progressive disease population. Based on a Wilcoxon test of the values in Table 8, the gene products of RAD54L,
CCR8, BXMAS2-10 and CXCR6 showed the strongest evidence of over-expression associated with progressive disease with p-values of 0.029, 0.035, 0.057 and 0.070, respectively.
Univariate Cox Proportional Hazards Results Evaluation of the association of individual gene product expression with survival time is effected using Cox proportional hazards regression. A set of preferably 2, 3, 4, 5 or 6 genes from Table 2a, Table 2b or Table 7 are identified. Over expression of these gene products is associated with survival time of individuals with progressive disease and can be used for staging and therapy selection. Ideally, over expression of the gene products is associated with survival time regardless of an individual's age, tumor stage, tumor grade or tumor size.
Based on a Cox proportional hazards regression analysis of values in Table 8, the gene products of RAD54L, B7-H4 and CDHl showed the strongest association with survival with p-values of 0.024, 0.073 and 0.084, respectively. Specifically, RAD54L expression over the median value was associated with a decreased survival time.
Survival Analyses
To conduct survival analyses gene product expression, select demographic and clinical variables are forced into a Cox proportional hazards model. To allow for selection of variables for inclusion, a penalized stepwise approach based on the Lasso and Least Angle Regression analyses may be employed. Use of conventional (unpenalized) stepwise approaches is undesirable in small sample settings. Using these methods gene sets from Table 2a, Table 2b or Table 7 may be identified as variables which are associated with survival time of individuals. Preferably the gene sets include 2, 3, 4 or 5 genes. Up- regulation or down-regulation of gene products from the gene set is associated with survival time for an individual.
Null and/or unstable results were obtained when all gene product expression, age, tumor grade and tumor size were forced into a Cox proportional hazards model. The first two genes selected via use of a penalized forward-stepwise approach (LARS-Lasso) were RAD54L and CDHl, which withstood cross validation.
In order to identify gene product signatures from genes in Table 2a, Table 2b or Table 7 useful for discriminating between disease free and progressive disease individuals, two disparate classifications techniques are suitable: Nearest Shrunken Centroids method (generalizes prototype methods and siagonal linear discriminant analysis), and Random Forests (combines tree-based classifiers obtained using bootstrap resampling). These techniques are suitable because they are effective in small sample settings featuring potentially correlated predictors (e.g. gene products), are designed to avoid overfitting and provide interpretable output with respect to which gene are driving classification. Additionally, the shrunken centroids analysis has been previously employed to identify sets of gene that characterize selected groups based on gene product expression. See Tibshirani et al, PNAS 99(10):3 6567-6572 (2002). Nearest Shrunken Centroids
Using the nearest shrunken centroids method comparable classification rates are obtained for a range of shrinkage parameters and gene product expression values corresponding to models with 3, 4, 5, 6, 7, 8, 9 or 10 genes from Table 2a, Table 2b or Table 7. Misclassification rates are ideally below 30 percent. Perfectly classified DF individuals and misclassified PD individuals indicates a preponderance of DF individuals. By varying prior probabilities (equivalently misclassifications cots) balanced results with comparable misclassification rates are attainable.
Comparable misclassification rates (-0.25) were obtained for a range of shrinking parameters and values corresponding to modules with 3 to 9 genes from Table 2a and Table 2b. In a 9 gene model, the gene product expression of B7-H4, CDHl, PR, CYR61, Mam005, SCGB 1D2, CXCR6, MMP9 and BXMAS2-10 had an overall misclassification rate of 0.24. Disease free individuals were perfectly classified, and only individuals were misclassified, reflecting the preponderance of disease free individuals.
Random Forests Using the random forests method sets of gene from Table 2a, Table 2b or Table 7 are identified which are most important to the method for classification of individuals as DF or PD. Summaries of individual an individual gene's contributions to classification are provided via variable importance measures. As with the nearest shrunken centroids method misclassification rates are ideally below 30 percent. Additionally, similar misclassification rates between methods is indicative of the accuracy of each method.
The top nine gene products contributing to classification by random forests were CCR8, RAD54L, TERT, CDHl, BXMAS2-10, SLAMF9, CXCR6, MMP9 and PR.
Reasonable concordance between sets of gene from Table 2a, Table 2b or Table 7 identified by the nearest shrunken centroids method and random forests method such as CXCR6, CDHl, PR, MMP9 and BXMAS2-10 demonstrates that the differential expression of the gene products classify an individual as falling into the disease free or progressive disease groups.
The statistical analyses conducted demonstrate that the expression levels of the gene products of the genes of Table 2a and Table 2b are useful for discriminating between progressive disease and disease free survival groups for the prognosis of individuals with breast cancer. Specifically, differential of RAD54L, CCR8, CXCR6, BXMAS2-10, B7- H4, CDHl, PR and MMP9 gene products are useful for disease free prognosis, survival determination, and group classification.
Example 4: ROC Analysis of Marker Panels for Breast Cancer Prognosis
The ability of a test or assay to discriminate diseased cases from normal cases or to discriminate two different populations of patients with different characteristics is evaluated using Receiver Operating Characteristic (ROC) curve analysis (Metz, 1978; Zweig & Campbell, 1993). ROC curves can also be used to compare the diagnostic performance of two or more laboratory or diagnostic tests (Griner et al., 1981).
An ROC curve is generated by plotting the sensitivity against the specificity for each value. From the plot, the area under the curve (AUC) can be determined. The value for the area under the ROC curve (AUC) can be interpreted as follows: an area of 0.84, for example, means that a randomly selected positive result has a test value larger than that for a randomly chosen negative result 84% of the time (Zweig & Campbell, 1993). When the variable under study can not distinguish between two result groups, i.e. where there is no difference between the two distributions, the area will be equal to 0.5 (the ROC curve will coincide with the diagonal). When there is a perfect separation of the values of the two groups, i.e. there no overlapping of the distributions, the area under the ROC curve equals 1 (the ROC curve will reach the upper left corner of the plot).
The 95% confidence interval for the area can be used to test the hypothesis that the theoretical area is 0.5. If the confidence interval does not include the 0.5 value, then there is evidence that the laboratory test has the ability to distinguish between the two groups (Hanley & McNeil, 1982; Zweig & Campbell, 1993). The P-value is the probability that the observed sample Area under the ROC curve is found when in fact, the true (population) Area under the ROC curve is 0.5 (null hypothesis: Area = 0.5). IfP is low (P<0.05) then it can be concluded that the Area under the ROC curve is significantly different from 0.5 and that therefore there is evidence that the laboratory test does have an ability to distinguish between the two groups.
ROC Analysis of Individual Gene Products
The sensitivity and specificity of each gene product to individually differentiate the disease free (DF; good prognosis) and progressive disease (PD; poor prognosis) populations was calculated through receiver operating characteristic (ROC) analysis. The gene products of four genes tested (RAD54L, CCR8, BXMAS2-10, CXCR6) had an AUC larger than 0.5 with a 95% confident interval. The P-values for the gene products of these genes showed that the expression results have the ability to distinguish between good and poor prognosis groups. Table 9 below shows the results of the Area Under the Curve (AUC) from the ROC analysis for the gene products in individuals with progressive disease (PD, n=14) versus individuals free of disease within 5 years (DF, n=31). The AUC values for RAD54L, CCR8, BXMAS2-10, and CXCR6 were 0.706, 0.699, 0.680 and 0.672, respectively. AUC values for gene products were calculated using the gene expression levels obtained by quantitative real time PCR as described previously in the TaqMan™ Gene Expression Profiling section and reported in Table 8.
Table 9. AUC Values for enes RAD54L, CCR8, BXMAS2 10, and CXCR6.
These results demonstrate that gene products of the genes of Table 2a and Table 2b can distinguish between disease free and progressive disease groups and are useful for the prognosis of individuals with breast cancer. ROC Analysis of Combination of Gene Products for
The ability of a combination of gene products to differentiate disease free (DF; good prognosis) and progressive disease (PD; poor prognosis) populations was determined by receiver operating characteristic (ROC) analyses of various mathematical relationships. The area under the curve (AUC) was calculated using the mathematical relationship of the gene product expression results in Table 8 above for the gene products of the genes in Table 2a and Table 2b.
Additive Combos
The sensitivity and specificity for two or more gene products of the genes in Table 2a and Table 2b in additive combination was calculated through (ROC analysis using the expression value of each gene listed in Table 8. Table 10 below shows the results of the Area Under the Curve (AUC) from the ROC analysis of gene product expression levels of RAD54L and CCR8 individually and in combination , and RAD54L and CXCR6 individually and in combination in individuals with progressive disease (PD, n-14) versus individuals free of disease within 5 years (DF, n=31)
Table 10. Additive Combination AUC Values.
These results demonstrate that gene products of the genes of Table 2a and Table 2b in additive combination can distinguish individuals with progressive disease (PD, n=14) from individuals free of disease within 5 years and are useful the prognosis of individuals with breast cancer.
Ratio and multiplicative Combos
Another method for calculating the predictive value of the association of the gene product expression of two or more genes is to use the ratio of the expression values or the product of the multiplication of the expression values. Previous reports proposed the use of a two-gene expression ratio (Ma et at, Cancer Cell. 2004 Jun; 5(6):607-16) as predictor of recurrence in ER-positive, invasive breast cancer patients treated with tamoxifen and the use of an interactive gene expression index (IGEI) (DeMuth et ah, Am J Respir Cell MoI Biol. 1998 JuI; 19(1): 18-24) to predict a malignant phenotype in human bronchial epithelial cells. The disclosure of Ma et at, and DeMuth et al, are hereby incorporated by reference. Table X below lists the calculated ratios and multiplicative results for gene product expression results in Table 8 above.
Table 11 below lists the gene product expression ratio and multiplicative values used in the ROC analyses below.
Table 12 below shows the results of the Area Under the Curve (AUC) from the ROC analyses for the ratios of gene product expression values for gene RAD54L/CCR8, RAD54L/CXCR6 and CCR8/CXCR6 in individuals with progressive disease (PD, n=14) versus individuals free of disease within 5 years (DF, n=31).
Table 12. AUC Values for ratios of ene products.
Table 13 below shows the results of the Area Under the Curve (AUC) from the ROC analyses for the ratios of gene product expression values for gene RAD54L x CCR8, CCR8 x CXCR6 and RAD54L x CCR8 x CXCR6 in individuals with progressive disease (PD, n=14) versus individuals free of disease within 5 years (DF, n=31).
Table 13. AUC Values for multiplication of gene products.
Results of ROC Analyses
The results from the ROC analyses of the gene product expression from different genes demonstrate that the expression of gene products of the genes from Table 2a and Table 2b used individually are useful for differentiating disease free (DF; good prognosis) and progressive disease (PD; poor prognosis) individuals. Furthermore, when the individual gene product expression values for the genes of Table 2a and Table 2b are used in additive combination for the ROC analysis the AUC is higher than the individual gene product AUCs as demonstrated in Table 10. Similarly, when the individual gene product expression values for the genes of Table 2a and Table 2b are used in mathematical relationships such as ratios or multiplication in different combination of two or more of the genes to obtain a new value that is used in the ROC analysis, we obtain higher AUC values compared to the AUC of each individual gene as demonstrated in Table 12 and Table 13.
These results demonstrate that the gene products of the genes of Table 2a and Table 2b, including RAD54L, CCR8, BXMAS2-10 and CXCR6, alone or in combination, are useful for differentiating individuals with progressive disease (PD) versus individuals free of disease within 5 years (DF) and prognosing them into poor outcome (progressive disease) and good outcome (disease free survival) groups.
Example 5: Bone Marrow Samples
The prognosis of an individual with breast cancer can be determined based on the gene product expression of a bone marrow sample. Bone marrow samples are usually obtained through aspiration. The bone marrow samples are often aspirated from the upper iliac crest, the posterior iliac crest, or the anterosuperior iliac spine. In the aspiration process, the individual's skin is incised and 2-5 mL of bone marrow is aspirated.
Using the gene products of Table 2a and 2b and the methods of Example 2 and 3, bone marrow samples from each individual are processed for analysis of gene products according to methods known by those of skill in the art. For example, see Barbaric D, et al, J. CHn. Pathol. 55:865-867 (2002).
Bone marrow samples from healthy individuals are used to determine a baseline level of expression for each of the gene products tested. All measurements of gene products are normalized against endogenous controls.
Specific markers that can be used individually or in combination to detect and/or predict breast cancer for an individual include BXMAS2-10, Mam005, WNT7A, SLAMF9, B7-H4, SCGB2A1, HIFlA, SCGB1D2, UGT2B11, MamO21, Mam018, MamO29 and Mmgb. Specific markers that are used to determine cancerous cells in the bone marrow of an individual regularly include CK-19 {see Slade MJ, et al, Int. J. Cancer! 14(l):94-100 (2005)) and mammaglobin (see Ooka M, et al, Breast Cancer Res. Treat. 67(2): 169-75 (2001).
Example 6: Blood Samples The prognosis of an individual with breast cancer can be determined based on the gene product expression of a peripheral blood sample. Peripheral blood samples are collected after consent from the individuals is obtained. For individuals with cancer, blood samples are often collected after surgery, and for individuals without cancer the blood can be collected at anytime. Using the gene products of Table 2a and 2b and the methods of Example 2 and 3, blood samples from each individual are processed for analysis of gene products according to methods known by those of skill in the art. From each individual and control donor 10 ml of blood (in PaxGene tubes) is collected. RNA is extracted from blood samples by methods known by those of skill in the art, or by use of commercially available kits such as Qiagene RNA collection kits which utilize the Qiagene RNA collection procedure. For analysis of RNA, an amplification step may be used to improve sensitivity using commercially available kits such as the Ovation™ System from Nugen™ (San Carlos, CA). Additionally, emerging amplification methodologies such as Whole Transcriptome Amplification (WTA) which does not demonstrate a 3' bias as seen in other RNA detection methodologies may be utilized. Available WTA services and forthcoming commercially available WTA kits include Ribo-SPIA™ WTA from Nugen™ and the TransPlex™ Whole Transcriptome Amplification Kits from Rubicon Genomics (Ann Arbor, MI). See Nugen™ website nugentechnologies with the extension . com/technology- wt-spia.htm of the world wide web and Rubicon Genetics website rubicongenomics with the extension .com/web/OmniPlex WTAKits.html of the world wide web. Blood samples from healthy individuals are used to determine a baseline level of expression for each of the gene products tested. All measurements of gene products are normalized against endogenous controls.
Specific markers that can be used individually or in combination to detect and/or predict breast cancer for an individual include BXMAS2-10, Mam005, WNT7A, SLAMF9, B7-H4, SCGB2A1, HIFlA, SCGB1D2, UGT2B11, MamO21, MamO18, MamO29 and Mmgb.
Specific markers that are used to determine cancerous cells in the peripheral blood of an individual regularly include CK-19 {see Stathopoulou A, et ah, J. Clin. Oncol., 20(16):3404-3412 (2002)) and mammaglobin {see CerveiraN, et ah, Int. J. Cancer 108(4):592-595 (2004)). In addition to these individual markers, several multi-marker sets are also used to detect cancerous cells in an individual's peripheral blood. These multi- marker sets consist of mammaglobin and beta-hCG {see Fabisiewicz A, et ah, Acta Biochim. Pol. 51(3):747-755 (2004)); CK-19 and beta-hCG {see Hu XC, et ah, Anticancer Res. 21(lA):421-424 (2001)); beta-hCG, c-Met, MAGE-A3 and GaINAc-T {see Taback B, et ah, Cancer Res. 61(24):8845-8850 (2001)); and plB, PS2, CK-19 and EGP2 {see Bosma AJ, et ah, Clin. Cancer Res. 8(6):1871-1877 (2002)). Example 7: Lymph Nodes
The prognosis of an individual with breast cancer can be determined based on the gene product expression of a lymph node sample. Lymph node samples are collected through several methods. Individuals found to have breast cancer undergo an axillary lymph node dissection (lymph node is surgically removed) or they have a sentinel lymphandenectomy performed. In order to obtain non-cancerous lymph nodes, oftentimes individuals having surgeries such as a cholecystectomy or a tonsillectomy are asked to provide samples of their lymph nodes.
Using the gene products of Table 2a and 2b and the methods of Example 2 and 3, lymph node samples from each individual are processed for analysis of gene products according to methods known by those of skill in the art.
Lymph node samples from healthy individuals are used as controls and to determine a baseline level of expression for each of the gene products tested. All measurements of gene products are normalized against endogenous controls. Specific markers that can be used individually or in combination to detect and/or predict breast cancer for an individual include BXMAS2-10, Mam005, WNT7A, SLAMF9, B7-H4, SCGB2A1, HIFlA, SCGB1D2, UGT2B11, MamO21, Mam018, MamO29 and Mmgb.
Specific markers that are used to determine cancerous cells in the lymph nodes of an individual include mammaglobin (see Min CJ, et ah, Cancer Res. 58(20):4581-4584 (1998) and Ooka M, et ah, Oncol. Rep. 7(3):561-566 (2000)) and CEA (see Min CJ, et ah, Cancer Res. 58(20) :4581-4584 (1998) and Mori M, et ah, Cancer Res. 55(15):3417-3420 (1995)). In addition to these individual markers, several multi-marker sets are also used to detect cancerous cells in an individual's lymph nodes. These multi-marker sets consist of mam, PJJP, CK- 19, mamB, MUC-I, and CEA (see Mitas M, et ah, Int. J. Cancer
93(2):162-171 (2001)); mam, B305D, GABApi, and B726P (see Zehentner BK, et ah, Clin. Chem. 48(8):1225-1231 (2002)); and mapsin, CX-19 and mam (see Manzotti M, et ah, Int. J. Cancer 95(5):307-312 (2001)).
1. A method for determining the prognosis for an individual having breast cancer comprising: determining the expression level of a plurality of gene products of the genes in Table 2a in a sample from an individual relative to a control, wherein the differential expression of a plurality of gene products relative to a control is indicative of the individual's prognosis.
2. The method of claim 1 wherein the expression level of a plurality of gene products of the genes in Table 2b is also determined and the differential expression of a plurality of gene products relative to a control is indicative of the individual's prognosis.
3. The method of claim 1 wherein the plurality of gene products comprises at least two gene products.
4. The method of claim 1 wherein the plurality of gene products comprises at least four gene products.
5. The method of claim 1 wherein the plurality of gene products comprises at least six gene products.
6. The method of claim 1 wherein the plurality of gene products comprises at least eight gene products.
7. The method of claim 2 wherein the gene products are selected from the group comprising RAD54L, CYR61, ECT2, CCR8, BXMAS2-10, ESRl, CXCR6, B7- H4, TERT, CDHl and CTSD.
8. The method of claim 7 wherein the gene products are selected from the group comprising RAD54L, CCR8, BXMAS2-10, CXCR6, CYR61, CDHl and B7-H4.
9. The method of claim 7 wherein over-expression of CYR61, ECT2, CCR8, ESRl, B7-H4, TERT, and CDHl gene products are indicative of a poor prognosis.
10. The method of claim 8 wherein over-expression of RAD54L, CCR8, BXMAS2- 10, CXCR6, CYR61, CDHl and B7-H4 gene products are indicative of a good prognosis.
11. The method of claim 7 wherein under-expression of ER and CTSD gene products are indicative of a poor prognosis.
12. The method of claim 1 wherein over-expression of some gene products from Table 2a are indicative of a good prognosis.
13. The method of claim 1 wherein under-expression of some gene products from Table 2a are indicative of a good prognosis.
