text large_stringlengths 118 417k | id large_stringlengths 47 47 | repo_tree_path large_stringclasses 2 values | source_dataset large_stringclasses 2 values | lang large_stringclasses 1 value | num_chars uint32 118 417k |
|---|---|---|---|---|---|
Brogdale National Apple Festival
Each day visitors will be able to enjoy orchard walks, fruit displays, juice tastings, a family apple trail, cider sales and more. Included in the ticket price, for the first time, visitors will also be able to harvest their own apples and enjoy the use of Brogdale’s lovely picnic field.
With very few events taking place at the moment, these Orchard Days are a great opportunity to spend time outside with the family while enjoying some fresh Kent fruit. Visitors will also be helping raise essential funds to save these unique orchards. | <urn:uuid:05a9fbb1-abe7-4fae-8a69-6faaa5e5352b> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 572 |
Since the start of the COVID-19 pandemic, livelihoods have been disrupted, agricultural production has faltered, and whole economies have cratered. As a result, hunger levels have surged.
More than 768 million around the world struggled with hunger in 2020, an increase of more than 100 million compared to the year before. In more than 43 countries, the threat of famine could cause 41 million people to starve. The World Food Programme is calling for $6 billion to address this dire situation.
Preventing famine should be a top priority for donor nations. But to end hunger once and for all, they need to do more than react to the latest humanitarian crisis. Further funds need to be raised in a sustained and well-coordinated way to ensure farmers can grow enough food for a growing population amid the intensifying climate crisis.
A new report by Donor Tracker maps funding levels for food security, nutrition, and agriculture and offers various recommendations for transforming the global food system.
Global Citizen spoke with the team at Donor Tracker to learn more about the report and to better understand the growing hunger crisis.
Global Citizen: Can you provide a bit of context for this report: What is the Donor Tracker and why did you write this publication on ODA for food and nutrition security?
Donor Tracker: Of course. So first of all, the Donor Tracker is an online platform that provides freely available evidence-based analysis of OECD development assistance committee (DAC) donors’ development policy and financing. It is one of the flagship initiatives of SEEK Development, which is a strategic and organizational consultancy focused on global development impact and based in Berlin.
The story behind Donor Tracker is that through SEEK’s work in the global development space, our team noticed a major gap in the landscape of available resources: There was no single source providing comprehensive information on donors' ODA, their development strategies, priorities, and decision-making processes. We saw that our colleagues at our peer organizations — many of whom are overworked and under-resourced – were forced to spend valuable time hunting for and piecing together information. And so, SEEK started the Donor Tracker.
Donor Tracker focuses on ODA of the 14 largest OECD DAC donors. We produce what we call "donor profiles," publish weekly policy updates covering news from our donors, and also write "Insights" reports that highlight key issues and trends in the development finance world; for example, this report on donor financing for food and nutrition security.
Because our aim is to elevate and support the work of advocates for global development (and of course, researchers, policy-makers, think-tank analysts, etc.) we try to time our analyses so that they can feed into important global conversations or decision-moments — so that advocates can go into these important discussions armed with the best and most up-to date information on the issues that matter to them. We decided to conduct this analysis of global food and nutrition security both because of the upcoming events and replenishments — for example, UNFSS and Nutrition for Growth Summit, and IFAD replenishment — and because of the intersection of food and nutrition security with other pressing issues of today, such as climate change and COVID-19.
What are some of the key financing trends around food security, nutrition, and agriculture? What areas need improvement and what countries can play a bigger role going forward?
Bilateral financing has actually gone up since 2015, but the number of hungry people has also gone up. You’d expect that as the financing goes up, the amount of hungry people would go down. One of the reasons that didn’t happen is because the global population is growing so fast.
In the last year, the number of hungry people has gone up to 768 million in 2020 from about 650 million in 2019. We’re at risk of losing all this great work that we’ve done over the past 10 years — that's one of the key insights of the report.
Bilateral financing has gone up but it doesn't even begin to meet the needs that we have now, let alone those going forward particularly when you take into consideration the effects of climate change, COVID-19, and conflicts. That’s something we really need to take into consideration when budgeting for alleviating poverty and hunger.
In terms of multilateral funding, we would have expected it to increase like bilateral funding, but it decreased by 9% from 2017 to 2019. It’s really important to flip that curve to meet the challenges of tomorrow.
We’re seeing investments in humanitarian assistance at the moment, and it's important to have that same urgency when investing in agriculture, nutrition, and food security. If we don’t invest in those aspects we may see a higher risk of famines in the future that may be more costly. It makes so much more sense to invest now than it does later.
How can investing in Global Goal 2: Zero Hunger impact other Sustainable Development Goals (SDGs)?
It's one of the goals that’s intricately linked to all of the other SDGs. If you take the example of a young child, if you don’t invest in nutrition for that child, you’ll see knock-on effects in terms of performance at school, their health, and their economic prospects. That’s something we have to think of. Eating is such an emotive experience, we all have to eat, it’s so important. Yet when you don’t have food it will affect every aspect of your life, and therefore every SDG.
There’s wasting and stunting, but if children are not being fed and nourished adequately, they also run the risk of becoming more obese later in life. That speaks to the double burden of malnutrition. We’ve primarily talked about it in terms of wasting and stunting but there’s another aspect, which is the risk of obesity in low- and middle-income countries.
What does it say about the global food system that so many people are denied nutritious food?
It’s completely broken. There’s another aspect that we haven’t discussed yet, which is the issue of food loss and food waste. Up to 40% of our food isn’t even eaten. It’s thrown out. It’s lost in transport. Let’s say you’re in Morocco, my parent’s country, you will see these big trucks with tomatoes. I will tell you that the tomatoes at the bottom of the truck will be mush by the time they arrive.
The global food system needs a complete overhaul if we want to provide people with the right calories, vitamins, and minerals. We’re going to have approximately 10 billion people in 2050. Production in developing countries would need to almost double. When we grow crops and they experience stress, they’re less likely to produce the nutrition we need, so the nutritional value of foods will be lower because of climate change.
It's a vicious cycle that's really hard to fix. We have to come together and really, piece by piece, unravel the complexity of this problem.
How has the pandemic affected financing for Global Goal 2?
There may have been an increase in ODA, but a large part went to health matters, humanitarian assistance, and, to a limited extent, agriculture and rural development.
A lot of the ODA that was provided by some donors has been in loans and not grants. ODA can be provided in different shapes and forms. Usually when it’s humanitarian assistance, it will be in grants, and longer-term investments are at times provided in loans. By sending loans instead of grants, you may be indebting countries that can't afford it.
The international community tends to have a reactive approach to food security, meaning funds often get deployed to deal with crises after they happen rather than to prevent crises in the first place. What would happen if we moved to a more proactive approach?
Ideally, the chances of famine would drop and we would see knock-on effects in terms of avoiding political instability and emerging conflicts. I remember many years ago when the Arab Spring happened, the last straw that broke the camel’s back was the price of grain going up. That’s the truth of the matter: People need to eat.
This report is ultimately a cry for help to please invest in sustainable agriculture, not only for food security but also for climate change. Around 21% to 34% of greenhouse gases come from the agriculture and food sectors. You cannot imagine solving climate change without looking at agriculture.
You also can’t just say we’re not going to do the reactive approach anymore because these emergencies need funding. The only way to be proactive is to scale up funding overall for ODA so we have more and better funding.
The World Food Programme has requested $5.5 billion to deal with the ongoing famine. If that humanitarian assistance isn’t provided it could lead to armed conflict that could take years to resolve.
The COVID-19 pandemic has disrupted the global food system in significant and long-lasting ways. How does this compare to the current and anticipated disruptions caused by climate change?
It's such a complicated question, because what is the cause and what is the effect? When it comes to agriculture, everything is the cause and everything is the effect. They’re constantly interacting with each other
The extreme weather events are going to be disastrous for people growing their crops. This has happened in countries like Haiti, where IFAD investments were wiped out after the hurricane.
Then there’s the losses due to the level of pests. The IPCC report has a relatively nuanced point on this that some crops will benefit from more CO2, but due to pests there is a higher risk of harvest loss. In addition to that, the nutrition of vegetables and fruit will be less because of the extremes in climate.
According to IFAD, there are three aspects to transforming the food system — resilience, diversified livelihoods, and system change.
When talking about resilience, how can we change crops or seeds to grow for the climate we are going to have? And then there’s the livelihoods of small farmers. Despite them growing most of the food in low-income countries, they’re disproportionately at risk of suffering from hunger. If we want to have farmers in the future, it has to become a sector where you can earn a livelihood.
We also need social protections to make sure that people don’t fall behind certain incomes and inclusive markets that allow more farmers to sell their crops at competitive prices, While farmers’ organizations can speak on their behalf and potentially provide loans where banks may not, it’s important to have a governance system that supports you when you need to be supported.
What can Global Citizens around the world do to support the effort to end hunger?
The most important thing is to get to know the issue. There are different ways to get to know the issue. You can read the research at the Donor Tracker and the insights we deliver and join seminars to get to know the issues and the people behind the issues so you know who you can support.
Don’t underestimate the power you have as a consumer and as a voter. Every time we purchase something in the supermarket, we may be voting for agriculture that isn’t kind to the environment and laborers who grow our food. Make sure your vote counts. Get to know the issues and hold your political party accountable. Sometimes as an individual, it’s a bit of a daunting experience, but doing something is better than doing nothing at all.
You can join the Global Citizen Live campaign to defend the planet and defeat poverty by taking action here, and become part of a movement powered by citizens around the world who are taking action together with governments, corporations, and philanthropists to make change. | <urn:uuid:bdb6fc7f-1263-432c-87df-ca3cf7687122> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 11,726 |
For over two decades, BIOTEC-NSTDA has been actively involved in algal research and development, aiming to promote sustainability in the Thai aquaculture industry. This work is primarily carried out by two research teams: the Fish and Shrimp Molecular Biology and Biotechnology Research Team, as well as the Biosciences and Systems Biology Research Team.
The Fish and Shrimp Molecular Biology and Biotechnology Research Team has established a longstanding collaboration with the Faculty of Science at Mahidol University. Dr. Vanvimon Saksmerprome, the team leader, highlighted the achievements of BIOTEC and Mahidol University in generating new knowledge and innovative solutions to support Thailand's aquaculture industry, particularly the shrimp industry. Their collaboration has led to the creation of Centex Shrimp, which focuses on studying shrimp diseases. The team has developed a novel platform for bioengineering microalgae to produce antiviral double-stranded RNA (dsRNA). This dsRNA serves as a feed supplement for shrimp, providing viral protection. The technology has proven to be effective in reducing the mortality rate caused by white spot disease by 70%.
In addition to its application in dsRNA production, this technology has the potential for producing other beneficial biomolecules for shrimp and other aquatic animals. “We hope to bring this technology to commercialization to strengthen both the biopharmaceutical and aquaculture industries,” said Dr. Vanvimon.
The Biosciences and Systems Biology Research Team, led by Dr. Apiradee Hongsthong, has been engaged in research collaboration with King Mongkut's University of Technology Thonburi (KMUTT) since 1987. Their initial joint study focused on spirulina cultivation using wastewater from a cassava starch factory, resulting in the establishment of the Algal Biotechnology Research Group. This group comprises researchers from both KMUTT and BIOTEC, and their research spans three main areas:
- Mass cultivation: This area encompasses breeding, feed development, and mathematical modeling of cultivation systems. The team has developed various cultivation systems, ranging from laboratory-scale to large-scale outdoor ponds, for the production of spirulina and other microalgae.
- High-value chemicals: The team investigates environmental factors that influence the production of bioactive compounds in spirulina. They also explore the extraction of valuable chemicals such as lipids, omega-3 fatty acids, phycocyanin, and polysaccharides, and characterizing these bioactive compounds.
- Molecular biology: This area focuses on understanding the mechanisms that regulate the synthesis of bioactive compounds. The team also works on bioengineering spirulina to produce specific chemicals and biomolecules.
“Our team possesses extensive knowledge and know-how in systems biology, allowing us to conduct comprehensive research encompassing algal cultivation, algal extracts, and value addition such as the production of bioactive peptides,” added Dr. Apiradee. The team has developed an AI-based platform called SmartBioPep for bioactive peptide analysis. While their research initially centered on spirulina, they have now expanded their investigations to include other types of algae to explore their commercial potential. The team has collaborated closely with leading companies in Thailand, conducting in-depth studies and technology transfers in areas such as algal cultivation and algal extracts. | <urn:uuid:e874769c-4746-4067-8b3f-201967b77da5> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 3,475 |
A RESOLUTION AUTHORIZING AN APPLICATION FOR EDWARD BYRNE MEMORIAL COMPETITIVE GRANT FUNDING FROM THE U.S. DEPARTMENT OF JUSTICE
WHEREAS, American Recovery and Reinvestment Act funding is available through the Edward Byrne Memorial Competitive Grant Program of the Department of Justice for the purpose of hiring civilian staff in law enforcement agencies in an effort to create and preserve jobs, and to increase civilian support to law enforcement agencies; and
WHEREAS, the staffing level of the Communications center has not increased since FY 2007; and
WHEREAS, the grant funds, if received, would allow the Sheriff to increase staffing levels on all shifts to a minimum of four (4) dispatchers, thereby improving dispatch and law enforcement response times to 911 calls; now, therefore, be it
RESOLVED by the Fauquier County Board of Supervisors this 14th day of May 2009, That the Board of Supervisors does hereby authorize staff to submit an application to the Department of Justice for the Edward Byrne Memorial Competitive Grant Fund Program for two entry level dispatcher positions; and, be it
RESOLVED FINALLY, That the County Administrator be, and is hereby, authorized to sign documents related to this grant application on behalf of Fauquier County.
A Copy Teste
Paul S. McCulla | <urn:uuid:73fe5c98-c819-438f-b4fa-55ae11b55b04> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,292 |
26 January 2022
‘There wasn’t the slightest provocation’ – Fulvio Grimaldi on Bloody Sunday
50th Anniversary of Derry’s Bloody Sunday
This piece is taken from: 'Massacre at Derry', produced by the Irish Civil Rights Movement after Bloody Sunday. In 1998 Guildhall Press published Grimaldi’s 'Blood in the Street'. The Civil Rights Movement booklet 'Massacre at Derry', has a range of first-hand accounts of the events of Bloody Sunday. This section was titled “What Fulvio Grimaldi Saw”.
On Monday, January 31, Signor Fulvio Grimaldi, an Italian photo journalist in Derry to report the march, described in a Radio Eireann interview what he saw:
“It was the most unbelievable. I have travelled many countries, I have seen many civil wars and revolutions and wars, I have never seen such a cold-blooded murder, organised, disciplined murder, planned murder.”
He said: “I was in the front line of the march as the march approached the barricade erected by the military in William Street. There were a few exchanges, a few throws of stones, not very heavy, and afterwards, about three or four minutes, the Army moved up with this water cannon and sprayed the whole crowd with coloured water. Then the crowd dispersed.
“Successively, it returned and threw some more stones: nothing as I have seen in other places in Northern Ireland, nothing really very heavy. After which gas was used massively by the Army, and the crowd dispersed towards the meeting place, which was at Free Derry Corner. As the crowd was moving away, I would say about a couple of thousand people - completely peaceful because they had been drenched with gas and they could hardly breathe, and many were sick - suddenly in the area behind Free Derry Corner - Rossville flats, I think it is called, the big square in front of those flats - the Army, the paratroopers, moved in on Saracens.
“And other paratroopers followed on foot, and they jumped out. The people were thinking they would be given another dose of gas and scattered very hurriedly and they really fled towards Free Derry Corner. The Army jumped out and they started shooting in all directions. I took pictures of this, I took recordings of this, and there is no doubt whatsoever that there wasn’t the slightest provocation.
“There hadn’t been one shot fired at them. There hadn’t been one nail bomb thrown at them. They just jumped out and, with unbelievable murderous fury, shot into the fleeing crowd.”
Signor Grimaldi was asked if at any stage before the paratroopers fired there might have been shots from the top of Rossville Flats. He replied: “I am absolutely certain, and it is proved by the tape, which records the whole following of events. Absolutely no shot, no nail bomb even, nothing at all. That crowd was dispersing.”
He was asked, in view of the fact that the Army claimed that they had been shooting at snipers on top of the flats, whether he had seen any dead and wounded other than in the streets. He went on: “Let me tell you what I saw. Now, they were only in the street and in the squares. I saw a man and his son crossing the street, trying to get to safety, with their hands on their heads. They were shot dead. The man got shot dead. The son, I think, was dying.
“I saw a young fellow who had been wounded, crouching against the wall. He was shouting ‘don’t shoot, don’t shoot’. A paratrooper approached and shot him from about one yard. I saw a young boy of 15 protecting his girlfriend against the wall and then proceeding to try and rescue her by going out with a handkerchief and with the other hand on his hat. A paratrooper approached, shot him from about one yard into the stomach, and shot the girl into the arm.
“I saw a priest approaching a fallen boy in the middle of the square, trying to help him, give him the last rites perhaps, and the army - I saw a paratrooper kneel down and take aim at him and shoot at him, and the priest just got away by laying flat on his belly. I saw a French colleague of mine who, shouting ‘press, press’ and raising high his arms, went into the middle to give help to a fallen person and I saw again paratroopers kneeling down and aiming at him, and it’s only by a fantastic acrobatic jump that he did that he got away.
“I myself got shot at five times. I was at a certain stage shielding behind a window. I approached the window to take some pictures. Five bullets went immediately through the window, and I don’t know how they missed.”
Signor Grimaldi was asked what the mood of the people in the Bogside had been while this was going on. He said: “It was panic, it was sheer despair, it was frustration. I saw people crying, old men crying, young boys, who had lost their friends of 14, 13 and 15 years, crying and not understanding. There was astonishment. There was bewilderment, there was rage and frustration.” | <urn:uuid:009ecc24-f820-4f34-adc4-7bb5b0a8647f> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 4,818 |
1. A Vile Politician and Vile Clergymen Deliberately Misdiagnosed Unfortunate Orphans as Psychiatric Patients to Make Money
To exploit the Canadian federal government’s subsidy program, Maurice Duplessis and Quebec’s Catholic Church conspired to turn unfortunate orphans into psychiatric patients. To implement their idea, they set up a system to falsely diagnose orphans as mentally deficient, in order to siphon more federal subsidy dollars into the Church’s coffers. As a first step, Duplessis signed an order that instantly turned Quebec’s orphanages into hospitals. That entitled their religious order administrators – and ultimately the Catholic Church of Quebec – to receive the higher subsidy rates for hospitals.
It took decades before the scandalous state of affairs was finally uncovered. By then, over 20,000 otherwise mentally sound Quebecoise orphans had been misdiagnosed with psychiatric ailments. Once they were misdiagnosed, the orphans were declared “mentally deficient”. It was not just a paperwork technicality. Once they were misdiagnosed as “mentally deficient”, the orphans’ schooling stopped, and they became inmates in poorly supervised mental institutions. There, the unfortunate children were often subjected physical, mental, and other abuse by nuns and lay monitors.
Where Did We Find This Stuff? Some Sources and Further Reading | <urn:uuid:ba14a046-12a5-45d6-b95d-cee6594b4e9b> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,359 |
Argent Flow Kitchen Mixer – Square
$258.30 – $419.00
Balanced and poised, displaying purity of the cylindrical form and reflecting the modern styling of cosmopolitan interiors.
Available in: Chrome, Matt Black, Brushed Gold and Brushed Nickel
- Argent colours including Matt Black are a high quality PVD finish ensuring a long, durable and stable finish backed by our 7year* finish warranty for residential when cleaned with appropriate cleaners, 15 years* warranty on the tap.
- Cartridge- high quality and durable European ceramic cartridges from Kerox
- Aerators- High quality Neoperl from Switzerland
Mains Pressure – WELS 4 Star Water Efficiency (6.5 L/min Water Consumption)
Brushed Gold, Brushed Nickel, Chrome, Matt Black | <urn:uuid:68197b06-0490-4d25-8115-92cac9eca653> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 729 |
For this week’s “Now and Then” column, Matt Brennan veered from his planned course.
I had originally planned on writing about two brilliantly constructed, unnerving examples of the “new Romanian Cinema” — 4 Months, 3 Weeks, and 2 Days and Police, Adjective, both of which I recommend. But last night, tired of waiting for Tropical Storm Lee to pass, I finally ventured out with a friend to see The Help (trailer below).
We are talking here about a movie that cost $25 million to make. Not a damn thing explodes. There’s nary a man in sight, except a few straw men for the ladies to knock down. It’s a period piece that feels, in certain moments, grossly oversimplified, cheaply emotional, messy, melodramatic, and overlong.
We are also talking here about a movie that has led three weekends in a row in an otherwise dismal late summer, raked in a cumulative $118.6 million domestically, and in the middle of a storm that has dumped close to 20 inches of rain, had every seat of a New Orleans theatre filled nearly a month after its release. All of which prompts the question: why?
Book club business and positive word-of-mouth are contributing factors, but you can’t lump Tate Taylor’s crowd pleaser in with Bridesmaids or Sex and the City. It has been said of all three that they “proved” women, as both stars and spectators, could carry a movie to the top of the box office. But that’s to suggest women go to the movies just because there’s a woman on screen, unable to decipher between the bawdy companionship of Bridesmaids and the weepy embrace of The Help. However much the success of The Help is due to female viewers, it’s not simply because they’re so desperate for a female protagonist that they’ll see anything. It’s because the film, whatever its flaws, is also an earnest attempt at dealing with the very problems of domesticity, friendship, love, marriage, and power (or lack thereof) that women of every stripe continue to face. For at least some in the audience, I imagine, The Help isn’t a period piece at all.
Based on my own unscientific sample — one screening at one cinema in one city — women are only part of The Help’s box office triumph. The theatre I attended in New Orleans was equally divided, by my rough head count, between men and women; the crowd skewed older than, say, Colombiana, with Zoe Saldana as a female lead, but it wasn’t ladies who lunch. What’s happening here, I think, is not unlike the rise in gold prices. When the economy’s in the tank, investors flee for the stability of gold; when the weekend’s offerings at the multiplex are prefab horror franchises and stale comedies, filmgoers flee to adult fare. Neither choice is a particularly risky one, and you may not win big, but you’re just as unlikely to lose.
A lot of ink has been spilled over The Help: arguments about its politics, femininity, historical accuracy. But the real issue, if we’re talking about its success, is not Skeeter Phelan (Emma Stone) deciding to write a book from the perspective of local maids (Viola Davis and Octavia Spencer) in 1960s Jackson, Miss. Because The Help may be grossly oversimplified, cheaply emotional, messy, melodramatic, and overlong. But it’s also rousing, uproarious, fiercely felt and acted within an inch of its life by some of the most talented actresses today. Nearly every one is believable, complicated, finely balanced. The cast provides an impressive display of emotional range in a part of the year when movies are usually drained of every drop. Bryce Dallas Howard, as the villainous Hilly Holbrook, pushes right up to monstrosity and then pulls back with a veil of tears — what starts off a bit too broad narrows until she’s just a woman, embittered and humiliated, unable to get what she wants. Jessica Chastain gives a brave tragicomic performance as the lonely, ditzy wife of a local heir, vacillating between bubbly and distraught.
The one that lingers longest, though, is the magnificent Viola Davis, roiling and raw. As Aibileen Clark, the first maid to agree to speak with Skeeter, she steals the movie from the opening minute. “How does it feel to take care of white children all day when your own are being looked after by someone else?” Skeeter asks. Davis conveys her near-incapacitating pain at having to respond with just the pace of her breathing and the gaze of her eye. “It feels…” she trails off. The Help, just as it’s getting underway, answers my earlier question. Why has it become so popular, despite its imperfections and the conventional wisdom that people don’t go to see things like this anymore? Because it feels. When it comes to movies, sometimes that’s all you ask.
[Photos and trailer courtesy of DreamWorks Studios and Participant Media] | <urn:uuid:b2d45ed6-05eb-4092-8999-e86dc5881bb1> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 4,723 |
From the NYC Archives Unconference website:
"The NYC Archives Unconference is a free event open to anyone interested in archives, to be held at Barnard College on Saturday, September 6th, 2014. What’s an unconference? We like THATCamp’s definition:
…an unconference is a highly informal conference. Two differences are particularly notable. First, at an unconference, the program isn’t set beforehand: it’s created on the first day with the help of all the participants rather than beforehand by a program committee. Second, at an unconference, there are no presentations undefined all participants in an unconference are expected to talk and work with fellow participants in every session.
Some components of the NYC Archives Unconference–a few workshops and other sessions–will be organized ahead of time, to allow us to allocate resources for them. However, the majority of sessions will be proposed, selected, and scheduled by participants–that’s YOU– in the days and weeks leading up to the unconference, and on the day of the unconference itself. We’re so excited to host a day that’s all about archives and features a diversity of voices and ideas.
We are also hoping to make this unconference as accessible as possible, particularly for archives students and new professionals. It is open to anyone interested in archives and is completely free. We are also trying to facilitate travel to and accommodations in New York City for any out-of-towners, and all sessions will be held in ADA-accessible facilities. Moreover, to ensure that the Unconference is a supportive and comfortable space for all participants, the day will be governed by a code of conduct.
The unconference is made possible by our fantastic sponsors–Barnard College; Queens College, City University of New York; the Archivists Round Table of Metropolitan New York, Inc.; and La Salle University–and our tireless planning committee: Alex Duryee, Alexandra Dolan-Mescal, Allie Janvey, Brigette Kamsler, Chris Arena, Dana Gerber, Dan Brenner, Dinah Handel, Jenny Ferretti, Jenna Freedman, Kristen Mapes, Leonora Lange, Martha Tenney, Maureen Callahan, Michael Miles, Natalie Pantoja, Nick Pavlik, Rebecca Goldman, Ryan Mendenahll, Sara Howard, Shannon O’Neill, Susan Kline, and Tamar Zeffren. Special thanks to our workshop leaders (who will be announced soon!)"
For more information, including registration, please visit: http://nycarchivesunconference.wordpress.com | <urn:uuid:383a1653-2654-46bd-8ee9-2651d1ff47c6> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 2,440 |
Dear Ontario Parents
Congratulations on a successful one-week strike, that has helped in bringing awareness, getting more parents to read the curriculum, and show the huge opposition to the new Sex-Ed curriculum. Now as kids go back to school as of Monday May 11th, please stay tuned for upcoming events during May and June. Parents now realize that they need to stand for their parental rights.
To get updates via email please continue to sign up and join our mailing list.
Copyright © 2018 | WordPress Theme by MH Themes | <urn:uuid:b8d8d318-7fd9-4d21-a5a7-4d63aaf47f1a> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 522 |
If you're still looking for a gift this holiday for that special sporty girl, look no further! Yesterday I jumped into a thorough women's gym bag search in desperate need of something before I leave town on Saturday. I decided to go with a cute and stylish gym bag instead of a true carry-on because of have been literally using a sporty Puma purse for all my gym and wrestling gear these last few months. It is really tiny and defiantly won't do for much longer. Happily, I came across a lot that I loved, and decided to do a blog about my findings. Since I don't have time to order online, I am going to have to get to a few locations today and see what I can find. Check out what I am loving!
This little beauty is on the smaller side. I love the pockets on the exteriorthat are flat and add texture and design to the front of the bag. It is convenient to put something like a phone, water bottle, or MP3 player in when on the move. The interior has multiple organizational pockets and the long and short handles are perfect for carrying different ways. The best part of this bag is that right now it is on sale for $20. It comes in black and silver as well, and would be a perfect gift for this season. I may need to order this just because it is such an amazing price!!!
A more traditional gym bag, this one comes in neon green and purple colors. Water resistant and durable with multiple compartments. Perfect for those who just want a touch of femininity to their bags.
I am always impressed at how Under Armour keeps up with current trends. I love this sleek black bag for it's classiness and durability. It is understated but comes with many bells and whistles. A separate side shoe compartment, a removable laundry bag, a computer tablet sleeve, and even a heat durable pocket to store a still warm hair iron when you are in a hurry. Although the price reflects this accessory, it is surely a statement athlete piece.
LuluLemon is definitely a front runner of fashionable fitness and yoga bags. With many to choose from each season, I choose this one to highlight because of it's soft traditional style. Lulu often makes hard shelled bags, which are lovely, but I am not in the market for this month. I want something durable and compact-able (in case I need to pack it down into my suitcase). I have also noticed how the hard shelled bags wear on the corners if you don't treat them with a lot of TLC.
For the ultra girly-girl. This lovely bag comes in vegan leather and sports a yoga mat holder, a clear jewelry pocket, a laptop compartment, a separate shoe bag, and a phone pocket inside. The designer of oGorgeous Bags is a fellow fitness blogger who has been blogging for many years and succeeding a the highest level!
Moving back into a reasonable price range is another cute Puma bag! Puma has really been getting it for me today. This bag zips closed securely below the handles and sports multiple interior pockets and a key holder cord. It also comes in two other bright and girly colors!
Please let me know if there are other amazing and cute gym bags you know of in the comments below! I am heading out to hunt for a bag I can leave town with on Saturday, and I am hoping that I find something! | <urn:uuid:77568846-9ebb-4d40-9225-a1021211c676> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 3,215 |
Living at Peace with our Un-peacefulness.
Post Traumatic Stress, Military and combat trauma are more than just a set of psychological symptoms, such as sleeplessness, anxiety, and depression. The more fundamental injuries are moral and spiritual in nature. Mindfulness-Meditation provides a road map that can support the practitioner in navigating a road to living at peace with un-peacefulness.
In this retreat we will learn meditation practices that are rooted in our daily life activities. These meditation practices can support us in coming to terms with the emotional, spiritual, and moral wounds of our training and combat services. Hundreds of Veterans have found these retreats invaluable in discovering how to live at peace with our un-peacefulness.
In Vietnam Claude AnShin Thomas, native of Pennsylvania, survived as a helicopter crew chief being shot down five times. On the fifth occasion, in mid-1967, he was shot down in the Mekong Delta. The pilot and commander were killed, and the gunner and Thomas were wounded. Thomas received 25 Air Medals, the equivalent of 625 combat hours, and 625 combat missions. Thomas also received the Distinguished Flying Cross and the Purple Heart.
1995 Claude AnShin Thomas became fully ordained as a Zen Buddhist in the Japanese Soto Zen tradition. He is the author of AT HELL’S GATE: A Soldier’s Journey from War to Peace (Shambhala 2004) and Bringing Meditation to Life (Oakwood Publishing, 2021). He has taken vows of mendicancy, meaning that he is reliant on the generosity of others for his sustenance. He has no permanent home but serves others through almost constant travel. So, the years and months of COVID have provided quite some challenges to this lifestyle. | <urn:uuid:8b37f70e-92e4-4c6f-90a5-b10e5cffda1b> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,721 |
As translated by Richard Pevear and Larissa Volokhonsky: When it rains, it pours. Without torture no science. Without effort, you can't even pull a fish out of the pond. My friends Sean Meighan and his beautiful Ukrainian wife Lilia kindly helped me to make this site and I really appreciate them. Clicks the "Like" button below to get daily updates on Facebook!
Adult Big Wet Butts Olivia O Lovely
Free Safe Ladyboy Clips
single..61..kids are grown and gone..its ME time Nice loving woman just dnt make me mad
Genrietta. Age: 18. NO OUT OF TOWN MEN
Latex Vs Nitrile Gloves
Porn-Photo 6 Filipino Penis Pics
My Pussy Is Wet
Adult Beautiful Woman Well It Turns
Lutera Oral Contraceptive
Christina Milian Boob - esbs-amicale.eu
Photo 1741 My Life Wopuld Suck Without You
Boob Lift Exercises
Side Boob Video
Les. Age: 24. Hello there! I want to your cock...
Marriage Agency Meetlovetoday And
|Corybantic at 09.02.2018 в 10:45|
|Solaced at 16.02.2018 в 03:35|
Had this done to me once, loved it.
|Marrone at 26.02.2018 в 04:45|
Then why do you even waste your time hating it?? Just mute the video and use your imagination or just ignore it, click away. BTW they're not relative at all, they're actors
|Danae at 05.03.2018 в 15:51|
They are amazing.
|Baden at 14.03.2018 в 12:39|
I'm a fan of Lilly ford but I don't dig that tan in this video, or look. Dunno, something about it is off-putting.
|Tabloid at 17.03.2018 в 17:01|
Another happy fapping
|Meteorology at 22.03.2018 в 10:50|
PLS SOMEONE, I NEED THE MUSIC
|Undergeneral at 26.03.2018 в 21:49|
chicagobulls232369 is my kik
|Bichons at 01.04.2018 в 09:30|
i wish I fucked her pussy.. can you fuck me....
|Bandsman at 04.04.2018 в 03:48|
Love the content and you all video quality
|Unforgiven at 06.04.2018 в 09:56|
So im going to assume thats her name, maybe im just making an ass out of u an me tho!?!?
|Lazily at 08.04.2018 в 17:05|
hit like if you think im sexier than her lol ..im single btw! hit me up if you are alone ..boreddddddd !
|Soxhlet at 10.04.2018 в 13:53|
Love the way you smile in the video. It really is awesome when you know a woman loves it.
|Quirked at 19.04.2018 в 02:45|
I honestly know her...I went to middle & high school with her
|Sinanan at 28.04.2018 в 11:07|
|Direr at 06.05.2018 в 04:01|
|Frappe at 16.05.2018 в 07:03|
last position was made for anal! would you do anal prone bone!? please!?
|Rodrigo at 21.05.2018 в 01:52|
nothing sexier than a girl who takes a load on the face.
|Sommerfe at 25.05.2018 в 05:19|
Hey guys does anyone have a good sci-fi show to recommend, like vikings or GoT, just finished vikings and dunno what to do with myself. GReat vid btw.
|Hollander at 30.05.2018 в 02:18|
Jelena the beautiful dark haired cuties swollen hard clit and wet pussy probably feels crazy good fucking another girls pussy. They always cum fast when she slides that sexy pussy inside them.
|Sisyphus at 30.05.2018 в 20:43|
best face in porn by far
|Feilong at 03.06.2018 в 21:43|
She always does such a good job
|Duong at 05.06.2018 в 01:38|
Amazing ♡ such a great video! You looked great and loved the way your man fucks you. So hot you two♡
|Pieshop at 07.06.2018 в 22:56|
Although, I do have to admit, the auto-rotate feature is awesome.
|Switching at 08.06.2018 в 16:14|
Jay Savage can fuck me any time! Love that big uncut cock!
|Concerning at 18.06.2018 в 00:26|
Your videos are so good I cry after watching them.
|Jeannie at 20.06.2018 в 09:06|
i remember this video... nice foot shots
|Genetta at 29.06.2018 в 08:05|
Fucked my girlfriend to this video last night....best two minutes of my life.
|Garey at 06.07.2018 в 19:48|
Hello beautiful. Will be fantastic taste your sperm and your beautiful girl
|Gregoire at 13.07.2018 в 05:30|
totally unrelated but anyone know where i can buy one of those pink bra-let things?
|Lartuen at 22.07.2018 в 12:45|
Love the top ! I'd love to give him my hole
|Casus at 26.07.2018 в 06:00|
thx so much :*
|Abases at 31.07.2018 в 00:50|
She's hot but that was boring.
|Meathook at 03.08.2018 в 22:28|
Wait, how did this bitch dry off so fast and put her hair in a ponytail. What conspericy theory is the capatilist scum hiding from us?
|Campanero at 10.08.2018 в 07:24|
|Kathryn at 11.08.2018 в 02:59|
mmm you are amazing !!!
|Cordobas at 16.08.2018 в 02:11|
the only time I have ever felt dick envy is when deepthroating a guy | <urn:uuid:0bd33649-19de-4bf5-9b50-19ae5c9eda03> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 4,351 |
CBD oil. What’s that?
If you are confused in regards to the differences between hemp oil and cannabidiol (CBD) oil, you are not alone. Even public health legislators are confused it seems.
While marijuana and hemp are related (like cousins), the amount of psycho-active ingredient (THC) that is in marijuana is extremely low in hemp. In the United States, several states have legislated to allow the use of “medical marijuana”, which permits the use of low-THC, high CBD strains of the plant.
There is mounting evidence that such compounds (i.e. cannabinoids, as opposed to cannabis) may have potential as pain-relieving medication http://www.ncbi.nlm.nih.gov/pubmed/18728714 , increased survival in cancer (this study was a mouse-model of breast cancer). Other work suggests that these plant compounds may be beneficial in a range of nervous system disorders such as multiple sclerosis, Parkinsons Disease, brain injury and stroke (http://www.ncbi.nlm.nih.gov/pubmed/12617697). One cannabinoid is licensed in the USA (nabilone) for use as an adjunct to chemotherapy to prevent or treat treatment-induced vomiting.
So what is the problem in Wellington?
You’ve possibly heard of a family’s bid to get this currently banned substance to treat a young man in a coma in Wellington Hospital. The doctors involved in this case have approved the use of CBD oil in the case of this young man, but getting it into the country is the next hurdle. You can help – sign the petition here. | <urn:uuid:2f0f9900-26ca-4867-9440-0a0890509f55> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,475 |
Huperzine A is derived from Chinese club moss Huperzia serrata, and is described as having several properties which may be beneficial for AD. This review looked for randomized trials comparing Huperzine A with control in patients with AD. Six trials were identified but most trials were of low methodological quality. Although Huperzine A seemed to have some beneficial effects on improvement of general cognitive function, global clinical status, behavioral disturbance and functional performance for patients with AD, the small trials with limited numbers of patients and the low methodological quality resulted in cautious assessment of the results. More large, high-quality randomized trials are needed.
From the available evidence, Huperzine A seems to have some beneficial effects on improvement of general cognitive function, global clinical status, behavioral disturbance and functional performance, with no obvious serious adverse events for patients with AD. However, only one study was of adequate quality and size. There is therefore inadequate evidence to make any recommendation about its use. Rigorous design, randomized, multi-centre, large-sample trials of Huperzine A for AD are needed to further assess the effects.
Alzheimer's disease (AD) has become a major public health problem around the world due to its increasing prevalence, long duration, caregiver burden, and high financial cost of care. The degeneration of acetylcholine-containing neurons in the basal forebrain has been implicated in the symptoms of AD. Cholinesterase inhibitors may block the degradation of acetylcholine, thus increasing the efficacy of the remaining cholinergic neurons. Huperzine A is a linearly competitive, reversible inhibitor of acetyl cholinesterase that is said to have both central and peripheral activity with the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These properties might qualify Huperzine A as a promising agent for treating dementia (including AD).
To assess the efficacy and safety of Huperzine A for the treatment of patients with AD.
The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group was searched on 1 February 2006 using the search term: huperzin*. The CDCIG Specialized register contains records from all major health care databases (MEDLINE, EMBASE, PsycINFO, CINAHL, SIGLE, ISTP, INSIDE, LILACS) as well as from many trials databases and grey literature sources. In addition, the CBM and AMED databases and relevant websites were searched and some journals were hand-searched. Specialists in the field were approached for unpublished material and any publications found were searched for additional references.
All relevant randomized controlled trials (RCTs) studying the efficacy and safety of Huperzine A for AD.
Data were extracted independently by two reviewers using a self-developed data extraction form and entered into RevMan 4.2.10 software. Meta-analyses were performed when more than one trial provided data on a comparable outcome on sufficiently similar patients. Random effects analyses were performed whenever heterogeneity between results appeared to be present. Standardized differences in mean outcome measures were used due to the use of different scales and periods of treatment.
Six trials including a total of 454 patients met our inclusion criteria. The methodological quality of most included trials was not high. It was shown that compared to placebo, Huperzine A had beneficial effects on the improvement of general cognitive function measured by MMSE (WMD 2.81; 95% CI 1.87 to 3.76; P < 0.00001) and ADAS-Cog at six weeks (WMD 1.91; 95% CI 1.27 to 2.55) and at 12 weeks (WMD 2.51; 95% CI 1.74 to 3.28), global clinical assessment measured by CDR (WMD -0.80; 95% CI -0.95 to -0.65) and CIBIC-plus (OR 4.32, 95% CI 2.37 to 7.90), behavioral disturbance measured by ADAS-non-Cog at six weeks (WMD -1.33, 95%CI -2.12 to -0.54) and at 12 weeks (WMD -1.52, 95% CI-2.39 to -0.65), and functional performance measured by ADL (WMD = -7.17; 95% CI -9.13 to -5.22; P < 0.00001). However, Huperzine A was not superior to placebo in the improvement of general cognitive function measured by Hasegawa Dementia Scale (HDS) (WMD: 2.78; 95% CI -0.17 to 5.73, P = 0.06) and specific cognitive function measured by Weshler Memory Scale (WMS) (WMD = 6.64; 95% CI -3.22 to 16.50; P = 0.19). No data were available on quality of life and caregiver burden. The adverse events of Huperzine A were mild and there were no significant differences of adverse events between Huperzine A groups and control groups. | <urn:uuid:fe9d0538-3ae9-42f0-8f25-3ccaad217b1a> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 4,691 |
Sample Thesis Statements for Compare/Contrast …
Compare and contrast thesis examples tend to compare and. Any compare and contrast essay compares two things, ideas, or people for the purpose of arriving at a conclusion. Thesis Statements. Not sure what type of paper you are writing.
Consider the following compare and contrast thesis. Be sure and utilize MLA formatting for the paper. 2) Your thesis (and essay) should stay within the parameters of the question or prompt.
These thesis statements offer a short summary of Of Mice and Men in terms thesis statement for comparative and contrast essays different elements that could be important in an essay.
Write a 2-3 page comparisoncontrast essay. Tracie hastate state the alternative hypothesis scourged and kill your invalidates capitularly.
COMPARE AND CONTRAST ESSAYS
You, the emerging writer, dont have it so easy. One of these is a compare and contrast essay. Experienced writers have lit- tle difficulty writing thesis sentences.
Have no clue how to create a good thesis for your comparative paper.
Somebody is writing compare and contrast thesis The thesis statement is the central part of an essay or research paper which reflects the purpose, main idea, or claim of the writing.
Thesis Statement Examples For Compare And Contrast Essay.
Curriculum vitae objetivo
And do you know our friends become fans of thesis statements for compare and contrast essays examples as the best book to read.
This part of essay writing has vexed essay money is the best motivator college students, but luckily, Im here to show you the ropes.
The thesis statement is the central part of an essay or research paper which reflects the purpose, main idea, or claim of the writing.
Formatting the CompareContrast Essay.
This will occur in the introduction. This will occur in the introduction.
- Thesis statement for compare and contrast essays
- gadgets essay in hindi
- writing a good research paper tips
Thesis Statement For Compare And Contrast Free Essays. Thesis-Statements-mb-pp. none Body - shows the comparative Comparison and Contrast Essays A comparison and contrast essay focuses on how two items or texts are similar, different, or o Use the conclusion to.
How to Write a Compare and Contrast Essay The traditional essay tips examples of student essays wont work with compare and contrast paper.
The grounds for comparison anticipates the comparative nature of your thesis. Welcome to the site for people who are passionate on thesis statement for comparative and contrast essays, best place to buy research paper, essay icc world cup 2011 and law and order essay.
Thesis statement for compare and contrast. | <urn:uuid:b6881e8c-e517-4f75-aee9-10a6908b7925> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 2,659 |
There are several options available when you consider what will happen to your body after you die. There, of course, are traditional burial and cremation options. However, with these options come two more options. You can also have your organs donated as part of an organ donor program, or you can have your body donated to science. The question many have is if your body will be returned for traditional burial or not. Most science organizations that accept body donation for science offer cremation. Here is how that process works and what you need to know if you are considering this type of option.
Donation of the Body
After you die, your body will be retrieved by the organization you choose for the full body donation. There are specific criteria for body donation based on each organization. If there is a current healthcare crisis, epidemic, or pandemic the service may require that you be free of that issue at the time of your death. They may also have criteria for their different research studies which may include only wanting full bodies for various cancer research or specific illness for further research and study. You will be informed of these criteria prior to agreeing for your body to be donated. If your body meets the criteria, the service will retrieve the body as soon as possible, usually within a few days.
The key reason that many people choose to donate to science and opt for the cremation service is that the cremation service is generally offered at no cost. The misconception to this is the belief that the entire cremation service from the local crematories is free. Though the cremation itself is at no cost, urns, burial choices, and memorial services still have a fee that must be paid. The services that carry a fee may vary depending on the different crematories. These fees can be paid through burial insurance, pre-planning burial payments, or paying at the time of service. Your cremains will be returned to the family following the full-body research by the research facility.
There is a misconception that each university, organization, or research facility requires a donor card or donor registration. The truth is, this ruling depends on where your body will be donated. For example, many places like Duke University, offer an Anatomical Gifts Program. This can be coordinated through your crematorium director and their crematorium services alongside the research organization.
If you believe that you would like to donate your body to science with a cremation option, contact local crematories. Many do have networking with various science organizations and research services that will gladly work with you and your final wishes. You can also discuss what will be done with your cremains following the cremation with the crematory director.Share | <urn:uuid:b6d6da29-bbc8-4343-b25a-5913580ce3ea> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 2,794 |
Statement ring with Rose quartz gemstone.
You can adapt the size so ring will always fit.
Measurements of gemstone approx 2,5 x 1,5cm
Rose Quartz has been regarded as a soothing calming crystal that promotes love and healing.
Ring Saudade Green Agate
Ring Saudade Blue Agate Cuff
Ring Rocky Rose Quartz
Ring Lindeza Silver | <urn:uuid:5d6f7bb0-c014-40b2-86ed-e4595e8d3276> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 322 |
SRS Audio Sandbox is a tool that modifies and improves the quality of the sound generated by your PC. It is an application for those who appreciate a decent quality and look to get better results. This software is a good program for computers which are not equipped with advanced sound cards.
SRS Audio Sandbox emulates a professional card to obtain great quality and it offers similar functionality but using software instead. It works fine even for your videogames, enhancing the audio effects. It supports all the popular media players, so you will be free to use it without worrying about compatibility issues with your PC.
How to use
SRS Audio Sandbox is pretty simple to use. SRS Audio Sandbox features a graphic equalizer, so you can adjust each band according to your preferences. The application has different default settings that can help you if you are a beginner. The tool runs in the background and enhances the sound player on all music programs, DVD movies, etc. The program brings you some “sliders” with which you will be free you to customize lots of settings. Trubass Level increases the perceived bass as you turn it up. Speaker size works this way: the smaller your speakers, the higher you set this slider. SRS Focus Level makes everything louder even when it’s still at the same volume. Room Size creates a virtual surround effect when used with headphones.
Also, the program enhances audio in video games using a variety of effects to enhance color, tone, etc. SRS Audio Sandbox is equipped with a graphic equalizer and many default profiles configured to suit the needs of audio. The software is compatible with the popular media players to avoid compatibility issues.
SRS Audio Sandbox 18.104.22.168 Features
Here you can see some of the features of this program:
- Easy-to-use interface design
- Amazing surround which runs from 2 speakers, using technology of SRS Labs state of art audio enhancement
- Deep & rich bass, that also works in small speakers
- Loads of presets for your videos, music, and games
- Custom settings for 2 or more headphones or speakers
If you are interested and you need some more information before you download this program, feel free to check the developer's webiste .
Minimum system requirements to download and run this program are listed below:
- Operating System: Windows 7 or higher
- Processor: 1 GHz or faster
- RAM Memory: 1 GB
- Hard Disk: 16 GB available
- DirectX 9 graphics device with WDDM 1.0 or higher driver graphic card compatible
This is one of those programs that may seem a bit fake when you read what they are supposed to do. But trust us; there is a difference between your standard audio and the quality you achieve with this app. It’s even more evident when you have two little speakers or even default speakers on a laptop. Of course this is not miraculous, but instead of sounding like a prewar radio, your audio will become pretty decent. Just download it and try its power for yourself.
- Enhances your PC audio easily
- Lots of sliders to customize every setting
- Supports most popular players
- Loads of presets
- Customizable for 2 or more speakers or headphones
- Heavy client | <urn:uuid:654e0fa7-088b-4119-ac22-dc14026b2b90> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 3,167 |
Monterey 2 Piece Spinner Set
Traveler's Choice's Monterey Collection features that ultimate balance between protection and weight with its durable micro-polyester material construction.
- 360 degree wheel spinners allow upright rolling in multiple directions providing easy maneuverability through crowds.
- Sleek multiple-stage retractable aluminum push-button handle system provides the comfort of being the perfect height.
- Two exterior pockets provide simple access for easy to reach items.
- Gusset allows for 2 inches of expansion.
Material: Durable Micro-weave Polyester
Carry On Overall Dimensions: 22" x 13.5" x 8.5" + 2" depth gusset
Carry On Packing Dimensions: 19" x 13.5" x 8.5" + 2" depth gusset
Carry On Weight:
Carry On Linear Dimensions:
Large Checked Overall Dimensions: 30" x 19" x 12.5" + 2" depth gusset
Large Checked Packing Dimensions: 27" x 19" x 12" + 2" depth gusset
Large Checked Weight:
Large Checked Linear Dimensions:
• 1 Carry-On Sized
• 1 Large Sized
At Traveler's Choice, we want you to be fully satisfied with every purchase you make. If you are not completely satisfied with the products you have purchased on our site. you may return the unused products within 30 days from the date of purchase. Learn more about our return policy.
In the unlikely event that there is a manufacturing defect in material or workmanship, we will be more than happy to help! Learn more about our warranty policy.
I purchased luggage as a gift. She loves it!
Favorite luggage set
I got this set for my twin sister, she wanted the navy blue 3 pc set last year but it sold out. Managed to get it this time and it was worth it, luggage is very high quality 5/5
Looks like quality luggage but we shall see. Kids headed to Canada at the end of the month. Thanks for the fast shipping
Bought as a gift for my significant other and she loved it!
They're light, easy rolling and they look expensive. | <urn:uuid:13d5834d-f714-4cfd-b416-c6c2acd5531b> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,907 |
Moose started partnering with this wonderful charity this year, 2020. Eat Up is doing amazing things Australia wide for children who would otherwise go hungry at lunchtime.
1 in every 8 Australian children arrives at school without the lunch they need to fuel their growing bodies and brains. Missing out on lunch has a big impact on these children, with hunger leading to fatigue and poor concentration. This commonly leads to learning difficulties and behavioral problems in school, with disadvantaged children falling further behind their peers. To date, Eat Up has provided more than 980,000 free school lunches to help children in Australia take advantage of their learning opportunities.
Our Partnership At A Glance
1,000,000 free school lunches to help children in Australia
Production line of yumminess!
At the core of Eat Up is the free school lunch program. The special part of our approach is engaging communities, schools, and corporate groups who (pre-COVID-19 restrictions) would come together to help prepare over 10,000 sandwiches every week. Eat Up delivers these sandwiches along with healthy snacks to more than 490 schools Australia wide. Schools freeze the cheese sandwiches on-site and toast them up each day for students who arrive to school hungry.
The Eat Up Delivery Van.
Our estimated 3500 volunteers ensure Eat Up’s program is inexpensive and sustainable, while raising awareness of food insecurity in the community. Volunteer sessions are fast and fun, with teams preparing more than 1000 sandwiches in less than an hour on-site at workplaces or in convenient public spaces. Sandwiches and donated snacks are then delivered direct to schools, who freeze the sandwiches until needed.
Adapting to COVID-19. Food Box delivery...
The outbreak of Covid-19 has seen families and students face unimaginable challenges and increased food insecurity. With school closures and students learning remotely Eat Up adapted its model to ensure students were able to access critical food supplies at home with their family by delivering emergency food boxes. These contain over 10kg of fresh fruit, vegetables, and staples like bread and pasta. With the support of companies like Moose Toys, Eat Up delivered over 20,000 emergency boxes for families by the end of Term 4, 2020 | <urn:uuid:25a96a9d-0eab-4f4c-84f3-98af24f13511> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 2,289 |
Obama not Black Enough Like Me For Morgan Freeman And Why It Matters
Damn, you know Obama is doing a bad job when blacks begin to disown him. The fact is, as ugly as the sentiment may be, Freeman isn't alone in it. On June 26, I posted: Is Obama losing his black "Essence"? I noticed comments similar to Freeman's in some reading involving Essence magazine.
“First thing that always pops into my head regarding our president is that all of the people who are setting up this barrier for him … they just conveniently forget that Barack had a mama, and she was white — very white American, Kansas, middle of America,” Freeman said. “There was no argument about who he is or what he is. America’s first black president hasn’t arisen yet. He’s not America’s first black president — he’s America’s first mixed-race president.”
Fact is, black voter participation was high in 2008 and Obama won an unprecedented proportion of it, even as a Democrat. They routinely carry the black vote. But by how much matters – most especially in Obama's case.
A decline in participation, along with a gap in enthusiasm for him, even among those who do show up, could prove disastrous for Obama's re-election chances. However unpleasant, Freeman's sentiments are relevant to the 2012 election. | <urn:uuid:feaa9dd0-ccc8-463e-a9d9-b38e8fd5a403> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,271 |
BRG overcomes adversity with diversity
Berry Recruitment Group (BRG) celebrated another year’s success at its annual awards ceremony which was held at the Kimpton Fitzroy Hotel in London.
Almost 200 of its staff from its 35 locations across the country gathered at the iconic venue and heard how the group’s turnover has risen to a touch under £70m.
BRG presented long service awards as well as ‘board recognition’ awards, ‘star performer’ awards, ‘best rookie’ awards as well as the best billers and branches. Staff from its growing head office operation in St Albans also received awards for their efforts.
BRG has three brands; Berry Recruitment, Wild Recruitment and Wild Berry Associates. It has made two acquisitions since last autumn and continues to grow organically.
The winners - 84 per cent of whom were women - took to the stage to receive their awards from Chairman Tony Berry. MD of the group, Chris Chown, addressed the room and told them on International Women’s Day that the hotel was on the site where famous suffragette Emmeline Pankhurst once lived.
He added: “As a business we need to embrace diversity and inclusion at all levels – not only internally but also in educating our clients.
“Companies which embrace diversity are much more likely to financially outperform their industry’s national average.”
He continued: “While we are all aware of the general business climate, the fact remains that unemployment is at its lowest since 1975.
“Research has shown that 80 per cent of businesses believe they will maintain or increase both their permanent and temporary headcount over the next year.
“Clients still say that their biggest concern is finding the right candidates.
“As a board we really value our staff – and we should value ourselves and our excellent service to customers.
“As a group we need to focus on clients, candidates and our own consultants.” | <urn:uuid:b38c5ba3-42ea-4bc8-9018-9f51035f5a2d> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,883 |
We all know we have to brush our teeth several times a day. Floss regularly. Don’t eat or drink sugar, alcohol, or soda. But even if we do all of this, cavities can occur.
Did you know there is actually a way to prevent them? Dental sealants form a protective layer over molars and premolars. They are safe to use on children; the procedure to apply them on the teeth is easy and painless. Want to know more? Learn all about the real pros and cons of dental sealants in this guide.
What are dental sealants?
Dental sealants are thin, protective coatings applied to the chewing surfaces of teeth, particularly the molars and premolars. These areas are more prone to decay due to their grooves and pits. That makes it challenging to clean them effectively with regular brushing and flossing. The sealant material is usually made of a safe, plastic resin that bonds to the tooth enamel, creating a barrier against harmful bacteria and acids that can lead to cavities. The back teeth are where nine out of ten dental caries occur.* So, dental sealants effectively prevent cavities.
The process of applying dental sealants
The application of dental sealants is quick and painless and is typically performed by a skilled dentist or dental hygienist. This can often be done on a routine checkup.
The procedure is very straightforward. It begins with thoroughly cleaning the teeth to remove any plaque or debris, ensuring that the sealant adheres effectively to the tooth surface.
Once the teeth are clean, we proceed to isolate them with a rubber dam or cotton rolls around them. This step is crucial as it helps to keep the teeth dry during the application process, ensuring the sealant bonds properly to the enamel.
With the teeth isolated and dry, we carefully apply the liquid sealant onto the chewing surfaces of the teeth. The sealant material is usually a safe plastic resin, which flows into the deep grooves and pits of the molars and premolars. By doing so, the sealant creates a protective barrier that acts as a shield against harmful bacteria and acids that can cause cavities.
After the sealant is applied, it quickly starts to bond with the enamel. In some cases, we may use a special curing light to expedite the hardening process, ensuring that the sealant sets properly and becomes durable. Once the sealant has fully set, we check the patient’s bite to ensure that there are no interferences or misalignment caused by the sealant application.
There is no drilling involved in the placement of dental sealants. In fact, that’s exactly what we aim to prevent.
The pros of dental sealants
There are many benefits to dental sealants, which have made them a widely recommended preventive treatment in modern dentistry.
- Protection against decay
Dental sealants act as a formidable barrier, shielding vulnerable tooth surfaces from bacteria and acids that cause decay. Studies have shown that sealants can reduce the risk of cavities by up to 80% * in the first year after placement, and continue to offer protection for several years.
- It’s a non-invasive and painless procedure
Unlike dental fillings, sealant application does not require drilling or tooth structure removal. It is a non-invasive and painless procedure, making it particularly suitable for children and people that have dental anxiety.
- Cost-effective preventive measure
Preventing dental problems is always more cost-effective than treating them when they occur. Dental sealants are an excellent investment in your long-term oral health, potentially saving you from the need for more extensive and expensive dental treatments down the road. A classic win-win.
When properly cared for, dental sealants can last for many years. Ten years, easily. During all this time, they’ll protect your teeth. Regular dental check-ups are still necessary, also to check that the sealants remain intact and functional.
- Improved oral health for children
Children are often more susceptible to cavities. They’re still learning to care for their teeth. Plus, they often eat more sweets. And, hopefully, fruits. As soon as permanent teeth come in (and are still free from decay), dental sealants can protect them in cavity-prone years. Applying sealants to their permanent molars as soon as they erupt can significantly reduce the risk of cavities and promote a lifetime of better oral health.
The cons of dental sealants
While dental sealants offer numerous advantages, you may also want to consider potential drawbacks that might influence your decision.
- They’re not for everyone
Dental sealants are primarily suitable for the chewing surfaces of molars and premolars. They may not be applicable to other areas of the mouth. Also, they’re meant to cover minor grooves. If the surface of your teeth is very irregular, or grooves are deeper than normal, sealants may not be possible.
- Timing of application
Sealants are most effective when applied to newly erupted, cavity-free teeth. If cavities have already formed, the tooth first requires a different dental treatment. The bacteria will first have to be removed completely.
Although dental sealants are durable, they are not permanent. Over time, the sealant material may wear off, requiring replacement to maintain the protective benefits. In people with acid reflux or with very acidic diets, they may not last as long. Teeth grinding will also impact their durability.
Often sealants are placed on the new teeth of growing children. However, the molars and premolars don’t all occur at the same time. They are usually placed throughout the years.
Some resin-based dental sealants contain BPA, although currently, most are BPA-free.
BPA stands for Bisphenol A. It can potentially leach out and enter the body, leading to concerns about its potential health effects. Research has suggested that BPA may have hormone-disrupting properties, as it can mimic estrogen, a natural hormone in the body.
However, there is very little BPA in dental sealants. Research conducted by the American Dental Association shows that BPA release from dental sealants is very low (.09 nanograms).
To understand this: 1 nanogram is equal to 0.000000001 grams. A grain of sugar weighs approximately 0.02 grams. Imagine taking an incredibly tiny fraction of a single grain of sugar, approximately 1/222,222,222 of a grain, and that’s roughly the amount of BPA released from dental sealants.
Furthermore, BPA disappears completely from saliva levels within 24 hours of placing the sealants.
The risks of BPA seem much smaller than those of tooth decay.
- Proper oral hygiene is still necessary
While dental sealants offer excellent protection, they do not replace the need for regular brushing, flossing, and dental check-ups. Proper oral hygiene practices remain crucial to maintaining overall oral health.
Dental sealants are a valuable tool in the prevention of tooth decay, particularly for children and teenagers. Their ability to provide exceptional protection against cavities, along with their non-invasive application, makes them a popular choice in modern dentistry.
At Mint Dental, we are committed to offering the most up-to-date information and expert dental care. If you have any questions about dental sealants or any other aspect of your oral health, don’t hesitate to reach out to us.
What causes cavities | <urn:uuid:9794ec32-3c8b-4023-9cda-9fabf675f5bc> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 7,317 |
© 2020 Auto/Mate, Inc. All Rights Reserved.
ALBANY, NY (April 28, 2014) – Auto/Mate Dealership Systems (www.automate.com) announced today that it has been selected as one of The Times Union Top Workplaces in New York’s Capital Region. It is the third consecutive year that Auto/Mate has been distinguished with the award.
The Top Workplaces are determined based solely on employee feedback. The employee survey is conducted by WorkplaceDynamics, LLC, a leading research firm on organizational health and employee engagement. WorkplaceDynamics conducts regional Top Workplaces programs with 40 major publishing partners across the United States. Over the past year, more than 5,000 organizations and 1 in every 88 employees in the U.S. have turned to WorkplaceDynamics to better understand what’s on the minds of their employees. Through its workplace improvement offerings, WorkplaceDynamics provides solutions, training and tools to help clients improve their workplace.
“The link between happy employees, happy customers and healthy organizational growth is very strong, which is why our managements’ top priorities are creating a great place to work and being the highest rated in customer satisfaction out of all dealership management system (DMS) providers,” said Mike Esposito, President and CEO of Auto/Mate.
The Times Union award recipients were selected based on criteria combining employee feedback, benefits packages and corporate culture. Some of Auto/Mate’s notable benefits include a company-sponsored wellness program, in-house gym, casual dress environment, community involvement, visiting cupcake trucks, employee discount programs at local businesses, company outings and more.
“Auto/Mate continues to grow and we currently have numerous openings for software development and car dealership professionals to join our team,” said Dave Druzynski, Director of Human Resources with Auto/Mate. “For job-seekers with a positive attitude and a passion to help our customers, Auto/Mate offers a rewarding career path with many advancement opportunities.”
For more information on current openings with Auto/Mate, contact David Druzynski at (877) 340-2677 or visitwww.automate.com/careers
The Times Union published the complete list of Top Workplaces on April 27th. For more information about the Top Workplaces lists and WorkplaceDynamics, please visit www.topworkplaces.com and www.workplacedynamics.com
Auto/Mate Dealership Systems is a leading provider of dealership management system (DMS) software to retail automotive dealerships. Its Automotive Management Productivity Suite (AMPS) is a user-friendly, feature-rich DMS in use by more than 1,000 auto dealers nationwide. Auto/Mate received the “Highest Rated DMS of 2012” and the “Highest Rated DMS of 2013” awards in the annual Driving Sales Dealer Satisfaction Awards.
Auto/Mate’s employees have more than 850 years of combined experience working in auto dealerships – the foundation of its “Designed By Car People For Car PeopleTM” slogan. For more information visit our website, follow us on Twitter@AutoMateDMS and subscribe to our blog at https://www.automate.com/blog/.
Carter West Public Relations
Auto/Mate Dealership Systems | <urn:uuid:3a4393f3-c1ba-4b76-95b5-2ff858268e27> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 3,199 |
NASHVILLE, Tenn. - Mindy McCready's funeral has been scheduled for Tuesday in her hometown of Fort Myers, Fla.
The funeral for the late country star will be held at Crossroads Church and will be private. A Friday news release says a memorial organized by friends and the music community is tentatively scheduled for March 6 at Cathedral of the Incarnation.
McCready committed suicide Sunday at her home in Heber Springs, Ark., days after leaving a court-ordered substance abuse treatment program. The 37-year-old mother of two died from a single gunshot to the head about a month after her longtime boyfriend David Wilson was believed to have killed himself in the same location.
Country music fans are mourning the loss of singer Mindy McCready while family and friends wonder what will happen to her two young sons.
Recently court-ordered to mental health and substance abuse rehabilitation, McCready lost custody of both Zander, 6, and 9-month-old Zayne.
McCready had just regained custody of Zander, who spent much of his young life in custody of the state of Florida. As soon as news broke that a judge took the boys away while McCready entered another rehab, Zander's father, Billy McKnight, decided to increase his efforts to gain custody of him.
"She was in turmoil," McKnight said. "She had demons that she wasn't beating and so it was constant."
McKnight, a Tampa resident, dated McCready for almost a decade. At one point, he was charged with beating her up.
But McKnight claims he's changed his ways and their son belongs here in Tampa.
"I haven't had any troubles with him. It's been a great relationship and it's going to be a great one again," said McKnight. "I have a home. I can provide for him. I'm stable. He'll know his family. He'll be in a good school."
McCready's attorney, Therese Truelove, doesn't buy it.
"She repeatedly told me that he threatened her on regular occasions and told her she would pay for taking his son from him," Truelove said. "And it just seemed like every time something went bad with Mindy, he'd capitalize on it for his own personal good."
Truelove helped McCready win custody of young Zander a few months ago, and she believes McKnight's increased pressure to reverse the decision in his favor may have sent McCready over the edge.
"I'd rather die than Billy have my child,' 'He's dangerous', 'He doesn't want anything to do with his other children, why mine?'" Truelove remembers McCready saying. "Obviously, there was a reason Zander was in state custody in Florida for a significant period of time. If he wanted to be a father, or wanted to be a part of Zander's life, he could have taken steps, just like Ms. McCready was taking."