14. The method of claim 2 wherein over-expression of some gene products from Table 2b are indicative of a poor prognosis.
15. The method of claim 2 wherein under-expression of some gene products from Table 2b are indicative of a poor prognosis.
16. The method of claim 1 where in the gene product is a RNA.
17. The method of claim 16 wherein the gene product expression level is determined by quantitative PCR.
18. The method of claim 1 wherein the gene product is a polypeptide.
19. The method of claim 18 wherein the gene product expression is determined by an assay comprising one or more antibodies.
20. The method of claim 1 wherein the sample is selected from the group consisting of tissues, cells and bodily fluids.
21. The method of claim 20 wherein the tissues or cells are from a fixed, waxed embedded specimen from said individual.
22. A method for improving the prognosis for an individual having breast cancer comprising modulating levels of a plurality of gene products in Table 2a or Table
2b .
23. The method of claim 22 wherein the plurality of gene products comprises at least two gene products.
24. The method of claim 22 wherein the plurality of gene products comprises at least four gene products.
25. The method of claim 22 wherein the plurality of gene products comprises at least six gene products.
26. The method of claim 22 wherein the plurality of gene products comprises at least eight gene products.
27. The method of claim 22 wherein modulating levels of gene products comprises increasing levels of gene products whose over-expression is associated with a good prognosis.
28. The method of claim 27 wherein the gene products are selected from the group comprising the gene products of Table 2a.
29. The method of claim 22 wherein modulating levels of gene products comprises decreasing levels of gene products whose under-expression is associated with a good prognosis.
31. The method of claim 22 wherein modulating levels of gene products comprises decreasing levels of gene products whose over-expression is associated with a poor prognosis.
32. The method of claim 22 wherein modulating levels of gene products comprises increasing levels of gene products whose under-expression is associated with a poor prognosis.
33. The method of claim 22 comprising administering to said individual an appropriate agonist or antagonist for a gene product of Table 2a which will improve the prognosis of said individual.
34. An isolated nucleic acid molecule comprising:
(a) a nucleic acid molecule consisting essentially of a nucleic acid sequence of Table 7;
(b) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a); or
(c) a nucleic acid molecule having at least 95% sequence identity to the nucleic acid molecule of (a).
35. The nucleic acid molecule according to claim 34, wherein the nucleic acid molecule is cDNA.
36. The nucleic acid molecule according to claim 34, wherein the nucleic acid molecule is genomic DNA.
37. The nucleic acid molecule according to claim 34, wherein the nucleic acid molecule is RNA.
38. The nucleic acid molecule according to claim 34, wherein the nucleic acid molecule is a mammalian nucleic acid molecule.
39. The nucleic acid molecule according to claim 38, wherein the nucleic acid molecule is a human nucleic acid molecule.
40. A set of three isolated nucleic acid molecules wherein: (a) each nucleic acid molecule consists essentially of a nucleic acid sequence encoding a portion of gene product described in Table 2a or Table 2b and (i) the first nucleic acid molecule is a forward primer 15 to 30 base pairs in length; (ii) the second nucleic acid molecule is a reverse primer 15 to 30 base pairs in length; and (iii) the third nucleic acid molecule is a probe 15- 30 base pairs in length; such that the forward primer and reverse primer produce an amplicon detectable by the probe wherein the amplicon bridges two exons and is 60 to 100 base pairs in length;
(b) each nucleic acid molecule selectively hybridizes to one of the three nucleic acid molecules of (a); or (c) each nucleic acid molecule has at least 95% sequence identity to the one of the three nucleic acid molecules of (a).
41. The set of nucleic acid molecules of claim 40 wherein the amplicon bridges at least two exons.
42. A method for determining the presence of a gene product of Table 2a or Table 2b in a sample, comprising the steps of:
(a) contacting the sample with a nucleic acid molecule of Table 7 under conditions in which the nucleic acid molecule will selectively hybridize to a gene product of Table 2a or Table 2b; and
(b) detecting hybridization of the nucleic acid molecule to a gene product of Table 2a or Table 2b in the sample, wherein the detection of the hybridization indicates the presence of a gene product of Table 2a or Table 2b in the sample.
43. The method of claim 2 wherein the presence of a plurality of gene products of Table 2a or Table 2b are detected in a sample.
44. A method for determining the presence of a cancer specific protein in a sample, comprising the steps of:
(a) contacting the sample with a suitable reagent under conditions in which the reagent will selectively interact with the cancer specific protein comprising an amino acid sequence with at least 95% sequence identity to the polypeptide encoded by a gene product in Table 2a or Table 2b; and
(b) detecting the interaction of the reagent with a cancer specific protein in the sample, wherein the detection of binding indicates the presence of a cancer specific protein in the sample.
45. The method of claim 44 wherein the presence of a plurality of gene products of Table 2a or Table 2b are detected in a sample.
46. A method for diagnosing or monitoring the presence and metastases of breast cancer in an individual, comprising the steps of:
(a) determining an amount of:
(i) a nucleic acid molecule consisting essentially of a nucleic acid sequence that encodes an amino acid sequence of a gene product in Table 2a or Table 2b; (ii) a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product in Table 2a or Table 2b; (iii) a nucleic acid molecule consisting essentially of a nucleic acid sequence of Table 7;
(iv) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (i), (ii) or (iii);
(v) a nucleic acid molecule having at least 95% sequence identity to the nucleic acid molecule of (i), (ii) or (iii); (vi) a polypeptide comprising an amino acid sequence with at least 95% sequence identity to the polypeptide encoded by a gene product in Table 2a or Table 2b; or
(vii) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule having at least 95% sequence identity to a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product of Table 2a or Table 2b; in a sample and;
(b) comparing the amount of the determined nucleic acid molecule or the polypeptide in the sample of the individual to the amount of the cancer specific marker in a normal control; wherein a difference in the amount of the nucleic acid molecule or the polypeptide in the sample compared to the amount of the nucleic acid molecule or the polypeptide in the normal control is associated with the presence of breast cancer.
47. The method of claim 46 wherein a plurality of:
(a) a nucleic acid molecule consisting essentially of a nucleic acid sequence that encodes an amino acid sequence of a gene product in Table 2a or Table 2b; (b) a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product in Table 2a or Table 2b;
(c) a nucleic acid molecule consisting essentially, of a nucleic acid sequence of Table 7;
(d) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (i), (ii) or (iii);
(e) a nucleic acid molecule having at least 95% sequence identity to the nucleic acid molecule of (i), (ii) or (iii);
(f) a polypeptide comprising an amino acid sequence with at least 95% sequence identity to the polypeptide encoded by a gene product in Table 2a or Table 2b; or
(g) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule having at least 95% sequence identity to a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product of Table 2a or Table 2b; is determined in a sample.
48. A kit for detecting a risk of cancer or presence of cancer in an individual, said kit comprising a means for determining the presence of: (a) a nucleic acid molecule consisting essentially of a nucleic acid sequence that encodes an amino acid sequence of the polypeptide encoded by a gene product in Table 2a or Table 2b;
(b) a nucleic acid molecule consisting essentially of a nucleic acid sequences of a gene product in Table 2a or Table 2b;
(c) a nucleic acid molecule consisting essentially of a nucleic acid sequence of Table 7;
(d) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a), (b) or (c); or (e) a nucleic acid molecule having at least 95% sequence identity to the nucleic acid molecule of (a), (b) or (c); or (f) a polypeptide comprising an amino acid sequence with at least 95% sequence identity to the polypeptide encoded by a gene product in Table 2a or Table 2b; or (g) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule having at least 95% sequence identity to a nucleic acid molecule comprising a nucleic acid sequence of a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product of Table
2a or Table 2b; in a sample.
49. The kit of claim 48 wherein said kit comprises the means for detecting the presence of a plurality of:
(a) a nucleic acid molecule consisting essentially of a nucleic acid sequence that encodes an amino acid sequence of the polypeptide encoded by a gene product in Table 2a or Table 2b;
(d) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a), (b) or (c); or (e) a nucleic acid molecule having at least 95% sequence identity to the nucleic acid molecule of (a), (b) or (c); or
(g) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule having at least 95% sequence identity to a nucleic acid molecule comprising a nucleic acid sequence of a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product of Table 2a or Table 2b; in a sample.
50. A method of treating an individual with breast cancer, comprising the step of administering a composition comprising: (a) a nucleic acid molecule consisting essentially of a nucleic acid sequence that encodes an amino acid sequence of the polypeptide encoded by a gene product in Table 2a or Table 2b; (b) a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product in Table 2a or Table 2b; (c) a nucleic acid molecule consisting essentially of a nucleic acid sequence of
Table 7;
(d) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a), (b) or (c); or
(e) a nucleic acid molecule having at least 95% sequence identity to the nucleic acid molecule of (a), (b) or (c); or
(f) a polypeptide comprising an amino acid sequence with at least 95% sequence identity to the polypeptide encoded by a gene product in Table 2a or Table 2b;
(g) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule having at least 95% sequence identity to a nucleic acid molecule comprising a nucleic acid sequence of a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product of Table 2a or Table 2b; or (h) an appropriate agonist or antagonist for a gene product of Table 2a or Table
2b; to an individual in need thereof, wherein said administration induces a therapeutic response against the breast cancer cell expressing the nucleic acid molecule or polypeptide.
51. The method of claim 50 wherein the composition comprises a plurality of:
(b) a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product in Table 2a or Table 2b;
(c) a nucleic acid molecule consisting essentially of a nucleic acid sequence of Table 7; (d) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a), (b) or (c); or
(g) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule having at least 95% sequence identity to a nucleic acid molecule comprising a nucleic acid sequence of a nucleic acid molecule consisting essentially of a nucleic acid sequence of a gene product of Table
2a or Table 2b; or
(h) an appropriate agonist or antagonist for a gene product of Table 2a or Table 2b;
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Alumni News Reading Room: Richard Kluger ’56
By Louis Jacobson ’92
Published in the November 9, 2016 Issue
What he’s reading: “Collapse by Jared Diamond. I love works that risk persuasive macro-judgments by taking intensive looks into particular cases in point by marshaling compelling details.”
Joshua Kluger
Indelible Freedom
Lots of Americans remember that John Peter Zenger had something to do with freedom of the press, but beyond that, Zenger’s story is largely unknown. So Pulitzer Prize-winning author Richard Kluger ’56 decided to write a book about him. The result — Indelible Ink: The Trials of John Peter Zenger and the Birth of America’s Free Press — was published in September.
In the 1730s, Zenger, a poor German immigrant printer, published the New-York Weekly Journal, a small newspaper. At the time, there were no guarantees of freedom of the press, either in the American colonies or anywhere else, but Zenger’s paper consistently riled top Colonial officials. With the financial backing of anonymous citizens, including New York Supreme Court Chief Justice Lewis Morris, the paper assailed the policies and habits of a British governor, William Cosby.
The newspaper was “not high art,” Kluger said, and often trafficked in satiric political allegories. “For its day, it was a sensation,” he said. Beyond pressing ink to paper, Zenger had nothing to do with the editorial jeremiads. But he became the newspaper’s public face — and the target of a counterattack by the governor and his allies. Zenger spent nearly a year in jail before facing a one-day trial in August 1735.
“There was almost no chance that he would win, but he did,” Kluger says. “And that was the beginning of press freedom in America and the world.” The case, skillfully argued by his lawyer, set today’s precedent that public accusations of wrongdoing cannot be considered libelous if they are true.
Kluger cites working for The Daily Princetonian during an era that featured journalistic giants-in-training like R.W. (Johnny) Apple ’57 and Robert Caro ’57 as a formative experience of his life.
The theme of social justice in Zenger’s story fits with many of Kluger’s previous books, whose topics include the Brown v. Board of Education Supreme Court decision; the rise and fall of tobacco; a bloody battle between Native Americans and white settlers in the 1850s; and the history of one of his former employers, the New York Herald Tribune.
“I was astonished that there had never been a full narrative about Zenger,” Kluger said. A big part of that, he explained, had to do with the lack of surviving documentation. Kluger had only two significant pieces of direct evidence to work with — scanned copies of Zenger’s newspaper and handwritten notes taken at the trial by Zenger’s lawyer.
Kluger fills out the book with research into the history of free expression during the reign of British monarchs — and found a shocking level of contempt for it. “You could be thrown into jail for criticizing the government, no matter if it was true or not,” he said. “In fact, [the truth] was in some ways a worse crime, because the truer it was, the more likely it was to upset the status quo.”
But thanks to Zenger, press freedom became “the key element in the democratic form of government. If there’s no free press, there’s no informed electorate.”
“Print has declined markedly with the rise of the internet, but there are so many more outlets for free expression,” Kluger said, noting continued strong protections against libel suits. He added: “I think American press freedom is more solid than ever.”
Following: Mark Herrmann ’79
Covering the legal world one post at a time
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Data Mining -- The Florida Power Play
In his latest edition of his "Tuesday 10," E.J. Hradek says the following about the Florida power play:
"If you're wondering how the Lightning gave up five power-play goals in a single game, here's one telling stat: They lost 12 of 16 short-handed faceoffs. When you consistently lose possession of the puck off the draw in the defensive zone, you're putting yourself in danger."
Yup, sure enough, Florida was 12-for-16 on the power play. But there is more to this story. Looking only at draws taken in the Florida offensive zone, Stephen Weiss was 8-1 all by himself. Tomas Kopecky took one (an won it). Of those ten draws, here is how they played out:
1. Weiss (win) at 4:35 of 1st period/goal scored by Kopecky at 6:15. According to the NHL.com play-by-play record, there were no intervening events outside the Florida offensive zone. Chalk one up for O-zone faceoff wins.
2. Weiss (win) at 14:09 of 1st period.
3. Weiss (win) at 16:21 of 1st period/goal scored by Weiss at 17:12. No intervening events outside the Florida offensive zone.
4. Kopecky (win) at 0:46 of 2nd period.
5. Weiss (win) at 1:43 of 2nd period/goal by Versteeg at 2:35. Between these events Tampa Bay won a neutral zone faceoff.
6. Weiss (win) at 18:39 of 2nd period/(end of period).
7. Weiss (win) at 8:33 of 3rd period.
8. Weiss (win) at 15:52 of 3rd period.
9. Weiss (loss) at 16:02 of 3rd period/goal by Garrison at 16:47
10. Weiss (win) at 19:28 of 3rd period/(end of period, but Tampa Bay did record two shots on goal).
Fine so far, although this is one instance. But consider this, too. Of the five power play goals scored by Tampa Bay in this game, they came from an average of more than 40 feet (according to distances recorded in the NHL.com play-by-play record). They were not exactly standing on the door-step.
Each of the five goals had a story, though...
1. Kopecky at 6:15/1st. The goal was scored from 56 feet, but it clearly hit a Tampa Bay defenseman's stick in front of goalie Dwayne Roloson and changed direction on its way to the net.
2. Weiss at 17:12/1st. Scored from a distance ot 47 feet, Roloson looked to be screened by his own player.
3. Versteeg at 2:35/2nd. A 20-fotter, Roloson looked to be slow getting across his crease to defend against a shot coming from a cross-ice pass.
4. Versteeg at 0:26/3rd. A goal from 26 feet out, looked to beat Roloson cleanly on short side.
5. Garrison at 16:47/3rd. Scored from 59 feet through a nice screen set up in front of Roloson, but that goal came after Florida lost the preceding faceoff.
What to conclude? The notion that taking a lot of shorthanded faceoffs -- and losing them -- especially in one's own zone is a bad way to play a hockey game. But it looks as if only two of the five goals can be attributed to that factor. One of those ended up being scored as a result of bad luck (if you are Roloson), it being scored off a teammate's stick deflection. By the same token, if you don't lose that D-zone faceoff, you aren't put in a situation where that can happen. Another came on what looked like a screen by Roloson's own teammate, but again...don't lose the D-zone faceoff, and it might not have unfolded that way.
Two other goals looked to be on Roloson for not being in a good position to stop the puck, and the fifth was off a long shot through a maze of players, the kind of play that doesn't depend on losing a D-zone draw.
A lot of things go into allowing (or scoring) power play goals, but two things we can safely say about this as the game is about to begin in another 90 minutes or so between the Caps and Panthers. One, Stephen Weiss seems to be pretty good about winning offensive zone draws on the power play. Second...
...don't take so many penalties.
Posted by The Peerless at 5:24 PM
Labels: Florida Panthers, stephen weiss, the peerless prognosticator, Washington Capitals
A TWO-point night -- Game 5: Caps 3 - Panthers 0
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The Peerless Prognosticator is ON THE AIR!!! -- Game 41: Penguins at Capitals, January 11th
Two of the hottest teams in the league – well, the league’s two hottest teams – renew an old and bitter rivalry on Wednesday night when the Pittsburgh Penguins visit Verizon Center to meet the Washington Capitals. Pittsburgh will bring the league’s second-longest active winning streak to the contest – five games, trailing only the Caps, who have wins in their last six contests and points in their last seven.
As you might expect, Sidney Crosby leads the Penguins in both goals and total points in the five-game streak (3-4-7). In one of the odd circumstances of his season so far, his league-leading 26 goals in 33 games is a 65-goal pace per 82 games (the number of goals Alex Ovechkin scored for a career-best in 2007-2008 in one of those Kennedy-Lincoln/Lincoln-Kennedy coincidences, in a manner of speaking). Crosby has also shown a certain “Ovechkinian” consistency in his goal scoring, too. He played his first 23 games this season without suffering consecutive games without a goal, and his season high streak without one is three games, a number he could tie if the Caps can keep him from finding the back of the net on Wednesday night. Crosby is 19-36-55, plus-1, in 39 career games against the Caps.
Defenseman Kris Letang has points in seven of his last nine games (1-9-10). Trouble for the Penguins is that he has only played in nine games since December 1st, missing seven games with a lower body injury. It is his second bout with injuries this season, having missed five games to an upper body injury in late October. And now, he is listed as "day-to-day" with what appears to be the flu. His availability will be a game-time decision. It is not as if the Penguins have suffered much in his absence, though. The Penguins are 18-6-3 with Letang in the lineup; 8-2-2 when he is out of the lineup. What might be of some concern to the club is the dropoff in his goal scoring from the blue line. After posting double-digit goal totals or on a pace to do so (as in the abbreviated 2012-2013 season) in each of the last five seasons, he is on a pace to finish with eight goals this season. He has one goal in his last 15 games. Letang is 4-9-13, minus-15, in 29 career games against Washington.
With Matt Murray injured and in “day-to-day” status (he has not played since December 28th), the goaltending duties are squarely on the shoulders of Marc-Andre Fleury again. He is riding a personal five-game winning streak into this contest with a 1.84 goals against average and a save percentage of .941. He has been streaky this season, though. Over his last 19 games, Fleury has a three-game winning streak followed by a six-game losing streak, then another three-game winning streak followed by a two-game losing streak before embarking on his current winning streak. One thing that hasn’t been streaky, at least not in a good way for the Penguins, is his road record. He is 2-3-3, 3.83, .886 in ten road appearances this season. Against the Caps, Fleury has a career record of 20-11-2, 2.56, .914, with three shutouts in 35 appearances.
1. Pittsburgh it taking a page from the Caps’ 2015-2016 notebook. They have yet to lose consecutive games in regulation time this season. Last season the Caps went the entire 82-game schedule without losing consecutive games in regulation.
2. Over their last 11 games, Penguin penalty killers are 31-for-34 in killing penalties (91.2 percent).
3. Pittsburgh will pose a special challenge to the league’s top scoring defense. The Penguins are averaging 4.38 goals per game over their last 16 contests and have scored more than five goals five times.
4. Who scores first hardly seems to matter to the Pens. When scoring first, they are 13-4-3 (.650 winning percentage). When opponents score first, they are 13-4-2 (.684 winning percentage).
5. For their sterling record, the Penguins are not an especially dominant possession team. Overall, they rank tenth in Corsi-for at 5-on-5 (51.40 percent; numbers from Corsica.hockey), but they do seem to tighten up when on the road (52.50 percent/4th).
1. On Thanksgiving, the Metropolitan Division standings looked like this:
After Monday’s games, the standings looked like this:
The records of the teams between Thanksgiving and Tuesday morning looked like this (ranked in order of points earned):
The Caps, playing at a slightly better pace (121 points) than they played over 82 games last season (120 points), lost ground to Columbus and barely tread water against Pittsburgh and the Rangers. Is the Metro bonkers, or what? You could have a Stanley Cup final four of these teams, at least the way they’ve played over the last six weeks, and not be cheated in terms of worthiness or talent.
2. In the six-game winning streak, the Caps have outscored opponents by a 20-9 margin, are 2-for-14 on power plays (14.3 percent), and are 28-for-31 killing penalties (91.2 percent). That minus-17 differential in power plays-to-shorthanded situations is a problem.
3. The Caps are tied for first in the league in wins when outshooting their opponents (18, with Pittsburgh). Both teams also happen to have seven wins and four losses in regulation when out-shot by opponents.
4. For all the shorthanded situations faced, the Caps still have the sixth-fewest penalty minutes per game in the league (8:37), largely a product of there being only two teams having taken more major penalties than the Caps’ five such infractions (Chicago and Carolina with four apiece).
5. Odd fact…only one team in the league (Colorado) has skated fewer 5-on-5 minutes than the Caps this season (1,800; numbers from Corsica.hockey).
The Peerless’ Players to Ponder
Pittsburgh: Chris Kunitz
Time doesn’t wait for anyone, and it doesn’t seem to be inclined to wait much longer for the end of Chris Kunitz’ career. After scoring a career-high of 35 goals in 2013-2014 (nine more than his next highest season and only 30-plus goal campaign), the 37-year old veteran of 13 seasons and almost a thousand regular and post-season NHL games has a total of 38 goals in 187 games since. Once a very efficient shooter (he had only one season in his first nine full seasons below 10 percent shooting and that, in in 2009-2010, was 9.9 percent), he is down to 10.0 percent in his last two-plus seasons and currently at a career-low (for a full NHL seasons) 6.7 percent. He has shown signs of life recently, recording goals in two of his last three games. On the other hand, he hasn’t scored a goal on the road in more than two months (in a 5-0 win over the Sharks in San Jose on November 5th, his only road goal this season). Kunitz is 10-8-18, plus-7, in 31 career games against the Capitals.
Washington: John Carlson
John Carlson’s mystery season continues. It is not his worst scoring season, but it has so far interrupted the incremental progress he made in goal scoring and points on a per-game basis over the previous six seasons. He is not having his worst plus-minus season, but it is a drop-off (plus-7) from what he posted last year (plus-16 in just 56 games). It is not his worst possession season, but he is under 50 percent Corsi-for at 5-on-5 (49.45) after a pair of seasons over 50 percent; numbers from Corsica.hockey). He is not logging an inordinate amount of ice time, his 23:23 in average ice time exceeded by last year’s average (23:42) and that of 2013-2014 (24:31), and is about one shift per game more than his career average (22:47).
But something seems, well…off with Carlson. Perhaps it is his suffering in comparison to Mike Green as a power play quarterback, at least in fans’ eyes. Perhaps it is unfortunate timing, his being on ice for critical goals (the Caps are 4-6-2 when he records a “minus” game). Perhaps it is a lingering hangover (or injury) from his World Cup participation. His ice time has been reined in a bit; he has had more than 24 minutes only twice in his last ten contests. But that ice time does seem to matter somewhat, if only coincidentally. The Caps are 12-3-1 in games in which he skated 23 minutes or less; 14-6-4 in games in which he skated more than 23 minutes. In two games against the Penguins this season he skated more than 24 minutes in each, the Caps winning one and dropping the other in a Gimmick. Go figure. Carlson is 4-8-12, plus-7, in 26 career games against Pittsburgh.
When the Penguins take the ice on Wednesday night, they will have played one game of hockey over the first ten days of January (a 6-2 win over the Tampa Bay Lightning last Sunday). Rest or rust? No matter. The Caps need to jump on this team early, just as they did with a three-goal first period on their way to a 7-1 victory over the Penguins on November 16th. And as for that five-game winning streak the Penguins are bringing into this game, they beat New Jersey in both ends of a home-and-home, Carolina, Montreal (in overtime), and Tampa Bay, Montreal the only one of those teams currently playoff-eligible. They haven’t beaten a playoff-eligible club on the road since before Thanksgiving, when they beat the New York Rangers, 6-1, at Madison Square Garden on November 23rd.
The difficulty for the Caps, as it always is against this team in particular, is that they don’t know the difference between embracing the moment and getting lost in it. Add in the attention being paid to Alex Ovechkin’s pursuit of his 1,000th NHL point in front of a national television audience, and being able to distinguish between the two and playing appropriately matters even more. Lately, the Caps are a team that plays with focus and resolve, going 13-2-3 since they lost to the New York Islanders, 3-0, back on December 1st, the last time the Caps lost a game by more than one goal. This could be a nail biter of a game. Then again, it might not. We’ll go with the latter.
Capitals 4 – Penguins 2
Labels: 2016-2017 nhl season, 2016-2017 pregame, NHL, Pittsburgh Penguins, the peerless prognosticator, Washington Capitals
A TWO-Point Night -- Game 40: Washington Capitals 4 - Montreal Canadiens 1
The Washington Capitals went to Montreal with the mission of extending their winning streak to six games, tying their longest of the season. Mission: accomplished. The Caps scored three third period goals to break a 1-1 tie and defeat the Canadiens, 4-1, on Monday night at Bell Centre.
Nicklas Backstrom opened the scoring mid-way through the first period. He started the play by digging out a loose puck in the corner to the right of goalie Carey Price and sliding it out to Alex Ovechkin at the left point. Ovechkin leaned into a shot that Price stopped. The rebound leaked out into the top of the crease where Backstrom was arriving. He took the puck on his backhand and wrapped it around Price’s left pad to make it 1-0, 11:03 into the period.
That was where the score stood until the third period when the Canadiens tied the game on a power play, Tomas Plekanec solving the chaos in front of goalie Braden Holtby to stuff in a loose puck at 7:18 of the period.
Less than a minute later, the Caps had the lead for good on a sparkling play by Evgeny Kuznetsov. Working his way around Max Pacioretty to collect a loose puck just outside the Montreal blue line, he then dangled around defenseman Jeff Petry to break in on Price. He lifted a shot past Price’s blocker, and the Caps had a 2-1 lead 8:12 into the third period.
Brett Connolly increased the lead less than three minutes later. Carey Price was a bit too lackadaisical in leaving the puck for Petry at the goal line to his right. It was just the opportunity Kuznetsov took advantage of, darting in front of Petry to collect the puck and circle around the Canadiens’ net. Coming out the other side, he spied Connolly coming into the offensive zone. Connolly took Kuznetsov’s pass and snapped a shot past Price to make it 3-1 at the 11-minute mark.
The Caps closed the scoring late in the third on a power play. NIcklas Backstrom and Marcus Johansson exchanged passes on the right side before Backstrom stepped out and sent a pass across to Alex Ovechkin at the top of the left wing circle. Ovechkin settled the puck and in one motion snapped a shot that snuck through and eluded Price’s glove on the far side to give the Caps a 4-1 win.
-- The win allowed the Caps to jump over the New York Rangers into third place in the Metropolitan Division and tie the Pittsburgh Penguins in points (57). Metropolitan Division teams now occupy the top four spots in the Eastern Conference standings.
-- Alex Ovechkin had a three point night (1-2-3) to bring him to within one point of 1,000 for his career. It was Ovechkin’s first two-assist game of the season. His goal was the 544th of his career, lifting him into a tie with the legendary Maurice “Rocket” Richard for 29th place all-time in NHL goal scoring. Next in Ovechkin’s sights in the all-time rankings is Michel Goulet with 548 goals.
-- Nicklas Backstrom and Evgeny Kuznetsov each had two-point games. For Backstrom it was his eighth multi-point game of the season, tying Marcus Johansson for the team lead. It was Kuznetsov’s seventh such game.
-- Liam O’Brien saw his first action of the season after his recent call-up from Hershey. He skated eight shifts and was the only Capital without a shot on goal (he did not have a shot attempt in 6:08 of ice time).
-- Brett Connolly’s fifth goal of the season came in another win. That’s 5-for-5 for Connolly in terms of goals and wins, and the Caps are 19-5-2 with him in the lineup.
-- The Caps enjoyed a 39-23 edge in shots on goal, their biggest shot differential on the road this season.
-- Karl Alzner had a good night in the underlying numbers, finishing a team-best plus-3 and blocking six of the 24 shots the Caps blocked on the evening.
-- The Caps were 4-for-4 on the penalty kill, extending their recent run of success to 56-for-59 in their last 14 games (94.9 percent).
-- Braden Holtby’s shutout streak ended at 167:18 when Tomas Plekanec scored in the third period. Nevertheless, he is 5-0-1, 1.11, .957, with two shutouts in his last six games.
-- The Caps enjoyed a 68-62 overall shot attempt advantage over Montreal, 56-47 at 5-on-5 (CF% of 54.37 percent; numbers from Corsica.hockey).
Even with T.J. Oshie out with an injury, the Caps kept humming along in one of the less friendly venues for road teams in the NHL. If anything, the Caps got stronger as the game went on, dominating the shot attempts from the 30-minute mark on. If there was a dark spot in that regard, it was that the fourth line of Jay Beagle, Daniel Winnik, and Tom Wilson, along with the defensive pair of Karl Alzner and John Carlson, were all under 50 percent CF at fives, the only Caps to do so.
Nevertheless, the Caps took advantage of a depleted team and abused goalie Carey Price far more than they did in their previous meeting, when the Caps managed only 21 shots in a 2-1 loss. The four goals allowed by Price tied his season high, while the 39 shots the Caps fired at him was the fourth-highest total he has faced (it might be worth noting that in the three games with higher shot totals, Price was 2-0-1).
It was a good start to the week, but now things get harder with the Pittsburgh Penguins coming to town on Thursday night. It will present an opportunity – two in fact. Alex Ovechkin could reach the 1,000 point mark in his career, and more important, the Caps could jump over the Penguins into second place in the Metropolitan Division with the Columbus Blue Jackets the only team remaining between them and the best record in the league.
Labels: 2016-2017 nhl season, 2016-2017 postgame, montreal canadiens, NHL, the peerless prognosticator, Washington Capitals
The Peerless Prognosticator is ON THE AIR!!! -- Ga...
A TWO-Point Night -- Game 40: Washington Capitals ...
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386 WordsMar 6, 20132 Pages
Evidence is mounting that, on earth, the “greenhouse effect” is bringing about significant changes in the climate. In The Greenhouse Effect Harold Bernard describes the dynamic as it works on earth. As a result of the burning of fossil fuels carbon dioxide builds up in the atmosphere. This gas is transparent to solar radiation, but opaque to thermal radiation. As a result it lets energy in from the sun, allowing it to heat the earth, but does not allow the heat generated to flow back into space. This causes global warming with all the political-economic consequences that that implies. Today there is a growing conviction in the scientific community that this is indeed happening (though the degree to which it is happening is something much argued over) and there is a growing concern that the results of this could have profound, even catastrophic, effects on ocean levels, agriculture, and many areas of economic concern to human beings. We tend to think of the greenhouse effect as an earthly phenomenon. However, one of our near neighbors in the solar system, Venus, has a pronounced greenhouse effect, and another neighbor, Mars, may have had a pronounced greenhouse effect in the past and still exhibits a very slight one today. Mars was once much different from what it is today. The contemporary surface of the planet shows features that reveal that there was once much running water there. Close studies of images of Mars reveal not only gross geological features that suggest that there was once flowing water on the surface, but also the presence of minerals, iron oxides, that are associated with a water rich environment. One way in which this is explained is that volcanism released carbon dioxide into the atmosphere thus creating a greenhouse effect that raised the temperature and allowed water to flow freely. This, however, was at a very ancient period. The
Global Warming In Canada Global warming has become one of Canada’s popular topics of debate. With the effects on the people and the world, it is a case that needs to be addressed rapidly. This ongoing issue of global warming is a matter that is in dire need of change. Through this climate change, our country and people have endured a lot of economical, environmental and health problems throughout the country. These major themes of Global warming have caused distress on our country, and without
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Literature Review Global warming is described by climate scientist as a phenomenon that contributes to increase of temperature which is near the earth surface as well as in the oceans which started in the mid-twentieth century and its has been projected to be a continuing process. Assessment done by intergovernmental panel on climate change has shown that global service temperatures has been increasing and its attribute to various reasons which include: increasing concentrations of the greenhouse
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impact Global Warming. This document will discuss these two opposing views. Aside from the opposing viewpoints on the effects of Global Warming, there are arguments on the burden of proof. Has science proven what causes Global Warming? Or does our history prove that Global Warming is just a part of nature? There are arguments on the causes of Global Warming; whether it is caused by humanity or whether it is caused by nature and more important there are arguments about the impact of Global Warming; some
Global Warming Student’s Name University Affiliation Global Warming Industrialization remains one of the most important discoveries of man as it enhanced the quality of life. However, with increased production, there were negative consequences to the environment occasioned by the discharge of toxic waste. These gases have led to an increase in the normal hotness of the earth. This increase has, in turn, led to various consequences to the many facets of human life such as economics, politics
Causes of Global Warming The Causes of Global Warming Have you ever wondered what it would be like to go out and not see any trees or animals? Well the way the atmosphere is heating up today you just might experience this kind of event in the future. My essay is in regards to global warming I believe it has a great impact on humans, not only during our present time, but also in our future generation. In this paper I am going to discuss the causes and the effects of global warming and how it
Global Warming: Today Global warming is one of the most pressing issues. Now people are increasingly realizing that global warming is an issue which cannot be ignored and particularly the impacts of Global warming on economy is very significant. Global Warming is the rise in Earth’s oceans and atmosphere average temperature and expectation of continuation. As the impacts of Global warming Glaciers are melting, sea levels are rising and cloud forests are drying due to higher level of greenhouse
Final Paper Global warming is a gradual increase in the overall temperature of the earth’s atmosphere. It is generally attributed to the greenhouse effect caused by increased levels of carbon dioxide, chlorofluorocarbons, and other products. There have been observable effects on the environment such as glaciers shrinking, ice on rivers and lakes are breaking up earlier, and also plant and animal rangers have shifted and trees are flowering sooner. The effects of global warming that scientist have
Global Warming Name Tutor Institution Course Date Whenever the word global warming is mentioned the word gets worried. Global warming has become a great challenge today. Currently global warming is the most trending debate on United Nations conferences and forums all these with an aim of finding valid solutions to this disaster. The scientists have proven that indeed there is global warming. Each debate and every speaker has a different opinion about the causes of global warming, but according
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Hillary Clinton calls Republican's impeachment pledge 'pathetic'
Oct 24th 2015 6:28AM
Hillary Clinton on Friday dismissed as "pathetic" a threat from a conservative lawmaker to impeach her on her first day as president if elected, a view she said must be "good politics with the most intense, extreme part of [Republican] base."
The Democratic presidential front-runner was also forced to defend her husband's record on civil liberties issues including same sex-marriage in a wide-ranging, exclusive interview with MSNBC's Rachel Maddow. The interview was set to air Friday evening at 9 p.m. ET on MSNBC.
SEE MORE ELECTION COVERAGE AT AOL.COM
Clinton laughed when Maddow confronted her with the threat from Alabama Republican Rep. Mo Brooks to try to depose Clinton on "day one" of her hypothetical presidency.
"Isn't that pathetic?" the former secretary of state said with a smile. "It's just laughable, it's so totally ridiculous." She characterized it as one of many GOP efforts to win over "the most intense, extreme part of their base."
WATCH: Clinton appears on The Rachel Maddow Show:
Maddow questioned Clinton on several fronts, including Syria policy, the future of the Veterans Administration, and what Maddow described as a personal concern that the Clintons have surrounded themselves with too many old friends who would want to "fight your wars again."
Maddow's toughest questions addressed Bill Clinton's legacy on civil rights and civil liberties. Many of President Obama's accomplishments on those issues, Maddow argued, involved "undoing things from the Clinton administration." In particular, Maddow cited Clinton's embrace of the Defense of Marriage Act and the Don't Ask, Don't Tell policy blocking gays from serving openly in the military.
Hillary Clinton defended her husband's record.
The Defense of Marriage Act, legislation Bill Clinton signed that defined marriage legally as between one man and one woman, was "a defensive action" to stymie what the Clintons believed was enough political momentum to amend the constitution to effectively bar gay marriage, Hillary Clinton said.
The tough-on-crime bill that her husband signed into law was a reaction to the "horrific crime rates of the 1980s," the former first lady added.
"There was just a consensus across every community that something had to be done," she said.
Clinton noted that she has since disavowed the law and was committed to reforming criminal justice policies. But Clinton framed her overall governing philosophy as one based on pragmatism, a realization that sometimes it's necessary to choose the lesser evil.
"I think that sometimes as a leader in Democracy you are confronted with two bad choices. It is not an easy position to be in, and you have to try to think what is the least bad choice, and how do I try to cabin this off from having worse consequences?" she said.
She embraced President Obama's tenure in office, however, saying she'd like to protect it and in fact "go farther" than he has on some issues.
Clinton spoke to Maddow fresh off her marathon testimony in front of the House panel investigating Benghazi during which, pundits say, she prevailed over 11 hours of pointed Republican questioning and attacks. Clinton blamed GOP partisans, saying the most conservative wing of the party forced many lawmakers to block needed legislation.
"There is this ideological purity test that, I think, unfortunately too many Republicans who know better are being subjected to," she said.
To move past the gridlock in Washington, Clinton said, "we've gotta break the stranglehold that the extremist views in the Republican Party have on too many people who are otherwise sensible."
When asked if President Obama was "naive" to have expected to work with Republicans in office, Clinton demurred, but said the president had been "bewildered" by GOP efforts to block in on issues like the economic stimulus package early in his first term, which was then overshadowed by the financial crisis and a deep recession.
"I spent a lot of time with him in the first four years and he was absolutely sincere [in trying to compromise], and he was often just bewildered that the evidence was clear, the results were going to flow, and the Republicans would privately say, 'Yeah, you're right, but I can't, or I won't.'"
In contrast, Clinton pledged to "go anywhere, talk to anybody, any time to try to find common ground, to try to achieve our national objectives," but she also said she'd "stand by my ground."
"I think it's a constant balance about where one begins and the other one ends," she said.