Truelove says the singer, though troubled, loved her boys. She blames McCready's decision to abduct Zander to Arkansas in 2011 on her desire to protect him from McKnight.
When asked why the state awarded custody to McCready instead of him, McKnight responded that a gag order is keeping him from spilling details he is dying to share.
According to McKnight, Mindy's harsh words toward him were always a show, but a show that ended tragically, and perhaps, inevitably.
"First thing I could think about was my son, how devastating this is going to be for him. It's horrific," McKnight said. "Praise God that at least they're safe." | <urn:uuid:21054737-6ba0-488d-bb07-d3465bc2a590> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 3,313 |
TicketsInventory.com is your source for all Arlington premium Sports, Concerts and theater events in Arlington. We are proud to be the premier Arlington Ticket broker!
No results found for Arlington
Sorry, no 'Arlington tickets' were found but other tickets may still be availableTry the following:
Buy with Other Brokers:
If you couldn't find 'Arlington' tickets with us, check other Arlington ticket outlets for great tickets posted for sale!
TicketsNow.com - Click here »
RazorGator.com - Click here »
Keep checking back :
FYI: New Arlington tickets often become available for purchase as the event date nears. | <urn:uuid:319685e0-088e-4f2b-a7b2-176ecf4db3a8> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 613 |
We designed our Online Banking with one main focus – convenience. With Online and Mobile banking you can manage your finances 24/7. See our easy-to-use tools in this video .
Sign up now and start making transfers, see your statement, and pay your bills on your time.
CardValet® Protect Your Debit Card Against Fraud
Now you can control your Forcht Bank debit card right from your smartphone. CardValet, a feature of the Forcht Bank mobile app, lets you lock or unlock your card, get instant alerts when your card is used, set spending limits, and more - all from your smartphone. It's the ultimate protection against debit card loss or fraud. Download the Forcht Bank mobile app with CardValet in the iTunes Store or Google Play.
View all of your bank accounts in one place – not just your Forcht Bank accounts. Financial View is a personal financial management tool that allows you to see an overview of your financial health. It even assists in setting savings goals.
- View accounts across more than 19,000 financial institutions— all from one site.
- See where you're spending money and manage your budget.
- It’s FR EE, easy to use, and available now within our online banking.
Now you can conveniently send money to family and friends with just your Forcht Bank Mobile Banking App or access to a computer. Popmoney® allows you to electronically send money to someone using their mobile phone number or email address. The money will come directly from your checking account and the person receiving the funds can deposit it directly into their account. Safe, secure and easy. View a demo .
While we hope to be your primary banking partner, we understand that you may have bank accounts at multiple banks. Now we've made it easier to manage all of your bank accounts from one convenient location - Forcht Bank's Online Banking.
- Tran sfer funds back and forth from different accounts to your Forcht Bank accounts
- Simply add, authorize and confirm your external bank accounts
Electronically pay your bills from Forcht Bank’s secure Online Banking. Never miss a due date again with the ability to set up payments in advance and even schedule recurring payments.
Enroll in Online Banking today to begin to managing all of your finances from one easy, secure location.
Get rid of the clutter with eStatements - the paperless statement from Forcht Bank. It's secure, fast and free!
- Receive your statement 3 to 4 days sooner
- Retrieve your statements online at your convenience
- Print out and/or save your statements on your computer
- Password protected and encrypted
- Added protection against identity theft
Bank Anytime, Anywhere.
Our mobile banking products allow you to manage your finances 24/7.
- Smartphone Apps
- Text Banking
- Mobile Browser Banking | <urn:uuid:29e50b2d-18ff-481f-82a2-e618197134cc> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 2,765 |
It never mattered that there was once a vast grieving:
trees on their hillsides, in their groves, weeping—
a plastic gold dropping
through seasons and centuries to the ground—
On this fine September afternoon from which you are absent
I am holding, as if my hand could store it,
an ornament of amber
you once gave me.
Reason says this:
The dead cannot see the living.
The living will never see the dead again.
The clear air we need to find each other in is
gone forever, yet
this resin once
collected seeds, leaves and even small feathers as it fell
which now in a sunny atmosphere seem as alive as
they ever were
as though the past could be present and memory itself
a Baltic honey—
a chafing at the edges of the seen, a showing off of just how much
can be kept safe
inside a flawed translucence. | <urn:uuid:11072a8b-90eb-4f45-927e-7bb711bba8d5> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 797 |
Tell Us About Your Classroom
Hi! Got questions?
Are you wondering about the big picture or the small details? About timing or even pricing? I’m the guy to get you answers. Call or email me with your questions, and I’ll help you take the steps to make learning visible in your classroom. | <urn:uuid:3d67dbd1-178c-4026-a4a1-ae243ba82971> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 286 |
I remember Rowling said something about Harry and Hermione having "charged moments" while Ron was away in Deathly Hallows. What are these "charged moments?" Is it something as simple as the stroke of his hair, or are we supposed to read between the lines here? Did anything happen between them? Immobulus 17:20, 14 July 2009 (UTC)
- Excerpt from the "Behind the Scenes" section of the Harry Potter aticle:
- In Harry, A History, Rowling discussed how Steve Kloves suspected that something might happen between Harry and Hermione in Deathly Hallows. She replied: "I had always planned that Harry's true soul mate, which I stand by, is Ginny, and that Ron and Hermione have this combative but mutual attraction. They will always bicker, there will always be rough edges there, but they are pulled together, each has something the other needs. [Kloves] felt a certain pull between them at that point. And I think he's right. There are moments when [Harry and Hermione] touch, which are charged moments. One when she touches his hair as he sits on the hilltop reading about Dumbledore and Grindelwald, and [two] the moment when they walk out of the graveyard with their arms around each other. Now the fact is that Hermione shares moments with Harry that Ron will never be able to participate in. He walked out. She shared something very intense with Harry. So I think it could have gone that way."
- Nick O'Demus 19:55, 14 July 2009 (UTC)
Oh, so is that it then? Just touching his hair? That's all that she implies? I must say, while I'm not a perverted guy, when I first read Deathly Hallows, my first reaction was "is something going on? Poor Ron." Immobulus 00:39, 15 July 2009 (UTC)
- Harry views Hermione as a sibling, not as a lover. PK Fwooper 00:00, 17 July 2009 (UTC)
Well you do have to read the immediate context of what happened in the book at those times.
- Harry Potter is standing in front his his dead parents grave. He wished he was sleeping down there under the snow with them, rather than being alive and having to suffer and fight Voldemort. He cries and tears roll down his cheeks. This is the first time in his life that Harry Potter cries.
If you had a friend, would you not hug you and comfort them? I you had anyone, would you not want them to hug you and comfort you at this moment? At times like these we feel sympathy even for our worst enemies, and Harry and Hermione had been the closest friends since childhood.
- Harry can't stand nother moment there. He put his arm around Hermione's shoulders, and she put hers around his waist, and together they walked out of the kissing gate, towards the dark church.
Yes this was a very 'charged moment' between two people. Things can happen between two people who share a moment like this. But this is Harry Potter and Hermione Granger. Harry had been attracted to Ginny, and Hermione was heartbroken, but deeply loved and missed Ron at this time. Had they both not been thinking of different people, this moment would have felt differently to either of them.
- Thereafter, a day later, Harry reads about Dumbledore in 'The Life and Lies of Albus Dumbledore', by Rita Skeeter.
- “Look what he asked from me, Hermione! Risk your life, Harry! And again! And again! And don’t expect me to explain everything, just trust me blindly, trust that I know what I’m doing, trust me even though I don’t trust you! Never the whole truth! Never!”
- “He loved you,” Hermione whispered. “I know he loved you.”
- “I don’t know who he loved, Hermione, but it was never me. This isn’t love, the mess he’s left me in. He shared a damn sight more of what he was really thinking with Gellert Grindelwald than he ever shared with me.”
- Harry picked up Hermione’s wand, which he had dropped in the snow, and sat back down in the entrance of the tent.
- “Thanks for the tea. I’ll finish the watch. You get back in the warm.”
- She hesitated, but recognized the dismissal. She picked up the book and then walked back past him into the tent, but as she did so, she brushed the top of his head lightly with her hand. He closed his eyes at her touch, and hated himself for wishing that what she said was true: that Dumbledore had really cared.
I do not think there is anything here. Harry Potter had almost died a few hours ago. He lost his wand. Now he's lost Dumbledore, all over again. Harry is angry at himself. He is angry at Dumbledore. He is also angry at Hermione because she was the one who broke his wand.
126.96.36.199 19:07, June 5, 2012 (UTC) | <urn:uuid:d2283d41-846f-4020-a38b-a32ee269840e> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 4,497 |
Online sports betting sites are definitely the basic necessities of an online betting system. As a result of rapid development and popularity of internet, even a kid can inform one that to gain access to some facilities on the internet; one has to use the services of an online site. Online sports betting is no exception to this rule. Online sports betting sites really are a must and necessity for a person considering the profession https://gertgambell.net of sports betting. It’s possible to also practice the primitive on-field betting sites thus excluding the betting sites, but with present day living nobody has the time to undertake it. So, it has expanded the business of sports betting sites and they have in their turn contributed to the expansion of the profession.
But, in order to achieve the main objective of the profession, i.e., earning profits, one has to make a right decision of the betting site. This is because of the increased amount of cheaters in the modern world. There are lots of people within the vast and open internet who would wish to cheat other people to make some money. One has to stay protected against these thugs in order to turn an investment into profit. So, you have to be really careful when it comes to choosing betting sites.
Another component that stresses upon the significance of choosing a good sports betting website is that sports betting sites really are a persons one and only partner in the profession. Although various friends and experts can offer someone many useful tips there is nothing that will help a novice like a betting site. This may be because they are the ones that proceed all of the transactions on the web and an individual has to make use of it for online sports betting. So, it is extremely clear that picking out the correct betting site is essential in the profession.
There may be many factors influencing a person’s selection of horse betting sites. The foremost will be a good winning percentage. This game is about getting profits which can only happen whenever a person is winning. Therefore, the winning percentage of the betting website is very important. You can check out various forums and newsgroups to check out reviews by different users. Second factor might be betting on the correct games.
There are a few games that provide more payouts than the others. So, it really is more profitable to bet on these games compared to normal games. These are normally games affected by a heavy lineup and tough competition. Third factor is a money-back guarantee. The website to which one is associated ought to provide this facility so that the bettor feels secure and may get all the money back when he desires to withdraw from the sites services. The final influencing factor should be the guidelines of the betting system. Each website has different rules and regulations that you has to follow. So, before investing, one need to ensure that one can comfortably follow those rules.Online sports betting sites therefore are an essential part of the profession and utmost care ought to be taken while choosing them. | <urn:uuid:30a882a5-7fe8-4658-8fe4-2995b45d1d43> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 3,096 |
The increased numbers of known populations is an encouraging sign about the penguin’s long-term survival chances.
A new colony of Adélie penguins has been discovered near Antarctica, substantially increasing the known populations of the knee-high creatures.
“It’s always good news when you find new penguins,” said P. Dee Boersma, director of the Center for Ecosystem Sentinels at the University of Washington, who was not involved in the new study. “The trends have not been good for so many of these species.”
Previous censuses of penguins had come close to these animals, living on the Danger Islands just off the end of the “thumb” of Antarctica, below South America. But satellite images of the islands revealed the pinkish-red stain of penguin guano, suggesting larger colonies than expected, said Heather Lynch, one of the five primary investigators on the new study, published this month in Scientific Reports.
After several years of preparation, a team of researchers traveled in 2015 to the Danger Islands near the Weddell Sea to do a more precise count on the nine-island archipelago. Using a drone doctored to work in the extreme climate of the region, the researchers were able to get a precise estimate of the numbers of breeding pairs of Adélie penguins in the region: about 750,000 (or 1.5 million individuals).
Most Read Nation & World Stories
- Marcus Lamb, head of Daystar, a Christian network that discouraged vaccines, dies after getting COVID-19
- Justices signal they'll OK new abortion limits, may toss Roe
- Omicron prompts swift reconsideration of boosters among scientists
- Trump tested positive for coronavirus before first debate
- Sports on TV & radio: Local listings for Seattle games and events
“The drone imagery is of a quality that just blows everything else away,” said Lynch, a quantitative ecologist at Stony Brook University. “You can see each penguin on the landscape.”
Lynch said researchers had already known about a population on Heroina Island, at the northeast end of the Danger Islands chain. Now they’ve found that sizable populations live on other islands near Heroina. “These new colonies totally change our appreciation of the Danger Islands as a penguin hot spot,” she said.
The greater numbers will help ensure that conservation efforts focus on keeping them safe, she said.
“This area falls between two marine-protected areas that are being planned right now,” she said. And until this discovery, the Danger Islands “wasn’t considered a high priority for protection.”
Boersma, who also is a co-chairwoman of the Penguin Specialist Group for the International Union for Conservation of Nature, agreed that finding penguins in some of the more remote spots on Earth is crucial. Now, she said, researchers need to watch them over time to track how they’re faring.
“We expect many of these species are going to be severely harmed and some already have,” said Boersma, noting that half the known population of Magellanic penguin chicks were wiped out in one storm. Continued government funding for satellites and other technology to track the animals is essential, she said.
One of the surprises of the study, Lynch said, was that the Danger Islands penguins don’t nest in a circular pattern, as would be expected, to provide the best protection from predators. Instead, they seem to be faithful to individual nesting spots, prizing habit over safety, she said.
The Adélie are not recent migrants to the Danger Islands. Photos taken in 1957 by seaplane show colony boundaries in virtually the same locations — now that researchers know what they’re looking for.
The discovery of so many new animals has raised questions about how they’re finding enough food. “What it is about the ocean right in that region that makes it so productive, is something we’d like to figure out,” Lynch said.
The penguins feed mostly on shrimplike krill, giving their guano the distinctive pinkish color that can be more easily seen from a satellite. The black-and-white animals tend to blend into the rocks and are harder to spot, she said.
There were plenty of challenges working in one of the coldest places on the planet, said Hanumant Singh, another study co-author. The batteries for the drones kept freezing and losing power, until the researchers began keeping them warm inside their jackets, said Singh, a professor in the Department of Electrical and Computer Engineering at Northeastern University in Boston. “If you warm them, they’ll keep flying,” he said.
They also had to manipulate the drones to operate at such a southern latitude, where the change in the Earth’s magnetic field close to the poles makes navigation more difficult, said Singh, who is also an associate scientist at the Woods Hole Oceanographic Institution, in Woods Hole, Massachusetts.
The global Adélie penguin population now numbers about 4 million pairs and has nearly doubled over the past four decades, for unknown reasons, Lynch said. But the population along the Western Antarctic Peninsula — one of the most rapidly warming places on the planet — has dropped substantially in recent years, she said.
Adélie are one of two penguin species that live on ice, and thus in some of the coldest places on Earth.
The biggest populations of Adélie penguins live in the Ross Sea, below and east of New Zealand.
While she remains anxious about the penguin’s long-term survival, Lynch said that finding new colonies is encouraging.
“Ecologists worry about having all your eggs in one basket,” she said. “We have a second basket now on opposite ends of the continent.” | <urn:uuid:544f3919-5eb1-4574-b53f-0a5364c7d927> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 5,575 |
Hasan returns to court with new judge
Updated 10:40 am, Tuesday, December 18, 2012
FORT HOOD – The case of Maj. Nidal Hasan goes before a new military judge who could decide to revisit every ruling her predecessor made against the man charged in the 2009 massacre at Fort Hood.
Relatives of one person killed don't want that to happen. They've already waited more than three years for the trial to begin.
"I expected a delay, certainly, because the judge is going to have to review the case, she's going to have to figure out if there's anything she wants to address," said Keely Vanacker, a Kerrville high school counselor whose father, retired Chief Warrant Officer 2 Michael Cahill, was killed trying to stop the shooting.
"I just hope it's not a complete start-over. I hope it is not going to be a complete re-do of every decision that's been made."
Col. Tara Abbey Osborn is scheduled on Tuesday to preside over a reset of the proceedings against Hasan, accused of killing 13 people and wounding 32.
The reset was ordered Dec. 3 by a military appeals court that removed the first trial judge, Col. Gregory Gross, saying he had displayed an "appearance of bias."
The hearing could lead the court to revisit every decision Gross made over 17 months of hearings. No one can say how just long that would take.
A judge who began her military career in 1988, Osborn is certain to get pushed back by a defense team that convinced the Court of Appeals for the Armed Forces to remove Gross from the case, arguing that he was biased against their client.
They also successfully battled his order to force Hasan to shave a beard he grew last summer in violation of Army regulations. In deciding that Gross had to go, the appeals court didn't act on his insistence that Hasan lose the beard.
All eyes will be on Osborn to see if she, too, demands that he shave, as well as whether she erases every decision Gross made since arraigning Hasan on July 20, 2011. Since then, he has ruled on motions in at least 17 hearings.
"I think she's got some challenges initially. My guess is the defense is going to request reconsideration on a lot of the motions that were decided by Gross, and I don't know exactly how she'll handle that," said South Texas College of Law professor Geoffrey Corn, a retired Army lawyer.
'Shooting from the hip'
Cahill's widow is frustrated by the long wait.
"I am worried it will take time," Joleen Cahill said. "However, if you have a very disciplined, efficient judge, it won't take that long. Judges can push the system and this new judge is going to have to push the system."
Neither the defense nor prosecutors would comment.
Colorado defense attorney Frank Spinner said Osborn probably won't review every motion. He said two unknowns could complicate the case - the possibility transcripts of those hearings haven't been made and will be required before she presses on, and the specter of bias in some of Gross's rulings.
"As I read (the Court of Appeals for the Armed Forces') opinion ... the relationship between Judge Gross and the defense had soured at some point, and so I don't know how the defense is going to deal with that," said Spinner, who has practiced before the court for the past 25 years.
Hasan's trial might start next spring or summer.
Spinner, who worked with Hasan's lead attorney, Col. Kris Poppe, in a past capital murder case, said the presence of a new judge complicates any prediction.
"This is new territory," he said, "so I'm just shooting from the hip on six months." | <urn:uuid:7f673868-b97b-4447-a6ad-9023542b90b2> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 3,516 |
Left: The face of 'Abdu'l-Bahá
Right: 'Abdu'l-Bahá as a younger man.
"'Abdu'l-Bahá" means "Servant of Bahá"
'Abdu'l-Bahá is the eldest son of Bahá'u'lláh and was appointed by Him as the Interpreter of His teachings and the Centre of His Covenant.
In His youth 'Abdu'l-Bahá suffered alongside Bahá'u'lláh in prison but when older He was able to travel to the West.
'Abdu'l-Bahá protected the Bahá'í Faith from division and passed on that duty to His grandson, Shoghi Effendi. | <urn:uuid:b4461806-0a78-4416-8695-4e3b5d1fe4a9> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 474 |
The New Saint Cuthbert’s Banner for Durham Cathedral
The original Saint Cuthbert’s banner (12th-14th century), destroyed during the Reformation in the mid 1500’s, was arguably the most significant ecclesiastical banner in the region. The Rites of Durham (translated by Fowler, 1903) narrates battles where victories were believed to be ‘afforded’ by the mere existence of this sacred artefact. Registered charity, the Northumbrian Association, commissioned a contemporary replica (completed in 2012) and the banner now enjoys public display at the entrance to Saint Cuthbert’s shrine close to the original position it occupied during the Middle Ages; which according to Dean Michael Sadgrove, is the “emotional and spiritual heart of the Cathedral”. Asides from its static exhibition, the banner is also used regularly at the discretion of the Dean and Chapter for processions and services throughout the year. | <urn:uuid:086c87df-03a2-47a2-8f49-90ef11aa470b> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 910 |
Game - Office Secretary 2. It's not easy to be a secretary. She has so much things to Free Adult Games - Full Sex Games - Free & Now · Hot Games · Cartoon.
Secretary dominates boss offered by pornburst.
Secretary dominates boss BrunettesHardcoreEuropean girlsItalian Porn. Similar porn seduccing secretary in office Boss uses horny secretary 48, Boss takes advantage in office 27, Secretary and the boss take it to the bathroom k Secretary seduced by her boss aecretary, Morgan Layne Teen Blowjob. This is free porn at its absolute best.
Thousands of sex videos covering every XXX you could ever want, with fresh new content updated daily. Enjoy our top notch most recent videos now.
Big tit amateur nudes explore their sexuality with massive cocks like it's their last day on earth! Looking for more experienced women? We've got mature pornstars who have been in the adult business for ages and can handle seduccing secretary in office biggest dicks in every juicy hole.
Business woman Oldy Redhead Drilled Aged. Business woman Office Tied up Bdsm.
Office Milf Big tits Business woman. Business woman Voyeur Babe Amateur.
Bring your Tits to Work. The Whore of Wall Street Ep A Whore Is Born. What Ever Came Over Them?
Six co-workers have a sudden afternoon of debauchery. Lunch Sex in the Office.
The Interview She was looking for a job, but found more. Surprise Visit Lover suprises me at work.
Hunter Watching While at work, two girls play while Hunter watches. Brown Eyed Girl A tale of interracial office lust. A boss, a secretary, an affair. You Rate Porn Young Girls Forum Hot Tiny Nude Vagina Hd Teen Anal Porn Panda Movies Hd Pornscum Dog Xxx Adult Comics Gallery Moms Try Sons Xxx Parody Movies You Watch Porn Pleasure Porn Video Blowjob Offive Clip Home Made Videos
News:NEVERTIRED - PERFECT SECRETARY EP.1 - 4/5 20 pages | 73 megabytes Sex Hot Games - Office Fuck (Android) 18 megabytes. Category: Porn Games.
Leave a Comment | <urn:uuid:8efc0bfd-6a32-4664-ab84-a23c1ce69d9d> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,937 |
•FD Kitchen & Bath•
Kitchen Designer in Morgantown, WV
Your Kitchen. Reimagined. The kitchen is arguably the most important room in your home. It’s where food is stored, prepared, and eaten; where family and friends gather to catch up on each other’s lives; and where many wonderful memories are made. It is truly the center of day-to-day life. So why settle for a kitchen that is cramped or outdated when you can have a beautiful, functional kitchen that is uniquely yours?
Morgantown, WV Kitchen & Bath Renovation Designer
FD Kitchen and Bath is a family-owned design and sales studio specializing in the design and installation of custom kitchens, baths, and closets in the greater Morgantown area.
Our experienced designers can help you:
- Create a design and draft a floor plan and elevations
- Develop a detailed budget and schedule
- Order products and materials
- Coordinate work with your contractor or act as the contractor
- Provide and oversee the installation and placement of the cabinets, appliances and other design elements
We service North Central West Virginia and Southwest Pennsylvania, including Morgantown, Fairmont, Bridgeport, Clarksburg, Cheat Lake, and Bruceton Mills and surrounding areas in WV, as well as Washington county in PA.
FD Kitchen & Bath
1214 Green Bag Road
Morgantown, WV 26508
Your business has a story worth telling. At Sparks Productions, we can help you engage with your audience in a compelling and creative way that will set you apart from your competitors. While you work with us, we understand video marketing isn’t one size fits all. Our creative process is thorough, which leads to effectively telling your marketing message. This a kitchen designer in Morgantown, WV project by Sparks Productions – Contact us if you’re a construction company interested in video production around the Morgantown, WV area. | <urn:uuid:10597a23-6a2c-473e-a493-e25980e6a5b7> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,857 |
The Knitted Odd-bod Bunch, ISBN: 9781906525415.
Welcome to the wonderfully weird world of Donna Wilson's odd-bods - a quirky yet lovable family of 35 of the strangest creatures you'll ever come across.
There's Rill, who's fond of caterpillars and worms and running around and is son of Ciryl the Squirrel, who likes marmalade but dislikes cottage cheese. Beryl the Dog loves sausage, egg and chips, but has a fear of fluffy slippers, while Bunny Blue is friendly but forgetful and has a passion for candyfloss. Olive Owl is small with a loud voice; she likes keeping an eye on things but dislikes flashing lights. Charlie Monkey, who lives on cheese and biscuits, likes to stand out in a crowd, while Ginge the Cat and Mitten Kitten form a formidable feline duo. These unique toys are so much fun and easy to knit using the clear instructions and simple patterns. With so many new friends to make, you'll have your own kooky collection in no time.
- Condition: New | <urn:uuid:5803a86d-da5e-476a-847c-247ed5d0a918> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 964 |
Our Beauty & the Best / Best Bet is Eminence Organic Skin Care for myriad reasons. Read why it’s so incredibly special.
In Beauty & the Best, we’ve rounded up three essential beauty-bolstering items from Pinrose, Hot Head & Kenneth Cole to make your summer lovelier.
Beauty Best Bet: Urban Hydration’s Lemon Sugar Scrub & Lemon Body Wash to make your summer skin glow with goodness!
Read why Snow Fox Skincare is a Beauty Best Bet for summer. Slather it on!
Have a teen with acne, or have acne yourself? PURE M.D. has a beautiful solution!
Are you ready for sandal season? Render your feet smooth and lushly hydrated with Karuna foot masks.
Yantra Beauty’s The bomb is a unisex, multi-purpose treat.
Upgrade your makeup brushes with Lilumia 2’s brush cleaner. Spring cleaning!
What is it like to be at The Running of the Bulls in Pamplona, Spain? We tell you!
Need an easy-to-remove, day-to-night, all-purpose eyeshadow kit? Rimmel London has it. Read more. | <urn:uuid:cce9578e-9f13-4275-93b8-48714a276cc8> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 957 |
This recently listed western North Carolina 159 acre property is an outdoor lover’s playground. Located within 1,500′ of the famed Blue Ridge Parkway, yet convenient to the four lane US 221 just four miles away and Marion only 17 minutes down the road, this property is very accessible. One nice feature is that it has frontage on a two lane paved road meaning you don’t have to deal with an access easement or right-of-way across someone else’s land. Almost the entire property is tucked away and hidden from view, but once you get onto the property, prepare to be amazed.
The 159 acres feature a mixture of gently rolling woodlands and field with outstanding views to the south, east and west. There are thousands of feet of rushing creeks and streams on this property including several substantial waterfalls. There is one that is more than a 100′ cascade. Imagine building a house overlooking one of these waterfalls!
But one of the best parts is that this property already has 1.6 miles of well built roads on it. These roads have held up extremely well, so much so that you can literally drive a Toyota Prius all over the place. That means you can access the entire property and all the numerous building sites with ease. You just don’t find this sort of thing every day.
So click here for a full description and interactive map. If you’re one of those looking for a private mountain playground that isn’t in the hinterlands that will provide recreation, relaxation and even sustainable living, this is it. Asking just $736,000, which is a tremendous value based on the infrastructure already in place. Call us today for a private showing. | <urn:uuid:29285f64-b895-4365-babc-45936fc12f5c> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,645 |
You are here: MEDICA Portal. MEDICA Magazine. Archive. Gynecology.
Mum Knows Best?
Mom's advice seems more
trustworthy than the doctor's
words; © Hemera
Researchers have found that pregnant and postnatal women, while wanting to do the best for their baby, do not follow medical advice without question and are more likely to adopt practices their mothers and grandmothers carried out during their pregnancies.
The study by Paula Nicolson and Rebekah Fox explores three recent generations of women’s experiences of pregnancy, questioning those who gave birth in the 1970s, 1980s and 2000s. The women who were interviewed said they knew their mothers and grandmothers had their best interests at heart when they offered them advice.
For the older women questioned, the advice from their female relations was their main source of information. The 1980s and 2000s group, however, had to reconcile what they heard from older generations with direct advice from their doctors, midwives and health visitors as well as the numerous health messages on the web and self-help books.
Nicolson says, “It is much to the credit of contemporary women that despite the unprecedented pressures from the media, medicine and the ‘pregnancy police’ that they are still able to filter-in the advice that really suits them from all these sources. Each of the three generations found ways to ‘resist’ what they considered inappropriate pressures from advisors and were more likely to follow advice given to them from their mothers and grandmothers even if it went against the medical professions advice.
“Women tend to discuss the advice they are given with their female relatives and this leads to resistance to some types of advice. For example, despite being advised to cut down on caffeine during pregnancy one woman we questioned said she continued to drink tea because her grandmother told her it relieved her morning sickness.”
Nicolson says women who take notice of general public health information about what is a healthy lifestyle, i.e not smoking, taking regular exercise, not taking drugs and drinking alcohol in moderation are those who are most likely to be in-tune with their bodies and can therefore ‘use’ guidelines but not be constrained by them. She added: “Taking all the guidelines too seriously leads to anxieties. Lack of self-confidence also can lead to worry about ‘doing the wrong thing’ which is potentially harmful.”
MEDICA.de; Source: Royal Holloway, University of London | <urn:uuid:41d057f0-1185-429d-91f1-66314fa81758> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 2,477 |
One was a rider known more for the Tour de France he lost than the two that he won. The other was a classics rider who won more accolades as a coach than for what he did on the bike.
They are Laurent Fignon and Franco Ballerini, two well-respected figures in the cycling community who died during 2010.
Fignon lost a long battle with cancer on August 30. He was 50. Known as “the professor” for his trademark wire-rim glasses and fluttering ponytail, the urbane Fignon was a marked contrast to his peers in the 1980s.
Fignon burst onto the scene in the early 1980s, winning back-to-back Tours de France in 1983-84. A knee injury kept him from his best for two seasons but he returned with third in the 1987 Vuelta a España and victory in the 1988 Milan-San Remo.
Fignon seemed back on top during the 1989 Tour in what later became one of the most famous showdowns in racing history. Fignon famously lost a 50-second lead in 24.5km in the final-day time trial, losing the race by the Tour’s smallest margin of 8 seconds to Greg LeMond.
Devastated by the loss, Fignon held on for a few more seasons before retiring in 1993. After retirement, he bought Paris-Nice in 2000 and sold it to ASO two years later in a deal that he said cost him money but saved the race.
He later found his voice and beguiled a new generation of fans with his expert commentary on French television during the Tour de France broadcasts. In his excellent autobiography, “When We Were Young and Carefree,” Fignon admitted to taking some banned doping products and didn’t hold any punches in recounting his career. He was diagnosed with cancer in April 2009, and despite chemotherapy treatments, he died the following summer. Fignon broadcast his final Tour on French TV in July, only to die five weeks later.
Ballerini became one of the most prolific classics riders of his generation and helped herald the Italian dominance of the northern classics in the mid-1990s as part of the Mapei juggernaut. The big, brawny Tuscan won two Paris-Roubaix (1995, 1998) and other one-day races such as Het Volk and Paris-Brussels.
Ballerini later became an incredibly successful national team coach, helping to soothe the egos and nerves of the perennial favorite Italians. After taking over as head coach, he delivered the Italians the rainbow jersey with Mario Cipollini in 2002 and followed that up with the Olympic gold medal for Paolo Bettini in 2004. His riders won three more rainbow jerseys in consecutive years from 2006-08.
Ballerini died of injuries suffered during a car rally race in Italy on February 7. He was 45.
Another notable Italian to die in 2010 was Dr. Aldo Sassi, who succumbed to a brain tumor on December 12. He was 51. Early in his career, Sassi helped prepare Francesco Moser for his successful run at the hour record in 1984. He later became general manager of the highly successful Mapei team and helped create the Mapei Training Centre in northern Italy and became an outspoken advocate of clean racing.
Among his clients were Cadel Evans and Michael Rogers. Ivan Basso promised Sassi he would never dope again and under Sassi’s guidance, won the 2010 Giro d’Italia. Never afraid to take on controversial riders, Sassi agreed to work with Riccardo Riccò. In April, however, doctors discovered a brain turmor. He underwent brain surgery and chemotherapy treatments, and worked until his final days.
The Vuelta a España was sent into mourning when Txema González, a popular Spanish soigneur on Team Sky, died of a sepsis blood infection in Sevilla on September 3. The entire team later pulled out of the race in honor of their staff member, who was 43.
In a bizarre story from Argentina, cyclist Armando Borrajo committed suicide on December 18 by jumping off the roof of his home. Borrajo had evidently been kidnapped and just days after his release jumped to his death in a mysterious ending. He was 34.
Cycling proved yet again to be a dangerous profession when it comes to training, and a handful of riders were killed while riding. Jure Robic of Slovenia was struck by a vehicle in a head-on collision in September while Jorge Alvarado of Mexico of the now-defunct Bahati team was struck down by a vehicle in San Bernardino, California, on April 8.
Thomas Casarotto, a promising young Italian rider, died after colliding with a car along the race route during the Giro del Friuli Venezia Giuli in September. He would have been 20 this week.