Click through to see more of Clinton's testimony on Capitol Hill:
Hillary Clinton testifies on Benghazi 10/21
Former Secretary of State and Democratic Presidential hopeful Hillary Clinton waits to testify before the House Select Committee on Benghazi on Capitol Hill in Washington, DC, October 22, 2015. AFP PHOTO / SAUL LOEB (Photo credit should read SAUL LOEB/AFP/Getty Images)
Former Secretary of State and Democratic Presidential hopeful Hillary Clinton arrives to testify before the House Select Committee on Benghazi on Capitol Hill in Washington, DC, October 22, 2015. AFP PHOTO / SAUL LOEB (Photo credit should read SAUL LOEB/AFP/Getty Images)
WASHINGTON, DC - OCTOBER 22: Democratic presidential candidate and former Secretary of State Hillary Clinton takes her seat prior to testifying before the House Select Committee on Benghazi October 22, 2015 on Capitol Hill in Washington, DC. The committee held a hearing to continue its investigation on the attack that killed Ambassador Chris Stevens and three other Americans at the diplomatic compound in Benghazi, Libya, on the evening of September 11, 2012. (Photo by Chip Somodevilla/Getty Images)
Former Secretary of State and Democratic Presidential hopeful Hillary Clinton arrives to testify before the House Select Committee on Benghazi on Capitol Hill in Washington, DC, October 22, 2015. AFP PHOTO/JIM WATSON (Photo credit should read JIM WATSON/AFP/Getty Images)
Hillary Clinton, former U.S. secretary of state and 2016 Democratic presidential candidate, speaks during a House Select Committee on Benghazi hearing in Washington, D.C., U.S., on Thursday, Oct. 22, 2015. Clinton said that she accepted responsibility for a lethal 2012 attack on the U.S. diplomatic mission in Benghazi, Libya and that she sought afterward to improve security for State Department workers abroad, as the House Benghazi panel investigating the incident began a hearing that may prove a turning point for her presidential campaign. Photographer: Pete Marovich/Bloomberg via Getty Images
Clinton acknowledged a need to have a "good, old-fashioned argument and fight about progressive values about the alternatives," but said some things should be above disagreement, like raising the debt limit.
"It is just beyond my understanding how anybody, despite how extreme he might be, would think it would be in America's interest to default on our debt," she said, perhaps a veiled jab at Republican presidential contender Ben Carson and some others in the field who has suggested he'd be open to a default to teach government spenders a lesson.
Clinton also defended her and Obama's record on Libya, which many critics from both sides of the aisle have argued was due in part to the Obama administration's successful effort to oust Libyan leader Moammar Gadhafi, which created a vacuum of power that was filled by extremists.
Clinton said a fledgling democracy had sprung up in Libya following the ouster, but it didn't have the proper resources to take root. She pledged to recommit support to the country.
"I'm not prepared to give up on Libya. I think we have to do more to invest in Libya," she said.
But on Syria, Clinton sounded less optimistic, saying the chaos there was a "different story but perhaps an even worse outcome" if mishandled.
Still, for a moment on Thursday night, after testifying on the situation in Libya for over 11 hours, Clinton said she took a momentary break from the pressures of international conflicts and the presidential race. After leaving the hearing, she said she invited the staff that helped prepare her to her home and they "sat around, eating Indian food and drinking wine and beer."
More from NBCNews.com:
Bush Campaign Slashes Staff in Major Restructuring
Paul Ryan Excited to Have GOP Support for Speaker
Hillary Clinton Clears October Hurdles
The Rachel Maddow Show
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No Bad Injuries In SUV-Pickup Truck Collision
In a wreck that looked worse than it was, a woman and two children, ages about 3 and less than a year old, and two people in an SUV were spared serious injury Thursday afternoon as a pickup truck with a Florida tag and the sport utility vehicle collided at the four-way stop intersection of City Boulevard and Baltimore Avenue, said a spokesman for the Waycross Fire Department.
Waycross Fire Battalion Chief Jimmy Brown did not this morning have the names of the people involved, but he said that everyone was checked out at the scene by Ware County Emergency Medical Technicians and no one was transported to a medical facility to be treated.
“It was really concerning to us because when it was called out, they told us there were children involved and that always is scary. So we really hit it to get there,” Brown said. “When we arrived, someone had already helped get the people out of the vehicles.”
Brown said he thought one of the children in the truck was about 3 or 4 years old and the other was much younger, less than a year old.
Brown did not know how the accident occurred, whether one of the drivers ran the stop sign at a four-way stop intersection, or who was at fault.
“They were trying to figure that out while we were out there but there was no agreement when we left,” said Brown.
Capt. Tommy Cox and Waycross Police Chief Tony Tanner were on the scene helping to investigate the cause of the crash, as were Waycross Fire Lt. Justin Godwin, Randy Deen and Corey Mooneyhan, all of the Havanna Avenue fire station.
Waycross police had not completed their report this morning.
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Here is a brief history of the Socialist Project. This is an exciting addition to the struggle to gain justice in a militarized, hyper-capitalist world:
“The Socialist Project does not propose an easy politics for defeating capitalism or claim a ready alternative to take its place. We oppose capitalism out of necessity and support the resistance of others out of solidarity. This resistance creates spaces of hope, and an activist hope is the first step to discovering a new socialist politics. Through the struggles of that politics – struggles informed by collective analysis and reflection – alternatives to capitalism will emerge. Such anti-capitalist struggles, we believe, must develop a viable working class politics, and be informed by democratic struggles against racial, sexist and homophobic oppressions, and in support of the national self-determination of the many peoples of the world. In Canada and the world today, there is an imperative for the Left to begin a sustained process of reflection, struggle and organizational re-groupment and experimentation. Neither capitalism nor neoliberalism will fade from the political landscape based on the momentum of their own contradictions and without the Left developing new political capacities. We encourage those who share this assessment to meet, debate and begin to make a contribution to a renewed socialist project in your union, school and community.”
View the site here
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Here is a nice post I have reproduced from Mondo Politico – I hope that is OK.
The Socialist Party is a companion party of the World Socialist Movement (“WSM”), which began with the founding of the Socialist Party of Great Britain in 1904. In effect, the WSM (and each of its companion parties, including the Socialist Party of Canada) says it seeks a non-violent revolution to replace capitalism with socialism, which it defines as “…a system of society based upon the common ownership and democratic control of the means and instruments for producing and distributing wealth by and in the interest of society as a whole.” Effectively, the WSM advocates a society in which everyone takes what one needs (somehow without consuming more than is produced), and produces only as much as one wants to produce: in which all labour is voluntary and unpaid, and in which the fruits of labour are free. It elaborates on that definition as follows:
“If there are wages and salaries, it is not socialism.
State ownership is not socialism.
Social programs are not socialism.
Socialism means democracy at all levels of society, including the workplace.
Socialism means a wageless, moneyless society.
Socialism means voluntary labour.
Socialism means free access to the goods produced by society.”
The WSM views government, at present, as being a tool of “the capitalist class”. It is strongly opposed to working with any other political parties, viewing virtually no other party as a socialist party: the WSM takes the position that history has shown other parties never to replace capitalism with socialism (as the WSM defines that term).
Wage Slave News
“A state of Constant Dread” blazed the headlines of “The Toronto Star” on January 13 2007, with the word “Dread” written in 2-1/2 x 11 inch type. “Poverty today,” it continued, “It’s fear. It’s loneliness. It’s not knowing whether your kids will have a decent place to sleep. In 2007, hidden in plain sight, one in six Canadians live in poverty.”
The Star’s editors, who have a long history of advocating reforms, have obviously decided something should be done about it, as it should, though the socialist answer may not be the one they seek. The article continued by giving some shocking figures – 70 000 people living in Toronto are on waiting lists for affordable housing. 14 150 Canadians were living in homeless shelters based on a 2001 census, and probably more by now. 120 “high poverty” neighbourhoods exist in Toronto, which is an amazing figure considering Toronto is considered one of North America’s most prosperous cities and the city most immigrants to Canada head for. 5% of Toronto families are earning less than $20 000 a year. 750 000 Canadians rely on food banks to feed their families.
The article, by David Olive, trots out more horrible statistics, but they all mean the same thing – for a sizable portion of Canada’s work force, things are really grim. Olive complains, first, that many who live in poverty are unable to do much to improve their condition. In the piecework factories in Toronto’s Spadina Avenue garment district, hourly wages are lower than even the lowest minimum wage (New Brunswick’s $6.70) due to the lax enforcement of the labour laws. Furthermore, too many are too busy working two jobs to organize and lobby politicians for a “better shake.” Olive’s second complaint is that these same politicians don’t care. In his words they lack the “political will”. Nevertheless there are a few well-meaning people around who are attempting to deal with the problem. It would be laughable, were it not so pathetic, that their attempts are doomed to end in failure.
Peggy Nash, the NDP MPP for Parkdale, High Park, Toronto, a riding where poverty is all too obvious, is typical of such well-meaning advocates. She admits that her Private Member’s Bill to raise the minimum wage to $10/hour for workers in banking, transportation, telecommunications and other sectors covered by the Federal Labour Law, is no panacea, “It’s just a start, a renewed effort to get people talking about why a G-8 nation tolerates so much poverty and suffering.” Nash says, “And with luck it will encourage provincial governments to raise their minimum wage levels. Nash, however, has a clear idea of how poverty affects people: “Poverty is fear, malnutrition, chronic bad health, loneliness, illiteracy, and inadequate job skills and no time or money to upgrade them.”
John Clarke, an organizer with the Ontario Coalition Against Poverty (OCAP), believes that only a widespread sense of outrage will rid us of “This evil.you have to challenge these injustices endured by our fellow citizens.only when politicians see that the public is active on its own discontent with the status quo will we see a difference.” Clarke bemoans that workers in poverty put a strain on the taxation system in the form of welfare payments, the cost of incarceration among poorly supervised kids whose parents are collectively working three or four jobs, and visits to emergency wards because they cannot afford preventive care. Clarke is obviously unaware that it is the capitalist class that pays the bulk of taxation. In November, Canada’s Food Banks Association noted that, “A majority segment of food bank clientŠle are working people who complain about not being able to obtain more than 25 hours of work per week from any given employer.” This makes them take on additional jobs. “Working night and day including graveyard shifts and no time for their spouse and kids and still not getting ahead,” says Clarke. John Murphy, chairman of The National Council for Welfare (an advisory body to the federal government’s Human Resources and Social Development Department) pointed out that, “Welfare incomes in every province remain far below the poverty line.”
Hugh MacKenzie, a research associate on the Inequality Project at the Canadian Centre for Policy Alternatives, cites three key elements of an anti-poverty strategy. These would be affordable housing, pharmacare and universal child care. MacKenzie says, “A family’s struggle to find housing sucks resources from nutrition and other essentials. Since going off traditional welfare means foregoing drug benefits, the absence of prescription drug coverage for working-poor families keeps them from climbing the welfare wall.” Therefore, it can be clearly seen, that for a person who needs prescription drugs, they can be worse off in a low paid job than being on welfare. Child care is essential, according to MacKenzie, “Because we live in a society where as soon as kids are in school, parents are expected to work, almost always outside the home.”
Nash is understandably concerned that the one hundred highest paid corporate CEOs in Canada are paid an average of $9 million a year and the $22 000 raise that Ontario MPPs recently voted themselves exceeds Ontario’s $19 032 in annual welfare assistance for a couple with two children, which represents a 17% drop since 1989. In one respect, Nash sees things clearly: “Our market economy is marvelous at creating wealth but there’s so little fairness in how that wealth is distributed.” So little? There is none. Her final thought is: “These huge and growing extremes in wealth and poverty are not in anyone’s interest.” – You sure said it lady!
The comments of Nash, Clarke, Murphy, and MacKenzie are included in this review because it shows how out of touch with reality these well-meaning people are. The anarchy of production of the capitalist system means there is no overall planning to match production with human need. Anyone can start up or ramp up production when sales and chances for profit are high. Inevitably a saturation point is reached when demand is lower than production and we have an overabundance of goods. Workers must be laid off and factories closed, creating a recession. Since the seeds of the next boom are to be found in that recession – cheap labour, raw materials, machinery, and factory rent – then we have the continual boom and bust cycles familiar to capitalist production. When opportunity presents itself to the capitalist to expand production, he must be able to find the necessary labour. This is where the poor, unemployed and welfare people come in. They are `the reserve army’ standing by on minimum benefits ready to be called on as required. In other words, they are a necessary part of the system and they won’t go away while the profit system exists, and the people mentioned above are simply attacking the symptoms, not the disease.
The source of all social wealth is human labour. The working class produces an abundance of wealth, so much so that poverty could be eliminated very quickly if a Socialist society, based on the common ownership of the means to produce that wealth were established. Poverty is an endemic part of capitalism and it cannot be different. The fundamental aspects of capitalism are the ownership of the tools of production by a tiny minority of the world’s population and the consequent wage-slavery of the majority. With production for profit, the capitalist tries to extract as much as possible from his workers, who inevitably resist and organize into unions to improve conditions as best they can, hence the class struggle.
Governments, dictatorial or democratic, exist to run the affairs of capitalism and therefore to preserve the status quo, which makes the continuation of poverty inevitable. This does not mean that there are no well-meaning politicians or political parties, but they cannot succeed in eliminating poverty within capitalism. For more than two centuries the profit system has held sway over this planet and none have succeeded in this endeavour yet. In 1945, the British Labour Party introduced the modern day welfare state which, in 1948, included medicare for all. Nobody would deny today that poverty exists in the UK and even their health system is in a mess and suffering from gross underfunding. Nor does it make sense to argue that we don’t have socialism yet, so in the meantime we need to fight for reforms to at least reduce the worst effects of poverty. This argument has been voiced by so many for so long that `in the meantime’ has become forever. The time is long past and too many people have suffered, are suffering, and will continue suffering until we attack the disease itself.
There is one way, and one way only, to abolish poverty, and that is to establish a socialist society in which the tools of production will be commonly owned and administered by the population as a whole in their own interests. In such a world, not only poverty but all the social evils created by the profit system will be abolished. Who would not want to abolish war, famine, crime, preventable disease, planned obsolescence, people having nervous breakdowns, and a host of other problems engendered by profit motives? Who would not want to replace them with a world where all will live in peace, harmony, and prosperity? This, dear reader, can be had as soon as people want it. So why not organize politically in the Socialist Party of Canada and its companion parties around the world to bring it to fruition.
Reproduced from the Socialist Party of Canada (Wage Slave News)
7 responses to “SOCIALISM: HUMANITY’S HIGHEST IDEAL”
stephen.reeves
People are poor in Western Societies because they do not have the brains or education to be anything else raising the minimum wage will not help, most on minimum wage are there for a short time as they move up the workforce, only the dumb ones stay on minumum wage, or single mothers who are too stupid to stop having kids, and lose the father somewhere, and expect everyone else to pay for them.
Or those working through college in fast-food restaurants.
All of this drivel would be extremely humorous (“wage slave”?) if it wasn’t concerning something so serious.
PS – the state of poverty existed and exists in nations under socialist government; more often more than a state under democracy. Are there people in Canada that actually follow this? How frightening.
Guy Watson
Drivel, Keith? A majority of voters chose a part last November that has not performed. It has not performed because it is heavilly supported by the interests the voters were trying to say “no” to. Wall street, Big Insurance, Pharmaceutical corporations, Banks “too big to fail” . If the voters can be trumped time and time again by “representatives” who vote with the corporations who line their pockets then we do not have Democracy. We have a form of Plutocracy, or government by the rich and powerful. If this is drivel than keith you need to go back to school and study a bit of what the founders of this country wanted. Nowhere is Capitalism mentioned. I have lived in Norway for 5 years as a resident. The medical system was great and the country more peaceful. Socialism is incorrectly associated with Communism. The two have nothing in common. In America we have neither Democracy or Capitalism, if capitalism is defined as a free market. Our politicians have chosen to use taxpayer money to subsidise the greedy groups listed about. We need a revolution to return this country to what it was envisioned — not what the rich have created but a place where working people have a fair chance to succeed.
ImpundaInsese
Kick-ass article, good looking website, added it to my favs!!
xrisi kampa
for socialist society is urgent the contestation by exploiteds class the relations of domination,perhaps is the time for contestation
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This following document sets forth the Privacy Policy for the Word On the Street website, www.wots.mobi.
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An Award for our ESOL Classes
The Welsh Refugee Council's is the proud recipient of the Inspire Award for Community Project of the Year 2016.
Eighteen months ago, a collaboration between Dr. Mike Chick of the University of South Wales and the Welsh Refugee Council saw the start of a project designed to improve access to free quality English classes for refugees and asylum seekers in the area. The project started with one class a week, accessed by around 15 students. Following funding from the Waterloo Foundation and Community Foundation in Wales, we are now able to run eight classes a week in our Cardiff offices, which are accessed by around 100 service users a week.
During term time, three classes a week are taught by students from the University of South Wales in their final year of studying TESOL (Teaching English to Speakers of Other Languages) as part of their assessed teaching practicum. The sessions are an important learning opportunity, both for the student teachers and the learners. One student teacher wrote: "Prior to my involvement with the Welsh Refugee Council, whilst I had empathy for refugees, I was rather ignorant as to what goes on. Now, not only do I understand the issues, I see refugees as people. I think we need to push awareness in local communities with local people, in order to change perceptions."
Our projects' capacity has increased to such an extent that we rely on a dedicated team of volunteer language teachers to help us meet the high demand for lessons. We have a
ESOL Award.jpg
lso been able to welcome a PGCE student from Cardiff University on a six-month teaching placement, which she passed with excellent results. In addition, one session a week led by Elizabeth Porter of Cardiff Libraries has helped 137 refugees and asylum seekers join the library, as well as gain valuable information on life in Cardiff, such as; navigating public transport, registering with GPs, council waste management and finding accommodation.
All our classes provide a lifeline for new arrivals in the area and are particularly helpful for those who have missed out on a space in Further Education, or who have aspirations towards Higher Education.
One learner said of his experience: "I choose [the Welsh Refugee Council] because it has best teachers. It's very good and it let me meet new people from other country and culture."
Another said: "When I arrived in the UK, it was extremely difficult for me to communicate. I had problems shopping, using transport and it made every detail of day-to-day life challenging. I was told about free English lessons at the Welsh Refugee Council and without the teachers there, I wouldn’t be able to do anything.”
We are extremely grateful to the University of South Wales lecturers and student teachers, Cardiff Library, our volunteers, staff, and funders The Waterloo Foundation and Community Foundation in Wales. Most importantly, we are indebted to our learners from the refugee, asylum seeking and migrant communities, without whom there would simply be no classes.
For more information on the project, please contact Bethan Roper at bethan@wrc.wales or call 02920 48900 and ask about the service
Tags: ESOL Education Learning English Files:
About the Award 4.73 MB
Press Release 420.29 KB
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Benazir Bhutto a Role Model
Benazir Bhutto was born on June 21st, 1953 in Karachi. She was the eldest daughter of Zulfiqar Ali Bhutto. She studied in Lady Jennings Nursery and was later sent to the Convent of Jesus and Mary that is in Karachi. She spent 2 years at Rawalpindi Presentation convent and then later was sent to Jesus and Mary Convent at Muree. At the age of 15 she passed her O level exams. She got into the U.S. Harvard University Radcliff College and passed out with a political science degree. She joined Oxford University in 1973. She completed her postgraduate course in 1977. She joined her father as an advisor.
Martial law was imposed by General Zia-ul-Haq in 1977. Benazir Bhutto went abroad on medical basis. She spent six and a half years in custody. For 2 years she went into exile. In the year 1985 Benazir came back to Pakistan to stand for the elections at the provincial assemblies. When she returned in the year 1986, a million people greeted her at Lahore. She took up many rallies all over Pakistan. She always wanted to restore democracy in Pakistan.
Benazir Bhutto’s Marriage and Prime Ministership
Benazir Bhutto got married to Asif Ali Zardari in Karachi, on December 18th 1987. She stood for many elections after this. She has three children. Benazir became the first woman Prime Minister of Pakistan when she was 35 years old. She removed the ban on trade unions and students. She lost her power due to differences with the president Ghulam Ishq Khan.