Others to have passed away this year include:
Fermo Camellini (I-F), 95
Won 1946 Paris-Nice, 1948 Flèche Wallonne, 7th 1947 Tour de France (plus stage win) & 8th in 1948
Lionel Cox (Aus), 79
Aussie track sprinter, won Olympic gold at 1952 Games (tandem with Russel Mockridge), silver medal in match sprint
Nino Defillipis (I), 78
Italian star of the 1950s and 60s. Won 1958 Tour of Lombardy, Italian champ in 60 and 62, 3rd in 62 Giro (won stages at Giro, Tour and Vuelta)
Lucien Gillen (Lux), 81
Track star, won 12 six-day races
Jean Kirchen (Lux), 90
1946 Luxembourg champion, 5th in Tour de France in 1948 and 1950, won 1952 Tour of Luxembourg
Guy Lapébie (F), 93
Olympic gold medal in 1936 Games in road team race, 3rd in 1948 Tour de France (plus stage winner), won eight six-day races
André Mahé (F), 90
Equal 1st in 1948 Paris-Roubaix (with Serse Coppi), won 1950 Paris-Tours
Radomir Simunek, Sr (Cz), 48
Was world cyclocross champion (amateur title in 1983 and 84, pro in 1991); Father of Radomir Simunek, Jr
Richard Van Genechten (B), 80
Won 1956 Flèche Wallonne (2nd in L-B-L same week), 1st 1958 Volta a Catalunya | <urn:uuid:b5321981-1acf-4b79-b6c0-8829744b531d> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 5,559 |
Since we last checked in, much has been accomplished. We’re bearing down on our fundraising, editing our first episode (1963-66), lining up our next interviews, and more.
We are fully ensconced in our headquarters – the incubator program at Ninth Street Independent Film Center in San Francisco. The space accommodates three workstations, a projection screen, and centralized storage for our growing digital and physical archive of Committee-related materials. We also have access to a 60-seat screening room which we used just this month for a viewing of Jerry Wainwright’s photography archives with Jerry’s family & interested parties. We love it here.
In the coming months we’ll host an office-warming, listening parties and screenings to support our vision of the episodic documentary The Committee: A Secret History of American Comedy. Stay tuned.
Interested and able parties can now support our work with a tax-deductible donation of cash, stock, or securities via our fiscal sponsor SFFILM. Our 2013 Kickstarter funds – which paid for most of our 30 + interviews – have been depleted, so we’re fortunate to have SFFILM as a partner as we begin a new round of fundraising.
Since January we’ve raised more than $10,000 in new funds, including a significant boost from the family of Committee friend and investor Maxwell Myers. We are looking to bulk up our production team, as well as our army of patrons. Please consider spreading the word about our project. We are confident in the demand for The Committee’s story, and we will pitch this project to anyone, anywhere.
Here are some more highlights from the last few months:
- We interviewed Ronnie Davis at his San Francisco home in February. Ronnie was a great host and subject, and gave us a very well-argued contrarian point of view regarding improvisational theater (and much more).
- We interviewed Kathy Lerner, Alan’s secretary and ex-wife of cast member Howard Hesseman. Kathy was forthcoming about the position of women in the counterculture, giving us an important point of view to consider in the #MeToo era and a lot of think about.
- We are finishing integrating new project management tools that are further organizing and tracking our work and allowing us to fold in volunteers and new team members into our project. This is a huge help in ensuring that we don’t lose track of the hundreds of archive elements and many investigative threads that we’ve discovered since we started.
- We uncovered a new piece of gold: The Marin County Medical Society-produced, Sid Davis Productions-distributed 18 minute educational short Too Tough to Care (1964). This hilarious piece of satire captures original Committe castmembers Scott Beach, Larry Hankin, Hamilton Camp, Dick Stahl, and Garry Goodrow, within two years of their arrival to San Francisco. This piece is smart, well-performed, and totally prescient, considering the tobacco-related lawsuits of the generations that followed. Enjoy.
Thanks for your interest in The Committee: A Secret History of American Comedy. We are always on the hunt for archival material – home movies, audio tape, print ads, whatever. If you’re sitting on something that might be valuable to our story, we’d like to see it. Hit us up!
Jamie Wright and Sam Shaw
There was a lot we wanted to ask David Ogden Stiers about a wide range of subjects.
David Ogden Stiers was approached twice by Alan Myerson to join The Committee, until he finally signed on in the summer of 1967, performing alongside Don Sturdy at The Committee Theater (“America Hurrah”, directed by Joe Chaikin) and then with the revue players at 622 Montgomery. 1967-68 was a peak transition year for The Committee, when the company was preparing to open up a run at The Tiffany in Los Angeles while maintaining two theaters in San Francisco and expanding its workshop program.
Stiers performed in two Del Close-directed shows at 622 Broadway in late 1967 and early 1968 and it’s a joy to imagine Stiers arriving at Juilliard with an understanding of the earliest beginnings of longform improvisation (The Committee’s fall ‘67 show included a Harold) and the experience of playing with Committee performers old and new, from Garry Goodrow to Gary Austin.
He flew east for Juilliard in 1968, but not before joining in on the fun at The Committee’s June Satirathon, which featured pretty much everybody. That Satirathon was recorded in full, and maybe someday we’ll find a full tape and hear him improvise, or even ask for suggestions. For now, we’ll settle with this gorgeous picture of David Ogden Stiers from that night, shot by the late John Byrne Cooke. RIP.
As we continue to research The Committee and interview members of its cast and community for our documentary film, it’s become clear that we are truly building the airplane while we are flying it. When we started, we imagined that our story would be a straight-forward, feature-length, “talking head” style documentary, with a heavy reliance on archival material.
Instead, given the nature of what we’ve uncovered in our research, we’re now producing the project as an episodic documentary, currently structured to be told in five parts. It is our intention not only to tell the story of The Committee, but also to shine a light on the particular joys and struggles of the individuals involved, and put their achievements in the context of their time.
We recognize that this is an ambitious vision. To help us toward this end, we have recently formed two important partnerships. The San Francisco Film Society (SFFILM) has taken us on as our fiscal sponsor, a partnership that will allow us to receive institutional grant funding and tax-deductible donations from individuals. This fiscal sponsorship is a key tool for fundraising and we can’t wait to introduce our project to funders, individuals and foundations alike.
Our second partner – Ninth Street Independent Film Center – has accepted us into their Incubator Program, which will allow us the use of an office space and screening room subsidized by The San Francisco Film Commission. We will move into the office, located in San Francisco’s Civic Center, later in the fall.
We’ve been working on this project for over five years at this point, and feel that our tilt to episodic storytelling, a fiscal sponsor, and workspace are major breakthroughs and will help us move faster and more efficiently. We will update this blog and our Facebook page with news of events and screenings. Thanks for your support and interest.
We had an amazing time this weekend visiting the Summer of Love exhibit at the de Young Museum with none other than Lisa Law (Flashing on The Sixties, The Hog Farm, The Jook Savages, and much more). Lisa photographed everything in the sixties, from Committee performances in San Francisco and LA, to Monterey Pop, Woodstock, Further, and everywhere else. Thanks, Lisa, for letting us tag along,
We lost another pioneer this week with the death of Gary Austin. When The Committee started its run at The Tiffany Theater in Los Angeles, Gary joined the cast in San Francisco under the direction of Del Close, and he was part of the company when it made its early breakthroughs in longform improvisational theater. Austin continued on with The Committee with various ensembles under various directors, evidently soaking up everything he quickly learned. It’s hard to imagine that The Committee’s cultural influence would be so widespread without Austin to evangelize their work. The Groundlings, which Austin founded in 1974, became a force in comedy that for years was matched only by The Second City in the talent that it attracted and nurtured. As a teacher of acting for forty years, Austin helped players bring their full selves to the stage and to play at the top of their intelligence. Thanks, Gary, for your commitment to elevating the art form and for your life of service. | <urn:uuid:8b6074b3-d981-4356-a9a8-158b61844aac> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 7,881 |
The Deutschlandlabor investigates popular clichés about the Germans and shows a diverse image of society. Of course Nina und David are also interested in football. There are also worksheets and teacher’s notes on the video.
The podcasts provide information about everything that happens in Germany, as well as on and around the football pitch. Each podcast has its own quiz. Additional lesson materials are available for teachers.
URL to podcasts: http://www.goethe.de/ins/us/saf/prj/stg/soc/pdc/enindex.htm
URL to lesson materials:
32 football nations will be battling it out to win the FIFA World Cup 2018 in Russia from 14th June onwards. PASCH students from these countries answer a variety of football-related questions.
Talking about football is not that easy. These words and expressions, complete with explanations, help students to do this.
From the World Cup quiz to player profiles: while the professionals are getting ready for the next game, “Deutsch für dich” offers free football-themed exercises to train up your German skills.
These materials prepare students (language levels A1+ and B1+) to put on their own Sportschau-style TV or radio show.
A resource pack for language levels A1 and B1, as well as educational material for extracurricular activities, was developed for the UEFA Euro 2012 in Poland. | <urn:uuid:388de144-8c02-477a-b72a-316491cd18b3> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 1,320 |
Bremenacht wrote:I haven't used VG+ in a while, but they used to (and probably still do) take... measures to ensure you're not charged VAT.
#9342107, By FabricatedLunatic Importing U.S 3ds. Is it a good idea?
FabricatedLunatic 13,055 posts
Seen 1 day ago
Registered 10 years ago | <urn:uuid:1f7082d4-f739-4eb9-acab-2feebdbc9558> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 278 |
Explore the beautiful islands of Orkney in our eco-friendly electric camper vans. With over 30 charging points across the islands, there's no costly fill-ups at a petrol pump.
Experience and Savour Independence.
JP Orkney's Camper Van Hire is a great option for fun days out and a comfortable night's sleep - and it's environmentally friendly too. The Nissan Dalbury E is the world's first all-electric camper van, giving you cooking facilities on hand, a warm shelter and no costly fill-ups at the petrol pump. The islands have over 30 charging points - on a full charge you can easily cover up to 150 miles, then rapid charge in 20 minutes for another 80 miles.
By combining electric vehicle hire and accommodation you'll reduce your holiday costs. You can pitch at one of Orkney's many campsites. Equipment and bedding is included, while car seats can be provided for little travellers and attached using Isofix brackets.
Our choice to use electric vehicles was an easy one: no nasty fumes and peaceful on the ears. We love our electric vans and we're sure you will too. | <urn:uuid:f3a8d464-1f91-49aa-8017-e42c8debc121> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,073 |
Avoiding Department Of Transportation Fines With Our Spring Special!
It looks like warm weather has finally returned, and as the old saying goes, that means it’s time for our second-longest Canadian season: construction! Trucks, rollers, pavers, cranes, and all kinds of other vehicles will be out in force in the coming months, working hard and doing what they do best.
But many of those vehicles have been sitting idle for several months, as the cold weather really blasted Calgary this year. That means all the hoses, pipes, and connections could have suffered damage over that time, and even the quality of the fluids inside the tanks and reservoirs could be reduced. And having a vehicle with multiple issues isn’t the kind of spring start you likely envisioned.
While you may think it’s not a big deal, and that you can get everything checked out down the road or as it flares up to give you trouble, here’s the thing. The Department of Transportation also knows all of this, and they’re ready to go on a spring roadside safety blitz, with checkstops popping up all over. And if there’s one piece of advice we can offer, it’s this: don’t start your season with hefty fines and lost time because you didn’t properly prep your heavy equipment, machinery, or trucks to be safe on the road!
Because of the nature of their work, safety standards can be very strict around this kind of equipment, and the DOT doesn’t take chances. Even small issues – like a functioning headlight that has a crack or hole in it – can be enough to shut you down due to the possibility of causing an accident later on, and some of these are so minor that you wouldn’t necessarily catch them on a simple walkaround.
It may sound like we’re exaggerating or fearmongering, but we simply want our clients to be able to do their jobs and get home safe to their families at the end of every day. That’s why West Tech Mobile has set up a Spring Special deal (details listed below), just for people like you – an all-in-one package designed to go over your vehicle’s systems and parts and ensure that it’s all in good shape for the season ahead. Tire pressure, lights, leaks from hoses, electrical connections…we’ll make sure you’re road-ready and have nothing to fear from a sudden checkstop on the highway.
With this kind of preventative maintenance, it’s much easier to pay once and have peace of mind than to be stuck footing a tow bill and a day of lost productivity, or to have something go wrong when you’re far away from home, out in the oilfield of northern Alberta, or outside any of the major cities and towns. It’s always better to catch and fix little problems, before they become big headaches.
Call West Tech Mobile in the industrial area of southeast Calgary today to find out more about our Spring Special – it doesn't take much time and you’ll be very glad you did!
Spring Special Includes...
Cooling system performance test, checking all fins, checking coolant strength, a/c performance test (hookup manifold gauge kit, check static pressures, etc), check vent temperatures, check cycle times on your compressors, check condition of drive belts, a visual inspection of condenser and fins, checking fan hub operation, pressure washing dirt and bugs found in fins, check the blower fan for functioning, check for any winter damages.
When purchasing this bundle receive an incredible 25% OFF!
This is only on until the first day of summer so be sure to...
On-site Truck And Equipment Inspections
The trucks, tractor-trailers and other heavy equipment with which we work have the potential to cause some major damage if they malfunction while moving – and that’s why there’s a rigorous set of inspections that need to be followed and kept current for them. But not all inspections are born equal, and today we’re going to talk about some of the different types, especially the Commercial Vehicle Inspection Program (CVIP), and where they can be performed.
Let’s start with preventative maintenance. Don’t be fooled – while we believe this is just as necessary as any mandatory inspections, it doesn’t officially count as one. These “in-between” inspections can be done either on-site or in our shop, and will help you get the most efficiency, life, and safety out of your engine and other components. They are not, however, meant to replace the strict procedures of official inspections at regular intervals.
Quarterly inspections, PDIs (pre-delivery inspections), and PPIs (pre-purchase inspections) are next up, and each of those can be done easily on the job site, minimizing lost time and productivity. It’s a good setup, because it means less stress about manoeuvring equipment around when you’ve already got a busy schedule, and having West Tech Mobile come to you is a perfect solution. We can also do repair inspections out of the shop – on the road, on a job site, etc. We’ll assess the situation and help make sure everything is safely working as it should.
This isn’t just limited to trucks, either. We can do these inspections on cranes, manlifts, jackstands, heavy machinery, and so on, all on-site and without further interfering with your logistics. This is possible because we have a professional engineer in our staff, experienced with everything including basic inspections, annual certifications, checkups, and structural magnetic particle inspections.
It’s important to know, though, that we (and everyone) cannot legally do CVIP inspections outside of a licensed facility, with a licensed inspector. While there are several reasons for this, the main one is that a lot of the necessary tools to do the full process cannot be moved from the facility. Since there are such stringent rules about CVIPs, it’s not something you want to rush, anyway – it’s the kind of thing you’ll want to plan ahead for so that it’s done well and done correctly.
If you’re overdue for any of these inspections (or if you simply want to make sure everything in your vehicle is functioning as it should), give West Tech Mobile a call today. If it’s possible, we’ll come to you, and if you have to come in to our shop, you’ll find that you’re leaving your equipment in very capable hands. We look forward to helping you get the most out of every bit of mileage.
CVIP versus Preventative Maintenance
It’s not always easy to maintain a single vehicle that gets used every day, let alone an entire fleet of them. Between dust and debris, bad driving conditions, extreme temperatures, and just plain old wear and tear, it won’t take long to run into trouble somewhere if you’re not keeping up with inspections! Today we’re going to talk about two similar maintenance and inspection routines – different, but each necessary in their own way.
The first one is the CVIP, or Commercial Vehicle Inspection Program. These mandatory inspections have high standards, set by the government, and are intended to ensure that any vehicle on the road is actually worthy of being there! They check out your brakes, steering, structural integrity, emissions systems, and the other parts of your vehicle that keep it running smoothly.
The second is preventative maintenance, or PM. While not strictly mandatory, this routine means you are getting regular check-ups on the overall function of your vehicle – everything from the tires being a little low on air, to the A/C needing a recharge soon, or even the door handle sticking now and then. The whole point of this program is to catch issues when they are small, fix them before they become large, and save you plenty of time and money along the way.
So why are they both needed? Couldn’t either one catch everything at a time?
While they are both done for the performance of your vehicle, CVIP is generally only concerned with the things that would make your driving unsafe, while preventative maintenance will catch any issue, even if it is only cosmetic or simply inconvenient. Beyond that, CVIPs are only done at specific intervals – in some cases, once a year – and let’s just say that there’s plenty that can happen to your vehicle in a year! While the inspection itself may have a fixed cost, if you run into surprises that you weren’t aware of, that cost can balloon substantially when you find them.
By using a consistent PM schedule, you have much more control over your time and money when it comes to what you’re spending on your heavy-duty equipment. Small issues are fixed before they become crippling. Large repairs can sometimes be dealt with in stages, helping to alleviate immediate expenses, and you’ll be aware of anything that might be problematic in the near future, allowing you to budget accordingly. And of course, you get the peace of mind knowing you won’t have any trouble while trying to get your work done, or when you’re heading home after a long day.
Many people wait until their truck is in the shop for a CVIP inspection, and are then blindsided with costs for repairs to joints, chassis parts, or other engine components that they didn’t expect. By using PM to your advantage, you can not only avoid this, but increase the longevity of your vehicle, too! Think of something simple, like engine oil: it’s critical to the function of your engine, but it’s not even one of the criteria in a CVIP inspection. If you’re waiting for them to catch an issue with it, you’ll be waiting a long time – so it’s better to be proactive.
Need even more benefits? Chances are, if you’re concerned about a CVIP, you use your truck or heavy equipment to make a living, and if that vehicle is out of commission for even a few days, you can lose hundreds – if not thousands – of dollars. You’re losing out twice, because you’re not only spending money on repairs, but you’re not making any while the repairs are being done! So if you want to make sure everything is running smooth, get started on preventative maintenance as soon as possible. For example, if you notice some leaky shocks and you get them fixed before they run dry, you just potentially saved thousands of dollars and a whole lot of stress; but if they technically pass the CVIP, and you forget about them for six months until you get pulled over? That’s going to be one big headache.
Just don’t risk it – get going on your preventative maintenance program today, to help make your CVIP routine painless and easy! With West Tech Mobile, we have our top technicians ready to serve you, and we can make sure that your job doesn’t get any harder than it already is. We’re always trying to keep our clients on the road, and giving them helpful tips on how to get the most out of their engines.
Give us a call at 403-265-5699 today to find out more about CVIPs, preventative maintenance/PM, and why we’re one of Calgary’s favourite heavy-duty maintenance shops! | <urn:uuid:2b58a190-380b-4e1c-8acf-f0244bdb70d4> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 10,754 |
We’re in a competition with China and other countries to win the 21st Century. -- Pres. Biden's address to Congress last night
Every gun that is made, every warship launched, every rocket fired signifies, in the final sense, a theft from those who hunger and are not fed, those who are cold and are not clothed. -- Pres. Eisenhower, 1953
That last quote is from Eisenhower's Chance For Peace speech in 1953. It took the former 4-Star General to warn us against the country's exploding post-war military budget. But as the Cold War deepened during his administration, political pressures for increased military spending mounted. By the time he left office in 1961, he felt it necessary to warn of the military-industrial complex in his farewell address.
I was reminded of Ike's warning last night, listening to Pres. Biden couch all of his ambitious (but not adequate) $6-trillion post-pandemic infrastructure rebuilding and jobs programs in jingoist, America First, anti-China, Cold War rhetoric.
Biden called on Congress to invest in infrastructure, education, child care, civil rights, and science calling them programs that will allow the U.S. to win a competition with China. Like Trump, Biden is committed to a distinctly anti-China global strategy rooted in fears of American decline.
Yes, those investments are exactly what we need. But not for the sake of winning some mythical and dangerous global race to the top. Remember, that was Arne Duncan's rationale for pushing testing madness and school privatization when he was Obama's ed secretary. My 4-year-old granddaughter doesn't need to be prepared in pre-school to compete with 4-year-olds in China or Switzerland for global hegemony, thank you.
It's this kind of thinking that has led to the global vaccine wars when international cooperation in the fight against the pandemic could have saved millions of lives and prevented the current catastrophe in India.
It has also led Biden to push for a bloated Pentagon budget that's even larger than Trump's. The rationale behind the push has to do with illusory U.S. imperial ambitions to impose its will on other countries and engage in regime change when it can. These ambitions leave me even more skeptical about his planned withdrawal of the remaining troops in Afghanistan. Are they really being brought home or simply being redeployed for continuing conflict in the region? Does a redeployment mean a new buildup of American military power to confront China and Iran?
Yes, according to a report in today's NYT:
The Pentagon is looking to place troops near Afghanistan to track and attack militant groups if they threaten the United States. Possibilities in the region include Tajikistan, Kazakhstan and Uzbekistan, but those countries are under the sway of Russia to one degree or another, Attack planes aboard aircraft carriers and long-range bombers flying from land bases along the Persian Gulf and even in the United States could strike insurgent fighters spotted by armed surveillance drones.
Or is the China yellow-peril ("they're closing in on us") fearmongering simply being used as a way to appeal to resistant Trump Party members in a vain attempt to build "bipartisan" support for his new initiatives? If it is, it's a pipe dream.
I also told President Xi that we will maintain a strong military presence in the Indo—Pacific just as we do with NATO in Europe – not to start conflict – but to prevent conflict."
He failed to explain how putting U.S. warships in the South China Sea would prevent conflict rather than inevitably provoke a new one.
China and other countries are closing in fast," warned Biden. "We have to develop and dominate the products and technologies of the future: advanced batteries, biotechnology, computer chips, and clean energy."
Other countries "closing in" on us? What a myopic, paranoid, us-against-them view of the world.
Winning the 21st Century? What the hell does that even mean? Is the 21st Century a game? How do you know if you've won or lost? Who won the 20th?
Biden's guns-and-butter strategy is bound to bump heads with his progressive initiatives. That's too bad. They're worthwhile initiatives. | <urn:uuid:d7873224-ba7a-4905-adeb-1b50c90bc8b6> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 4,160 |
After almost eight months of being a "Museum on the Move", the Fond du Lac Children's Museum will host a grand re-opening today.
After being a "Museum on the Move" for almost eight months, the Children's Museum of Fond du Lac will hold its Grand Re-Opening activities on the weekend of August 16-18, 2013.
The Grand Re-Opening event will be held at the Museum's brand new location in the Waterfront District at 75 W. Scott Street, and will include past favorite exhibits as well as some exciting new features.
One of the biggest additions to the Museum is the over 10,000 square feet of outdoor space, called WinnePLAYgo. This fenced play area focuses on nature and exploring the state of Wisconsin, and will allow children and ... | <urn:uuid:bf66c7cd-150e-48de-bbcd-f84ad220659a> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 731 |
Yes when folder browsing it shows no .flac files whatsoever. Including the same files it originally accepted when I first got the player. However after looking at other peoples solutions i found renaming the files from .flac to .fla does seem to work. However like I mentioned earlier All of my albums are ripped to flac format. So I have 1000s of songs and I don't wish to rename every one of them. Not exactly what Cowon advertises. Anyway what I've been wanting to know is why something that worked flawlessly when first purchased suddenly doesn't accept reimporting of the same file type i.e. flac.
I have contacted Cowon dealer several times but all they do is ask for info I already gave them. Like "when did I discover this issue?" And that would be when I wanted to add new songs to the player.
But as I stated even the files that were originally transferred and working perfectly when I first used the J3 they no longer register even when going through Folders>J3>Music. =( | <urn:uuid:4a07e57e-123f-476a-938a-4c917464109d> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 982 |
Sit up and take notes, Kippers, this is no jokeApril 1, 2015 12:19
Egypt 2011 tourism revenues seen down by a third
Egypt expects to earn about $9 billion from tourism in 2011, down by about a third on a year earlier after many visitors were deterred by an uprising that toppled Hosni Mubarak in February and unrest that followed, a senior official said on Tuesday.
December 13, 2011 3:59 by Reuters
Tourism is a major source of revenue for Egypt. Analysts say bookings for its beach resorts, mostly far from the turmoil, appear to have recovered faster than visits to areas in the centre of the country where most pharaonic ruins are found.
“We ended up the year 2010 with revenue of $12.5 billion. This year so far we have had fluctuations in the number of visitors… We started the year with a drop of 80 percent, then it got better through the year,” Hisham Zaazou, senior assistant to the tourism minister, told Reuters.
“We expect around 30 to 35 percent less revenue than last year, which means it is going to be around $3.5 billion to $4 billion less, so we are speaking about a figure around $9 billion,” he added. (Reporting by Shaimaa Fayed; Writing by Edmund Blair; editing by Anna Willard) | <urn:uuid:31e815c4-4043-4b4a-ac65-026e1c46ebed> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,201 |
Acknowledged as a nationwide analysis chief within the fields of mathematics and science training, this department combines the expertise of its internationally recognized faculty with the vitality and innovation of its rising young students. Members in the NC State Health Plan noted that none of their wellness advantages have been being diminished, even as the plan threatened to cripple employers and the state, and will value taxpayers more than $300 million this 12 months to maintain solvent. BCBSNC noticed income of $186 million final yr. Actually, in order to receive affordable health coverage, participation in preventive wellness is increasingly becoming necessary, however not as a result of it has been proven to save medical prices or to be effective. In keeping with the database on health plans saved by AthenaHealth , which manages digital medical information and billing for greater than 19,500 medical providers nationwide, BCBSNC sent out 250,000 reminders … Read More “Department Of Mathematics And Science Education College Of Georgia College Of Schooling”
The Science requirements reflect a brand new imaginative and prescient for science training that connects scientific data, in genuine ways, to actual-world drawback fixing and innovation. This search will return all the net documents which comprises the words ‘website positioning’ and ‘guidelines’ and which are PDF documents. This operator is useful find precious sources. This programme is obtainable by the Division of Baby, Family, and Education Research, which is part of Utrecht College’s School of Social and Behavioural Sciences. The programme is based within the analysis priority space of Training and Learning , which is embedded in local, national, and international research networks.
Science Class Experiments brought to you by Science House. These videos are 2 to three minutes in size and show the steps of easy science experiments. The experiments are designed to inspire and excite children of all ages, with little or no set-up time and utilizing only … Read More “Kendriya Vidyalaya, Nal Campus, Bengaluru”
Croatian Technique of Education, Science and Technology is, amongst different issues, directed at schooling that actively promotes comprehensive individual development of every pupil and student, promotes social equality and democratic values and strongly contributes to the social and financial improvement in Croatia. one hundred forty. Margolis A, Baum A, de Quirós FGB, Joglar F, Fernández A, García S, Arredondo AL, Hersh WR, Curso en línea de Informática Biomédica para Puerto Rico: resultados de una experiencia de colaboración panamericana (Online course in Biomedical Informatics for Puerto Rico: results of a Pan-American collaboration), Investigación en Educación Médica, 2015, 4: 60-sixty eight.
So relatively than burn a e book written by three excellent PhD scientists, please contemplate what they need to say. Fred Singer is one of the few remaining great Jewish physicists of the twentieth century. He obtained his PhD in Physics from Princeton University in 1948 below John Wheeler, J. Robert … Read More “Have interaction, Educate, Empower!”
Croatian Technique of Schooling, Science and Technology is, amongst other issues, directed at training that actively promotes comprehensive particular person improvement of each pupil and student, promotes social equality and democratic values and strongly contributes to the social and economic development in Croatia. Figure three.5. Asian college students as a percentage of all Bachelor’s degrees in the physical sciences. 27. Hersh W, Ehrenfeld J, Scientific Informatics , in Skochelak SE, Hawkins RE (eds.), Well being Techniques Science, 2017, a hundred and five-116. eight. Hersh WR, The standard of knowledge on the World Extensive Net, Journal of the American School of Dentists, 1999, sixty six: 43-forty five.
M. R.: One of the massive errors we’ve made in training during the last one hundred years is creating the sharp divide between the tutorial and the vocational course of study. That divide has limited our understanding of the intellectual content of vocational information … Read More “Grasp’s Applications”
The Training and Science Committee looks at how New Zealanders are educated, from early childhood by means of to tertiary schooling, as well as science, research and technology. This one is the teacher model of cause #1. Word walls assist preserve the category on track. When I’m able to level to a reminder on the wall and shortly get that one scholar over that speed bump, class runs so much more easily. I believe in answering all questions, especially these “you should have learned this three years in the past” questions. It is an honor to have students ask questions that are not on grade-level and I never, ever, ever use “should” in my instructing. Asking these questions signifies that they trust me with their insecurities and this means a lot to me. That being stated, random math questions improve the likelihood that the rest of the class will start … Read More “Kenya High Commission Training” | <urn:uuid:42afb413-f99b-47fe-a4f4-f0e055d611c8> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 5,107 |
The New 2014 Chevy Silverado And 2014 GMC Sierra
View Single Post
12-14-2012, 01:47 AM
In a tent
I would still pick a Tundra or F150 over the Chevy.
of the site do not see these ads.
View Public Profile
Find More Posts by 53x12 | <urn:uuid:8459f1b7-5bfb-4b25-91b9-c69f5c0fcc42> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 227 |
This blog is an online collaboration for math teachers. It is an attempt to harness the power of math teachers to create math literate learning events for their students.
SpringerLink - Journal Article
discussions of significantmathematical content. This tension in teaching was not easily resolved;throughout the school year
tags: discourse, math, sherin
JSTOR: Cognition and Instruction, Vol. 21, No. 2 (2003), pp. 175-207
tags: discourse, math, knuth
JSTOR: Journal for Research in Mathematics Education, Vol. 25, No. 6 (Dec., 1994), pp. 608-636
tags: discourse, math
Talking mathematics in school ... - Google Books
discussion and critique a conceptual framework that applies a situative perspective on learning to the study of learning to teach mathematics
Glogster - Poster Yourself - Annotated
Easy way to create mashups of video, audio, graphics, and text, and publish for sharing.
tags: web2.0, poster, write2learn, write2pub
Stellarium is a free open source planetarium for your computer. It shows a realistic sky in 3D, just like what you see with the naked eye, binoculars or a telescope.
tags: astronomy, science, dialog, instruction, iboards
Post a Comment | <urn:uuid:f0f6fbe6-9d1f-48e6-af1d-42d6e1cba059> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 1,170 |
BA (Hons) Illustration alumnus, Tom Hovey, graduated from AUB in 2006, and has achieved a tremendous amount since! We caught up with Tom about his time at AUB and illustrating one of the UK's most popular television shows.
"I loved my time at AUB on the BA (Hons) Illustration course. I had just finished a Sequential Illustration HND which was quite focused, so I really relished the chance to experiment with new media, styles and techniques. I really enjoyed my time in Bournemouth.
AUB was such a creative place where people from all courses and disciplines mixed, hung out and collaborated.
After graduating in 2006, I lived in Bristol for a few years, but I found most of the work I was getting was putting on live drawing and mural shows in London. So in 2010 I made the move to London, with no real work to speak of.
Luckily a mate who worked in TV suggested that I apply for a job in the edit of a new cookery show. So with no TV experience, or idea about how edits worked I blagged my way in and started 2 days later! It turned out that I was in an edit suite of the first series of the Great British Bake Off with the series director and editor.
Within a couple of days I had told them my lack of ambition for a career in TV, and that I was really an aspiring illustrator. This led to the director approaching me in the second week saying that he felt there was a visual element missing from the show, and maybe I could come up with some ideas!
I pitched a few ideas and got the gig.
Eight years, three channels, several awards and a couple of thousand cakes later and I'm still here!"
See more about Tom and his work on his website. | <urn:uuid:065fe246-6a86-4ff0-af95-2d1c9a12fb5d> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,644 |
Paul Stanley, KISS Frontman, Turns 65 Today.
Paul Stanley of KISS turns 65 today.
Best wishes to Stanley Eisen who would later be known as Paul Stanley from the rock band, KISS. #Capricorn
KISS is more than marketing, pyrotechnics, blood spitting, and smoking guitars; they are larger than life.
Offstage and in his book, Face the Music: A Life Exposed Paul Stanley comes across as a human being with real feelings. The autobiography is fascinating and painfully honest.
Check out our Paul Stanley Gallery!
Powered by Facebook Comments | <urn:uuid:18e1631a-bfa6-4ce3-9b19-4a25040684a5> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 535 |
CMS delivers perfect in-house functionality and flexibility to manage every aspect of a client's website. Our team builds a dynamic CMS website to make it easy for every user to add, edit and manage the same with ease.
Vantage Droid provides expertise WordPress support and maintenance services including regular updates to WordPress core, themes, plugins, custom development and WordPress support desk with optimistic professionalism.
As WIX is one of the most prevailing and flexible platform, it has great power to create impact. Hence, we build WIX sites with more dedication by implementing best practices to meet today’s need.
Shopify & Square Space
Shopify & Square Space are considered as top of the strapping E Commerce platform and it is loved by most of the top companies and agencies as well as best platform for Drop shipping and Amazon Store. We design Shopify & Square Space websites with excellent features fixed with lot of great things out of the box. | <urn:uuid:ea78089c-e8cf-45a8-beb6-22854ad95a1f> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 969 |
Have you found, downloaded or received an UPZ file, but don't know which software program is required to open it?
Before attempting to open an UPZ file, you'll need to determine what kind of file you are dealing with and whether it is even possible to open or view the file format.
Answer: Files which are given the .UPZ extension are known as Starmoney Agent Download files, however other file types may also use this extension. If you are aware of any additional file formats that use the UPZ extension, please let us know.How to open a UPZ file:
The best way to open an UPZ file is to simply double-click it and let the default assoisated application open the file. If you are unable to open the file this way, it may be because you do not have the correct application associated with the extension to view or edit the UPZ file.
This file format was added to our database by a visitor to this site, but no additional information was provided. We have yet to investigate this file type further, or there was not enough information available at the time to report accurately on the format.
Please check back soon for more information as we are constantly updating our file descriptions based on search frequency.
Tip: Try to open the UPZ file using a text-editor such as Notepad, as many file types contain simply contain unformatted plain-text and can viewed correctly using this method. | <urn:uuid:2a36d410-7c7b-428c-ac9f-7840471026b7> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,389 |
The 2018 Fairway Galle Literary Festival is delighted to welcome author Pankaj Mishra.
Pankaj Mishra is an Indian essayist, novelist and historian based in the UK.
In 2014, Yale University awarded him the Windham–Campbell Literature Prize (valued at $150,000 one of the largest prizes in the world of its kind) in recognition of his far-reaching work.
Pankaj was the Visiting Fellow for 2007–08 at the Department of English, University College, London, UK., and a Fellow of the Royal Society of Literature in 2008.
In November 2012, “Foreign Policy” magazine named him one of the top 100 global thinkers, and in 2015, “Prospect” nominated him to its list of 50 World Thinkers.
His works include Butter Chicken in Ludhiana: Travels in Small Town India (1995), as well as From the Ruins of Empire: The Intellectuals Who Remade Asia (2012).
His latest book Age of Anger: A History of the Present (2017) about the transition to modernity and the rise of the right wing as well as how other modern ‘ills’ have had a lively and broad reception globally.
In Age of Anger, Pankaj accounts for the resurgence of reactionary and right-wing political movements in the late 2010s. He argues that nationalist, isolationist, and chauvinist movements, ranging from terror groups such as ISIS to political movements such as Brexit, have emerged in response to the globalization and normalization of Western ideals such as individualism, capitalism, and secularism.
“Now with the victory of Donald Trump,” Mishra writes, “it has become impossible to deny or obscure the great chasm .?.?. between an elite that seizes modernity’s choicest fruits while disdaining older truths and uprooted masses, who, on finding themselves cheated of the same fruits, recoil into cultural supremacism, populism and rancorous brutality.”
“Bracing…The first essential read of the Trump Era” – Vogue
Learn more about Pankaj Mishra: | <urn:uuid:8095e8ee-f8a8-4f67-9973-e7dcd766f2f1> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,894 |
At Tsinghua PBCSF, students are deeply involved with the community. To foster students’ self-development, the School organizes a myriad of campus activities, including academic workshops, social work, sports, and cultural events.
PBCSF Students’ Union, established on April 28, 2012, exists to represent the interests of all PBCSF students. The Union is a member of Tsinghua Graduate Union. Its mission is to provide every PBCSF student with a wide range of student services designed to meet their needs on campus.
Union Structure & Function
The Union offers support of all kinds to students of all backgrounds.
It consists of the President, Vice-Presidents, Department Directors, Vice-directors, and Staff. There are 5 departments with specific responsibilities: Internal Communication, Education, Entertainment, Sports, and Welfare.
From hosting internal entertainment activities including welcome party, New Year party, to hosting movie nights and singing competitions, The Union does a great deal to enrich students’ lives on campus. | <urn:uuid:6f74b2e9-0620-4f07-868a-ba2cade44c90> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,037 |
ABOUT USNafis Products is carefully handcrafted hot condiments and sauces using habanero and scotch bonnet peppers with a rich blend of spices and vegetables.While most hot sauces are diluted and offer mostly heat, our condiments are uniquely inspired by our Senegalese traditions, and provide both a delicious savory taste as well as heat.Our products are all natural, vegan, & preservative-free.Simply add any NAFI’S condiment to a plate of rice, or use as a base for soup and stews. The versatility of our products will amaze you. They make great rubs for grilling and can be diluted for marinades, salad dressings, and much more. Naturally low in fat and sodium, NAFI’S condiments are a healthy addition to any meal!Our simmering sauces are rich and creamy ready to be served over rice, bulgar wheat or quinoa, with your meats and veggies, or just veggies!You will create a delightful and healthy meal for your family and friends. NAFI’S will soon become your favorite secret ingredient.
Don't Take Our Word For it! Here's What Our Customers Think:
I loved this little shop! Full of eco-friendly products to help us live with less waste. Laura was so friendly and helpful. Great location. I'm so happy to have a zero-waste shop here in the Phoenix area!
I love this zero waste shop! They have everything from lifestyle goodies to a bulk refillery, it's all a necessity. And at such reasonable prices theres zero reason to not shop here.
Wonderful little shop that has many products to offer. The prices are very reasonable, if not, better that what most shops charge for similar items. Very informative and are ready to help answer any questions you may have.
Spend $x more to Unlock Free ShippingFree shipping when you order over XXYou Have Qualified for Free ShippingSpend $x to Unlock Free ShippingYou Have Achieved Free ShippingFree Shipping For Over $100 toFree Shipping Over $x toYou Have Achieved Free ShippingFree shipping when you order over XXou Have Qualified for Free Shipping | <urn:uuid:585abd8e-cd48-41eb-abc9-9abecca5e130> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,992 |
The Nutcracker and the Mouse King is a story written in 1816, almost 50 years before Lewis Carroll’s Alice’s Adventures in Wonderland, by E. T. A. Hoffmann, in which young Marie Stahlbaum's favorite Christmas toy, the Nutcracker, comes alive and, after defeating the evil Mouse King in battle, whisks her away to a magical kingdom populated by dolls. Directions: 1) After reading the short paragraph of information about The Nutcracker and the Mouse King, watch the 1973 animated video link of The Nutcracker and the Mouse King. You may want to pause and answer the questions as you watch. 3) Tap to be able answer questions 3) Answer all questions provided on the template. You will type your answers directly on to the template. Tap EDIT NOTE to type answers. 4) Tap the to submit to Mrs. Manhart. You may need to tap more than once. Remember NOT to log off until you see "Waiting For Teacher Approval." | <urn:uuid:0e3b3a3a-ab5d-4d8d-99f7-1b96e7a18e55> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 905 |
Fall 2016 End of Season Customer Feedback
We value the feedback from our customers, and would appreciate you taking a few moments to answer a few questions about your visit to Southern Belle Farm this 2016 fall season. Thank you for choosing Southern Belle Farm where "We grow family traditions"! We're getting ready for Christmas -- and hope to see you again soon! You can contact us anytime through our website SouthernBelleFarm.com. | <urn:uuid:77ec4bf5-a4e7-44d8-86a4-b486422236e9> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 435 |
For more information about special education services for school age children and preschool children, contact your child's school or contact:Great Valley School DistrictStudent Services Department47 Church RoadMalvern, PA 19355610-889-2125, X52113Andrea Dinsmore, M.Ed.,Director of Student ServicesRobin Streeter,Administrative Assistant ContactDr. Karen Taratuski, Psy.D.,Coordinator of Psychological Services ContactEmily Braskey, M.Ed.,General Wayne Elementary
Out of DistrictElise Powell, M.Ed., BCBA.,Charlestown ElementaryK.D. Markley Elementary
K-12 Autistic Support (all locations)Dr. La'Keidra McDougal, Ed.D.,Great Valley Middle SchoolGreat Valley High SchoolOut of DistrictChristine Izard, M.Ed.,Professional on Assignment ContactCertified School PsychologistCCIU Technical College High School LiaisonGreat Valley Middle SchoolGreat Valley High SchoolMegan Regan Basquill,Administrative Assistant ContactJane Trimble, MSS., LSW.,Student Services Coordinator ContactSocial WorkStudent Assistance ProgramMental Health ServicesDiane Moriarity,Clerical Assistant Contact
Educational Support Services in Great Valley School District
The Great Valley School District is committed to working with parents to provide our students with quality educational experiences that will encourage them to be successful learners. In line with this commitment, a variety of services have been implemented to address the needs of students who need specialized instruction in order to experience success in the learning process.
CHILD STUDY TEAMS AND INSTRUCTIONAL SUPPORT TEAMS
Students in need of additional support are initially assisted through child study or instructional support teams. Parents are encouraged to be active members of these teams. Meetings are held regularly to analyze students' learning difficulties and to develop strategies to help students meet with success in their regular education classes. At grades K through 8 the instructional support team concept is utilized, while in grades 9 to 12 the child study team is the first line of intervention.
MULTIDISCIPLINARY TEAM EVALUATION
Students who may require special education services are referred by the instructional support team or child study team for a multidisciplinary evaluation of their learning needs.
This evaluation gathers pertinent information on the child's performance from teachers, counselors, psychologists, and parents. Information is compiled into a comprehensive evaluation report that includes recommendations on the child's eligibility for Special Education Services. All information collected is protected in accordance with State and Federal law and by the District's policy on confidentiality of student records. In order to request a multidisciplinary team evaluation for a school age child, a parent should contact their child's teacher, guidance counselor, instructional support teacher, or principal. The initial involvement of the child study team or instructional support team however, is recommended to be an important first step in assessing a student's educational strengths and needs.
SPECIAL EDUCATION SERVICES
The Great Valley School District provides special education services for all eligible students in grades K — 12. Special education programs are either operated by our school district or the Chester County Intermediate Unit. Students with more significant needs receive their education at Approved Private Schools. Services by disability area are as follows:
- Visual impairment including Blindness
- Deaf - Blindness
- Hearing Impairment including Deafness
- Intellectual Disability
- Multiple Disabilities
- Traumatic Brain Injury
- Emotional Disturbance
- Specific Learning Disability
- Speech and Language Impairment
- Other Health Impairment
- Orthopedic Impairment
CHAPTER 15/SECTION 504 EVALUATIONS
For those students who have a handicapping condition that requires accommodations or services to appropriately access their regular education program, an evaluation for an educational service agreement can be requested. Students receiving services under this category are typically children who are not eligible for special education services, yet demonstrate a documented disability that requires special consideration within the educational setting. In order to request a Section 504 evaluation a parent should contact their child's school counselor or building principal.
INSTRUCTIONAL SUPPORT PLANS
An Instructional Support Team (IST) is available to provide instructional support to all elementary and middle school teachers and students. Instructional Support is coordinated by a support teacher who provides at-risk students and their teachers, strategies and interventions to better access their educational program. Instructional Support also serves as a screening process for students thought to be in need of specially designed instruction. At anytime during this process, a referral for a multidisciplinary team evaluation may be initiated by parents or the school team. This ongoing system meets criteria specified in Chapter 14. Parents may request instructional support through their building administrator or support teacher.
Special education services are also available to preschool children. The Great Valley School District works in cooperation with the Intermediate Unit to provide programs for preschoolers who have been identified as eligible for special education. | <urn:uuid:7a9cdff0-9856-4e1b-9872-d0830006648e> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 5,407 |
Clue: When the Great Lakes were formed
We have 1 answer for the clue When the Great Lakes were formed. See the results below.
- When mammoths lived
- Quaternary division
- It ended about 10,000 years ago
- Quaternary period event
- Hardly a cold snap
- Pleistocene Epoch, familiarly
- Cooling-off period
- When modern elephants first appeared
- When glaciers advanced
- Paleontological topic
Last Seen In:
- New York Times - June 14, 2009
- New York Times - January 06, 2002
Found an answer for the clue When the Great Lakes were formed that we don't have? Then please submit it to us so we can make the clue database even better! | <urn:uuid:9e979492-00ee-4e64-99e2-d257fe91b12d> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 630 |
Although I toil for months each summer to put together the "perfect" curriculum plan for my school year, rarely does my plan remain un-edited once fall arrives. I think it is always a good idea to evaluate the success and use-ability of my chosen curriculum a few weeks into the school year. By the end of September, I use a few key questions to assess the materials I've purchased/borrowed and make adjustments accordingly. (This post contains affiliate links. Please see my disclosure policy for full details.)
This year, after sensing a definite deficiency in my PLAN, I added in two new elements to our 2013-2014 curriculum.
This year, our church is trying something new in the Children's Ministry Department. And I LOVE it! Using materials from Children Desiring God, they have put together a curriculum that ensures that each of my children, no matter the age, will be learning the same thing...at their level. Take home packs are sent home each week so that families are able to prepare for the upcoming week's lesson and memorize a verse ALL TOGETHER. (No more frazzled momma trying to help four kids memorize 4 different Sunday School verses and 4 different Wednesday night verses EVERY WEEK...phew!)
The take-home materials can usually be completed in three short at-home sessions. While we absolutely love God's Promises, our chosen Bible curriculum for the year, we also find much value in what our Children's Ministry Department at church is attempting. We have decided to do the Sunday School lessons three nights a week and God's Promises the remaining four nights.
Middle Boys' Science
Although my original plan was for Blonde Warrior (1st Grade) to join the older kids for Noeo Science Chemistry I and for Greased Lightning to enjoy a few science-themed read-alouds throughout the year, it quickly became apparent that Noeo Science was sometimes too lengthy for a 1st grader's attention span and the science read-alouds just didn't offer the "hands-on" that a fun science lesson should provide. So, PLAN B became the solution to both problems.
Blonde Warrior still enjoys doing Chemistry with the older kids, but in addition, he now joins Greased Lightning twice a week for a "Littles"-friendly science time.
Over the years, I have been collecting a handful of Let's Read and Find Out Science books. They are a series of books each featuring a separate science topic and occasionally include simple project suggestions. Up until this year, I don't think we have EVER read them. They have been packed away in the basement for SOMEDAY. Well, "someday" has arrived.
|New Editions of Let's Read and Find Out Science|
I was able to find several more titles in the series at the library and have created a "science" basket for the two middle boys. Once a week, I let one of them pick a book from the basket. We read half the book THAT day and save the other half for some other day later that week. I have no real plan, schedule, or order to how and when each book will be read. The boys choose whichever book looks interesting to them at that moment. If there is a simple science project listed in the book and we have the required materials, we do it. Sometimes, we explore the topic further with interesting videos on youtube, and sometimes we don't.
I've purposed to keep this science-time very simple. In true preschool-style, I am focusing more on providing a fun introduction to many different topics instead of diving head-long into lengthy unit-studies.
A Quick Peek
In case you're curious, so far our special "science time" has been such a treat for both me and my little boys. So often, the busyness of teaching elementary kids demands that the little guys just "tag along" and try to keep up at their level. While I don't doubt the validity of THAT kind of learning, I also think it's nice when my little boys can experience learning RIGHT AT THEIR LEVEL.
Here's one quick example. Last week, we read Ducks Don't Get Wet, and learned that every duck has a special oil gland that prevents them from getting wet while in the water. Afterward, we conducted a simple science project to demonstrate what happens to water when it is on a duck's back.
We gathered two paper bags, cooking oil, a basting brush, and water. We painted one of the bags with oil and then poured water on both bags. My boys were able to visually see how the oil on a duck's feathers helps to resist water. We then discussed WHY we thought God may have designed ducks this way. Learning AT THEIR LEVEL.
Have you done any curriculum tweaking this year? How and Why? | <urn:uuid:1ced03cb-0504-45ea-ad39-31b32a12e056> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 4,556 |
A visit was made to the home of MICHEAL EVERITT to discover what an amazing collection of stotfold artefacts he has collected over the years. Below are some photos that starts to touch upon his collection…more details to follow. Thank you Micheal for your contributions and hospitality, it really is greatly appreciated.
Thank for the input from eight members of Stotfold’s, Knit and Knatter. With Bedfordshire’s tradition of lace-making we thought it a good idea to discuss the project with the local community group. We discussed knitting patterns and how the aesthetic of these ‘diagramatical patterns were perhaps similar to that of ‘typewriter art…..more information to follow… Here’s a… Read more »
As the collaborative creative sessions take place gathering feedback is extremely important to how the project develops and is finally realised. As well as gathering feedback through conversation during the sessions, informal forms were kindly filled in by the participants. I’ve broken down the separate questions and entered the answers below them. Some forms were… Read more »
Mollie Jennings who has been wonderful in her enthusiasm and her contributions to the project, both creatively and providing some really interesting local stotfold history. Thanks you to yourself and your friend Sheila who participated in collaborative exercise with artist Emily Tracy. There’s a wealth information that came about…here’s a snipit of the session…Like the… Read more »
As part of the collaborative process we have also been gathering signatures form the people that have taken part. It’s hoped that they will appear somewhere in the final artworks.
We’d like to say thank you to everyone that contributed their time and energy into taking part in a creative session exploring memories and local history of the Stotfold area. These memories and time lines related to the respective institutions of the attendees. Using a grid format to enter details, this visual format presented a… Read more »
I had great time checking out the workings of Stotfold Mill, and look forward to reading their publication, “They’ll Never Do It!”… More news to follow.
On the 7th December the project went to see Stotfold Bowls Club to chat with some of its members who kindly offered their time and knowledge of the clubs history and the rules of play for bowls. With the help of artist Emily Tracy, the members looked at presenting some of the club’s heritage through the… Read more »
PART 3 TYPE WRITER ETONBURY ART WORKSHOP &%^)_+
Part 3 of the typewriter art workshops took place at Etonbury Academy on the 7th December. Thanks to everyone involved especially to art teacher Miss Gahagan, and some great work done by pupils, Paige Taylor 8IB and Jess Beedle 8BM….more news to follow…
PART 2 TYPE WRITER ART WORKSHOP (*@£%
Part 2 of the creative sessions took place and the pupils are starting to create some confident work. Next session 7th December. More news to follow….
FURTHER COLLABORATIVE EVENTS COMING SOON…
With the assistance of Artist Emily Tracy further collaborative events are starting to be organised with a variety of community clubs and groups. Aswell as the current creative sessions with Etonbury Academy, we are currently in discussion with, Stotfold Bowls Club Womens Institute The Salvation Army Stotfold Mill Stotfold Library readers group Stotfold has a number… Read more »
PART 1 TYPE WRITER ART WORKSHOP %$^&*
Tom undertook the first of series of workshops with pupils from Etonbury Academy. more news to follow…and it’s trickier than you think…
CREATIVE SESSIONS WITH ETONBURY ACADEMY
Thank you Etonbury Academy for contributing some great work! I think over the three sessions we started to develop some good ideas for the project and I really appreciated all of their hard work and enthusiasm. In particular a few pupils really contributed some confident work, Jess Beede / Paige Taylor / Tige Burns. Perhaps… Read more »
WORKING STEAM WEEKEND
Date: Sat, 10 Oct, 2015 – Sun, 11 Oct, 2015 Time: 10:30 am – 5:00 pm Working Steam Weekend – I had a great time and was so impressed with how vibrant the event was. this says it all… A unique collection of steam driven machinery on display, including ploughing and threshing demonstrations. The mill be open… Read more »
Lovely copies of Stotfold Mill’s past
Foyle Special Collections Library
It is planned to use Typewriter art as an inspiration to introduce text into the final artworks which will enable a variety of narrative to be introduced into the artworks in a visually dynamic fashion – To see some fine examples of Typewriter art, I visited the beautiful Foyle Special Collections Library in London. Amongst other examples, the… Read more »
artwork ideas – STEAM
The imagery of steam will be depicted using two overlapping visual languages; a bold linear style, which will be visible from afar, and a 17th and 18th century intaglio style referencing past industrial use of steam power in agriculture.
inaugural STOTFOLD STEAM FAIR VISIT
Had a really great day…this event needs no introduction to the locals of Stotfold. | <urn:uuid:b4e4133c-670a-4ca9-97e5-c6f2494a4bbd> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 5,086 |
These Polish guard dogs where extremely aggressive.
From what I know about farm and guard dogs, the guard dog is supposedly a full-time member of the flock, unlike the herding dog. The behaviour characteristics of the guarding dogs differ radically from those of the herding dogs, the result of centuries of breeding for selective traits that make for a successful guard dog. The physical characteristics and behaviour of herding dogs differ from those of guarding dogs. The primary goal when raising a guard dog is to ensure complete socialisation and bonding with the animals that will, in the near future, be in its care, however I’m not sure this is true of the above dogs. | <urn:uuid:716fead4-bf05-4bbe-ba8f-4339665ba7e8> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 677 |
Gene Therapy to the Retina and the Cochlea
- 1Department of Biomedical Engineering, University of Houston, Houston, TX, United States
- 2Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- 3Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- 4College of Optometry, University of Houston, Houston, TX, United States
- 5Depatment of Biology and Biochemistry, University of Houston, Houston, TX, United States
Vision and hearing disorders comprise the most common sensory disorders found in people. Many forms of vision and hearing loss are inherited and current treatments only provide patients with temporary or partial relief. As a result, developing genetic therapies for any of the several hundred known causative genes underlying inherited retinal and cochlear disorders has been of great interest. Recent exciting advances in gene therapy have shown promise for the clinical treatment of inherited retinal diseases, and while clinical gene therapies for cochlear disease are not yet available, research in the last several years has resulted in significant advancement in preclinical development for gene delivery to the cochlea. Furthermore, the development of somatic targeted genome editing using CRISPR/Cas9 has brought new possibilities for the treatment of dominant or gain-of-function disease. Here we discuss the current state of gene therapy for inherited diseases of the retina and cochlea with an eye toward areas that still need additional development.
Over 2.2 billion people worldwide experience vision impairment or irreversible vision loss1, and over 466 million people worldwide experience serious hearing loss2, making these the most prevalent sensory impairments. Many forms of vision and hearing loss are inherited and current treatments only provide patients with temporary or incomplete relief. Because many inherited sensory defects have identified disease genes, developing effective genetic therapies has been a primary research goal for several decades. Recent exciting advances in gene therapy have shown promise for the treatment of inherited retinal and cochlear diseases, both in the area of gene replacement and in the area of targeted genome editing (e.g., CRISPR/Cas9) to correct underlying genetic defects. However, there are still substantial limitations hampering widespread clinical use of genetic therapies in the retina and cochlea, including issues of distribution and uptake of the vectors by the target cells, a limited window of opportunity for treatment in degenerative disorders, attenuation of gene expression after a period of time, and efficiency/off-target concerns with novel genome editing strategies.
Inherited Diseases of the Retina
The retina is the transparent, light-sensitive tissue at the back of the eye (Figure 1A) responsible for capturing light and converting it to an electrical signal to be delivered to the visual cortex in the brain where conception of vision occurs. The retina has evolved into a multi-cellular laminated structure, within which the different cells are organized and interconnected to maximize the efficiency and resolution of light perception (Figure 1B). The primary cells involved in the detection of light are the retinal rod and cone photoreceptors. Rods are necessary for low-light or “night” vision while cones perform bright-light color vision perception. The leading causes of irreversible vision loss are age-related eye diseases including age-related macular degeneration, diabetic retinopathy, glaucoma, and cataract3 (reviewed in Haddad et al., 2006; Simo-Servat et al., 2013; Singh and Tyagi, 2018). While these highly prevalent retinal diseases are not monogenic, they do often have a genetic component that contributes to disease in combination with environmental or other factors. In addition, inherited retinal dystrophies/diseases (IRDs) affect roughly 1 in 1380 individuals with an estimated 36% of the population as healthy carriers of one or more IRD causing mutations (Hanany et al., 2020). Combined, this underscores the need for the development of genetic therapies targeting the retina.
Figure 1. Schematic Illustrations of the Cochlea and Retina. (A) The structure of the eye, (B) layers of the retina (Sc, sclera; CBV, choroidal blood vessel; BM, Bruch’s membrane; RPE, retinal pigment epithelium; PR, photoreceptors; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer) and (C) The structure of the inner ear, (D) cross-section of the cochlea and a close-up of the Organ of Corti. Shown are selected genes which are associated with disease in humans. Genes marked in red represent a selection of those that have been evaluated successfully in animal models while those in blue have been evaluated in human clinical trials. Images were created with BioRender.com.
IRDs are a group of retinal dystrophies caused by mutations in over 271 different known genes (with many still unknown), that can target various cells within the retina. Virtually all inheritance patterns are represented in IRD genes including autosomal dominant, autosomal recessive, X-linked, digenic, polygenic, and even mitochondrial disorders. IRD genes expressed in photoreceptors can lead to various macular degenerations/dystrophies and retinitis pigmentosa (RP) and are involved in ocular development, phototransduction, cellular metabolism, and in the development and maintenance of photoreceptor structure. Mutations in retinal pigment epithelium (RPE) genes include those involved in retinoid recycling, cellular metabolism, and cellular homeostasis and can lead to macular dystrophies as well as Leber’s Congenital Amaurosis (LCA). Mutations in retinal ganglion cell IRD genes are largely associated with mitochondrial function, but also include regulators of intracellular transport and transcription, and can lead to optic atrophy. A summary of known IRD genes can be found at: https://sph.uth.edu/retnet/sum-dis.htm.
Depending on the gene, the onset of disease varies from birth to adulthood. Photoreceptor dystrophies are the most common within the retina and can be classified by the primary affected cell type and whether central or peripheral vision is lost first. RP and rod-cone dystrophies typically affect rods first, while macular dystrophies/degenerations and cone-rod dystrophies often affect cones first (Rattner et al., 1999). However, it is worth noting that in many cases of macular dystrophy, where macular cones are the first cells targeted, the causative gene is expressed in the adjacent RPE, with vision loss arising due to secondary cone damage. Patients with RP and rod-cone dystrophies often initially present with night-blindness which is followed by gradual peripheral vison loss (Ferrari et al., 2011). As the patients’ visual fields gradually shrink over time, irreversible vision loss eventually ensues (Ferrari et al., 2011). Individuals with cone-rod dystrophies have a rapid loss of central vision early in their life, which is followed by gradual peripheral vison loss (Morimura et al., 1998; Fukui et al., 2002; Klevering et al., 2004).
Current treatment options to correct the more mild symptoms of vision loss include corrective lenses or contacts and more permanent laser correction surgery. In more severe cases where progressive vision loss occurs due to retinal degeneration, a more invasive approach is necessary. These advanced therapeutic options are all still in development or in early clinical use and include gene therapy, gene editing, reprogramming, cell therapy, optogenetic therapies, and retinal prostheses. The time at which these therapies are useful varies greatly. For maximum efficacy, gene therapy needs to be delivered in the early stage of disease to prevent further degeneration. In contrast, other options have a wider therapeutic window, but have had less success thus far, both in development and in clinical use (Maeda et al., 2019; Wood et al., 2019).
Inherited Diseases of the Cochlea
The inner ear is a small, fluid-filled compartment (Figure 1C) encased in the temporal bone and located at the base of the skull. The acoustic energy from sound is converted to an electrical impulse that the brain perceives as hearing through a multi-step process. Sound waves hit the tympanic membrane (eardrum) which vibrates the attached ossicular chain (three small ear bones). This vibration is transmitted to the fluid in the cochlea and basilar membrane (Figure 1D), and resulting fluid waves are sensed by the hair cells in the organ of Corti through mechanotransduction. The specialized sensory hair cells in the cochlea comprise a single layer of inner hair cells (IHCs) responsible for converting the mechanical signal into an electrochemical one, and three layers of outer hair cells (OHCs) involved in modulating and amplifying auditory signals. Mechanical deflection of stereocilia on the surface hair cells results in depolarization, and subsequent signal transmission to the auditory cortex (Rubel and Fritzsch, 2002). The differentiation of sound frequencies is facilitated by the length of the cochlea and the stiffness of the basilar membrane (Manoussaki et al., 2006).
Sensorineural hearing loss (SNHL), defined as the presence of a deafness-causing etiology in the cochlea or auditory nerve, accounts for more than 90% of hearing loss in adult patients. Approximately 50–60% of all cases of congenital deafness are directly linked to genetic factors, with higher numbers in developed countries (Marazita et al., 1993; Smith et al., 2005). Currently there are 49 identified genes known to be responsible for autosomal dominant non-syndromic hearing loss, 76 autosomal recessive genes, and 5 X-linked genes4 and (Duman and Tekin, 2012; Yuan et al., 2020) with many more remaining to be mapped. These genes play a role in a variety of processes including hair bundle development/function, hair cell adhesion, synaptic transmission, cochlear ion homeostasis, cellular homeostasis/energy generation, and regulation of the extracellular matrix (reviewed in Dror and Avraham, 2010; Stamatiou and Stankovic, 2013; Zhang W. J. et al., 2018). As in the retina, disease onset can vary from birth to late adolescence. The pattern and progression of symptoms in patients help identify what mutation(s) may be involved and determine whether interventions, genetic or otherwise, may be beneficial.
Current treatment options focus on amplifying sound through hearing aids or electrical stimulation of auditory neurons via cochlear implants for individuals with severe deafness. Cochlear implants are currently the most successful sensory prosthetics available, allowing deaf individuals to understand speech (Wilson and Dorman, 2008; Roche and Hansen, 2015). However, their effectiveness is limited to quiet spaces and suffers from poorly detailed sensory perception (Muller and Barr-Gillespie, 2015; Roche and Hansen, 2015; Weiss et al., 2016). In addition, while highly beneficial, cochlear implants merely treat the symptoms of hearing loss without addressing the underlying cause, so cochlear gene therapy has been an exciting therapeutic goal.
Syndromic Sensory Inherited Diseases
In addition to inherited disease genes affecting a single tissue (e.g., the retina or the cochlea), there are a large variety of disease genes that are syndromic, affecting multiple tissues. Structural parallels in photoreceptors and cochlear hair cells mean that there are also a large number of disease genes that cause dual syndromic deafness and blindness. These genes often induce photoreceptor degeneration rather than optic atrophy and are frequently classed under the larger umbrella of ciliopathies. The most common form of dual deafness and irreversible vision loss involves the many genes associated with Usher syndrome (El-Amraoui and Petit, 2014; Mathur and Yang, 2015, 2019). Usher syndrome is clinically broken down into three types, Ush1, Ush2, and Ush3, due to the severity of hearing and vision loss, presence or absence of vestibular problems, and the age of onset for the symptoms (Millan et al., 2011). Patients with Ush1 are born with severe hearing loss, have abnormal vestibular systems, and progressive vision loss due to RP beginning during childhood. Individuals with Ush2 are born with mild to severe hearing loss and have progressive vision loss starting during adolescence. People with Ush3 develop hearing loss during adulthood and vision loss during adolescence and develop vestibular abnormalities. The types are further subdivided due to the underlying genetic cause. The proteins associated with each type are localized into similar regions in the retina and cochlea (Figure 2) and often associate or interact with one another, thus mutations in several genes can lead to similar patient phenotypes.
Figure 2. Site of Usher proteins in the retina and the cochlea. Shown are illustrations of the photoreceptor and hair cell highlighting the regions affected by different Usher syndrome genes. Ush1 genes/locations are shown in cyan, Ush2 genes/locations in purple, and Ush 3 genes in lime green. Hair cell legend structures: ankle links (purple), lateral links (green), contact region (gold), tip link (red), kinocilium links (blue), kinocilium (K). Images were created with BioRender.com.
Other disease genes with multiple affected areas include many of the retinal disease genes that cause optic atrophy such as MECR and ACO2 which are also associated with cerebellar defects and ataxias (Heimer et al., 1993; Sharkia et al., 2019). In other cases, these disorders also have a deafness component, for example in the case of TIMM8A, which is associated with deafness-dystonia-optic neuropathy syndrome (Tranebjaerg, 1993). However, these syndromic disorders are very complex, and in some cases, different mutations in the same gene lead to isolated optic atrophy or ataxias, such as the case of AFG3L2 (Di Bella et al., 2010; Colavito et al., 2017). Some syndromic forms of vision loss such as Batten disease affect the brain and bipolar cells, the inner retinal neurons responsible for conveying signals from photoreceptors to ganglion cells (Kleine Holthaus et al., 2020). These various syndromic diseases highlight molecular similarities in various sensory disorders, and suggest that examining sensory disorders from a broader, non-organ-specific perspective may be beneficial.
Commonalities Between the Retina and the Cochlea
Favorable Biological Characteristics
One problem with systemic delivery or delivery to systemic organs besides rapid clearance/excretion of the vector is potential activation of the immune system. In contrast, both the eye and the ear represent accessible local delivery sites that are fairly protected from the systemic immune system. This permits a prolonged half-life for delivered material and reduces the chance of a systemic immune response or off-target effects in other parts of the body.