She returned to power and nominated her own president, Farroq Ahmad Khan Leghari. He removed her government on charges of corruption in 1996.
Benazir Bhutto’s Contribution for Pakistani Women
Benazir Bhutto had also fought for women’s health, social and discrimination issues. She had plans to set up police stations of women, banks and also courts. She always spoke against abortion. She was one among the forefront to form the council of women world leaders. Daughter of the East is one among her published books.
Benazir Bhutto was assassinated when on her rally for the PPP on December 27th, 2007 at Liaquat National Bagh. She was killed by a gunman and bomb blasts that killed many others.
As a politician, wife and mother, Benazir fulfilled her responsibilities to the fullest. Thus being an icon to many women. Especially muslim women. Benazir was against violence on woman. Traditionally, muslim women are stuck to household cores and would not venture outside. But Benazir’s zest for life, her charisma was so good that she became a role model to many.
Bhutto was not only a mentor to women but she became a mentor to many politicians also. Many political figures spoke about Benazir as being a good human being and so also a good politician. After her assassination there were many politicians from all over the world who were shocked and spoke in grief about Benazir.
From getting the best of education and being a great leader. Benazir has done it all. She fought for democracy until death. Her intelligence and charm has an everlasting print in everybody’s mind.
Top Pakistani TV Drama Actresses
Top 10 Pakistani/ Lollywood Movies– Pakistani Film Industry
Top 5 Pakistani Wicket Keepers of All Time –...
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Cathie Hallam
Cathie became involved with the Choir when her son, Tom, joined in 1993. It didn’t take long for her to put up her hand to help, at first with the Wardrobe/Stagewear Team, but Cathie’s involvement lasted long beyond her son’s retirement from the Choir in 1998. Cathie continued her work with the wardrobe team, acting as Team Leader for a number of years.
She also helped out with caring roles throughout her involvement, at first at events like Installations and concerts, attended weekend workshops and ultimately became Caring Team Leader, attending or supervising at least six Summer Music Schools, countless weekend workshops and acting as Carer for an amazing four international tours including USA 1998, Rome 2000, USA 2000, USA & Canada 2002. Cathie was “Choir Mum” to a generation of Choir boys, being a constant, calm beacon at the helm of the Caring Team.
Throughout these years, Cathie has also been a huge support for the music and administrative teams and a strong influence on the Choir community. Cathie was a founding member of the Team Leaders Council, involved with the Friends of the Choir and participated in a variety of strategic planning initiatives. In addition she was a Registered Member of the Institute from 1999 to 2006 and with her husband, Ken, has been a regular benefactor and concert attendee, continuing to support the work of the Choir.
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28 February 2019 - The Communities Committee last night (Wednesday 27 February) agreed to support Essex Police by investing £150,000 into the training and employment of three full-time police officers annually for the next two years.
The additional Community Policing Team officers will respond to the priorities identified in the Safer Basildon Partnership Strategy, which was approved at Full Council in July 2018. These include tackling gangs and drug related crime, burglary, anti-social behaviour and knife crime.
Cllr Andy Barnes, Chairman of the Communities Committee, added: "We are committed to working with our partners to shape a borough where people are happy and healthy, and we understand that cracking down on crime is key to achieving this.
"In order to meet the priorities set out in the Safer Basildon Strategy, a robust response is needed as issues arise. We know that a lack of resources can have an effect on the immediacy of action, which is why we are putting money into tackling crime and increasing community safety."
District Commander, Temporary Chief Inspector Steve Parry, added: "This is a really generous offer. I am really excited for the future of the Safer Basildon Partnership.
"When combined with the increased uplift of six officers as a result of the recent precept increase, the Community Policing Team will be better resourced to tackle key issues and alongside its partners make Basildon a safer place."
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Celtics notebook: Robert Williams, Jayson Tatum…
SportsCeltics
Celtics notebook: Robert Williams, Jayson Tatum lost to back issues
Charlotte Hornets guard Dwayne Bacon (7) reaches for a basket while being covered by Boston Celtics defenders Kyrie Irving (11) and Robert Williams (44) in the first half of an NBA basketball game Saturday, March 23, 2019, in Charlotte, N.C. (AP Photo/Jason E. Miczek)
By Steve Bulpett | stephen.bulpett@bostonherald.com | Boston Herald
CHARLOTTE, N.C. — The Celtics began Saturday evening without two of their centers, then added a casualty to the list.
Rookie Robert Williams got the first start of his career, but didn’t make it to halftime before suffering a bruised lower back that could, according to coach Brad Stevens, keep him out a while. Jayson Tatum suffered a back injury, as well, but the hurt he sustained in the latter moments of the 124-117 come-from-ahead loss to the Hornets does not appear as serious.
“Bruised, lower back contusion, whatever that means,” Stevens said. “But I’m guessing we’re looking at a Jaylen (Brown) time frame from this year, at least. Tatum’s being looked at for the same thing. I don’t know how bad his issue is.”
Brown was out three games over nearly two weeks after his fall in Dallas.
Tatum said he was all right as he pulled on his shoes after the game. He will be examined Sunday back in Boston and said, pending the results, he would like to play against the Spurs that night “if they let me.”
It was set up for a big night for Williams. The cult that has named him “Timelord” nearly blew up Twitter with joy when it was learned he would start.
But he went down hard and remained on the floor a few minutes after failing on an attempt to jam home a Marcus Smart missed layup. Williams fell backward and landed on his back, staying put as the Hornets went to the other end and scored. He was then tended to by Celtic medical personnel and taken to the dressing room with 1:37 left in the half.
It took Williams very little time to make a more significant mark after he won the opening tip. Hornets guard Dwayne Bacon drove down the left side of the lane and clearly was oblivious to the fact the Timelord was lurking in the same ZIP code. Bacon thought he had an opening and released his shot, but Williams swatted it hard at the Celtic bench — the place he had begun every game of his professional career until now. (Williams got Bacon again with three minutes left in the second period, besmirching the latter’s Florida State education in the process.)
Stevens, Smart talk
Stevens followed through on a planned conversation with Smart, a chat that seemed all the more needed after the excitable guard said Friday he would repeat the behavior that got him ejected from Wednesday’s loss in Philadelphia for shoving Joel Embiid.
Smart, who was fined $50,000 by the league for his act, did say he had to be more judicious with his actions, but added he wouldn’t hesitate to defend himself if, as was the case when Embiid caught him with an elbow on a pick, he is not protected by the officials. He acknowledged, too, that he’s aware his absence hurt the Celts in what turned into a loss.
That last point is key for Stevens.
“I’ll keep exactly what we talked about between us, but the gist of it is we are all responsible to our team,” the coach said before the game. “And so, ultimately, one of the best abilities is availability, and he knows how important he is. So at the end of the day, that’s a big deal.
“He is a tough guy. He’s a competitive guy, and that’s one of the reasons we need him late, because that’s something I think he brings a contagiousness about him with.”
Monroe on radar
The Celtics were working on the possibility Saturday of bringing back Greg Monroe on a 10-day contract. The 6-foot-11 power forward-center was set to take a physical and have a talk with the Celts’ basketball brass.
If things work out, it will be a reunion for Monroe, who got into 26 games and averaged 10.2 points in 19.1 minutes after signing with the C’s in February 2018. He went to Toronto as a free agent last August and was traded by the Raptors in February to Brooklyn, which released him.
The idea behind Monroe for the Celtics is based on Aron Baynes‘ injury troubles this season. The club is happy with Daniel Theis and Williams, but could probably use more bulk if Baynes is unavailable. And having cleared waivers before March 1, Monroe would be eligible to participate in the playoffs if he signs and stays.
Baynes, Hayward better
Speaking of Baynes, his left ankle has improved greatly, and it’s possible he could be available Sunday when the Celts host San Antonio. The same can be said for Gordon Hayward, who missed his third game under the league’s concussion protocol after taking a hit against Atlanta last Saturday.
“Both really encouraging,” Stevens said. “We flew Aron home (Friday) to be seen by a foot specialist, and he feels really good about it. He could play sooner than we thought, which is really encouraging. And Gordon’s right around the corner. So I would not rule either of them out for (Sunday) based on what I’ve heard, which, for Aron, was kind of a surprise (Friday).”
Kyrie, Green home in
According to Kyrie Irving, there has yet to be a plan set for him taking off games for rest over the final nine games of the season.
“Probably play it as it goes,” he said. “We’ll see.”
As for the desire to get at least into the fourth seed and the chance to open their first-round series at the Garden, Irving said, “If you don’t have homecourt advantage, your odds are already stacked up against you, but that’s just percentages. That’s just facts. And then also seeding, that’s really important. But you’ve just got to go in with that mindset anything’s possible, and what we’re capable of doing when all of us are healthy and we’re all on the floor and we’re playing well, we’re a very tough team to play against, whether we’re on the road or at home. So we’ve just got to come in with that focus, you know, whether we’re home or away.”
Stevens has a similarly larger view of the process.
“I think you’d always prefer to be the home team,” he said, “but at the same time, the other team’s playing, too. They’re a heck of a team.
“And there’s a reason we’re in the spot we are in. We haven’t played as well as we’d like at times this year. Other times we’ve played well. So my biggest focus is on, no matter who’s available, playing well.”
Birthday time
Yesterday had additional meaning for two Celtics, with Irving turning 27 and Hayward 29.
“We celebrate birthdays, I guess, but I never get invited,” Stevens said. “Happy birthday to those guys. It’s amazing how young they are when you consider how good they’ve been.”
Steve Bulpett
Steve Bulpett is in his 34th season covering the Celtics. In addition to being the dean of NBA beat writers in continuous service with a team, he's also followed the Celtics as a home and away beat longer than anyone in franchise history. The native of Lynn and Swampscott is a graduate of the University of Dayton, where he pursued dreams of playing basketball and becoming a lawyer. Reality intervened on the court, but he found a way to stay involved in the game. He left UD with an intramural hoop championship (teammates with sportscaster Dan Patrick) and a journalism degree.
Follow Steve Bulpett @SteveBHoop
Red Sox notes: Closer Nathan Eovaldi could return this weekend
Celtics hope Kemba Walker, Enes Kanter can solve chemistry problem
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Favourite Marches and Hymn Settings of The Salvation Army
Marches include: Amsterdam Congress; A.R.C Centennial March; Balga Citadel; Brazil ‘75; Cairo Red Shield; California; Camp Fellowship; Cobham Hall; Croydon Citadel; Danforth Citadel; Etobicoke Youth; Hadleigh Camp; Hollinwood; In the King’s Service; Minneapolis IV; New Commission; Norwich Citadel; Powerpoint; Rosehill; Rousseau; South Coast; Spirit of Endeavour; The Fount; The Young Salvationist; Visitors Acclaimed; Victory Parade; Washington Salute 125; Wisbech Citadel; Zimbabwe Centenary.Hymns include: A Gaelic Blessing; Amazing Grace!; As the Deer; Be Still for the Presence of the Lord; Blacow; Come, Beautiful Christ; Deep and Wide; Deep River; Fall Afresh; From Earth’s Confusion; He Cares for Me; I Know Thou Art Mine; I Love You, Lord; I Need Thee; I Vow to Thee, My Country; I Will Enter His Gates; In Perfect Peace; It is Jesus; Knowing You; Lift Up the Banner; Lord, With My All I Part; Make Me a Channel of Your Peace; Martyn; ‘Mid All the Traffic; Morning Star; Of Whom I Sing; People Need the Lord; Peter, James and John; Pie Jesu; Praise Him with Song!; Prayer of Childhood; Prayer of Thanksgiving; Reverie; Sacrament; Serenity; Share My Yoke; Someone Cares; Stand Up for Jesus!; Standing Somewhere in the Shadows; Swing Hosanna; The Pearl; The Reason; This is My Story; Thy Will to See; Whiter than the Snow; You Know that We Love You!.
Brilliant Beatles
There have been many arrangements of Beatles' songs for various kinds of ensembles, so rather than just producing a further medley of Beatles' hits, Peter Kleine Schaars has added a new twist to them with this excellent new work. All You Need Is Love and With a Little Help from my Friends pass by in a swing march, Michelle sounds like a newly composed ballad and When I'm Sixty Four is played in Dixie swing style. A Hard Day's Night is transformed into a funk theme with a samba interlude, Let It Be into a slow march, and Ob-La-Di, Ob-La-Da in a rock beat. Experience The Beatles as you have never heard them before.
Blaze - Phil Lawrence
Cornet/trumpet sounds have been changing for some years; they are becoming heavier, more robust, slower vibratos. The dynamic level now pushed out by your average solo cornet is 30% more than it was some 35/40 years ago. This, is mainly due to the bore size of instruments and mouthpiece sizes (as in bigger), and, demands of modern day works for band on the player/soloist, and of course a greater demand of styles on the player, and progressive teaching methods. The technical styles in Blaze are about these changes.In Blaze I have clearly blended symphonic blowing styles of the trumpet plus the virtuosic attributes of today's modern cornet player. Many solo cornets parts (more past than present) in band are often clearly defined between low A and top C above the stave. Orchestral trumpet players need a working range of another fourth at either end of this defined range; I have incorporated this range into the concerto. The low register is much explored, and the average tessitura throughout is constantly varied below and above the stave from pedal Eb to super F# opt. The ideology of this blend of course makes sense as the original dedication is to Rod Franks, LSO, and of course blending with that is Rod's history at Black Dyke Mills Band.The concerto is ten minutes long and in one movement comprising of four sections and one solo cadenza, with one section only appearing once, an episode. This singular section was a revised addition and dedicated to Richard Marshall who gave the first premier in New Zealand in June 2003. For the purists the form is thus, A, B, A (vari), C (episode). D (slow movement), E (3/8 episode 1), D (vari), E, (episode 2). A (last move), B, A (developed) = (coda finale).The compositional style? Well, I hope quintessentially, 21st C English with an element of nostalgia (modal/old English). There are some hints at jazz playing styles and rhumba, but romantic English I would say, and especially the slow movement.Blaze is also very bold; the title itself reflects this, full of bravura and constant amazement, offering little respite for the soloist and sapping much stamina. The opening statement from the soloist is without accompaniment; just as a matador stands alone in the ring for the first few seconds, and looks at the mass crowd in defiance, he thinks, "you are here to see me die", so the soloist stares the audience back in the face, and opens with the richest, largest sound (not loudest) one can muster, thus throwing the gauntlet down to the ears of all who might disbelieve what they are about to encounter, a gladiatorial cornet, a Blaze from the stage.For the soloist, it is a non-stop Blaze of sound, electrifying technique, sage-like musicianship, super-human stamina and sheer matador-like bravura with 10th Dan mastery of over-all control, a test beyond the reasonable. And for the audience? Of course, a BLAZE never to be forgotten. Phil LawrenceThis work can be heard performed by cornet soloist Richard Marshall & the Grimethorpe Colliery Band on their award winning album entitled 'BLAZE'
Estimated delivery 5-7 days
Carol of the Bells - Mykola Dmytrovych Leontovych
Christmas time is my favourite time of year. I love the festive spirit and all the Christmas music both traditional and modern.This piece is based on the traditional Ukrainian Bell Carol that was composed by the Ukrainian composer Mykola Dmytrovych Leontovych. Throughout the piece you hear a four note ostinato that is the backbone to the music. I have taken those ideas and motifs and have mixed them with some of my own to create this piece of Christmas music.For something different I have given this piece two endings for the conductor to choose. The first ending is at bar 189 (page 18 in the score) where there is the repeated four bar ostinato section in the solo cornets and percussion that is marked "Keep repeating and fade to nothing". This is so the piece can either fade to nothing or for a bit of originality the piece can fade into the next piece during a concert programme.For ending number two you need to cut from bar 189 to 193 (bypassing ending one). And continue to the end. The choice of endings should bring some interesting performances of this wonderful traditional Christmas piece.Paul Lovatt-Cooper
Don't Sit Under the Apple Tree - Stept - Bjorn Morten Kjaernes
"Don't Sit Under the Apple Tree (With Anyone Else but Me)" is a popular song that was made famous by Glenn Miller and by the Andrews Sisters during World War II. Its lyrics are the words of two young lovers who pledge their fidelity while one of them is away serving in the war.Originally titled "Anywhere the Bluebird Goes", the melody was written by Sam H. Stept as an updated version of the nineteenth-century English folk song "Long, Long Ago". Lew Brown and Charles Tobias wrote the lyrics and the song debuted in the 1939 Broadway musical Yokel Boy. After the United States entered the war in December 1941, Brown and Tobias modified the lyrics to their current form, with the chorus ending with "...'till I come marching home".In 1942 the song was featured in the film Private Buckaroo as a performance by the Andrews Sisters with the Harry James orchestra and featuring a tap dancing routine by The Jivin' Jacks and Jills. It was featured in the films Twelve O'Clock High (1949), With a Song in My Heart (1952), Kiss Them for Me (1957), A Carol for Another Christmas (1964), In Dreams (1999) and The Master (2012). It also featured in the mini-series The Pacific. You can use the song both on musical concerts, movie concerts or just as a happy jazz tune on your next concert.On the sections (like from bar 25), please work carefully to make a good balance with all parts, and that each chord is balanced. With 4-part harmonies sometimes you need to hold back certain notes to make the accord sound good.If you want to open up for a longer improvisation, you can repeat 65 to 81, but then change the part 2 in bar 80 from Eb to a D on the repeat. The accord will be an F6 instead of F7 (on beat 3 and 4 in bar 80) Have fun and enjoy!
DescriptionThe Once and Future King is a suite of three movements; each movement was inspired by an Arthurian legend. The first movement, 'Tintagel', concerns the famous Cornish promontory said to be the birthplace of King Arthur. In Arthur's time, Tintagel was part of the court of King Mark of Cornwall and the music imagines a visit by the King of the Britons to his Cornish neighbour and the place of his birth, reflecting the ceremony and drama of such an occasion; the music is strongly antiphonal, contrasting the more strident fanfares of the cornets and trombones with the warmth of the saxhorns and tubas.The second movement, 'Lyonesse', takes its inspiration from the mythical land which once joined Cornwall to the Isles of Scilly. One legend claims that after the disastrous battle of Camlan where Arthur and Mordred were both killed, the remnants of Arthur's army were pursued across Lyonesse to Scilly, whereupon Merlin cast a spell to sink Lyonesse behind them and drown the pursuers. Some say the bells of the 140 churches inundated that day can still be heard ringing. All the material in this movement derives from two short motifs heard in counterpoint at the very beginning, which are intentionally dissonant and bitonal in character.The final movement, 'Badon Hill', takes its title from the legendary site of Arthur's last battle with the Saxons and is a lively toccata based on the medieval secular song L'Homme Armee ('The Armed Man'). The music uses a number of medieval devices including "hocketing" (passing melody from one voice to another). The actual site of Badon Hill is unknown but it has been associated with Badbury Rings in Dorset and a lot of evidence now points towards the town of Bath. Arthur's victory at Badon Hill was the last great victory for Celtic Britain over the Saxon invaders, but in the end only set the conquest back by a few decades. Arthur himself was dead by then, betrayed and defeated by his nephew Mordred, but it is said that Arthur only sleeps and will return in a time of dire need – hence the legend that Arthur's dying words were: Bury me in Britain, for I am the Once and Future King.