The inside of the eye, including the retina, is isolated from the systemic circulation by the blood-retinal barrier and the blood-aqueous barrier, maintained by tight junctions between retinal pigment epithelial cells; between vascular endothelial cells in the ciliary processes, Schlemm’s canal inner wall endothelial cells and the iris vasculature; and between the cells in the non-pigmented ciliary epithelium (Campbell and Humphries, 2012; Coca-Prados, 2014). Thanks to these barriers, the eye has a limited immune system with only local immune and inflammatory responses present to maintain homeostasis, allowing the retina to be immune-privileged (Zhou and Caspi, 2010; Cunha-Vaz et al., 2011). Likewise, the cochlea is also isolated and surrounded by bone with even less access to the rest of the body. The endothelial cells lining the cochlear blood vessels form the blood-labyrinth barrier (BLB) or blood-cochlea barrier (BCB), which is comparable to the blood-brain barrier (BBB) in its ability to tightly regulate the exchange of macromolecules and ions between the blood system and the inner ear. The BLB maintains the homeostasis of the inner ear and isolates it from any pathogens found in the blood, allowing the inner ear to also maintain relative immune-privilege (Salt and Hirose, 2018).
Another benefit of genetic therapies for both the retina and cochlea is the need to deliver only small amounts of therapeutic agents, which is due to the ability to deposit material directly to or in very close proximity to the target cells, allowing for greater chance of uptake by the desired cells with limited loss due to systemic distribution.
In addition, the majority of the cells in both the retina and cochlea are post-mitotic and fully differentiated. This provides both opportunities and challenges for gene delivery. One substantial advantage is that the lack of cell division permits evaluation of changes in gene expression over time (for example due to vector loss or epigenetic changes) without concern about dilution of non-integrated vectors by cell division. Similarly, non-integrated vectors are not lost over time due to cell proliferation. In contrast, post-mitotic cells can be harder to transfect and target than dividing ones, making it more difficult to achieve cellular uptake of therapeutic vector. In addition, the non-proliferating nature of retinal and cochlear sensory cells means that in general once lost, cells are gone forever. Though research effort has been focused on combatting this by the use of stem cells or by regenerating cochlear hair cells, in general the degenerative nature of disease when post-mitotic cells are affected means the therapeutic window is narrow, as treatments delivered after too many cells have died will not be effective.
Testing and Development Benefits
From a therapeutic development standpoint, the bilateral nature of the retina and cochlea is also beneficial. Treating only one eye or cochlea allows the contralateral eye/cochlea to serve as an internal control for analysis, since the treatment rarely escapes the treated eye/cochlea. However, leakage from one ear to the other after scala tympani injections has been reported (Lalwani et al., 2002b), so restriction of therapeutic agents to a single eye or retina should be confirmed prior to interpreting resultant functional data.
Another benefit of developing and testing gene therapies in the retina and cochlea is that there are a variety of ways to perform non-invasive functional testing to assess therapeutic efficacy in both animal models and humans. The non-invasive nature of these tools also enables measurements to be performed longitudinally, essential for efficiently evaluating the duration of therapeutic effects. In vivo imaging in the retina includes spectral-domain optical coherence tomography (OCT) and fundus imaging/angiography to assess distribution of tagged genetic vectors and retinal structure. Non-invasive functional testing in the retina include electroretinography (ERG) to measure retinal neuronal responses, as well as optokinetic tracking (OKT) to measure visual acuity (Cai et al., 2010; Koirala et al., 2013). In vivo cochlear functional testing includes assessments of auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE) to evaluate inner ear function. Imaging modalities can be used in parallel, including computed tomography (CT) and magnetic resonance imaging (MRI) to evaluate cochlear structure (Razek and Huang, 2012; Al-Rawy et al., 2017).
The Use of Animal Models to Study Retinal and Cochlear Inherited Diseases
Preclinical gene therapy studies are an essential component of therapeutic development. They are used to assess safety and efficacy, but are also used to assess a variety of other parameters that can have a huge influence on outcomes. These can include (1) optimizing vector content, including promoter/enhance choice, gene sequence, inclusion of intronic and untranslated region (UTR) sequences, etc.; (2) evaluating methods to prevent gene silencing, such as elimination of CpG islands, the inclusion of insulators, etc.; (3) testing methods to promote or prevent genomic integration, such as the inclusion of transposases or S/MARs; (4) evaluating vector packaging, including the use or development of various viral compaction methods, engineering novel viral serotypes to enhance tissue tropism, engineering novel non-viral vectors; (5) assessing delivery methods; (6) assessing cellular uptake and targeting of vectors, including vector/particle optimizations to enhance cellular uptake; and (7) evaluating gene expression levels, knockdown efficiency, or duration of expression. The length of this list highlights how much development and testing often occurs before genetic therapies can even be evaluated for their ability to elicit functional improvement in the target disease.
Animal studies are necessary to fully understand the effects of gene therapy in a true organ microenvironment and to investigate the toxicities involved in long-term studies. The majority of preclinical retinal and cochlear studies have used rodents as preferred animal models. Mice have well characterized genomes, with genetic, biological, and behavioral characteristics similar to humans, and their genomes can be easily manipulated which is a boon for studies of inherited diseases. Guinea pigs have also been used for evaluation of auditory dysfunction as they are susceptible to noise induced hearing loss, making them a commonly used model for optimizing gene delivery approaches and to assess the efficacy of gene-based treatments not targeted to a specific disease gene (for example delivery of growth factors for general neuroprotection) (Chen et al., 2018; Pinyon et al., 2019; Lafond et al., 2020). Final preclinical studies for both safety and efficacy use larger animal models, including pigs, dogs, and non-human primates, as these animals may better mimic the anatomy or immune system of human structures or because they offer further evidence of efficacy, for example in the RPE65 dog model (Kelley et al., 2018; Maddalena et al., 2018; Ding et al., 2019; Gyorgy et al., 2019; Gardiner et al., 2020; Ivanchenko et al., 2020).
Retinal Animal Models
There is an extensive body of literature using mouse models for retinal gene therapy (for example, there are over 1,700 PubMed hits for “mouse retinal gene therapy”) and for the study of IRD disease mechanisms (e.g., Sakamoto et al., 2009; Sakami et al., 2014; Chakraborty et al., 2020; Genc et al., 2020). However, there are some differences between the mouse and human eye that make evaluation in larger animals prudent. First, in contrast to the human retina which is developed at birth, the cells of the mouse retina are not fully produced prenatally. While the first wave of retinogenesis begins during embryonic stages (E11–E18), including horizontal cells, cone photoreceptors, some amacrine cells, and retinal ganglion cells, the second wave of retinogenesis takes place postnatally (P0–P7) with the rod photoreceptors, bipolar interneurons, and Müller glial cells (Cepko et al., 1996; Heavner and Pevny, 2012). Thus studies showing effective gene therapy after early postnatal treatment in mice may not translate well to humans. There are also structural differences in addition to the obvious size difference, most notably the larger relative size of the lens and the lack of a macula in mice. The flatter lens in human eyes (compared to mice) means that the relative intravitreal volume is quite different, critical for designing and evaluating dosing strategies. Also important is the lack of a macula in the mouse eye. The macula is both very fragile and the primary site of pathology for many IRDs, so the lack of a macula in the mouse can make it challenging to test therapies that need to target the macula or adjacent areas. In addition to lacking a macula, the rod:cone ratio in mice is much higher than in humans, making studies on cone-specific macular dystrophies more challenging (Volland et al., 2015). In spite of this, many successful preclinical studies (further discussed below) have used mice to assess gene therapies in models of cone or macular dystrophies, however, modeling the physical constraints of the macula is challenging in rodents. Testing gene therapies in non-human primates allows for a better approximation of how results will translate clinically, especially with regards to vector delivery, uptake, and gene expression (Yiu et al., 2020). Non-human primates also have a macula, which is advantageous for developing treatments for both IRDs and other macula-targeted disease such as age-related macular degeneration (Picaud et al., 2019). However, there are several limitations to using non-human primate models, including cost, ethical concerns, and perhaps most importantly, the lack of models for IRDs. One rare early exception to the lack of non-human primate genetic models was a squirrel monkey model in which trichromatic vision was restored to animals lacking the L-opsin gene by the delivery of an adeno associated virus (AAV) 2/5 vector (Mancuso et al., 2009). However, in general, functional efficacy of IRD treatments has not been evaluated in non-human primates due to the historical lack of genetic flexibility.
Slowly however, there are signs that this lack of genetic primate models may be changing due to the genome-editing capabilities of CRISPR-based genome editing strategies. Germline knockout models in non-human primates have been established (Niu et al., 2014), but the long life-span and singleton birth pattern make germline models in non-human primates practically prohibitive. More recently however, a somatic, macular knockout model of CNGB3-associated achromatopsia has been generated in monkeys using AAV9-mediated delivery of a CRISPR/Cas9-based construct (Lin et al., 2020). Similarly, somatic, AAV5-mediated delivery of a CRISPR/Cas9 GUCY2D knockdown construct was used to generate a macaque model of cone-rod dystrophy (McCullough et al., 2019). While still in the early stages, these innovative genome editing tools may pave the way for expanded use of large animal models.
Cochlear Animal Models
Mice are also widely used as genetic models for hearing loss. Mouse models of hearing loss have been created using a variety of genetic approaches, ranging from traditional knockouts to modern gene-edited germline models (see for example Charizopoulou et al., 2011; Michel et al., 2017; Schrauwen et al., 2018; Zhang H. et al., 2018). The major difference between the mouse and human auditory system is the timeline of development. Mice are naturally born deaf and don’t begin to hear until ∼P14, as the final development of the organ of Corti occurs early postnatally. This is a practical disadvantage for gene therapy for congenital deafness, firstly because delivery in rodent models during the early postnatal period—while likely to be successful—would be difficult to mimic clinically since the corresponding human developmental stage occurs in utero. Secondly, it has been proposed that in many cases of congenital deafness the cellular and molecular disease process has already started in utero, making effective postnatal interventions all the more difficult to achieve. While mice are widely used in genetic studies, guinea pigs are more notably used in cochlear studies involving cochlear implants due to easier and more reproducible surgical access to the inner ear compared to other rodent models (Wysocki, 2005; DeMason et al., 2012; Mistry et al., 2014) and their susceptibility to noise-induced hearing loss. The guinea pig also has a hearing range which is more conducive to human hearing comparisons, compared to other small rodent species (Heffner and Heffner, 2007).
In addition to developmental differences, there are also anatomical differences between the mouse and human ear that are relevant to the evaluation of gene therapies. The human cochlea and labyrinth are approximately 20-fold larger than rodents and 3 to 4-fold larger than monkeys (Ren et al., 2019). Studies have found that inner ear volumes correlated with animal body mass across different species while looking at mice, rhesus monkeys, and humans (Ekdale, 2013; Dai et al., 2017) suggesting that the larger size of primates might enable them to serve as intermediate models for translation of rodent findings into humans. In addition to inner ear volume differences, there are also anatomical differences between the human and mouse ear that have implications for gene/drug delivery. Intratympanic delivery is a common way to deliver drugs destined for the inner ear in patients and rodent models, and it is thought that drugs have some permeability through the otic capsule (the bony structure surrounding the cochlea) in addition to through the round window membrane. However, the human otic capsule is significantly thicker than that in mouse and guinea pig, so human drug/therapeutic delivery throughout the length of the cochlea may not be well-modeled by rodent studies (Mikulec et al., 2009).
Assessments of audiovestibular function after saline injection into the oval or round window in non-human primates showed no evidence of toxicity as assessed by auditory function, histology, or behavior suggesting that drugs and therapies can be delivered to the primate ear (Dai et al., 2017). Consistent with this observation, primate models have been used to evaluate genetic therapies; for example, transmastoid injection in the round window of AAV9 carrying a GFP reporter achieved >90% transduction of both inner and outer hair cells in one of their test animals but no clear transduction of hair cells in the other (Gyorgy et al., 2019). In addition, as with the retina, the lack of genetic models for hearing loss in primates has also prevented their widespread use for testing of therapeutic efficacy, and as yet, no CRISPR/Cas9 non-human primate models of SNHL have been reported.
Delivery Methods for Gene Therapy
Delivery of Genes to the Retina
Delivery of genetic therapies to the retina typically involves subretinal, intravitreal, or suprachoroidal injection of material, with variations on the site of entry (Figure 3A). Subretinal injections deliver material between the photoreceptors and the RPE. This is the most widely used method for therapies targeting photoreceptors or RPE since material is in close proximity to most target cells. However, the method is invasive, causing retinal detachment at the site of injection, and has greater potential for complications during the procedure. Intravitreal injections avoid these issues by delivering into the vitreous cavity of the eye. This procedure is in routine clinical practice for the delivery of anti-angiogenesis agents to treat neovascularization associated with diseases such as age-related macular degeneration (Todorich et al., 2014). However, material delivered intravitreally typically has poor penetration into the outer retina (Farjo et al., 2006; Dias et al., 2019), due both to the content of the vitreous itself as well as to the inner limiting membrane which forms a physical barrier between the retina and the vitreous. Identifying ways to improve delivery of genetic material to the outer retina after intravitreal delivery has been a critical research goal in the past several years. Many methods have been tried, including making genetic modifications to AAV capsids (Petrs-Silva et al., 2009; Dalkara et al., 2013), including agents to digest or disrupt the inner limiting membrane (Dalkara et al., 2009; Cehajic-Kapetanovic et al., 2011), application of electrical currents (Song et al., 2019, Song C. et al., 2020), and the inclusion of adjuvants such as tyrosine kinase inhibitors or proteasome inhibitors (Dias et al., 2019). Modification of viral capsids led to almost complete transduction of the outer retina after intravitreal injection in the mouse retina, but did not achieve this milestone in larger animal models such as dog and non-human primate (Mowat et al., 2014; Boyd et al., 2016; Ramachandran et al., 2017). This highlights an area where testing in larger animals is essential due to the relative (and absolute) difference in vitreous volume and inner limiting membrane thickness between mice and other larger animals (Matsumoto et al., 1984; Puk et al., 2006; Dalkara et al., 2009). Consistent with this, many intravitreal optimization studies are now being done in large animals, including sheep and non-human primates (Ross et al., 2020; Song H. et al., 2020), and overall this field has made significant advancements. While all of the above-mentioned studies were designed to optimize delivery of AAV-based gene therapies to the outer retina, researchers are also experimenting with ways to enhance non-viral gene delivery to the outer retina after intravitreal delivery. For example, various agents, such as chloroquine and hyaluronic acid, have been incorporated into non-viral delivery complexes in order to enhance uptake, but thus far they have met with limited success (Devoldere et al., 2019; Mashal et al., 2019).
Figure 3. Injection sites into the retina and the cochlea. Shown are (A) the three major injection sites for delivery to the retina and (B) the three main injection locations for the cochlea. Images were created with BioRender.com.
More recently, suprachoroidal injection has gained prominence for gene delivery to the outer retina. In this method, material is delivered between the choroid and the sclera (Figure 3A), a region largely accessible only in larger animals. It is further complicated by the need for advanced imaging techniques, such as OCT, to visualize and inject through the use of novel microneedles (Patel et al., 2011; Kim et al., 2014; Yiu et al., 2014; Willoughby et al., 2018). The most notable advantage of this approach is the potential ability to reach the outer retina without performing a disruptive subretinal injection, and many groups are exploring this new avenue. Recently, a phase 3 clinical trial using suprachoroidal injection to deliver triamcinolone for the treatment of uveitis with macular edema reported no serious adverse events related to the treatment and positive efficacy outcomes, paving the way for future clinical use of this delivery method (Yeh et al., 2020). Various groups are testing the use of this method for retinal gene therapy with AAVs in a variety of animal models including rats, pigs, and non-human primates with generally promising results (Touchard et al., 2012; Ding et al., 2019; Yiu et al., 2020). Some groups have also been testing suprachoroidal delivery with non-viral methods, but few full published results are available yet (Kansara et al., 2020). The suprachoroidal approach has great promise for less invasive delivery to the retina, but there are concerns about penetrating through multiple layers of tissue (from the choroid through the RPE into the retina) and about initiating immune responses. One alternative approach that has been shown to induce better retinal transduction with attenuated immune responses in non-human primates is transscleral microneedle-based subretinal delivery (Yiu et al., 2020), which may be another delivery method for further exploration.
Delivery of Genes to the Cochlea
As the cochlea is encased in bone (Figure 1C), the delivery of material to the right location without creating significant damage that may lead to further hearing loss is a major challenge. Largely because of this delivery challenge, the field of cochlear gene therapy has been slower to develop than retinal gene therapy. Yet in the last few years, preclinical studies targeting the cochlea have rapidly increased in number, as tools and methodologies have improved. Modes of delivery for the cochlea involve cochleostomy in the lateral wall of the cochlear basal turn, canalostomy in the semicircular canal or injections through the round window, scala media, or posterior semicircular canal (Figure 3B). Cochleostomy, in which a hole is drilled in the basal cochlea into the endolymphatic space and material is thereby injected directly into the scala media, has been shown to be reasonably efficient in generating AAV-mediated gene expression in the inner ear (Shibata et al., 2009; Yoshimura et al., 2018). However, the procedure has been shown to have higher potential to induce hearing loss than round window membrane injection (Chien et al., 2015; Delmaghani and El-Amraoui, 2020). Round window membrane injections have been successfully used in early postnatal mice (Akil et al., 2012; Askew et al., 2015; Landegger et al., 2017; Pan et al., 2017), and very recent studies have shown this method to be effective in adult non-human primates (Gyorgy et al., 2019; Ivanchenko et al., 2020). Others have shown reporter gene or therapeutic gene expression in the murine inner ear after in utero injection of AAV2 into the otocyst (Miwa et al., 2013; Hu C. J. et al., 2020), potentially important given the very early onset of many forms of congenital deafness. Canalostomy involves injection in the posterior semicircular canal, and has been shown to efficiently transduce inner and outer hair cells after treatment of adult mice and is reported to have less chance of leading to damage (Suzuki et al., 2017). Canalostomy can also be combined with round window membrane injection to further improve inner ear transduction in adult mice (Yoshimura et al., 2018). While much remains to be refined in the area of cochlear gene delivery, recent successes using non-human primate models support an optimistic view for the future of human cochlear gene delivery.
Gene Therapy in the Retina and Cochlea
Preclinical Gene Therapy in the Retina
The earliest proof-of-principle studies for retinal gene therapy took place in the early 1990s and involved gene supplementation via transgenesis in spontaneously occurring IRD models (Lem et al., 1992; Travis et al., 1992). While paving the way for several decades of further development, even these early studies highlighted one of the most challenging, and as yet incompletely resolved, issues in retinal (and cochlear) gene therapy: levels of expression. For both recessive IRD genes as well as autosomal dominant genes associated with haploinsufficiency, generating enough expression to mediate full rescue remains problematic (Ali et al., 2000; Cai et al., 2009). Shortly after these initial transgenesis studies, efforts were made to use adenovirus to transduce the retina (Bennett et al., 1994; Li et al., 1994), but safety concerns and lack of efficiency led to a shift to the use of AAV (Ali et al., 1996). More recently, lentivirus has been used for retinal gene therapy, especially for targeting neovascularization, but lentiviruses have thus far been fairly ineffective at targeting photoreceptors (Kalesnykas et al., 2017; Becker et al., 2018; Holmgaard et al., 2019). In the intervening 25 years, AAV-mediated retinal gene therapy had been used in a vast number of different preclinical IRD models, including those targeting photoreceptors (e.g., Rho, Prph2, Nmnat, Abca4, Cngb3, Rpgr), retinal ganglion cells (e.g., Xiap), Müller cells (e.g., Vegfa, Dp71), bipolar cells, (Cln3), and the RPE, (e.g., Rpe65, Lrat) (Ali et al., 2000; Batten et al., 2005; Mookherjee et al., 2015; Georgiadis et al., 2016; Becker et al., 2018; Zhang et al., 2019; Barboni et al., 2020; Greenwald et al., 2020; Kleine Holthaus et al., 2020; McClements et al., 2020; Wassmer et al., 2020; Figure 1B). Notable successes with these models led to testing in larger animal models, in particularly RPE65 and RPGR dog studies providing further support for the efficacy of AAVs (Bainbridge et al., 2015; Beltran et al., 2015; Gardiner et al., 2020; Song C. et al., 2020).
Much recent work in the field of retinal gene therapy with AAVs has focused on evolving viral capsids to improve transduction efficiency and refine the type of cells that can be targeted. This has been successful in the mouse, where novel engineered viral capsids have been shown to be much more efficient that parent viruses (Dalkara et al., 2013; Khabou et al., 2016; Frederick et al., 2020). Because viral tropsims can also be species specific, recent work on directed evolution of AAV capsids has used the non-human primate model (Byrne et al., 2020). This approach involves injection with libraries generated with cap gene variants, harvesting the retina, performing PCR to enrich cap gene variants present (i.e., that transduced cells) and reformulating virus. This selection process is repeated several times with additional steps included in subsequent rounds to increase diversity in cap genes. The exciting end result was the identification of novel AAV variants capable of efficiently transducing non-human primate cones after intravitreal injection, a key therapeutic goal that had not been achieved previously (Byrne et al., 2020).
While AAV-mediated therapies have been remarkably successful, there have been some concerns. Though largely considered safe, some studies have shown that the AAV vector is able to move from the eye to other areas of the body, from both intravitreal (Dudus et al., 1999; Han et al., 2012) and subretinal injection (Weber et al., 2003). Along with potential systemic distribution and immunogenicity, another challenge with AAV is its loading capacity. Standard AAVs can only accommodate genes which are <5 kbp (Wu et al., 2010), smaller than many IRD genes such as USH2A and ABCA4. There have been advancements in AAVs which increase capacity to 10 kbp, through dual AAV vectors. Dual AAV vectors split the load into two fragments which are then co-delivered and recombine in the target cell though either homologous recombination or trans-splicing strategies (Xu et al., 2004; Ghosh et al., 2011; Trapani et al., 2014). Though initially the efficiency of this approach was limited, additional novel strategies to overcome size limitations are being studied including the use of oversized AAV, trans-splicing dual AAV, overlapping dual AAV, and hybrid dual AAV (reviewed in Trapani, 2019). However, as a result of these potential limitations, for many years there has been interest in the development of non-viral gene delivery methods.
Though many different non-viral formulations have been successfully used to transfect cells, fewer have been successful in vivo. One of the most successful has been polylysine DNA nanoparticles complexed with polyethylene glycol. These nanoparticles are non-immunogenic, and have the capacity to compact up to 20 kbp of DNA (Fink et al., 2006). Importantly, they have demonstrated robust transfection, sustained for up to 15 months, in both photoreceptors and the RPE in the mouse retina (Farjo et al., 2006; Han et al., 2012; Koirala et al., 2013). This translated into improved functional outcomes in Prph2, Rho, Abca4, and Rpe65-associated IRD models (Cai et al., 2009, 2010; Koirala et al., 2013; Han et al., 2014, 2015). Other non-viral retinal gene therapy formulations have also recently been shown to promote improvement in murine IRD models. For example, solid lipid nanoparticles carrying the human RS1 gene have been shown to mediate structural improvement in the mouse Rs1h knockout model of X-linked juvenile retinoschisis (Apaolaza et al., 2015, 2016). Another lipid-based system has also recently shown promising results. The ECO-lipid ((1-aminoethyl) iminobis[N-(oleicylcysteinyl-1-amino-ethyl) propionamide]) based system incorporates a pH sensitive endosomal escape mechanism to help promote release and preservation of DNA after uptake by cells. This system is multifunctional and can be conjugated to other compounds to facilitate targeted cell uptake. It has recently been used to deliver plasmid DNA and mediate improvements in the Rpe65 and Abca4 IRD models (Sun et al., 2017, 2020).
The vast majority of IRD model recue studies have involved gene supplementation to treat loss-of-function or haploinsufficiency-associated mutations. However, many IRD gene mutations are gain-of-function or dominant-negative alleles and for many years researchers have recognized the need for more complex therapies capable of knocking down mutant genes while also supplementing with the correct allele. This approach has been tested in a dog model of adRP; a mutation-independent shRNA targeting rhodopsin was paired with an RNAi-resistant human RHO cDNA (in AAV), and shown to promote long-term protection of retinal structure and function (Cideciyan et al., 2018). Proof-of-principle studies using RNAi-based approaches to knock down mutant transcripts have also been evaluated in mice for the treatment IRD associated with Prph2, Impdh1 (RP10), Guca1a (cone-rod dystrophy), and Pde6b (RP) with varying levels of success (Tam et al., 2008; Tosi et al., 2011; Petrs-Silva et al., 2012; Jiang et al., 2013).
More recently, CRISPR/Cas9 based genome-editing approaches have gained popularity in preclinical studies to correct dominant IRD mutations. These approaches hold great promise for somatic gene editing, and various approaches have been tried. Perhaps the most obvious strategy is correcting IRD mutations using homology directed or micro-homology repair-based approaches. This has been tried in an RPGR model carrying a Cas9 transgene. AAV2/8 was used to deliver an RPGR-targeted gRNA and a region of homologous DNA carrying the corrected sequence (Hu S. et al., 2020). This study reported sequence correction in a large percentage of cells but the benefits were only apparent after ∼6 months, likely due to the overall inefficiency of homology directed repair. In addition, a challenge with homology-based repair approaches is the small carrying capacity of AAV. Designing a construct for delivery of Cas9, a homologous DNA segment for repair, and the gRNA can be challenging. To overcome this challenge, other groups have used two separate AAVs, one carrying the Cas9 and one carrying the gRNA and homologous region. This approach was used to target Rpe65, and reported homology-directed repair efficiencies in excess of 1%. Though this seems low, it was sufficient to mediate functional improvement. Other groups have taken advantage of an alternative repair pathway called micro-homology-mediated end joining, where a much shorter (∼20 bp) homologous region is supplied, and the whole expression cassette (Cas9, gRNAs, and homology region) fit into a single AAV. A study using this approach to target a Gnat1 model reported improvement in light-sensitivity and visual acuity (Nishiguchi et al., 2020). An alternative approach for gain-of-function mutations is to target the mutant allele for knockout rather than correcting the mutation. While genes associated with haploinsufficiency may require concurrent gene supplementation, this approach has the benefit of relying on more efficient non-homologous end joining mechanisms rather than on the less efficient homology-based repair mechanisms. It has been tried with success in both rat and mouse models of rhodopsin-associated IRD (Bakondi et al., 2016; Giannelli et al., 2018; Patrizi et al., 2021). In addition to using CRISPR/Cas9 for gene editing, there are several alternative approaches that utilize a dead (d)Cas9/gRNA to target a transcriptional regulator to the appropriate place in the genome. A recent exciting study used this approach to target the VPR transcriptional activator (dCas9-VPR) to the M-opsin gene (Opn1mw) with an Opn1mw-specific gRNA where it activates gene transcription (Bohm et al., 2020). When dCas9-VPR/Opn1mw-gRNA under the control of the rhodopsin promoter was delivered to the Rho± retina, researchers observed expression of M-opsin in rods, and importantly, improvements in scotopic vision and retinal structure. Genome editing in the mouse retina has also been attempted for Pde6b-associated RP (using electroporation), Cep290-associated LCA (further discussed below), and Gucy2d-associated cone-rod dystrophy (Ruan et al., 2017; McCullough et al., 2019; Vagni et al., 2019). Somatic genome-editing, and non-genome editing CRISPR-based therapeutic strategies are likely to become increasingly prevalent, particularly as tools to block chronic Cas9 activity, suppress immune responses, and increase the efficiency of homology directed repair are developed (reviewed in Nakamura et al., 2021).
The earliest clinical retinal gene therapy trials used AAV2 based vectors to deliver RPE65 for the treatment of LCA (Bainbridge et al., 2008; Cideciyan et al., 2008; Maguire et al., 2008), with groups reporting varying degrees of improvement and persistence of effect. In initial phase I/II clinical trial using the AAV2/2 vector carrying RPE65 cDNA with an RPE65 promotor, investigators observed improved visual function for 3 years (Bainbridge et al., 2008, 2015). Another group using rAAV2 carrying hRPE65 driven by the ubiquitous, chicken β-actin (CBA), promotor found no significant side-effects after 12 months but reported no significant improvement in vision (Hauswirth et al., 2008; Cideciyan et al., 2009). A follow-up done 6 years later saw progressive vision loss, reduced retinal sensitivity, and thinning of the photoreceptor outer nuclear layer (Jacobson et al., 2015). The third initial trial was conducted by Spark Therapeutics Inc. (Philadelphia, PA) using AAV2-hRPE65v2 with a CBA promotor (at three different doses) and reported sustained improvement after 2 years regardless of the dosage, with the greatest improvement in the younger children (Maguire et al., 2008, 2009). A few years later Spark Therapeutics Inc. released its results from a phase 3 clinical trial data using LuxturnaTM (voretigene neparvovec, AAV2-hRPE65v2) in patients with vision loss associated with RPE65. Bilateral subretinal injections of the highest dose tested in the prior trial found improved vision with no adverse effects or immune response after 1 year (Russell et al., 2017). This is the first phase 3 clinical trial to report significant gene therapy efficacy for IRD, and after submission to the FDA, Luxturna was approved for use and is now in clinical practice.
Since then, several other clinical trials for retinal gene therapy have been undertaken (Figure 1B). Recently promising results from a PhaseI/II trial for CNGA3-associated achromatopsia were published showing that the AAV vector was well-tolerated and initial measures of efficacy were promising, including improvement in visual acuity, contrast sensitivity, and cone function [NCT02610582 (Fischer et al., 2020)]. Many other retinal gene therapy clinical trials are currently ongoing or recruiting, targeting RPGR and PDE6B-associated RP, CNGA3 and CNGB3-associated achromatopsia, RPE65-associated LCA, RS1-associated x-linked retinoschisis, and ND4-associated optic neuropathy5. All of these studies utilize an AAV-based delivery method, and thus far non-viral retinal gene therapy has not yet progressed to clinical testing. Excitingly, the first retinal gene therapy trial to use CRISPR/Cas9-based genome editing has recently started recruiting (NCT03872479). The trial, which targets CEP290-associated LCA is not only a milestone in retinal gene therapy, but also represents the first time CRISPR-based treatments will be delivered directly into the body in any trial, and results are eagerly anticipated. This study uses an AAV5 vector to deliver Cas9 and CEP290 specific gRNAs and was effective in both a humanized CEP290 mouse model and in a non-human primate model (Fischer et al., 2020).
Cochlear Gene Therapy
As in the retina, the earliest cochlear gene therapy took the form of proof-of-principle studies utilizing transgenic overexpression to rescue hearing in mutant models with hearing loss (Fujiyoshi et al., 1994; Ahmad et al., 2007). By the late 1990s, researchers were exploring ways to deliver AAVs and adenoviruses to the middle and inner ear often using the guinea pig model described above (Lalwani et al., 1996, 1998; Mondain et al., 1998). Subsequently, an extensive number of functional studies were undertaken to genetically deliver antioxidants or neurotrophic factors to the ear for the treatment or prevention of noise- and pharmaceutical-induced auditory toxicity, rather than for inherited cochlear diseases (e.g., Bowers et al., 2002; Lalwani et al., 2002a; Kawamoto et al., 2003b, 2004; Liu et al., 2008). However, neither of these approaches targets or corrects the underlying genetic defect in the case of inherited forms of hearing loss. Excitingly, in 2012 a model of congenital deafness was rescued by delivery of a gene therapy vector. This landmark study used an AAV1 vector delivered by either round window membrane injection or cochleostomy to generate Vglut3 expression in a Vglut3 knockout mouse model of hereditary deafness. This study demonstrated almost complete rescue of ABR recordings for over one year (69 weeks was the longest time evaluated) after delivery at P10-12 (Akil et al., 2012). Subsequently, antisense oligonucleotides were used to correct splicing in an Usher syndrome mouse model (Ush1c) leading to functional improvements in low-frequency hearing (Lentz et al., 2013; Ponnath et al., 2018; Wang et al., 2020). Since then, some AAV-mediated functional and/or structural rescue has been reported in multiple inherited models of deafness, including those associated with mutations in the gap junction gene connexin 26, the potassium channel subunit Kcnq1, the stereocilia gene whirlin, the antioxidant gene Msr3b, the usher 1C gene harmonin, the usher 3 gene clarin, the gene Slc26a4, and the ion channel Tmc1, among others (Yu et al., 2014; Chang et al., 2015; Iizuka et al., 2015; Chien et al., 2016; Kim et al., 2016; Pan et al., 2017; Dulon et al., 2018; Nist-Lund et al., 2019; Lan et al., 2020; Figure 1D).
Delivery of therapeutics to neonatal mice allows for therapeutic intervention before the organ of Corti develops fully, thus allowing for administration before early postnatal degeneration has begun, and this approach has been taken by several groups (Landegger et al., 2017; Pan et al., 2017). For example, AAV-mediated expression of Ush1g, a submembrane scaffold protein necessary for morphogenesis of the sensory stereocilia in cochlear hair cells, was delivered into Sans null mutant (Ush1g–/–) mice at P2.5 and found to preserve hair cell function near wild-type levels (Emptoz et al., 2017). Critically, studies such as this one demonstrate that cochlear AAV-mediated gene delivery can generate protein that folds, transports, and functions properly, and that early delivery prior to full development can prevent hair cell degeneration.
Delivering AAV to older/adult mice (compared to neonates) results in a drop in efficiency and duration of expression. For example, AAV-mediated delivery of Vglut3 led to better and longer lasting recovery after neonatal delivery (P1-3) than later delivery (P10) (Akil et al., 2012), although good results were reported for P10-12 delivery as well. A more recent investigation using a modified AAV2 vector to deliver harmonin at either P0-1 or P10-12 found improvement in the function and structure of the P0-1 treated mice with no treatment effects in those treated at P10-12 (Pan et al., 2017). However, other recent studies have achieved good gene expression in hair cells without damaging the organ of Corti after delivery in adult animals, with delivery at either 6 or 10 weeks of age (Suzuki et al., 2017; Tao et al., 2018; Yoshimura et al., 2018). Although gene expression was lower in most cases than with neonatal delivery, it is encouraging that post-development delivery for cochlear therapy is becoming more effective.
As in the retina, there has been great interest in designing optimized AAVs for cochlear delivery. This includes several new synthetic AAVs such as Anc80L65, which has shown very high efficiency in transducing both inner and outer hair cells after injections at 7 weeks of age through the posterior semicircular canal (Suzuki et al., 2017; Hu C. J. et al., 2020). As in the retina, the limited capacity of AAV (<5 kbp) is a significant limitation. This is particularly problematic since many cochlear disease genes, such as those associated with Usher syndrome, are too large to be delivered by AAV. As a result, the dual-AAV strategy, in which one AAV carried the 5′ end of the gene (in this case the congenital deafness gene otoferlin), while the second AAV carried the 3′ end has also been evaluated in the cochlea. Although this requires recombination of the two cDNAs after delivery, researchers reported stable otoferlin gene expression and improvement in hearing after dual-AAV delivery, suggesting it may be a useful therapeutic approach (Akil et al., 2019).
A number of non-viral gene therapy strategies have also been tested in the cochlea. One of the earliest was a study in which cationic liposomes were microinjected into the guinea pig cochlea, and short-term reporter gene expression was observed in the organ of Corti (Wareing et al., 1999). Lipid core nanocapsules have been evaluated for their ability to penetrate through the round window membrane for subsequent material delivery (Zou et al., 2008). Polyethyleneimine (PEI)/DNA complexes and quaternized chitosan coupled Na-carboxymethyl-beta-cyclodextrin complexes have also been tested for their ability to generate reporter gene expression, but overall transfection efficiency still has room for improvement (Tan et al., 2008; Ren et al., 2010).
CRISPR/Cas9 and somatic genome editing strategies have also begun to be applied to the cochlea. One major potential benefit of this approach is that if the endogenous gene error can be corrected in enough cells, the challenge of generating sufficient levels of expression from an exogenous transgene is circumvented. While some groups are working on optimizing individual steps in the path to effective in vivo cochlear genome editing (Tang et al., 2016; Kang et al., 2020; Zhao et al., 2020), other groups have directly applied genome editing technology to models of inherited deafness. Gao et al. used cochleostomy to deliver a cationic liposome formulation containing a Cas9-gRNA ribonucleoprotein (RNP) complex targeting a mutant Tmc1 allele to the scala media at P0-2. They reported improved preservation of hair cells at 8 weeks post-injection and improved ABR thresholds at 4 weeks post-injection compared to uninjected controls (Gao et al., 2018). These exciting preliminary studies demonstrate the potential for future application to somatic genome editing for cochlear diseases.
In spite of rapid advancements in preclinical testing of cochlear gene therapies since 2012, this strategy has not made the jump to widespread clinical testing. Only one gene therapy Phase I/II safety and tolerability clinical trial for severe hearing loss has been completed (NCT02132130). The study involved intralabyrinthine delivery of recombinant adenovirus carrying the Hath1/Atoh1 transcription factor (Figure 1D). This transcription factor has been widely evaluated in preclinical studies to promote hair cell regeneration, however few data are available about the trial and its findings have not yet been reported, although as of September 2020, the study is listed as “completed” and results are eagerly awaited (Crowson et al., 2017).
Role of Time of Delivery and Duration of Effect on the Outcomes
While progress is being made for both retinal and cochlear gene therapy, it is necessary to remember one of the key limiting factors of gene therapy for inherited dystrophies: time. Due to the nature of degenerative hereditary diseases, unless intervention is applied early, the optimal therapeutic window will be missed. In many cases patients may not even know they have a genetic disorder until symptoms are severe enough to see their physician, at which point, the progression of the disease is often far enough along that affected cells are dead or dying. This is particularly challenging in the case of degenerations that affect neuronal cells, since there is, as yet, no effective way to regenerate or replace lost neurons (although this is a goal of the stem cell transplantation field). To a certain degree, this is an area where cochlear gene therapy is ahead of retinal gene therapy. There have been extensive preclinical studies focused on regeneration of hair cells in deafened mice (largely in non-genetic models) by delivery of the transcription factor Math1 (also known as Hath1/Atoh1) (Kawamoto et al., 2003a; Shou et al., 2003; Baker et al., 2009; Kraft et al., 2013), and several of these studies have produced promising results. However, while cochlear regeneration of hair cells may be more within reach than photoreceptor regeneration, the earlier onset of many forms of congenital deafness (compared to inherited irreversible vision loss) counteracts some of this benefit. In studies with mice, this issue can be partially overcome by the fact that the sensory organs of the eye and ear are not fully developed at birth, and thus therapy can be administered very early in the course of the pathology. However, this advantage is lost in the transition to human patients. Individuals with an early developmental disorder would need to have therapy administered while still in the womb, which introduces additional challenges to the already complex nature of cochlear gene delivery. Regardless of the time-of-onset, early detection and intervention in patients is key to effective treatment. Clinical support for this idea comes from early reports from the LCA retinal gene therapy trials. RPE65-associated LCA is an early onset disease (in contrast to many inherited retinal diseases), and in the initial phase 1 clinical trial the greatest improvement was observed in the younger children (Maguire et al., 2008, 2009). The need for intervention early in the disease process also highlights the need for treatments and delivery strategies that do not themselves result in vision or hearing loss. Both subretinal injection and cochlear delivery methods have the potential to impair function (Wang et al., 2013), so optimizing delivery approaches should remain a key research goal.
In addition to delivery at the appropriate time in the course of the disease pathology, an additional concern is the potential need for repeat dosing. The ideal gene therapy would be effective long-term after delivery of a single dose. However, generating and maintaining sufficient levels of gene expression remains a challenge. Improving duration of expression at levels high enough to maintain functional rescue is essential (Adijanto and Naash, 2015; Hardee et al., 2017; Goswami et al., 2019; Patil et al., 2019; Wang et al., 2019).
In the case of the retina, the current measures of therapeutic longevity come from the early LCA trials, where results have been variable. Some groups reported functional visual improvement up to 3 years despite cell degeneration still taking place (Cideciyan et al., 2013; Testa et al., 2013), while other groups reported that the improvement in vision diminished in patients after 3 years (Bainbridge et al., 2015; Jacobson et al., 2015). In other cases, it has been reported that the beneficial effects are more durable, persisting at the 4 year follow-up (Maguire et al., 2019) however, different trials have used different outcome measures to assess improvement. The mechanism underlying limited duration of effects is unclear, however it has been suggested that the virally-expressed RPE65 levels declined over time to below the levels necessary to remain therapeutically relevant (Bainbridge et al., 2015). It is also possible that loss of non-transduced RPE cells led to such severe stress in the retina that the transduced RPE cells were insufficient to prevent the eventual photoreceptor degeneration. Clearly, these findings highlight both the promise and vast room for continued technical and scientific advancement needed for clinical application of retinal and cochlear gene therapy.
Both the eye and cochlea are organs which have favorable anatomy for gene therapy with small sizes that can be easily treated with small doses of therapeutics, a contralateral control and easy non-invasive analytical techniques. They are also sites of many different forms of inherited hearing loss and irreversible vision loss caused by several hundred known genes, and thus they are prime targets for novel therapies. The monogenic nature of most inherited diseases of the eye and ear make gene therapy an attractive method to potentially correct causative genetic defects and cure disease, rather than just treating symptoms. There are various limitations and challenges still to face including (1) the limited number of patients carrying any given mutation, although allele-independent approaches are being developed, (2) limited carrying capacity of common viral-delivery methods, (3) the rapid progression of degeneration in some pathologies, (4) limited distribution and longevity of gene expression after single-dose treatments, (5) difficulty transfecting/transducing post-mitotic cells, and (6) the need for delivery methods that are less invasive. Yet all these areas are being actively studied, and outcomes with genetic therapies are likely to keep improving. Another area that has seen rapid progress in the last decade is genetic diagnosis. The accessibility and accuracy of genetic testing in the past few years has improved drastically (Shearer et al., 2011; Lin et al., 2012; Furutani and Shimamura, 2017; Men et al., 2017; Furutani et al., 2019). As genetic testing and screening improve, the ability to identify causative pathogenic alleles and potential at-risk individuals increases. Earlier screening and diagnosis are essential to earlier intervention.
The commonalities between the eye and the ear, coupled with the numerous syndromic genetic disorders with both an auditory and visual component mean that coordination between the fields is likely to be beneficial. Collaboration and resource sharing between groups studying both the retina and the cochlea may help advance the development of clinically relevant therapies for both vision and hearing loss, and lead to significantly improved quality of life in patients.
RC wrote initial draft and created the figures. SMC, MRA, and MIN were editors of final draft. All authors contributed to the article and approved the submitted version.
This study was supported by the grants from the National Institutes of Health (R01 EY018656, R01 EY10609, and R01 EY026499 to MIN and MRA and P20 GM125528 to SMC).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- ^ https://www.who.int/en/news-room/fact-sheets/detail/blindness-and-visual-impairment
- ^ https://www.who.int/en/news-room/fact-sheets/detail/deafness-and-hearing-loss
- ^ https://www.cdc.gov/visionhealth/basics/ced/index.html
- ^ https://hereditaryhearingloss.org/
- ^ https://clinicaltrials.gov/
Ahmad, S., Tang, W., Chang, Q., Qu, Y., Hibshman, J., Li, Y., et al. (2007). Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness. Proc. Natl. Acad. Sci. U.S.A. 104, 1337–1341. doi: 10.1073/pnas.0606855104
Akil, O., Dyka, F., Calvet, C., Emptoz, A., Lahlou, G., Nouaille, S., et al. (2019). Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proc. Natl. Acad. Sci. U.S.A. 116, 4496–4501. doi: 10.1073/pnas.1817537116
Akil, O., Seal, R. P., Burke, K., Wang, C., Alemi, A., During, M., et al. (2012). Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron 75, 283–293. doi: 10.1016/j.neuron.2012.05.019
Al-Rawy, A. S., al-Shatouri, M., El Tabbakh, M., and Gad, A. A. (2017). Systematic approach by computed tomography and magnetic resonance imaging in cochlear implantation candidates in Suez Canal University Hospital. Egypt. J. Radiol. Nucl. Med. 48, 877–884. doi: 10.1016/j.ejrnm.2017.08.005
Ali, R. R., Reichel, M. B., Thrasher, A. J., Levinsky, R. J., Kinnon, C., Kanuga, N., et al. (1996). Gene transfer into the mouse retina mediated by an adeno-associated viral vector. Hum. Mol. Genet. 5, 591–594. doi: 10.1093/hmg/5.5.591
Ali, R. R., Sarra, G. M., Stephens, C., Alwis, M. D., Bainbridge, J. W., Munro, P. M., et al. (2000). Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat. Genet. 25, 306–310. doi: 10.1038/77068
Apaolaza, P. S., Del Pozo-Rodriguez, A., Solinis, M. A., Rodriguez, J. M., Friedrich, U., Torrecilla, J., et al. (2016). Structural recovery of the retina in a retinoschisin-deficient mouse after gene replacement therapy by solid lipid nanoparticles. Biomaterials 90, 40–49. doi: 10.1016/j.biomaterials.2016.03.004
Apaolaza, P. S., Del Pozo-Rodriguez, A., Torrecilla, J., Rodriguez-Gascon, A., Rodriguez, J. M., Friedrich, U., et al. (2015). Solid lipid nanoparticle-based vectors intended for the treatment of X-linked juvenile retinoschisis by gene therapy: in vivo approaches in Rs1h-deficient mouse model. J. Control Release 217, 273–283. doi: 10.1016/j.jconrel.2015.09.033
Askew, C., Rochat, C., Pan, B., Asai, Y., Ahmed, H., Child, E., et al. (2015). Tmc gene therapy restores auditory function in deaf mice. Sci. Transl. Med. 7:295ra108. doi: 10.1126/scitranslmed.aab1996
Bainbridge, J. W. B., Mehat, M. S., Sundaram, V., Robbie, S. J., Barker, S. E., Ripamonti, C., et al. (2015). Long-term effect of gene therapy on Leber’s congenital amaurosis. N. Engl. J. Med. 372, 1887–1897. doi: 10.1056/NEJMoa1414221
Bainbridge, J. W. B., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., et al. (2008). Effect of gene therapy on visual function in Leber’s congenital amaurosis. N. Engl. J. Med. 358, 2231–2239. doi: 10.1056/NEJMoa0802268
Baker, K., Brough, D. E., and Staecker, H. (2009). Repair of the vestibular system via adenovector delivery of Atoh1: a potential treatment for balance disorders. Adv. Otorhinolaryngol. 66, 52–63. doi: 10.1159/000218207
Bakondi, B., Lv, W., Lu, B., Jones, M. K., Tsai, Y., Kim, K. J., et al. (2016). In vivo CRISPR/Cas9 gene editing corrects retinal dystrophy in the S334ter-3 rat model of autosomal dominant retinitis pigmentosa. Mol. Ther. 24, 556–563. doi: 10.1038/mt.2015.220
Barboni, M. T. S., Vaillend, C., Joachimsthaler, A., Liber, A. M. P., Khabou, H., Roux, M. J., et al. (2020). Rescue of defective electroretinographic responses in Dp71-null mice with AAV-mediated reexpression of Dp71. Invest. Ophthalmol. Vis. Sci. 61:11. doi: 10.1167/iovs.61.2.11
Batten, M. L., Imanishi, Y., Tu, D. C., Doan, T., Zhu, L., Pang, J., et al. (2005). Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital amaurosis. PLoS Med. 2:e333. doi: 10.1371/journal.pmed.0020333
Becker, S., Wang, H., Simmons, A. B., Suwanmanee, T., Stoddard, G. J., Kafri, T., et al. (2018). Targeted knockdown of overexpressed VEGFA or VEGF164 in muller cells maintains retinal function by triggering different signaling mechanisms. Sci. Rep. 8:2003. doi: 10.1038/s41598-018-20278-4
Beltran, W. A., Cideciyan, A. V., Iwabe, S., Swider, M., Kosyk, M. S., McDaid, K., et al. (2015). Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease. Proc. Natl. Acad. Sci. U.S.A. 112, E5844–E5853. doi: 10.1073/pnas.1509914112
Bohm, S., Splith, V., Riedmayr, L. M., Rotzer, R. D., Gasparoni, G., Nordstrom, K. J. V., et al. (2020). A gene therapy for inherited blindness using dCas9-VPR-mediated transcriptional activation. Sci. Adv. 6:eaba5614. doi: 10.1126/sciadv.aba5614
Bowers, W. J., Chen, X., Guo, H., Frisina, D. R., Federoff, H. J., and Frisina, R. D. (2002). Neurotrophin-3 transduction attenuates cisplatin spiral ganglion neuron ototoxicity in the cochlea. Mol. Ther. 6, 12–18. doi: 10.1006/mthe.2002.0627
Boyd, R. F., Sledge, D. G., Boye, S. L., Boye, S. E., Hauswirth, W. W., Komaromy, A. M., et al. (2016). Photoreceptor-targeted gene delivery using intravitreally administered AAV vectors in dogs. Gene Ther. 23, 223–230. doi: 10.1038/gt.2015.96
Byrne, L. C., Day, T. P., Visel, M., Strazzeri, J. A., Fortuny, C., Dalkara, D., et al. (2020). In vivo-directed evolution of adeno-associated virus in the primate retina. JCI Insight 5:e135112. doi: 10.1172/jci.insight.135112
Cai, X., Conley, S. M., Nash, Z., Fliesler, S. J., Cooper, M. J., and Naash, M. I. (2010). Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa. FASEB J. 24, 1178–1191. doi: 10.1096/fj.09-139147
Cai, X., Nash, Z., Conley, S. M., Fliesler, S. J., Cooper, M. J., and Naash, M. I. (2009). A partial structural and functional rescue of a retinitis pigmentosa model with compacted DNA nanoparticles. PLoS One 4:e5290. doi: 10.1371/journal.pone.0005290
Cehajic-Kapetanovic, J., Le Goff, M. M., Allen, A., Lucas, R. J., and Bishop, P. N. (2011). Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. Mol. Vis. 17, 1771–1783.
Chakraborty, D., Strayve, D. G., Makia, M. S., Conley, S. M., Kakahel, M., Al-Ubaidi, M. R., et al. (2020). Novel molecular mechanisms for Prph2-associated pattern dystrophy. FASEB J. 34, 1211–1230. doi: 10.1096/fj.201901888R
Chang, Q., Wang, J., Li, Q., Kim, Y., Zhou, B., Wang, Y., et al. (2015). Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome. EMBO Mol. Med. 7, 1077–1086. doi: 10.15252/emmm.201404929
Charizopoulou, N., Lelli, A., Schraders, M., Ray, K., Hildebrand, M. S., Ramesh, A., et al. (2011). Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat. Commun. 2:201. doi: 10.1038/ncomms1200
Chen, H., Xing, Y., Xia, L., Chen, Z., Yin, S., and Wang, J. (2018). AAV-mediated NT-3 overexpression protects cochleae against noise-induced synaptopathy. Gene Ther. 25, 251–259. doi: 10.1038/s41434-018-0012-0
Chien, W. W., Isgrig, K., Roy, S., Belyantseva, I. A., Drummond, M. C., May, L. A., et al. (2016). Gene therapy restores hair cell stereocilia morphology in inner ears of deaf Whirler mice. Mol. Ther. 24, 17–25. doi: 10.1038/mt.2015.150
Chien, W. W., McDougald, D. S., Roy, S., Fitzgerald, T. S., and Cunningham, L. L. (2015). Cochlear gene transfer mediated by adeno-associated virus: comparison of two surgical approaches. Laryngoscope 125, 2557–2564. doi: 10.1002/lary.25317
Cideciyan, A. V., Aleman, T. S., Boye, S. L., Schwartz, S. B., Kaushal, S., Roman, A. J., et al. (2008). Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc. Natl. Acad. Sci. U.S.A. 105, 15112–15117. doi: 10.1073/pnas.0807027105
Cideciyan, A. V., Hauswirth, W. W., Aleman, T. S., Kaushal, S., Schwartz, S. B., Boye, S. L., et al. (2009). Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum. Gene Ther. 20, 999–1004. doi: 10.1089/hum.2009.086
Cideciyan, A. V., Jacobson, S. G., Beltran, W. A., Sumaroka, A., Swider, M., Iwabe, S., et al. (2013). Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc. Natl. Acad. Sci. U.S.A. 110, E517–E525. doi: 10.1073/pnas.1218933110
Cideciyan, A. V., Sudharsan, R., Dufour, V. L., Massengill, M. T., Iwabe, S., Swider, M., et al. (2018). Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector. Proc. Natl. Acad. Sci. U.S.A. 115, E8547–E8556. doi: 10.1073/pnas.1805055115
Colavito, D., Maritan, V., Suppiej, A., Del Giudice, E., Mazzarolo, M., Miotto, S., et al. (2017). Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene. Biomed. Rep. 7, 451–454. doi: 10.3892/br.2017.987
Dai, C. K., Lehar, M., Sun, D. Q., Swarthout, L., Carey, J. P., MacLachlan, T., et al. (2017). Rhesus cochlear and vestibular functions are preserved after inner ear injection of saline volume sufficient for gene therapy delivery. Jaro J. Assoc. Res. Otolaryngol. 18, 601–617. doi: 10.1007/s10162-017-0628-6
Dalkara, D., Byrne, L. C., Klimczak, R. R., Visel, M., Yin, L., Merigan, W. H., et al. (2013). In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci. Transl. Med. 5:189ra76. doi: 10.1126/scitranslmed.3005708
Dalkara, D., Kolstad, K. D., Caporale, N., Visel, M., Klimczak, R. R., Schaffer, D. V., et al. (2009). Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous. Mol. Ther. 17, 2096–2102. doi: 10.1038/mt.2009.181
DeMason, C., Choudhury, B., Ahmad, F., Fitzpatrick, D. C., Wang, J., Buchman, C. A., et al. (2012). Electrophysiological properties of cochlear implantation in the gerbil using a flexible array. Ear Hear. 33, 534–542. doi: 10.1097/AUD.0b013e3182498c28
Devoldere, J., Wels, M., Peynshaert, K., Dewitte, H., De Smedt, S. C., and Remaut, K. (2019). The obstacle course to the inner retina: hyaluronic acid-coated lipoplexes cross the vitreous but fail to overcome the inner limiting membrane. Eur. J. Pharm. Biopharm. 141, 161–171. doi: 10.1016/j.ejpb.2019.05.023
Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., et al. (2010). Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat. Genet. 42, 313–321. doi: 10.1038/ng.544
Dias, M. S., Araujo, V. G., Vasconcelos, T., Li, Q., Hauswirth, W. W., Linden, R., et al. (2019). Retina transduction by rAAV2 after intravitreal injection: comparison between mouse and rat. Gene Ther. 26, 479–490. doi: 10.1038/s41434-019-0100-9
Ding, K., Shen, J., Hafiz, Z., Hackett, S. F., Silva, R. L. E., Khan, M., et al. (2019). AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression. J. Clin. Invest. 129, 4901–4911. doi: 10.1172/JCI129085
Dudus, L., Anand, V., Acland, G. M., Chen, S. J., Wilson, J. M., Fisher, K. J., et al. (1999). Persistent transgene product in retina, optic nerve and brain after intraocular injection of rAAV. Vis. Res. 39, 2545–2553. doi: 10.1016/s0042-6989(98)00308-3
Dulon, D., Papal, S., Patni, P., Cortese, M., Vincent, P. F., Tertrais, M., et al. (2018). Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome. J. Clin. Invest. 128, 3382–3401. doi: 10.1172/JCI94351
Emptoz, A., Michel, V., Lelli, A., Akil, O., de Monvel, J. B., Lahlou, G., et al. (2017). Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G. Proc. Natl. Acad. Sci. U.S.A. 114, 9695–9700. doi: 10.1073/pnas.1708894114
Farjo, R., Skaggs, J., Quiambao, A. B., Cooper, M. J., and Naash, M. I. (2006). Efficient non-viral ocular gene transfer with compacted DNA nanoparticles. PLoS One 1:e38. doi: 10.1371/journal.pone.0000038
Ferrari, S., Di Iorio, E., Barbaro, V., Ponzin, D., Sorrentino, F. S., and Parmeggiani, F. (2011). Retinitis pigmentosa: genes and disease mechanisms. Curr. Genomics 12, 238–249. doi: 10.2174/138920211795860107
Fink, T. L., Klepcyk, P. J., Oette, S. M., Gedeon, C. R., Hyatt, S. L., Kowalczyk, T. H., et al. (2006). Plasmid size up to 20 kbp does not limit effective in vivo lung gene transfer using compacted DNA nanoparticles. Gene Ther. 13, 1048–1051. doi: 10.1038/sj.gt.3302761
Fischer, M. D., Michalakis, S., Wilhelm, B., Zobor, D., Muehlfriedel, R., Kohl, S., et al. (2020). Safety and vision outcomes of subretinal gene therapy targeting cone photoreceptors in achromatopsia: a nonrandomized controlled trial. Jama Ophthalmol. 138, 643–651. doi: 10.1001/jamaophthalmol.2020.1032
Frederick, A., Sullivan, J., Liu, L., Adamowicz, M., Lukason, M., Raymer, J., et al. (2020). Engineered capsids for efficient gene delivery to the retina and cornea. Hum. Gene Ther. 31, 756–774. doi: 10.1089/hum.2020.070
Fujiyoshi, T., Hood, L., and Yoo, T. J. (1994). Restoration of brain stem auditory-evoked potentials by gene transfer in shiverer mice. Ann. Otolrhinollaryngol. 103, 449–456. doi: 10.1177/000348949410300606
Fukui, T., Yamamoto, S., Nakano, K., Tsujikawa, M., Morimura, H., Nishida, K., et al. (2002). ABCA4 gene mutations in Japanese patients with Stargardt disease and retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 43, 2819–2824.
Gao, X., Tao, Y., Lamas, V., Huang, M., Yeh, W. H., Pan, B., et al. (2018). Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature 553, 217–221. doi: 10.1038/nature25164
Gardiner, K. L., Cideciyan, A. V., Swider, M., Dufour, V. L., Sumaroka, A., Komaromy, A. M., et al. (2020). Long-term structural outcomes of late-stage RPE65 gene therapy. Mol. Ther. 28, 266–278. doi: 10.1016/j.ymthe.2019.08.013
Genc, A. M., Makia, M. S., Sinha, T., Conley, S. M., Al-Ubaidi, M. R., and Naash, M. I. (2020). Elimination of a retinal riboflavin binding protein exacerbates degeneration in a model of cone-rod dystrophy. Invest. Ophthalmol. Vis. Sci. 61:17. doi: 10.1167/iovs.61.6.17
Georgiadis, A., Duran, Y., Ribeiro, J., Abelleira-Hervas, L., Robbie, S. J., Sunkel-Laing, B., et al. (2016). Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65. Gene Ther. 23, 857–862. doi: 10.1038/gt.2016.66
Ghosh, A., Yue, Y. P., and Duan, D. S. (2011). Efficient transgene reconstitution with hybrid dual AAV vectors carrying the minimized bridging sequences. Hum. Gene Ther. 22, 77–83. doi: 10.1089/hum.2010.122
Giannelli, S. G., Luoni, M., Castoldi, V., Massimino, L., Cabassi, T., Angeloni, D., et al. (2018). Cas9/sgRNA selective targeting of the P23H Rhodopsin mutant allele for treating retinitis pigmentosa by intravitreal AAV9.PHP.B-based delivery. Hum. Mol. Genet. 27, 761–779. doi: 10.1093/hmg/ddx438
Greenwald, S. H., Brown, E. E., Scandura, M. J., Hennessey, E., Farmer, R., Pawlyk, B. S., et al. (2020). Gene therapy preserves retinal structure and function in a mouse model of NMNAT1-associated retinal degeneration. Mol. Ther. Methods Clin. Dev. 18, 582–594. doi: 10.1016/j.omtm.2020.07.003
Gyorgy, B., Meijer, E. J., Ivanchenko, M. V., Tenneson, K., Emond, F., Hanlon, K. S., et al. (2019). Gene transfer with AAV9-PHP.B rescues hearing in a mouse model of usher syndrome 3A and transduces hair cells in a non-human primate. Mol. Ther. Methods Clin. Dev. 13, 1–13. doi: 10.1016/j.omtm.2018.11.003
Haddad, S., Chen, C. A., Santangelo, S. L., and Seddon, J. M. (2006). The genetics of age-related macular degeneration: a review of progress to date. Surv. Ophthalmol. 51, 316–363. doi: 10.1016/j.survophthal.2006.05.001
Han, Z., Banworth, M. J., Makkia, R., Conley, S. M., Al-Ubaidi, M. R., Cooper, M. J., et al. (2015). Genomic DNA nanoparticles rescue rhodopsin-associated retinitis pigmentosa phenotype. FASEB J. 29, 2535–2544. doi: 10.1096/fj.15-270363
Han, Z., Conley, S. M., Makkia, R., Guo, J., Cooper, M. J., and Naash, M. I. (2012). Comparative analysis of DNA nanoparticles and AAVs for ocular gene delivery. PLoS One 7:e52189. doi: 10.1371/journal.pone.0052189
Hanany, M., Rivolta, C., and Sharon, D. (2020). Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases. Proc. Natl. Acad. Sci. U.S.A. 117, 2710–2716. doi: 10.1073/pnas.1913179117
Hauswirth, W. W., Aleman, T. S., Kaushal, S., Cideciyan, A. V., Schwartz, S. B., Wang, L. L., et al. (2008). Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a Phase I Trial. Hum. Gene Ther. 19, 979–990. doi: 10.1089/hum.2008.107
Heimer, G., Gregited byory, A., Hogarth, P., Hayflick, S., Ben Zeev, B., Stephens, K., et al. (1993). “MECR-Related Neurologic Disorder,” in GeneReviews((R)), eds M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, and L. J. H. Bean (Seattle, WA: University of Washington).