Don't Sit Under the Apple Tree - Stept-Brown-Tobias - Bjorn Morten Kjaernes
"Don't Sit Under the Apple Tree (With Anyone Else but Me)" is a popular song that was made famous by Glenn Miller and by the Andrews Sisters during World War II. Its lyrics are the words of two young lovers who pledge their fidelity while one of them is away serving in the war. Originally titled "Anywhere the Bluebird Goes", the melody was written by Sam H. Stept as an updated version of the nineteenth-century English folk song "Long, Long Ago". Lew Brown and Charles Tobias wrote the lyrics and the song debuted in the 1939 Broadway musical Yokel Boy. After the United States entered the war in December 1941, Brown and Tobias modified the lyrics to their current form, with the chorus ending with "...'till I come marching home".In 1942 the song was featured in the film Private Buckaroo as a performance by the Andrews Sisters with the Harry James orchestra and featuring a tap dancing routine by The Jivin' Jacks and Jills. It was featured in the films Twelve O'Clock High (1949), With a Song in My Heart (1952), Kiss Them for Me (1957), A Carol for Another Christmas (1964), In Dreams (1999) and The Master (2012). It also featured in the mini-series The Pacific. You can use the song both on musical concerts, movie concerts or just as a happy jazz tune on your next concert. On the sections (like from bar 25), please work carefully to make a good balance with all parts, and that each chord is balanced. With 4-part harmonies sometimes you need to hold back certain notes to make the accord sound good. If you want to open up for a longer improvisation, you can repeat 65 to 81, but then change the part 2 in bar 80 from Eb to a D on the repeat. The accord will be an F6 instead of F7 (on beat 3 and 4 in bar 80) Have fun and enjoy!
Black dyke brass band
abba medley
brass band photographs
piano brass band
(march)
holy night
Howard lorriman
solo euphonium
best marches
hymn of
into night
jazz christmas
bach brass band
furioso polka
portrait of city
judges of the secret
air from bach
Lake of the Moon
martin carron
Peter the wolf
true comrades
in memoriam: for the fallen
Jean-Francois Michel
in the stone brass band
dark abyss
How d
Snell
a time for
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Family of Slain Border Patrol Agent Brian Terry: Trump’s ‘Going to Give Us Answers’
Photo: Facebook/Kelly Terry-Willis
The family of slain U.S. Border Patrol Agent Brian Terry may finally see some light at the end of the tunnel after Republican presidential presumptive nominee Donald Trump promised them some answers.
Kent Terry, the brother of Agent Brian Terry, met with Mr. Trump along with his older sister Michelle, he said in an interview with Breitbart Texas Thursday evening. “He told us how sorry he was about Brian’s senseless death,” Kent said. “Mr. Trump said it was shameful on this administration for starting a scandal like this and shameful for what they’re doing about it.”
The scandal revolves around two of the guns found at the scene of Agent Terry’s December 2010 murder in southern Arizona. Terry was on patrol with members of his team searching for Mexican “rip-crews” that come into the U.S. from Mexico to steal drug shipments or rob illegal aliens. When his team found the rip-crew a gun battle ensued and Brian Terry was mortally wounded. He later died from his wounds.
Two of the guns that were found were eventually tied to a gun running operation that became known to the world as “Fast and Furious.” The stated goal was to put guns into the hands of criminals and track them back to Mexico to discover the distribution network. Things went horribly wrong and two of those guns ended up at the scene of Terry’s murder.
Despite congressional hearings and promises from the government, the Terry family still does not really know what happened that night and no one in the government has been punished for their failed operation that led to Terry’s death, and that of potentially thousands of Mexican citizens.
“Bob, Mr. Trump is very sincere about this country and the way it is heading,” Kent continued. “He also is very sincere about Brian’s death. Yes, he promised us if he becomes president, he will open the books on Fast and Furious. He has my vote!”
Kent’s sister, Kelly Terry-Willis agrees with her brother about Trump’s sincerity on the issue of Brian’s murder. “All my family has ever wanted from the day Brian was murdered is truth, “Kelly told Breitbart Texas Thursday evening.” I want people to grow a conscious and come clean as to what transpired, what was covered up and what the hell were they thinking.”
She said she has heard many promises by many people. “If Mr. Trump can get those skeletons out and expose the truth then my family can finally get closure and justice for Brian,” Kelly explained. “I think there are a lot of people scared that just might happen. It may take time and we will be patient, but the truth always reveals itself. I hope Trump can make that happen.”
Brian’s big sister, Michelle Terry-Balogh told Breitbart Texas, “I honestly felt Mr. Trump means what he says, He was very aware of the details on the fast and furious program. He gave us hope of finally holding those involved in the botched gun program accountable. Not only do the victims’ families deserve the truth, but my brother Brian who was killed protecting each and every one of us deserves it as well.”
Michelle was with her brother Kent during the meeting with the presidential candidate.
Kent continued his conversation with Breitbart Texas saying, “It’s funny. I liked Trump before he even made it this far. He is a fighter and I like that.”
Breitbart Texas asked him if he really believed Trump could deliver on his promise. “I think he is the man that will,” Kent firmly responded. “It seems things are finally falling into place.”
In December, it will be six years since the brother of these three brave family members was killed. Brian Terry was killed on his last shift before he was scheduled to come home to Michigan for a Christmas break.
Many people have asked a lot of questions, but the Obama administration has put up roadblocks at every attack point. Congress seems to have come to a dead end, for now.
In an interview with Fox News Channel’s Sean Hannity, Kent asked, “”Where’s Issa, where’s Grassley, where’s Gowdy, where’s Chaffetz? They were all pit bulls at the beginning of this Fast and Furious and all of a sudden they just shut it off like a light bulb.” He was referring to the congressional leaders who have thus far failed in their efforts to deliver answers to what really happened on the night Brian Terry was murdered and who should be held accountable for Fast and Furrious and all of the lives that have been lost.
Bob Price serves as associate editor and senior political news contributor for Breitbart Texas and is a member of the original Breitbart Texas team. Follow him on Twitter@BobPriceBBTX.
Border / Cartel ChroniclesPoliticsBorder PatrolBrian TerryFast and Furious
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Home › News › Northern Ireland
I was not a member of the IRA but I will never disassociate myself, says Adams
The former Sinn Fein leader was speaking as he gave evidence to an inquest into a disputed shooting in west Belfast in 1971.
Former Sinn Fein President Gerry Adams, arrives at Laganside Court (Liam McBurney/PA)
Gerry Adams has repeated his denial that he was a member of the IRA, but said he will never disassociate himself from the organisation.
https://www.belfasttelegraph.co.uk/news/northern-ireland/i-was-not-a-member-of-the-ira-but-i-will-never-disassociate-myself-says-adams-38092068.html
https://www.belfasttelegraph.co.uk/news/northern-ireland/article38092065.ece/a73ce/AUTOCROP/h342/bpanews_3bb146e5-0133-48b4-a803-6b56bbb97261_1
The former Sinn Fein president was giving evidence to a fresh inquest into the killing of 10 people in the Ballymurphy area of Belfast in 1971.
The episode dubbed the “Ballymurphy massacre” started on August 9 as the British Army moved into republican strongholds to arrest IRA suspects after the introduction by the Stormont administration of the controversial policy of internment without trial.
A new inquest at Belfast Coroner’s Court is examining the deaths of 10 civilians, including a Catholic priest and a mother of eight, between August 9 and 11.
The victims of the shootings (PA)
Claims that IRA gunmen were in the area at the time have been disputed during the inquest hearings.
David Heraghty, counsel for coroner Siobhan Keegan, put to the Louth TD that he was a senior member of the IRA in the area at the time.
Mr Adams responded: “I was not a member of the IRA, I have never disassociated myself from the IRA and I never will until the day I die.
“I understand that victims of the IRA won’t like what I am saying… I deeply regret there was a war.”
He praised the “maturity of the IRA” for “embracing the peace process” and “fading” away.
A barrister for the Ministry of Defence pressed Mr Adams, suggesting he was sworn into D Company of the IRA in 1966.
Mr Adams responded: “That’s not correct.”
The barrister put to Mr Adams that he was commander of the IRA in the Ballymurphy area in November 1969.
Mr Adams responded: “That’s not correct. I gave a full answer to this question when it was put to me by Mr Heraghty.”
Families outside Laganside Court in Belfast (Liam McBurney/PA)
Earlier in the hearing, Mr Adams detailed how, during the mid to late 1960s, he was involved with republicanism, describing himself as an “organiser” and a member of Sinn Fein.
The Provisional IRA is believed to have been founded in 1969, and went on to become the dominant force in violent Irish republicanism until the Good Friday Agreement in 1998.
Mr Adams told the inquest that in 1969 he was in the minority as not having been involved with the military wing of republicanism.
“I had the distinction of having been active since the mid 1960s and having been involved in the type of agitated activity. I continued with that,” he told the inquest.
“The military tendency within republicanism was the dominant tendency.”
Generals did what generals do. Individual soldiers were ordered to pacify, subdue and kill the enemy Gerry Adams
He described Ballymurphy in 1971 as being under a “heavy” and “aggressive occupation” by the British Army and claimed CS gas and rubber bullets were frequently deployed against residents.
“The British government opted for the military option and reneged on its political responsibilities, and handed it over to the generals,” he told the inquest.
“Generals did what generals do. Individual soldiers were ordered to pacify, subdue and kill the enemy, and the enemy in this case were the decent people of Ballymurphy.
“It is hardly surprising that the Provisional IRA came into the ascendancy fairly quickly.”
Mr Adams said he did not witness any of the deaths despite his home being in Divismore Park.
He said at that time he rarely slept at his family home following an incident when masked men called at the front and side doors looking for him, when he was staying with a friend in nearby Springhill Crescent.
Mr Adams said his father and brother Liam were interned on August 9, and soldiers had asked for him.
Asked whether the IRA had attacked the Army on August 9, Mr Adams told the inquest he did not have direct knowledge of the Provisional IRA’s actions, but he understood it ordered no engagement with the British Army that day.
He said there had been a rumour in the area that a gunman from the Official IRA had fired on the Henry Taggart Memorial Hall where the Army was based, but added that the “bush telegraph” in those days was “sometimes accurate and sometimes inaccurate”.
He said it had been a “sensible decision” by the Provisional IRA not to “engage the British Army”, for the “safety of the community and safety of the volunteers”.
The inquest continues.
DUP's Nelson McCausland to take part in west Belfast Feile
Former DUP MLA Nelson McCausland is set to take part in an event at the 2019 west Belfast Feile an Phobail.
Belfast Trust apologises after radiotherapy delays
Belfast Trust has apologised to patients after a number were affected by radiotherapy delays at the Northern Ireland Cancer Centre.
Lords overwhelmingly back abortion liberalisation for Northern Ireland despite...
A liberalisation of abortion in Northern Ireland has been overwhelmingly backed by peers.
Same-sex marriage for Northern Ireland could be delayed until 2020 after Lords amendments
Revised proposals have been agreed to ensure that MP-backed moves to allow same-sex marriage in Northern Ireland can be introduced.
The Open: Updates as Rory McIlroy predicts big Open legacy and completes morning... The Open
Harry Potter star Radcliffe unearths tragic Northern Ireland roots on Who Do You... News
The Open: Rory McIlroy completes first practice round and Tiger Woods hails... The Open
Ruth laughs as Eamonn Holmes blasts erectile dysfunction ad claims News
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Jon Chase
News - Harvard Gazette
What Russia wants
Read more about What Russia wants
Putin and his government seek respect, stability from next U.S. administration, panel says.
Announcement - Managing the Atom Project, Belfer Center
2016-2017 Harvard Nuclear Policy Fellowships
Read more about 2016-2017 Harvard Nuclear Policy Fellowships
The Project on Managing the Atom offers fellowships for pre-doctoral, post-doctoral, and mid-career researchers for one year, with a possibility for renewal, in the stimulating environment of the Belfer Center for Science and International Affairs at the Harvard Kennedy School. The online application for 2016-2017 fellowships opened December 15, 2015, and the application deadline is January 15, 2016. Recommendation letters are due by February 1, 2016.
Bennett Craig
“Afghanistan: Covering America’s Longest War”
Read more about “Afghanistan: Covering America’s Longest War”
“It’s been the same war fought 12 times over,” said Sean Carberry, former Afghanistan correspondent for NPR, in a public address on April 27 entitled “Afghanistan - Covering America’s Longest War.” As part of the Future of Diplomacy Project’s annual “South Asia Week,” jointly sponsored by the India and South Asia Program at Harvard University, Sean Carberry was joined by fellow Afghanistan-based journalist, Anand Gopal, who also shared reflections on covering the complex conflict. Their insightful remarks, concerning the different layers of conflict at play in Afghanistan, were moderated by the project’s Executive Director, Cathryn Clüver.
News - Women’s International League for Peace and Freedom
China’s Nuclear Modernization
Read more about China’s Nuclear Modernization
In “China’s Nuclear Modernization,” a chapter in Assuring Destruction Forever: 2015 Edition (edited by Ray Acheson, published by Reaching Critical Will, a project of the Women’s International League for Peace and Freedom), Hui Zhang contributes to a summary of global nuclear modernization.
News - Managing the Atom Project, Belfer Center
Fresh Ideas for the Future: Symposium on the NPT Nuclear Disarmament, Non-proliferation, and Energy
Read more about Fresh Ideas for the Future: Symposium on the NPT Nuclear Disarmament, Non-proliferation, and Energy
On April 28, the Project on Managing the Atom joined the James Martin Center for Nonproliferation Studies at the Middlebury Institute of International Studies at Monterey, The Netherlands government, and the United Nations Office for Disarmament Affairs (UNODA) in convening nuclear nonproliferation experts from around the world at the United Nations to participate in a Symposium on the 2015 Nonproliferation Treaty (NPT) Review Conference.
Secretary Albright on Negotiation: Photo Gallery
Read more about Secretary Albright on Negotiation: Photo Gallery
The Future of Diplomacy Project proudly hosted former U.S. Secretary of State Madeleine K. Albright at the Spangler Center in April through the American Secretaries of State Project, jointly directed by Harvard Business School and Harvard Law School's Program On Negotiation. Led by Faculty Directors, Professor Nicholas Burns of the Harvard Kennedy School, Professor James Sebenius of the Harvard Business School, and Professor Robert Mnookin from Harvard Law School, the program seeks to interview former Secretaries of State to gain their insights into how modern diplomacy and negotiation can be used effectively in response to "intractable" conflicts.
The Future of Diplomacy Project in 2014: Photo Gallery
Read more about The Future of Diplomacy Project in 2014: Photo Gallery
Hosting speakers such as US Secretary of State Henry A. Kissinger, President of Turkey Dr. Abdullah Gül, and China's Ambassador to the US Cui Tiankai, the Future of Diplomacy Project has had an amazing year in 2014, pursuing its mission to promote public understanding of modern diplomatic practice in response to complex international issues.
Symposium on the Non-Proliferation Treaty, Nuclear Disarmament, Non-proliferation, and Energy: Fresh Ideas for the Future
Read more about Symposium on the Non-Proliferation Treaty, Nuclear Disarmament, Non-proliferation, and Energy: Fresh Ideas for the Future
The ninth Review Conference of the Treaty on the Non-Proliferation of Nuclear Weapons (NPT) will be held at the UN Headquarters in New York from April 27-May 22, 2015. This is the fourth such conference since the indefinite extension of the NPT in 1995. Participating governments will discuss nuclear disarmament, non-proliferation, and the peaceful use of nuclear energy with a view to arriving at consensus on a number of issues.
News - Belfer Center for Science and International Affairs, Harvard Kennedy School
Harvard’s Belfer Center Launches One-Stop Website for Nuclear Security Facts, Analysis
| March 3, 2014
Read more about Harvard’s Belfer Center Launches One-Stop Website for Nuclear Security Facts, Analysis
Harvard Kennedy School’s Belfer Center for Science and International Affairs today launches a new website – Nuclear Security Matters – that provides policymakers, researchers, journalists, and the interested public with a wealth of facts, analysis, key documents, and other resources critical to the 2014 Nuclear Security Summit goal of preventing nuclear terrorism around the globe.
Nuclear Security Matters was developed by the Belfer Center’s Project on Managing the Atom with input from Center nuclear experts Graham Allison, Matthew Bunn, Trevor Findlay, Gary Samore, William Tobey, and others.
New Book by Graham Allison and Robert Blackwill Explores Global Insights of “Grand Master” Lee Kuan Yew
Read more about New Book by Graham Allison and Robert Blackwill Explores Global Insights of “Grand Master” Lee Kuan Yew
When Lee Kuan Yew speaks, who listens? Presidents, prime ministers, chief executives, and all who care about global strategy.
Graham Allison and Robert D. Blackwill, two leading strategic thinkers, asked Lee Kuan Yew the toughest questions that matter most to thoughtful Americans weighing the challenges of the next quarter century. The result is their new book, Lee Kuan Yew: The Grand Master’s Insights on China, the United States, and the World – published today by MIT Press.
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Home Tags Posts tagged with "european parliament"
European Parliament Lifts Marine Le Pen’s Immunity over ISIS Pictures
French far-right leader Marine Le Pen has lost immunity from prosecution after she tweeted pictures of ISIS violence.
Her position as a member of the European Parliament has so far meant she could not be prosecuted.
Marine Le Pen is under investigation in France for posting three images of ISIS killings in 2015, including the beheading of American journalist James Foley.
She is currently running to be French president.
Opinion polls suggest Marine Le Pen is on course to win the first round in April, but centrist Emmanuel Macron is gaining ground and looks likely to beat her in a second round in May.
A Le Figaro/LCI poll on February 26 put Emmanuel Macron – who was unveiling his manifesto at the same time as it was revealed Marine Le Pen had lost her immunity – on 58% in the run-off, against 42% for Le Pen.
The European Parliament vote – carried by a “big majority”, according to acting parliament speaker Dimitrios Papadimoulis – confirmed a preliminary decision taken on February 28 by the legal affairs committee of the European Union legislature.
Marine Le Pen had dismissed efforts to lift her immunity as “part of the system that wants to stop the French people’s candidate that I am”.
The allegations date back to December 2015, when she tweeted the pictures in response to a journalist who drew an analogy between her anti-immigration Front National (FN) party and ISIS extremists.
James Foley’s parents accused Marine Le Pen of using the image of their son for her own political ends.
However, the vote only lifts Marine Le Pen’s immunity in this particular case and will not cover a separate investigation into whether the FN misused European Parliament funds.
Marine Le Pen has refused to attend a police interview over the latter allegations. She denies wrongdoing and claims that they are a plot to derail her campaign.
Marine Le Pen Refuses to Repay Misspent EU Funds
France’s far-right leader Marine Le Pen missed a European Parliament deadline to return more than 300,000 euros ($321,000) it says she has misspent.
Marine Le Pen had until midnight to repay the money, but said she had no intention of doing so.
According to the European Parliament, the French presidential candidate wrongly used the funds to pay an aide at the National Front’s headquarters in Paris.
Marine Le Pen says she is the victim of a politically motivated vendetta.
If she does not repay the money, the parliament could now respond by withholding as much as half of her salary and allowances, which her opponents say total almost €11,000 a month.
Marine Le Pen is one of the front-runners in the French presidential election to be held in April and May. If she wins, she has promised a Brexit-style referendum on France’s membership of the EU.
Polls suggest that Marine Le Pen will make it to the run-off where she is likely to face conservative candidate Francois Fillon or centrist Emmanuel Macron.
“I will not submit to the persecution, a unilateral decision taken by political opponents… without proof and without waiting for a judgement from the court action I have started,” she told Reuters on January 31.
The money the European Parliament wants returned was used to pay the salary of Catherine Griset, a close friend of Marine Le Pen as well as her cabinet director.
The funds were conditional on Catherine Griset spending most of her working time in Brussels or Strasbourg.
However, the parliament says most of Catherine Griset’s time was instead spent working in the National Front’s headquarters in Paris. The party will face a second demand for 41,554 euros in wages paid to her bodyguard.
Marine Le Pen also tried to distance herself from financial allegations overshadowing Republican candidate Francois Fillon, who has vigorously denied that his wife was paid 834,000 euros for fake jobs.
Asked if she would pay back the money, the far-right leader told AFP: “To pay the money back, I’d have had to have received the funds, but my name isn’t Francois Fillon.”
Quite apart from her refusal to pay back the funds, Marine Le Pen might struggle to find the money. Her party has been unable to raise funds from French banks and has had to seek financing abroad.
In 2014, the FN received a €9 million loan from Russian lender First Czech-Russian Bank, which collapsed in 2016.
Refugee Crisis: 120,000 Additional Migrants to Be Distributed Among EU Countries
In a “state of the union” annual address in front of the European Parliament, European Commission President Jean-Claude Juncker has announced plans that offer a “swift, determined and comprehensive” response to Europe’s migrant crisis.
Under the proposals, 120,000 additional asylum seekers will be distributed among EU countries, with binding quotas.
It comes after a surge of thousands of mainly Syrian migrants pushed north through Europe in recent days.
Jean-Claude Juncker told the European Parliament it was “not a time to take fright”.
He was heckled by UK anti-European Union politician Nigel Farage, but dismissed his comments as “worthless”.
Germany, the main destination for many migrants, supports quotas, but some EU countries oppose a compulsory system.
Hungary – a key point on a migrant route – has been warned to expect an additional 40,000 migrants by the end of next week.
In a separate development Australia, which has been under pressure to do more to help displaced people, has announced plans to take in more Syrian refugees.
The Australian government said it would accept 12,000 Syrian refugees from persecuted minorities.
During his address, Jean-Claude Juncker outlined the priorities of the European Commission.
He opened his speech by admitting the European Union was “not in a good situation… There is a lack of Europe in this union, and a lack of union in this union”.
He said tackling the crisis was “a matter of humanity and human dignity”.
“It is true that Europe cannot house all the misery in the world. But we have to put it into perspective.
“This still represents just 0.11% of the EU population. In Lebanon refugees represent 25% of the population, which has just a fifth of the wealth of the EU. Who are we to never make such comparisons?”
Among Jean-Claude Juncker’s proposals:
EU member states to accept their share of an additional 120,000 refugees, building upon proposed quotas to relocate 40,000 refugees which were set out in May (though governments then only actually agreed to take 32,000)
A permanent relocation system to “deal with crisis situations more swiftly in the future”
Commission to propose list of “safe countries” to which migrants would generally have to return
Efforts to strengthen the EU’s common asylum system
A review of the so-called Dublin system, which states that people must claim asylum in the state where they first enter the EU
Better management of external borders and better legal channels for migration
“It’s 160,000 refugees in total that Europeans have to take into their arms and I really hope that this time everyone will be on board – no rhetoric, action is what is needed,” Jean-Claude Juncker told the European Parliament.
The proposals will be discussed by EU home affairs ministers on September 14 in Brussels.
The new plans would relocate 60% of those now in Italy, Greece and Hungary to Germany, France and Spain.
The numbers distributed to each country would depend on GDP, population, unemployment rate and asylum applications already processed.
Countries refusing to take in migrants could face financial penalties.
The Czech Republic, Slovakia, Poland and Romania have opposed the idea of mandatory quotas.
On September 8, though, Poland appeared to soften its position. PM Ewa Kopacz said Poland would accept more migrants than the 2,000 it first offered to take.
Germany has welcomed Syrian migrants, waiving EU rules and saying it expects to deal with 800,000 asylum seekers this year alone – though not all will qualify as refugees and some will be sent back.
The mass migration has seen those seeking an end to persecution, conflict and hardship travel by boat, bus, train and on foot, from Turkey, across the sea to Greece, through Macedonia and Serbia, and then to Hungary from where they aim to reach Austria, Germany and Sweden.
Pope Francis arrives in Strasbourg to address European Parliament and Council of Europe
Pope Francis is visiting Strasbourg where he will address the European Parliament and Council of Europe on social and economic issues.
The Pope is expected to speak about anti-immigration sentiment and unemployment during his four-hour trip.
Many of Strasbourg’s Catholics are upset that he will not meet them or visit the city’s cathedral.
Some Catholics have accused the Pope of neglecting Europe since his election in 2013.
Pope Francis visited the Italian island of Lampedusa in July 2013 to meet and pray for illegal immigrants, and went to Albania in September. The Pope has said that he is planning a second visit to France in 2015.
Residents of Strasbourg have been told they can watch both of the pontiff’s speeches on a giant screen that will be installed inside the cathedral, which is celebrating its millennial anniversary.
Pope Francis is making the second papal visit to Strasbourg after Pope John Paul II visited the city in 1988.
Pope John Paul II addressed the European parliament where he was heckled by Northern Irish MEP the Rev Ian Paisley.
During his speech the late Pope called Europe “a beacon of civilization”.
However, Pope Francis has called Europe a “tired” continent which worships the “idol of money”.
In Strasbourg, Pope Francis is expected to call for greater tolerance and inclusion in response to the success nationalist parties have seen in parts of Europe.
In May, several of these parties performed strongly in the European parliamentary elections.
Pope Francis is also thought likely to address Europe’s ongoing economic crisis and the social problems that it has created.
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EU alarm over US spying claim
Martin Schulz, the head of the European Parliament, has demanded “full clarification” from the US over a report that key EU premises in America have been bugged.
Martin Schulz said that if this was true, it would have a “severe impact” on ties between the EU and the US.
The report, carried by Germany’s Der Spiegel magazine, cites a secret 2010 document alleging that the US spied on EU offices in New York and Washington.
Fugitive whistleblower Edward Snowden leaked the paper, Der Spiegel says.
Edward Snowden – a former contractor for the CIA and also the National Security Agency (NSA) – has since requested asylum in Ecuador.
According to the document – which Der Spiegel says comes from the NSA – the agency spied on EU internal computer networks in Washington and at the 27-member bloc’s UN office in New York.
The document also allegedly referring to the EU as a “target”.
It is not known what information US spies might have got, but details of European positions on to trade and military matters would have been useful to those involved in negotiations between Washington and European governments.
In a statement on Saturday, Martin Shultz said: “On behalf of the European Parliament, I demand full clarification and require further information speedily from the US authorities with regard to these allegations.”
The European Parliament has demanded full clarification from the US over a report that key EU premises in America have been bugged
Der Spiegel also quotes Luxembourg Foreign Minister Jean Asselborn as saying: “If these reports are true, it’s disgusting. The United States would be better off monitoring its secret services rather than its allies.”
The US government has so far made no public comments on the Spiegel’s report.
Edward Snowden is believed to be currently staying at Moscow’s airport. He arrived there last weekend from Hong Kong, where he had been staying since he revealed details of top secret US surveillance programmes.
The US has charged him with theft of government property, unauthorized communication of national defense information and willful communication of classified communications intelligence.
Each charge carries a maximum 10-year prison sentence.
On Saturday, US Vice-President Joe Biden and Ecuadorian President Rafael Correa held a telephone conversation about Edward Snowden’s asylum request.
According to Rafael Correa, Joe Biden had “passed on a polite request from the United States to reject the request”.
The left-wing Ecuadorian leader said his answer was: “Mr. vice-president, thanks for calling. We hold the United States in high regard. We did not seek to be in this situation.”
If Edward Snowden ever came to “Ecuadoran soil” with his request, he added, “the first people whose opinion we will seek is that of the United States”.
Quito earlier said it was willing to consider Edward Snowden’s request but only when he was physically in the Latin American country.
Meanwhile, White House spokeswoman Bernadette Meehan said only that Joe Biden and Rafael Correa had held a wide-ranging conversation.
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UK demands further cuts at EU budget summit
British PM David Cameron says he will not accept an European Union budget deal unless further cuts are made in negotiations in Brussels.
EU leaders are gathering for a two-day summit to try to strike a seven-year spending deal, after a previous meeting in November failed.
But David Cameron said the figures being proposed “need to come down. And if they don’t… there won’t be a deal”.
The European Commission head called for “a spirit of responsibility” in talks.
Jose Manuel Barroso said: “Further delays will send out a very negative message at this time of fragile economic recovery. The risk is that positions will harden and will be even more difficult to overcome.”
The formal meeting has been delayed by several hours, apparently to allow more time for discussions on a compromise.
David Cameron has met his counterparts from Denmark, the Netherlands and Sweden – leaders who are potential allies in the tough negotiations.
High EU expenditure at a time of cutbacks and austerity across the continent is the main issue dividing the 27 member states.
The Commission – the EU’s executive body – had originally wanted a budget ceiling of 1.025 trillion euros ($1.4 trillion) for 2014-2020, a 5% increase. In November that ceiling was trimmed back to 973 billion euros, equivalent to 943 billion euros in actual payments.
But with other EU spending commitments included, that would still give an overall budget of 1.011tn euros.
British PM David Cameron says he will not accept an European Union budget deal unless further cuts are made in negotiations in Brussels
The UK, Germany and other northern European nations want to lower EU spending to mirror the cuts being made by national governments across the Continent.
An EU source says any extra cut would probably be made to growth-related spending in areas such as energy, transport, the digital economy and research.
The biggest spending areas – agriculture and regional development – are largely ring-fenced because of strong national interests, the source said, speaking on condition of anonymity.
Whatever is agreed has still to go to the European Parliament, and MEPs are big backers of EU spending.
Scheduled to begin at noon on Thursday, the summit has been put back to 19:30. “We needed more time to work on the compromise proposal,” an unnamed EU official told AFP news agency.
A grouping led by France and Italy wants to maintain spending but target it more at investment likely to create jobs.
The split in the EU reflects the gap between richer European countries and those that rely most on EU funding.
The argument for higher spending is supported by many countries that are net beneficiaries, including Poland, Hungary and Spain.
Others, mostly the big net contributors, argue it is unacceptable at a time of austerity.
Germany, the UK, France and Italy are the biggest net contributors to the budget, which amounts to about 1% of the EU’s overall GDP.
Analysts say failure to reach an agreement on its seven-year budget would mean the EU falling back on more expensive annual budgets.
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Ernst Strasser sentenced to four years in jail for bribe-taking
Former Austrian Interior Minister and Euro MP Ernst Strasser has been sentenced to four years in jail after being convicted of bribe-taking.
The conservative Austrian People’s Party MP was exposed by reporters from the UK’s Sunday Times, who secretly filmed him while posing as lobbyists.
They showed him being offered a 100,000-euro ($130,000) annual payment in exchange for influencing EU legislation in the European Parliament.
Ernst Strasser, 56, denied any wrongdoing.
He said he had resigned to protect his party.
He said he had guessed that the “lobbyists” were fake, but had played along with the ruse in order to find out what was actually motivating the pair, who dined with him before the Sunday Times expose in March 2011.
Former Austrian Interior Minister and Euro MP Ernst Strasser has been sentenced to four years in jail after being convicted of bribe-taking
Presiding Judge Georg Olschak said he did not believe Ernst Strasser’s defence that he thought the journalists were US secret agents whom the politician had wanted to expose.
“That is probably one of the most outlandish things I have heard in my 20-year career,” said Judge Georg Olschak.
“You won’t find a single court in Austria to believe that argument.”
The judge told Ernst Strasser few people had damaged Austria’s reputation as much as he had.
Alexandra Maruna, for the prosecution, said Ernst Strasser had “massively harmed European politics” and deserved to be punished for abusing confidence in elected officials.
One of four MEPs caught up in a “cash-for-laws” scandal in 2011, he plans to appeal against the verdict.
Ernst Strasser served as Austrian interior minister from 2000 to 2004 and in the European Parliament from 2009 to 2011.
EU Parliament sprayed with milk by farmers protesting at falling dairy prices
Angry farmers protesting at falling dairy prices in the EU have sprayed fresh milk at the European Parliament and riot police in Brussels.
Thousands of dairy farmers, accompanied by hundreds of tractors, descended on the Belgian capital on Monday for two days of demonstrations.
Disruption has continued, with EU officials hindered from reaching their offices by tractors blocking roads.
Farmers want an increase of up to 25% in their prices to cover costs.
EU milk is often sold at below production costs due to a drop in international demand and increased competition.
The European Milk Board (EMB), which is coordinating the protest, says small farmers are being forced out of business.
In Belgium, for example, the wholesale price for a litre of milk is 0.26 euros ($0.34) but the cost of producing it is 0.40 euros, the board said.
The EU is the world’s largest milk producer and in 2010 nearly 47% of its 123 billion euro budget went on subsidies and other forms of financial aid for farmers, including dairy producers.
Angry farmers protesting at falling dairy prices in the EU have sprayed fresh milk at the European Parliament and riot police in Brussels
Police guarding the European Parliament found themselves being squirted with jets of milk on Monday as protesters directed hoses at the building.
A trailer of hay was set alight on the nearby Place du Luxembourg, where a mock gallows was erected with what appeared to be a hanging dummy of a farmer.
“Politics are really killing us,” Belgian farmer Julien Husquet was quoted as saying by the Associated Press news agency.
“It has to change very quickly at the European level. The way it is going, we are in big trouble.”
“It’s very simple: you can’t live off milk anymore,” French farmer Leopold Gruget told AFP news agency.
“If I go on, it’s thanks to European aid… If they do it [phase out subsidies] there will be no more small and medium producers here in five years.”
Some of the largest farmers’ contingents have come from Denmark, France, Germany, the Republic of Ireland, the Netherlands, Poland and Spain, the EU Observer reports.
Erwin Schopges, head of the EMB in Belgium, said Tuesday’s protests would be “symbolic” and calmer.
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EU 2013 budget talks collapse
EU talks about 2013 budget have collapsed, after negotiators from the EU and member states were unable to agree on extra funding for 2012.
The EU Commission and European Parliament had asked for a budget rise of 6.8% in 2013.
But most governments wanted to limit the rise to just 2.8%.
The failure of the talks will dent hopes of agreement on the 2014-2020 budget, which is up for discussion later this month, correspondents say.
Friday’s dispute was over an extra 9 billion euros ($12 billion) in “emergency funding” for 2012, to cover budgets for education, infrastructure and research projects.
But Germany, France and other governments questioned the funding, and eight hours of talks produced no agreement.
“Under these conditions, we felt that negotiations which hadn’t really begun by six o’clock in the evening couldn’t reasonably be expected to finish during the night,” said the parliament’s lead negotiator, Alain Lamassoure.
At the European parliament, UK Conservative MEPs clashed with Parliament President Martin Schulz, a German Social Democrat, over the extra 9 billion euros shortfall for 2012.
In 2012 the budget was 129.1 billion euros, a 1.9% increase on 2011.
Among the schemes facing a shortfall this year is the Erasmus student exchange programme.
It has allowed nearly three million young Europeans to study abroad since it was launched 25 years ago.
In an open letter to EU leaders on Friday more than 100 famous Europeans, including film directors and footballers, warned that “thousands could miss out on a potentially life-changing experience”.
Friday’s talks did produce a declaration of political will to provide 670 million euros to earthquake victims in Italy, but no agreement on how to finance it, the European Parliament said.
It said that if no agreement on the 2013 budget could be reached in the next 21 days, the European Commission would look to revise its budget proposal.
The UK’s Financial Secretary to the Treasury, Greg Clark, said the EU needed to practice “fiscal discipline”.
“The UK and a number of other countries were very clear from the outset that the Commission and the European Parliament should not be asking taxpayers for billions of extra euros when the spending in member states is being reduced,” he said.
The UK government, led by the Conservatives, has also objected to a proposed increase in the multi-year budget for 2014-2020, threatening a veto if necessary.
An EU summit aimed at reaching a deal on that budget will be held on 22-23 November.
European Parliament rejects the 27 governments’ position on 2013 budget
The European Parliament has rejected the 27 EU governments’ position on next year’s EU budget, triggering hard bargaining to reach a deal.
In a vote in Strasbourg the MEPs backed the European Commission’s call for a 6.8% budget rise for 2013.
A MEPs’ report deplored a decision by the Council – the 27 governments – to cut that figure to 2.79%.
The MEPs also adopted proposals on the 2014-2020 budget, ahead of a key leaders’ summit next month.
The Commission, however, argues that the cuts proposed by the Council would harm Europe’s growth efforts, hitting research and small firms.
In 2012 the EU budget was 129.1 billion euros ($168.5 billion), a 1.9% increase on 2011.
The Commission says 2013 is the last year of the EU’s current seven-year financial period – the time when bills for existing projects have to be paid, hence the need for a budget increase.
The Commission’s proposal for the long-term budget, called the Multiannual Financial Framework (MFF), sets the ceiling at just over one trillion euros, that is, 1.03% of EU gross national income (GNI).
The biggest items of spending, accounting for about 80% in total, are agriculture and cohesion funds – aid for Europe’s poorer regions. France is especially keen to maintain agriculture spending, while cohesion is a big issue for the ex-communist countries in Eastern Europe.
The European Parliament’s budget committee calls for spending levels for those major budget items to be at least maintained at the 2007-2013 level.
But the MEPs also call for “significant increases” in the budgets for competitiveness, small and medium enterprises (SMEs), sustainable infrastructure and research and innovation. They see those budget areas as growth-enhancing.
The parliament’s lead negotiators in the 2014-2020 budget talks are Ivailo Kalfin, a Bulgarian from the Social Democrat group (S&D) and Reimer Boege, a German from the conservative European People’s Party (EPP).
The MEPs’ plan includes a controversial call for EU “own resources” – that is, to fund the EU from direct taxation, such as sales tax (VAT), instead of the current system of national contributions.
The MEPs’ report says the current system polarizes the EU into “two opposing camps” – the net contributor countries on the one hand, and the net beneficiary countries on the other.
The report says the EU budget financing “should return to a genuine system of own resources, as provided for in the Treaty of Rome and all successive EU treaties”. It calls the system of national contributions “non-transparent and unfair” and “not subject to parliamentary control at either European or national level”.
ACTA back under scrutiny as European Parliament prepares to carry out key votes
The controversial Anti-Counterfeiting Trade Agreement (ACTA) is back under scrutiny as the European Parliament prepares to carry out a series of key votes.
ACTA seeks to curb the spread of illegally downloaded copyrighted material online.
However, critics say it is a potential threat to freedom of speech online.
To date 22 member states have signed the treaty – but it is yet to be formally ratified by the EU.
The Committee on Legal Affairs (Juri), Committee on Civil Liberties (LIBE) and the Committee on Industry, Research and Energy (ITRE) will each vote on the crucial concerns surrounding the proposals.
While the agreement covers the counterfeiting of physical items, such as pharmaceuticals, it is the measures relating to pirated material on the internet that have caused most concern among campaigners.
The agreement suggests setting international standards over how copyright infringements are dealt with. Preventive measures include possible imprisonment and fines.
The three committees will issue judgements on the possible impact of the treaty on the trading rights of the European Union; the human rights impact on citizens, and the possible effects on related industries.
The controversial Anti-Counterfeiting Trade Agreement (ACTA) is back under scrutiny as the European Parliament prepares to carry out a series of key votes
The outcomes will influence the decision of the International Trade Committee (INTA) which will vote on 20-21 June to determine the formal recommendation on ACTA to the European Parliament. INTA’s appointed rapporteur on ACTA, David Martin, has strongly condemned the treaty.
In April, David Martin said: “The intended benefits of this international agreement are far outweighed by the potential threats to civil liberties.”
Rapporteurs advising LIBE and ITRE have also recommended rejecting the treaty, concurring with David Martin’s comments.
However, Marielle Gallo, who has advised Juri, has said she is not against the agreement.
The INTA vote will heavily influence the final decision on ACTA by the European Parliament. This vote is expected to take place on 2 July.
If it passes, the agreement will then come into force across the EU. If rejected, ACTA will be scrapped entirely.
The treaty has provoked discontent across the world since an initial draft was released by Wikileaks in 2008.
Open-rights campaigners argued the measures were being debated in secret.
Across Europe thousands of protesters demonstrated to voice their objections to the agreement.
The treaty’s backers have said it would not alter existing laws, and would instead provide protection for content creators in the face of increasing levels of online piracy.
Nevertheless, the proposals have encountered a slew of objections.
In February, the European Commission referred the matter to the European Court of Justice to judge on whether ACTA complied with human-rights laws.
This process was expected to delay ratification proceedings, but members of INTA voted to go ahead with pre-planned timetable.
Euro MP Kader Arif, who resigned from his post as rapporteur for ACTA in January, said he did so in protest at the “masquerade” of negotiations.
Meanwhile, several countries distanced themselves from the agreement, including Germany and Poland, where large protests took place.
Most recently, lawmakers in the Netherlands urged rejection of the treaty over fears that it breached the country’s constitution.
The UK, which signed the treaty in January, said it still backed ACTA.
Outside the EU, the treaty also has the support of the US, Australia, Canada, Japan, Morocco, New Zealand, Singapore and South Korea.
EU cuts the cost of mobile phone calls within Europe
European Parliament has passed regulations to make using a mobile phone abroad significantly cheaper.
The plans, which were voted in by a huge majority, include imposing a price cap on operators.
From July, using mobile data in Europe will not cost more than 70 eurocents per megabyte – far less than current rates.
Consumers will also be able to choose a different operator abroad from the one they use at home.
It is hoped this split-network approach – which comes into force in 2014 – will encourage greater competition.
The first changes will come into effect from 1 July. Calls will be capped at 29 eurocents per minute, plus VAT.
European Parliament has passed regulations to make using a mobile phone abroad significantly cheaper
The EU said the regulations were designed to prevent “bill shock” – the moment when travelers discover they have totted up huge bills after making calls and using data applications, such as maps, while away.
“In a borderless Europe, there is no place for charges that diverge so much at home and abroad,” said MEP Ivo Belet.
The EU said the changes could mean savings for a “typical” businessman of more than 1,000 Euros in a year.
The EU said that from 2014 customers would be able to choose their mobile networks upon arrival in a country, or signing up to a contract before leaving.
Currently, mobile users are forced to use their standard domestic operator when travelling abroad – or to use alternative arrangements, such as a cheap pre-paid handset.
Under the new regulations, customers can choose a different operator with a more attractive travel tariff before leaving – without changing their number.
MEP David Martin says ACTA should by rejected by the European Parliament
Euro MP David Martin has said the controversial Anti-Counterfeiting Trade Agreement (ACTA) should be rejected by the European Parliament.
David Martin, the British MEP responsible for its report on ACTA, said the treaty threatened civil liberties.
His comments came less than three months after the previous rapporteur, Kader Arif, resigned from his post in protest at the plans.
To date, 22 EU member states have signed the agreement.
However, the treaty will need to be ratified by the European Parliament before it can be enacted.
David Martin has strongly advised that this ratification should not happen.
“The intended benefits of this international agreement are far outweighed by the potential threats to civil liberties,” he said in a written recommendation to the European Parliament.
“Given the vagueness of certain aspects of the text and the uncertainty over its interpretation, the European Parliament cannot guarantee adequate protection for citizens’ rights in the future under ACTA.”
Euro MP David Martin said ACTA should be rejected by the European Parliament
An early discussion paper for ACTA was made public by Wikileaks in 2008, and the treaty has caused considerable controversy since.
Earlier this year, thousands of protesters demonstrated in cities including Berlin and Warsaw to share their objection to the agreement, which critics say will stifle freedom on the internet.
The “real world” action was in addition to several co-ordinated online attacks on the websites of various governments across Europe.
Concern over the treaty was heightened further when the European Commission asked the European Court of Justice to rule on its legality. The decision is still pending.
Kader Arif, who resigned as the EU’s rapporteur for ACTA on 27 January, described the negotiations as a “masquerade”.
He said: “I condemn the whole process which led to the signature of this agreement: no consultation of the civil society, lack of transparency since the beginning of negotiations, repeated delays of the signature of the text without any explanation given, reject of Parliament’s recommendations as given in several resolutions of our assembly.”
Despite these concerns, the agreement has been backed by the majority of EU member states.
A debate on the EU’s adoption of ACTA is expected to take place in June.
EU court asked to rule on ACTA legality
The EU’s highest court has been asked to rule on the legality of ACTA, the controversial anti-piracy agreement.
The Anti-Counterfeiting Trade Agreement (ACTA) has been criticized by rights campaigners who argue it could stifle free expression on the internet.
European Union trade head Karel De Gucht said the court will be asked to clarify whether the treaty complied with “the EU’s fundamental rights and freedoms”.
The agreement has so far been signed by 22 EU member states.
The European Commission said it “decided today to ask the European Court of Justice for a legal opinion to clarify that the ACTA agreement and its implementation must be fully compatible with freedom of expression and freedom of the internet”.
Several key countries, including Germany and Denmark, have backed away from the treaty amid protests in several European cities.
The EU's highest court has been asked to rule on the legality of ACTA
ACTA is set to be debated by the European Parliament in June.
While countries can individually ratify the terms of the agreement, EU backing is considered vital if the proposal’s aim of implementing consistent standards for copyright enforcement measures is met.
As well as the 22 European backers, the agreement has been signed by the United States, Japan and Canada.
Karel De Gucht told a news conference on Wednesday: “Let me be very clear: I share people’s concern for these fundamental freedoms… especially over the freedom of the internet.
“This debate must be based upon facts, and not upon the misinformation and rumour that has dominated social media sites and blogs in recent weeks.”
However, Karel de Gucht went on to say that the agreement’s purpose was to protect the creative economy.
“[ACTA] aims to raise global standards for intellectual property rights,” he said, adding that the treaty “will help protect jobs currently lost because counterfeited, pirated goods worth 200bn euros are currently floating around”.
ACTA’s backers face strong opposition within the EU. Viviane Reding, the commissioner for justice, fundamental rights and citizenship, took to Twitter to outline her worries on the treaty.
“For me, blocking the Internet is never an option,” she wrote in a statement.
“We need to find new, more modern and more effective ways in Europe to protect artistic creations that take account of technological developments and the freedoms of the internet.”
What is ACTA?
• The Anti-Counterfeiting Trade Agreement (ACTA) is an international treaty aiming to standardize copyright protection measures.
• It seeks to curb trade of counterfeited physical goods, including copyrighted material online.
• Preventative measures include possible imprisonment and fines.
• Critics argue that it will stifle freedom of expression on the internet, and it has been likened to the controversial Stop Online Piracy Act (SOPA).
• ACTA has been signed by 22 EU members, but is yet to be ratified by the European Parliament.
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Home Tags Posts tagged with "lenin moreno"
Julian Assange Arrested In London Following Ecuador’s Withdrawal of Asylum
Julian Assange, the co-founder of WikiLeaks, has been arrested at the Ecuadorian embassy in London.
The Metropolitan Police arrests Assange for “failing to surrender to the court” over a warrant issued in 2012. He is found guilty and faces up to 12 months in prison, as well as extradition over US charges of conspiracy to commit computer intrusion.
Julian Assange took refuge in the Ecuadorian embassy in 2012 to avoid extradition to Sweden over an assault case that has since been dropped.
At Westminster Magistrates’ Court on April 11, he was found guilty of failing to surrender to the court.
Julian Assange now faces US federal conspiracy charges related to one of the largest ever leaks of government secrets.
The UK will decide whether to extradite him, in response to allegations by the DoJ that he conspired with former US intelligence analyst Chelsea Manning to download classified databases.
Julian Assange, 47, faces up to five years in US prison if convicted on the charges of conspiracy to commit computer intrusion.
His lawyer, Jennifer Robinson, said they would be fighting the extradition request. She said it set a “dangerous precedent” where any journalist could face US charges for “publishing truthful information about the United States”.
Jennifer Robinson said she had visited Julian Assange in the police cells where he thanked supporters and said: “I told you so.”
Julian Assange had predicted that he would face extradition to the US if he left the embassy.
After his arrest, the Australian national was initially taken to a central London police station before appearing in court.
Dressed in a black suit and black polo shirt, Julian Assange waved to the public gallery and gave a thumbs up. He pleaded not guilty to the 2012 charge of failing to surrender to the court.
Finding him guilty of that charge, District Judge Michael Snow said Julian Assange’s behavior was “the behavior of a narcissist who cannot get beyond his own selfish interest”.
He sent Julian Assange to Southwark Crown Court for sentencing, where he faces up to 12 months in prison.
The court also heard that during Assange’s arrest at the embassy he had to be restrained and shouted: “This is unlawful, I am not leaving.”
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Julian Assange Questioned by Sweden’s Chief Prosecutor
Why is Ecuador protecting Julian Assange?
Julian Assange set up WikiLeaks in 2006 with the aim of obtaining and publishing confidential documents and images.
WikiLeaks hit the headlines four years later when it released footage of US soldiers killing civilians from a helicopter in Iraq.
Chelsea Manning was arrested in 2010 for disclosing more than 700,000 confidential documents, videos and diplomatic cables to the anti-secrecy website.
She said she only did so to spark debates about foreign policy, but US officials said the leak put lives at risk.
Chelsea Manning was found guilty by a court martial in 2013 of charges including espionage. However, her jail sentence was later commuted.
She was recently jailed for refusing to testify before an investigation into WikiLeaks’ role in revealing the secret files.
The indictment against Julian Assange, issued last year in the state of Virginia, alleges that he conspired in 2010 with Manning to access classified information on Department of Defense computers. He faces up to five years in jail.
Chelsea Manning downloaded four databases from US departments and agencies between January and May 2010, the indictment says. This information, much of which was classified, was provided to WikiLeaks.
The DoJ described it as “one of the largest compromises of classified information in the history of the United States”.
Cracking a password stored on the computers, the indictment alleges, would have allowed Manning to log on to them in such a way as to make it harder for investigators to determine the source of the disclosures. It is unclear whether the password was actually broken.
Julian Assange had been in the Ecuadorian embassy in London since 2012, after seeking asylum there to avoid extradition to Sweden on a rape allegation.
The investigation into the alleged rape, which he denied, was later dropped because he had evaded the arrest warrant. The Swedish Prosecution Authority has said it is now considering whether to resume the inquiry before the statute of limitations runs out in August 2020.
Scotland Yard said it was invited into the embassy on April 11 by the ambassador, following the Ecuadorian government’s withdrawal of asylum.
Ecuadorian president Lenin Moreno said his country had “reached its limit on the behavior of Mr. Assange”.
The president said: “The most recent incident occurred in January 2019, when WikiLeaks leaked Vatican documents.
“This and other publications have confirmed the world’s suspicion that Mr. Assange is still linked to WikiLeaks and therefore involved in interfering in internal affairs of other states.”
Lenin Moreno’s accusations against Julian Assange also included blocking security cameras at the embassy, accessing security files and confronting guards.
Ecuador Elections 2017: Accusations of Electoral Fraud as Lenin Moreno is Declared Winner
Accusations of fraud sparks over Ecuador’s presidential elections after early results projected victory for the incumbent party’s candidate.
Results show former VP Lenin Moreno of the Socialist Party has 51.12% of the vote, with just 4% of districts still waiting to be counted.
However, challenger Guillermo Lasso had already begun celebrations after an exit poll predicted his victory.
Guillermo Lasso demanded a recount, and called on supporters to take to the streets.
He also alleged electoral fraud had been used to grant victory to his opponent.
In a series of tweets, Guillermo Lasso told the public to “peacefully defend your vote” and said he was “going to defend the will of the people”.
Final official results have yet to be announced.
If Lenin Moreno is declared the winner, he will continue a decade of left-wing leadership begun by President Rafael Correa in 2007.
Image source Wikipedia
He would also become one of a small number of disabled world leaders – he became paraplegic after being shot in the back during a robbery in 1998.
An apparent victory for Lenin Moreno was welcomed by WikiLeaks founder Julian Assange – as Guillermo Lasso had vowed to evict him from his asylum in the country’s London embassy if victorious.
Julian Assange tweeted that he “cordially invites” Guillermo Lasso to leave the country within 30 days – referencing the timeframe the candidate gave for Assange’s own eviction.
Guillermo Lasso, a former banker who wants to promote foreign investment, called for a recount after Lenin Moreno started to take a lead in the preliminary results.
Exit polls released on April 2 had suggested an extremely tight race.
A poll by Periles de Opinion had shown Lenin Moreno leading with 52.2%, while a poll by Cedatos showed Guillermo Lasso winning with 53.02%.
Incumbent President Rafael Correa, meanwhile, tweeted criticism of what he termed “violence” in several cities as early results emerged.
Local media reported that some of Guillermo Lasso’s supporters had gathered in the capital of Quito, as well as the city of Guayaquil. According to The El Comercio newspaper, the crowd removed barriers placed in the road, and bottles were thrown by some in Guayaquil.
When he was first elected in 2007, Rafael Correa was one of a group of left-wing leaders in power in Latin America.
However, in the decade since, conservative politicians have taken power in Argentina and Brazil. A victory for Guillermo Lasso would have continued that trend.
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Morning Glories: For a Better Future by Nick Spencer
Morning Glory Academy is one of the most prestigious prep schools in the country... but something sinister and deadly lurks behind its walls. When six gifted, but troubled, students arrive, they find themselves trapped and fighting for their lives as the secrets of the academy reveal themselves!
I've only just started reading graphic novels this year, and still can't call myself an expert on them in any way at all. I'm starting to find now, however, that I'm growing to love them. I love the fast pace, I love the gory pages, and I see them as quick adrenaline rushes of books. This is probably down to the fact that I have been recommended all the right books, but remains true nonetheless.
The story begins with the kids being brought to the school. This was done really well, with small flashes of their home life and backgrounds. They all fit into general stereotypes: the clever leader, the shy one, the mysterious one, the arsehole, the bitchy slut, the psycho. It reeked of The Breakfast Club, but they know that; someone even mentions Judd Nelson at one point. The students are collated in a prestigious boarding school, where strange things begin to happen. By strange I mean attempted murder from the teachers, ghosts, a cult in the basement, and a doppelganger who just blew my mind completely. Strange is perhaps an understatement.
I realise the book is first in a series of six, but I didn't finish it feeling completely satisfied. Nothing was explained, and this means you have to read the next one, then probably the next one, all the way to the sixth one. Surely something could have been tied up at the end? Something small? I feel a lot was thrown at me, and although I managed to deal with it, and follow the story, nothing was resolved.
This opening novel in the series seems to built on unanswered questions. There are layers upon layers of mystery just waiting to be unravelled in the following installments. My only issue is that with all the mystery points having been plotted, and all insinuations all made, I'm not sure the next chapters will be able to link all of these together. I suppose there's only one way to find out, and I will.
Labels: american, boarding school, books in 2013, ghosts, graphic novel, illustrated, macabre, murder, mystery, physics, school, supernatural, suspense, teenage, violence
Jake said...
Sounds interesting, I'll maybe give it a look.
You mentioned that it's not a self contained story. This'll be because this isn't technically a graphic novel, it's a trade paperback. I'll try not to bore you too much with the differences but basically, a graphic novel is a comic specifically written for a long format whereas a trade paperback is a collection of stories previously released as individual issues. If these issues aren't written into specific arcs then the TP can feel a little unfinished. You're meant to read the whole shebang really, it can be annoying and very expensive.
If you're just getting into comics I'd reccomend Watchmen (another TP but it's the whole set in one book), Blankets and Clumsy. They're all great books.
I'd also recommend Cerebus which is a 6000 page series all written anddrawn by one man. It's awesome....well...mostly...
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Home » About us » Mission and vision
The Bioenergy Association vision is: Economic growth and employment built on New Zealand’s capability and expertise in forestry, wood processing and bioenergy production from waste - leading to new business opportunities which by 2050 could more than double biomass energy supply up to 27% of the country’s energy needs, with a consequential 15% reduction in greenhouse gas emissions*. [* compared to 2017]
To support its members to build successful businesses based on bioenergy and biofuels
To encourage the use of New Zealand's abundant biomass resources and provide renewable energy in the form of heat, electricity and transport fuels, sustainably and cost-effectively
To promote the environmental benefits of bioenergy, including greenhouse gas mitigation and waste avoidance, to the wider community
To facilitate implementation of commercial bioenergy projects that contribute to business resilience and regional economic benefits.
Bioenergy Strategy
The Bioenergy Association has led the sector development of a strategy to achieve the vision. The Bioenergy Strategy sets out a pathway across the biogas, wood energy and liquid biofuels sectors leading to the achievement of economic growth, employment and environmental outcomes, including greenhouse gas mitigation.
Achievement of the strategy would result in establishment of a $6billion sector.
The Government’s 50:50 proposal1 aims to reduce net CO2e emissions by 31 million tonnes annually by 2050. It is estimated that the New Zealand Bioenergy Strategy could deliver by 2040 biofuels which could provide nearly 40% of the greenhouse gas emissions needed. Transport using biofuels would provide most of the estimated CO2e savings at just under 11 million tonnes per year or 35% of the total required.
Link to the Government's Business Growth Agenda
The Bioenergy Strategy is firmly linked to the Government's Business Growth Agenda.
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Researchers receive $1.8 million to investigate progression, relapse of rare blood cancer
Indiana University School of Medicine researcher Reuben Kapur, PhD, has received more than $1.8 million to research the mechanisms that lead to a rare blood cancer called acute myeloid leukemia (AML). Kapur will closely examine the interaction between certain cellular mutations believed to contribute to the development and relapse of AML. The grant was awarded by the National Cancer Institute and will support this project for the next five years.
Kapur conducts his research at the Herman B Wells Center for Pediatric Research and the IU Simon Cancer Center, where he focuses on blood-related disorders, such as juvenile myelomonocytic leukemia and Diamond-Blackfan anemia. AML, which is most often diagnosed in adults, affects the maturation process of new blood cells and is known for its quick progression.
While chemotherapy is often curative for AML, relapse is not only common but is the leading cause of death in patients over 60 years old. These patients, who make up about 90 percent of all people with the condition, have only a 15 percent overall cure rate. Kapur’s work may help identify the underlying factors that lead to the disease and discover new targets for prevention of relapse.
Earlier studies from Kapur demonstrated that certain mutations on blood stem cells can result in high levels of a long non-coding RNA called Morrbid. His research team found that Morrbid enhances the survival and spread of pre-leukemic cells. Now, Kapur will expand on this knowledge by determining the driving forces behind progression of pre-leukemic cells to AML and relapse.
Reuben Kapur, PhD, is the Frieda and Albrecht Kipp Professor of Pediatrics, director of the Hematologic Malignancies and Stem Cell Biology research program at the Wells Center and co-director of the Hematopoiesis, Hematologic Malignancies and Immunology research program at the IU Simon Cancer Center.
The project referenced above is titled Role of Shp2 in FLT3-ITD induced leukemogenesis, project number 2R01CA134777-06A1. Funds have been awarded by the National Cancer Institute.
The post Researchers receive $1.8 million to investigate progression, relapse of rare blood cancer appeared first on Newsroom.
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