Holmgaard, A., Alsing, S., Askou, A. L., and Corydon, T. J. (2019). CRISPR gene therapy of the eye: targeted knockout of vegfa in mouse retina by lentiviral delivery. Methods Mol. Biol. 1961, 307–328. doi: 10.1007/978-1-4939-9170-9_19
Hu, C. J., Lu, Y. C., Tsai, Y. H., Cheng, H. Y., Takeda, H., Huang, C. Y., et al. (2020). Efficient in utero gene transfer to the mammalian inner ears by the synthetic adeno-associated viral vector Anc80L65. Mol. Ther. Methods Clin. Dev. 18, 493–500. doi: 10.1016/j.omtm.2020.06.019
Hu, S., Du, J., Chen, N., Jia, R., Zhang, J., Liu, X., et al. (2020). In Vivo CRISPR/Cas9-mediated genome editing mitigates photoreceptor degeneration in a mouse model of X-Linked retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 61:31. doi: 10.1167/iovs.61.4.31
Iizuka, T., Kamiya, K., Gotoh, S., Sugitani, Y., Suzuki, M., Noda, T., et al. (2015). Perinatal Gjb2 gene transfer rescues hearing in a mouse model of hereditary deafness. Hum. Mol. Genet. 24, 3651–3661. doi: 10.1093/hmg/ddv109
Ivanchenko, M. V., Hanlon, K. S., Devine, M. K., Tenneson, K., Emond, F., Lafond, J. F., et al. (2020). Preclinical testing of AAV9-PHP.B for transgene expression in the non-human primate cochlea. Hear. Res. 394:107930. doi: 10.1016/j.heares.2020.107930
Jacobson, S. G., Cideciyan, A. V., Roman, A. J., Sumaroka, A., Schwartz, S. B., Heon, E., et al. (2015). Improvement and decline in vision with gene therapy in childhood blindness. N. Engl. J. Med. 372, 1920–1926. doi: 10.1056/NEJMoa1412965
Jiang, L., Li, T. Z., Boye, S. E., Hauswirth, W. W., Frederick, J. M., and Baehr, W. (2013). RNAi-mediated gene suppression in a GCAP1(L151F) cone-rod dystrophy mouse model. PLoS One 8:e57676. doi: 10.1371/journal.pone.0057676
Kalesnykas, G., Kokki, E., Alasaarela, L., Lesch, H. P., Tuulos, T., Kinnunen, K., et al. (2017). Comparative study of adeno-associated virus, adenovirus, bacu lovirus and lentivirus vectors for gene therapy of the eyes. Curr. Gene Ther. 17, 235–247. doi: 10.2174/1566523217666171003170348
Kang, W., Zhao, X., Sun, Z., Dong, T., Jin, C., Tong, L., et al. (2020). Adeno-associated virus vector enables safe and efficient Cas9 activation in neonatal and adult Cas9 knockin murine cochleae. Gene Ther. 27, 392–405. doi: 10.1038/s41434-020-0124-1
Kansara, V., Muya, L., Wan, C. R., and Ciulla, T. A. (2020). Suprachoroidal delivery of viral and nonviral gene therapy for retinal diseases. J. Ocul. Pharmacol. Ther. 36, 384–392. doi: 10.1089/jop.2019.0126
Kawamoto, K., Sha, S. H., Minoda, R., Izumikawa, M., Kuriyama, H., Schacht, J., et al. (2004). Antioxidant gene therapy can protect hearing and hair cells from ototoxicity. Mol. Ther. 9, 173–181. doi: 10.1016/j.ymthe.2003.11.020
Kawamoto, K., Yagi, M., Stover, T., Kanzaki, S., and Raphael, Y. (2003b). Hearing and hair cells are protected by adenoviral gene therapy with TGF-beta1 and GDNF. Mol. Ther. 7, 484–492. doi: 10.1016/s1525-0016(03)00058-3
Kelley, R. A., Conley, S. M., Makkia, R., Watson, J. N., Han, Z., Cooper, M. J., et al. (2018). DNA nanoparticles are safe and nontoxic in non-human primate eyes. Int. J. Nanomed. 13, 1361–1379. doi: 10.2147/IJN.S157000
Khabou, H., Desrosiers, M., Winckler, C., Fouquet, S., Auregan, G., Bemelmans, A. P., et al. (2016). Insight into the mechanisms of enhanced retinal transduction by the engineered AAV2 capsid variant -7m8. Biotechnol. Bioeng. 113, 2712–2724. doi: 10.1002/bit.26031
Kim, M. A., Cho, H. J., Bae, S. H., Lee, B., Oh, S. K., Kwon, T. J., et al. (2016). Methionine sulfoxide reductase B3-targeted in utero gene therapy rescues hearing function in a mouse model of congenital sensorineural hearing loss. Antioxid. Redox Signal. 24, 590–602. doi: 10.1089/ars.2015.6442
Kim, Y. C., Edelhauser, H. F., and Prausnitz, M. R. (2014). Targeted delivery of antiglaucoma drugs to the supraciliary space using microneedles. Invest. Ophthalmol. Vis. Sci. 55, 7387–7397. doi: 10.1167/iovs.14-14651
Kleine Holthaus, S. M., Aristorena, M., Maswood, R., Semenyuk, O., Hoke, J., Hare, A., et al. (2020). Gene therapy targeting the inner retina rescues the retinal phenotype in a mouse model of CLN3 batten disease. Hum. Gene Ther. 31, 709–718. doi: 10.1089/hum.2020.038
Klevering, B. J., Maugeri, A., Wagner, A., Go, S. L., Vink, C., Cremers, F. P. M., et al. (2004). Three families displaying the combination of Stargardt’s disease with cone-rod dystrophy or retinitis pigmentosa. Ophthalmology 111, 546–553. doi: 10.1016/j.ophtha.2003.06.010
Koirala, A., Conley, S. M., Makkia, R., Liu, Z., Cooper, M. J., Sparrow, J. R., et al. (2013). Persistence of non-viral vector mediated RPE65 expression: case for viability as a gene transfer therapy for RPE-based diseases. J. Control Release 172, 745–752. doi: 10.1016/j.jconrel.2013.08.299
Lafond, J. F., Tenneson, K., Emond, F., Foucault, C., Vogel, S., and Boubekeur, H. (2020). Evaluation of a model of long-term middle ear catheterization for repeat infusion administration and cochlear hair cell injury in guinea pigs. Toxicol. Pathol. 48, 586–592. doi: 10.1177/0192623320916635
Lalwani, A. K., Han, J. J., Castelein, C. M., Carvalho, G. J., and Mhatre, A. N. (2002a). In vitro and in vivo assessment of the ability of adeno-associated virus-brain-derived neurotrophic factor to enhance spiral ganglion cell survival following ototoxic insult. Laryngoscope 112(8 Pt 1), 1325–1334. doi: 10.1097/00005537-200208000-00001
Lalwani, A. K., Walsh, B. J., Reilly, P. G., Muzyczka, N., and Mhatre, A. N. (1996). Development of in vivo gene therapy for hearing disorders: introduction of adeno-associated virus into the cochlea of the guinea pig. Gene Ther. 3, 588–592.
Lalwani, A., Walsh, B., Reilly, P., Carvalho, G., Zolotukhin, S., Muzyczka, N., et al. (1998). Long-term in vivo cochlear transgene expression mediated by recombinant adeno-associated virus. Gene Ther. 5, 277–281. doi: 10.1038/sj.gt.3300573
Lan, Y. Y., Tao, Y., Wang, Y. F., Ke, J. Z., Yang, Q. X., Liu, X. Y., et al. (2020). Recent development of AAV-based gene therapies for inner ear disorders. Gene Ther. 27, 329–337. doi: 10.1038/s41434-020-0155-7
Landegger, L. D., Pan, B., Askew, C., Wassmer, S. J., Gluck, S. D., Galvin, A., et al. (2017). A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat. Biotechnol. 35, 280–284. doi: 10.1038/nbt.3781
Lem, J., Flannery, J. G., Li, T., Applebury, M. L., Farber, D. B., and Simon, M. I. (1992). Retinal degeneration is rescued in transgenic rd mice by expression of the cGMP phosphodiesterase beta subunit. Proc. Natl. Acad. Sci. U.S.A. 89, 4422–4426. doi: 10.1073/pnas.89.10.4422
Lentz, J. J., Jodelka, F. M., Hinrich, A. J., McCaffrey, K. E., Farris, H. E., Spalitta, M. J., et al. (2013). Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat. Med. 19, 345–350. doi: 10.1038/nm.3106
Li, T., Adamian, M., Roof, D. J., Berson, E. L., Dryja, T. P., Roessler, B. J., et al. (1994). In vivo transfer of a reporter gene to the retina mediated by an adenoviral vector. Invest. Ophthalmol. Vis. Sci. 35, 2543–2549.
Lin, Q., Lv, J. N., Wu, K. C., Zhang, C. J., Liu, Q., and Jin, Z. B. (2020). Generation of nonhuman primate model of cone dysfunction through in situ AAV-Mediated CNGB3 ablation. Mol. Ther. Methods Clin. Dev. 18, 869–879. doi: 10.1016/j.omtm.2020.08.007
Lin, X., Tang, W. X., Ahmad, S., Lu, J. Q., Colby, C. C., Zhu, J., et al. (2012). Applications of targeted gene capture and next-generation sequencing technologies in studies of human deafness and other genetic disabilities. Hear. Res. 288, 67–76. doi: 10.1016/j.heares.2012.01.004
Liu, Y., Okada, T., Shimazaki, K., Sheykholeslami, K., Nomoto, T., Muramatsu, S. I., et al. (2008). Protection against aminoglycoside-induced ototoxicity by regulated AAV vector-mediated GDNF gene transfer into the cochlea. Mol. Ther. 16, 474–480. doi: 10.1038/sj.mt.6300379
Maddalena, A., Tornabene, P., Tiberi, P., Minopoli, R., Manfredi, A., Mutarelli, M., et al. (2018). Triple vectors expand AAV transfer capacity in the retina. Mol. Ther. 26, 524–541. doi: 10.1016/j.ymthe.2017.11.019
Maeda, A., Mandai, M., and Takahashi, M. (2019). Gene and induced pluripotent stem cell therapy for retinal diseases. Annu. Rev. Genomics Hum. Genet. 20, 201–216. doi: 10.1146/annurev-genom-083118-015043
Maguire, A. M., High, K. A., Auricchio, A., Wright, J. F., Pierce, E. A., Testa, F., et al. (2009). Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 374, 1597–1605. doi: 10.1016/S0140-6736(09)61836-5
Maguire, A. M., Russell, S., Wellman, J. A., Chung, D. C., Yu, Z. F., Tillman, A., et al. (2019). Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutation-associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology 126, 1273–1285. doi: 10.1016/j.ophtha.2019.06.017
Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Mingozzi, F., Bennicelli, J., et al. (2008). Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N. Engl. J. Med. 358, 2240–2248. doi: 10.1056/NEJMoa0802315
Mancuso, K., Hauswirth, W. W., Li, Q., Connor, T. B., Kuchenbecker, J. A., Mauck, M. C., et al. (2009). Gene therapy for red-green colour blindness in adult primates. Nature 461, 784–787. doi: 10.1038/nature08401
Marazita, M. L., Ploughman, L. M., Rawlings, B., Remington, E., Arnos, K. S., and Nance, W. E. (1993). Genetic epidemiological studies of early-onset deafness in the U.S. school-age population. Am. J. Med. Genet. 46, 486–491. doi: 10.1002/ajmg.1320460504
Mashal, M., Attia, N., Martinez-Navarrete, G., Soto-Sanchez, C., Fernandez, E., Grijalvo, S., et al. (2019). Gene delivery to the rat retina by non-viral vectors based on chloroquine-containing cationic niosomes. J. Control Release 304, 181–190. doi: 10.1016/j.jconrel.2019.05.010
Mathur, P. D., and Yang, J. (2019). Usher syndrome and non-syndromic deafness: functions of different whirlin isoforms in the cochlea, vestibular organs, and retina. Hear. Res. 375, 14–24. doi: 10.1016/j.heares.2019.02.007
McClements, M. E., Barnard, A. R., Charbel Issa, P., and MacLaren, R. E. (2020). Assessment of AAV dual vector safety in theAbca4 (-/-) mouse model of stargardt disease. Transl. Vis. Sci. Technol. 9:20. doi: 10.1167/tvst.9.7.20
McCullough, K. T., Boye, S. L., Fajardo, D., Calabro, K., Peterson, J. J., Strang, C. E., et al. (2019). Somatic gene editing of GUCY2D by AAV-CRISPR/Cas9 alters retinal structure and function in mouse and macaque. Hum. Gene Ther. 30, 571–589. doi: 10.1089/hum.2018.193
Men, C. J., Bujakowska, K. M., Comander, J., Place, E., Bedoukian, E. C., Zhu, X. S., et al. (2017). The importance of genetic testing as demonstrated by two cases of CACNA1F-associated retinal generation misdiagnosed as LCA. Mol. Vis. 23, 695–706.
Michel, V., Booth, K. T., Patni, P., Cortese, M., Azaiez, H., Bahloul, A., et al. (2017). CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival. Embo Mol. Med. 9, 1711–1731. doi: 10.15252/emmm.201708087
Mikulec, A. A., Plontke, S. K., Hartsock, J. J., and Salt, A. N. (2009). Entry of substances into perilymph through the bone of the otic capsule after intratympanic applications in guinea pigs: implications for local drug delivery in humans. Otol. Neurotol. 30, 131–138. doi: 10.1097/mao.0b013e318191bff8
Mistry, N., Nolan, L. S., Saeed, S. R., Forge, A., and Taylor, R. R. (2014). Cochlear implantation in the mouse via the round window: effects of array insertion. Hear. Res. 312, 81–90. doi: 10.1016/j.heares.2014.03.005
Miwa, T., Minoda, R., Ise, M., Yamada, T., and Yumoto, E. (2013). Mouse otocyst transuterine gene transfer restores hearing in mice with connexin 30 deletion-associated hearing loss. Mol. Ther. 21, 1142–1150. doi: 10.1038/mt.2013.62
Mondain, M., Restituito, S., Vincenti, V., Gardiner, Q., Uziel, A., Delabre, A., et al. (1998). Adenovirus-mediated in vivo gene transfer in guinea pig middle ear mucosa. Hum. Gene Ther. 9, 1217–1221. doi: 10.1089/hum.1998.9.8-1217
Mookherjee, S., Hiriyanna, S., Kaneshiro, K., Li, L., Li, Y., Li, W., et al. (2015). Long-term rescue of cone photoreceptor degeneration in retinitis pigmentosa 2 (RP2)-knockout mice by gene replacement therapy. Hum. Mol. Genet. 24, 6446–6458. doi: 10.1093/hmg/ddv354
Morimura, H., Fishman, G. A., Grover, S. A., Fulton, A. B., Berson, E. L., and Dryja, T. P. (1998). Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc. Natl. Acad. Sci. U.S.A. 95, 3088–3093. doi: 10.1073/pnas.95.6.3088
Mowat, F. M., Gornik, K. R., Dinculescu, A., Boye, S. L., Hauswirth, W. W., Petersen-Jones, S. M., et al. (2014). Tyrosine capsid-mutant AAV vectors for gene delivery to the canine retina from a subretinal or intravitreal approach. Gene Ther. 21, 96–105. doi: 10.1038/gt.2013.64
Nishiguchi, K. M., Fujita, K., Miya, F., Katayama, S., and Nakazawa, T. (2020). Single AAV-mediated mutation replacement genome editing in limited number of photoreceptors restores vision in mice. Nat. Commun. 11:482. doi: 10.1038/s41467-019-14181-3
Nist-Lund, C. A., Pan, B., Patterson, A., Asai, Y., Chen, T., Zhou, W., et al. (2019). Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders. Nat. Commun. 10:236. doi: 10.1038/s41467-018-08264-w
Niu, Y., Shen, B., Cui, Y., Chen, Y., Wang, J., Wang, L., et al. (2014). Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell 156, 836–843. doi: 10.1016/j.cell.2014.01.027
Pan, B., Askew, C., Galvin, A., Heman-Ackah, S., Asai, Y., Indzhykulian, A. A., et al. (2017). Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat. Biotechnol. 35, 264–272. doi: 10.1038/nbt.3801
Patel, S. R., Lin, A. S. P., Edelhauser, H. F., and Prausnitz, M. R. (2011). Suprachoroidal drug delivery to the back of the eye using hollow microneedles. Pharmaceut. Res. 28, 166–176. doi: 10.1007/s11095-010-0271-y
Patrizi, C., Llado, M., Benati, D., Iodice, C., Marrocco, E., Guarascio, R., et al. (2021). Allele-specific editing ameliorates dominant retinitis pigmentosa in a transgenic mouse model. Am. J. Hum. Genet. 108, 295–308. doi: 10.1016/j.ajhg.2021.01.006
Petrs-Silva, H., Dinculescu, A., Li, Q., Min, S. H., Chiodo, V., Pang, J. J., et al. (2009). High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol. Ther. 17, 463–471. doi: 10.1038/mt.2008.269
Petrs-Silva, H., Yasumura, D., Matthes, M. T., LaVail, M. M., Lewin, A. S., and Hauswirth, W. W. (2012). Suppression of rds expression by siRNA and gene replacement strategies for gene therapy using rAAV vector. Adv. Exp. Med. Biol. 723, 215–223. doi: 10.1007/978-1-4614-0631-0_29
Picaud, S., Dalkara, D., Marazova, K., Goureau, O., Roska, B., and Sahel, J. A. (2019). The primate model for understanding and restoring vision. Proc. Natl. Acad. Sci. U.S.A. 116, 26280–26287. doi: 10.1073/pnas.1902292116
Pinyon, J. L., von Jonquieres, G., Crawford, E. N., Duxbury, M., Al Abed, A., Lovell, N. H., et al. (2019). Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes. Hear. Res. 380, 137–149. doi: 10.1016/j.heares.2019.06.002
Ponnath, A., Depreux, F. F., Jodelka, F. M., Rigo, F., Farris, H. E., Hastings, M. L., et al. (2018). Rescue of outer hair cells with antisense oligonucleotides in usher mice is dependent on age of treatment. J. Assoc. Res. Otolaryngol. 19, 1–16. doi: 10.1007/s10162-017-0640-x
Ramachandran, P. S., Lee, V., Wei, Z., Song, J. Y., Casal, G., Cronin, T., et al. (2017). Evaluation of dose and safety of AAV7m8 and AAV8BP2 in the non-human primate retina. Hum. Gene Ther. 28, 154–167. doi: 10.1089/hum.2016.111
Ren, L. L., Wu, Y., Han, D., Zhao, L. D., Sun, Q. M., Guo, W. W., et al. (2010). Math1 gene transfer based on the delivery system of quaternized chitosan/Na-carboxymethyl-beta-cyclodextrin nanoparticles. J. Nanosci. Nanotechnol. 10, 7262–7265. doi: 10.1166/jnn.2010.2822
Ross, M., Obolensky, A., Averbukh, E., Ezra-Elia, R., Yamin, E., Honig, H., et al. (2020). Evaluation of photoreceptor transduction efficacy of capsid-modified adeno-associated viral vectors following intravitreal and subretinal delivery in sheep. Hum. Gene Ther. 31, 719–729. doi: 10.1089/hum.2020.023
Ruan, G. X., Barry, E., Yu, D., Lukason, M., Cheng, S. H., and Scaria, A. (2017). CRISPR/Cas9-mediated genome editing as a therapeutic approach for Leber congenital amaurosis 10. Mol. Ther. 25, 331–341. doi: 10.1016/j.ymthe.2016.12.006
Russell, S., Bennett, J., Wellman, J. A., Chung, D. C., Yu, Z. F., Tillman, A., et al. (2017). Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 390, 849–860. doi: 10.1016/S0140-6736(17)31868-8
Sakami, S., Kolesnikov, A. V., Kefalov, V. J., and Palczewski, K. (2014). P23H opsin knock-in mice reveal a novel step in retinal rod disc morphogenesis. Hum. Mol. Genet. 23, 1723–1741. doi: 10.1093/hmg/ddt561
Sakamoto, K., McCluskey, M., Wensel, T. G., Naggert, J. K., and Nishina, P. M. (2009). New mouse models for recessive retinitis pigmentosa caused by mutations in the Pde6a gene. Hum. Mol. Genet. 18, 178–192. doi: 10.1093/hmg/ddn327
Schrauwen, I., Chakchouk, I., Acharya, A., Liaqat, K., Nickerson, D. A., Bamshad, M. J., et al. (2018). Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment. BMC Med. Genet. 19:122. doi: 10.1186/s12881-018-0618-5
Sharkia, R., Wierenga, K. J., Kessel, A., Azem, A., Bertini, E., Carrozzo, R., et al. (2019). Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects: delineation of an emerging neurometabolic syndrome. J. Inherit. Metab. Dis. 42, 264–275. doi: 10.1002/jimd.12022
Shibata, S. B., Di Pasquale, G., Cortez, S. R., Chiorini, J. A., and Raphael, Y. (2009). Gene transfer using bovine adeno-associated virus in the guinea pig cochlea. Gene Ther. 16, 990–997. doi: 10.1038/gt.2009.57
Shou, J., Zheng, J. L., and Gao, W. Q. (2003). Robust generation of new hair cells in the mature mammalian inner ear by adenoviral expression of Hath1. Mol. Cell. Neurosci. 23, 169–179. doi: 10.1016/s1044-7431(03)00066-6
Singh, M., and Tyagi, S. C. (2018). Genes and genetics in eye diseases: a genomic medicine approach for investigating hereditary and inflammatory ocular disorders. Int. J. Ophthalmol. 11, 117–134. doi: 10.18240/ijo.2018.01.20
Song, C., Dufour, V. L., Cideciyan, A. V., Ye, G. J., Swider, M., Newmark, J. A., et al. (2020). Dose range finding studies with two RPGR transgenes in a canine model of X-Linked retinitis pigmentosa treated with subretinal gene therapy. Hum. Gene Ther. 31, 743–755. doi: 10.1089/hum.2019.337
Song, H., Bush, R. A., Zeng, Y., Qian, H., Wu, Z., and Sieving, P. A. (2019). Trans-ocular electric current in vivo enhances AAV-mediated retinal gene transduction after intravitreal vector administration. Mol. Ther. Methods Clin. Dev. 13, 77–85. doi: 10.1016/j.omtm.2018.12.006
Song, H., Zeng, Y., Sardar Pasha, S. P. B., Bush, R. A., Vijayasarathy, C., Qian, H., et al. (2020). Trans-ocular electric current in vivo enhances AAV-mediated retinal transduction in large animal eye after intravitreal vector administration. Transl. Vis. Sci. Technol. 9:28. doi: 10.1167/tvst.9.7.28
Sun, D., Sahu, B., Gao, S., Schur, R. M., Vaidya, A. M., Maeda, A., et al. (2017). Targeted multifunctional lipid ECO plasmid DNA nanoparticles as efficient non-viral gene therapy for Leber’s congenital amaurosis. Mol. Ther. Nucleic Acids 7, 42–52. doi: 10.1016/j.omtn.2017.02.005
Sun, D., Schur, R. M., Sears, A. E., Gao, S. Q., Vaidya, A., Sun, W., et al. (2020). Non-viral gene therapy for stargardt disease with ECO/pRHO-ABCA4 self-assembled nanoparticles. Mol. Ther. 28, 293–303. doi: 10.1016/j.ymthe.2019.09.010
Suzuki, J., Hashimoto, K., Xiao, R., Vandenberghe, L. H., and Liberman, M. C. (2017). Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction. Sci. Rep. 7:45524. doi: 10.1038/srep45524
Tam, L. C., Kiang, A. S., Kennan, A., Kenna, P. F., Chadderton, N., Ader, M., et al. (2008). Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10). Hum. Mol. Genet. 17, 2084–2100. doi: 10.1093/hmg/ddn107
Tan, B. T., Foong, K. H., Lee, M. M., and Ruan, R. (2008). Polyethylenimine-mediated cochlear gene transfer in guinea pigs. Arch. Otolaryngol. Head Neck Surg. 134, 884–891. doi: 10.1001/archotol.134.8.884
Tang, Z. H., Chen, J. R., Zheng, J., Shi, H. S., Ding, J., Qian, X. D., et al. (2016). Genetic correction of induced pluripotent stem cells from a deaf patient with MYO7A mutation results in morphologic and functional recovery of the derived hair cell-like cells. Stem Cells Transl. Med. 5, 561–571. doi: 10.5966/sctm.2015-0252
Tao, Y., Huang, M. Q., Shu, Y. L., Ruprecht, A., Wang, H. Y., Tang, Y., et al. (2018). Delivery of adeno-associated virus vectors in adult mammalian inner-ear cell subtypes without auditory dysfunction. Hum. Gene Ther. 29, 492–506. doi: 10.1089/hum.2017.120
Testa, F., Maguire, A. M., Rossi, S., Pierce, E. A., Melillo, P., Marshall, K., et al. (2013). Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital amaurosis type 2. Ophthalmology 120, 1283–1291. doi: 10.1016/j.ophtha.2012.11.048
Todorich, B., Yiu, G., and Hahn, P. (2014). Current and investigational pharmacotherapeutic approaches for modulating retinal angiogenesis. Exp. Rev. Clin. Pharmacol. 7, 375–391. doi: 10.1586/17512433.2014.890047
Tosi, J., Sancho-Pelluz, J., Davis, R. J., Hsu, C. W., Wolpert, K. V., Sengillo, J. D., et al. (2011). Lentivirus-mediated expression of cDNA and shRNA slows degeneration in retinitis pigmentosa. Exp. Biol. Med. 236, 1211–1217. doi: 10.1258/ebm.2011.011053
Touchard, E., Berdugo, M., Bigey, P., El Sanharawi, M., Savoldelli, M., Naud, M. C., et al. (2012). Suprachoroidal electrotransfer: a nonviral gene delivery method to transfect the choroid and the retina without detaching the retina. Mol. Ther. 20, 1559–1570. doi: 10.1038/mt.2011.304
Tranebjaerg, L. (1993). “Deafness-dystonia-optic neuronopathy syndrome,” in GeneReviews, eds M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens, et al. (Seattle, WA:University of Washington).
Travis, G. H., Groshan, K. R., Lloyd, M., and Bok, D. (1992). Complete rescue of photoreceptor dysplasia and degeneration in transgenic retinal degeneration slow (rds) mice. Neuron 9, 113–119. doi: 10.1016/0896-6273(92)90226-4
Vagni, P., Perlini, L. E., Chenais, N. A. L., Marchetti, T., Parrini, M., Contestabile, A., et al. (2019). Gene editing preserves visual functions in a mouse model of retinal degeneration. Front. Neurosci. 13:945. doi: 10.3389/fnins.2019.00945
Volland, S., Esteve-Rudd, J., Hoo, J., Yee, C., and Williams, D. S. (2015). A comparison of some organizational characteristics of the mouse central retina and the human macula. PLoS One 10:e0125631. doi: 10.1371/journal.pone.0125631
Wang, L., Kempton, J. B., Jiang, H., Jodelka, F. M., Brigande, A. M., Dumont, R. A., et al. (2020). Fetal antisense oligonucleotide therapy for congenital deafness and vestibular dysfunction. Nucleic Acids Res. 48, 5065–5080. doi: 10.1093/nar/gkaa194
Wang, Y. F., Sun, Y., Chang, Q., Ahmad, S., Zhou, B. F., Kim, Y. J., et al. (2013). Early postnatal virus inoculation into the scala media achieved extensive expression of exogenous green fluorescent protein in the inner ear and preserved auditory brainstem response thresholds. J. Gene Med. 15, 123–133. doi: 10.1002/jgm.2701
Wareing, M., Mhatre, A. N., Pettis, R., Han, J. J., Haut, T., Pfister, M. H., et al. (1999). Cationic liposome mediated transgene expression in the guinea pig cochlea. Hear. Res. 128, 61–69. doi: 10.1016/s0378-5955(98)00196-8
Wassmer, S. J., De Repentigny, Y., Sheppard, D., Lagali, P. S., Fang, L., Coupland, S. G., et al. (2020). XIAP protects retinal ganglion cells in the mutant ND4 mouse model of leber hereditary optic neuropathy. Invest. Ophthalmol. Vis. Sci. 61:49. doi: 10.1167/iovs.61.8.49
Weber, M., Rabinowitz, J., Provost, N., Conrath, H., Folliot, S., Briot, D., et al. (2003). Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery. Mol. Ther. 7, 774–781. doi: 10.1016/s1525-0016(03)00098-4
Weiss, R. S., Voss, A., and Hemmert, W. (2016). Optogenetic stimulation of the cochlea-A review of mechanisms, measurements, and first models. Netw. Comput. Neural Syst. 27, 212–236. doi: 10.1080/0954898x.2016.1224944
Willoughby, A., Vuong, V., Cunefare, D., Farsiu, S., Noronha, G., Danis, R. P., et al. (2018). Choroidal changes after suprachoroidal injection of CLS-TA, triamcinolone acetonide injectable suspension, in eyes with macular edema secondary to retinal vein occlusion. Invest. Ophthalmol. Vis. Sci. 59:5969.
Wood, E. H., Tang, P. H., De la Huerta, I., Korot, E., Muscat, S., Palanker, D. A., et al. (2019). Stem cell therapies, gene-based therapies, optogenetics, and retinal prosthetics: current state and implications for the future. Retina 39, 820–835. doi: 10.1097/IAE.0000000000002449
Xu, Z. P., Yue, Y. P., Lai, Y., Ye, C. Y., Qiu, J. M., Pintel, D. J., et al. (2004). Trans-splicing adeno-associated viral vector-mediated gene therapy is limited by the accumulation of spliced mRNA but not by dual vector coinfection efficiency. Hum. Gene Ther. 15, 896–905. doi: 10.1089/hum.2004.15.896
Yeh, S., Khurana, R. N., Shah, M., Henry, C. R., Wang, R. C., Kissner, J. M., et al. (2020). Efficacy and safety of suprachoroidal CLS-TA for macular edema secondary to noninfectious uveitis: phase 3 randomized trial. Ophthalmology 127, 948–955. doi: 10.1016/j.ophtha.2020.01.006
Yiu, G., Chung, S. H., Mollhoff, I. N., Nguyen, U. T., Thomasy, S. M., Yoo, J., et al. (2020). Suprachoroidal and subretinal injections of AAV using transscleral microneedles for retinal gene delivery in nonhuman primates. Mol. Ther. Methods Clin. Dev. 16, 179–191. doi: 10.1016/j.omtm.2020.01.002
Yiu, G., Pecen, P., Sarin, N., Chiu, S. J., Farsiu, S., Mruthyunjaya, P., et al. (2014). Characterization of the choroid-scleral junction and suprachoroidal layer in healthy individuals on enhanced-depth imaging optical coherence tomography. JAMA Ophthalmol. 132, 174–181. doi: 10.1001/jamaophthalmol.2013.7288
Yoshimura, H., Shibata, S. B., Ranum, P. T., and Smith, R. J. H. (2018). Enhanced viral-mediated cochlear gene delivery in adult mice by combining canal fenestration with round window membrane inoculation. Sci. Rep. 8:2980. doi: 10.1038/s41598-018-21233-z
Yu, Q., Wang, Y., Chang, Q., Wang, J., Gong, S., Li, H., et al. (2014). Virally expressed connexin26 restores gap junction function in the cochlea of conditional Gjb2 knockout mice. Gene Ther. 21, 71–80. doi: 10.1038/gt.2013.59
Yuan, Y. Y., Li, Q., Su, Y., Lin, Q. F., Gao, X., Liu, H. K., et al. (2020). Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls. Eur. J. Hum. Genet. 28, 231–243. doi: 10.1038/s41431-019-0510-6
Zhang, H., Pan, H., Zhou, C., Wei, Y., Ying, W., Li, S., et al. (2018). Simultaneous zygotic inactivation of multiple genes in mouse through CRISPR/Cas9-mediated base editing. Development 145:dev168906. doi: 10.1242/dev.168906
Zhang, W. J., Kim, S. M., Wang, W. W., Cai, C. Y., Feng, Y., Kong, W. J., et al. (2018). Cochlear gene therapy for sensorineural hearing loss: current status and major remaining hurdles for translational success. Front. Mol. Neurosci. 11:221. doi: 10.3389/fnmol.2018.00221
Zhang, Y., Wang, S., Xu, M., Pang, J., Yuan, Z., and Zhao, C. (2019). AAV-mediated human CNGB3 restores cone function in an all-cone mouse model of CNGB3 achromatopsia. J. Biomed. Res. 34, 114–121. doi: 10.7555/JBR.33.20190056
Zhao, X., Jin, C., Dong, T., Sun, Z., Zheng, X., Feng, B., et al. (2020). Characterization of promoters for adeno-associated virus mediated efficient Cas9 activation in adult Cas9 knock-in murine cochleae. Hear. Res. 394:107999. doi: 10.1016/j.heares.2020.107999
Zou, J., Saulnier, P., Perrier, T., Zhang, Y., Manninen, T., Toppila, E., et al. (2008). Distribution of lipid nanocapsules in different cochlear cell populations after round window membrane permeation. J. Biomed. Mater. Res. B Appl. Biomater. 87, 10–18. doi: 10.1002/jbm.b.31058
Keywords: retina, cochlea, gene therapy, nanoparticles, animal models
Citation: Crane R, Conley SM, Al-Ubaidi MR and Naash MI (2021) Gene Therapy to the Retina and the Cochlea. Front. Neurosci. 15:652215. doi: 10.3389/fnins.2021.652215
Received: 11 January 2021; Accepted: 22 February 2021;
Published: 17 March 2021.
Edited by:Jacqueline Reinhard, Ruhr-University, Germany
Reviewed by:Elvir Becirovic, Ludwig Maximilian University of Munich, Germany
Erica Lucy Fletcher, The University of Melbourne, Australia
Copyright © 2021 Crane, Conley, Al-Ubaidi and Naash. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | <urn:uuid:bd2fab97-459e-45b1-8395-99eb07ab5384> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 114,395 |
Deri Park makes up part of the depressing list of grounds in the London area to disappear in the last twenty or so years. As in so many cases, with the ground went the club and it was no different in the case of Rainham Town FC.
The club were formed in 1945 and moved to Deri Park in 1948 after playing their initial matches at Rainham Working Men's Club Ground. The first match at Deri Park was played against near neighbours Woodford Town who were beaten 4-1.
During the 50's and 60's the club switched between the Delphian League, Athenian League and Metropolitan League. The Metropolitan League in the early 60's had the third teams of most of the top London professional sides. In 1963 Rainham won the shield for the highest placed Amateur side.
From 1964 the club played in the Athenian League Division Two and by the early seventies had sank to the depths of having to apply for re-election. Happier times were to follow when the club finished runners up to Alton Town and promotion to Divsion One was achieved.
The club installed floodlights at this time and on 23rd October 1974 Orient visited Deri Park in a match to mark the official 'switching on', Rainham lost 4-1.
From 1977/78 the club joined the Isthmian League where they were to stay until they folded and went out of business. This season also marked there best run in the FA VASE where they reached the 5th Round. Victories versus Canvey Island, Tiptree United, Crown &; Manor, Egham Town and Diss Town set up an away tie with Almondsbury Greenway where they lost 2-1. Almondsbury went on the beat Burnham in the QF (after a 2nd match as the original tie at Almondsbury which they won 2-0 was ordered to be replayed as the pitch was ruled too small) before loosing out to Blue Star in the SF 4-2 on agg. Greenway were a force to reckoned with in the Vase at that time as in 76/77 they reached the 5th round, 77/78 semi final, 78/79 finalists.
Rainham's best performance in the FA Cup came when they reached the 3QR in 1958 beaing Aveley, Brentwood & Warley and Ilford before loosing out to Chelmsford City. The following season victories versus Leytonstone and Brentwood & Warley moved them into the 3rd QR again where they lost to Woodford Town. In 1993 the club played their last FA Cup fixture versus local rivals Purfleet being soundly beaten 5-1. Also in 1993 the last Vase fixture was played versus Hanwell Town resulting in a 5-2 defeat.
Rainham lost versus Colchester United AET in the semi final of the Essex Senior Cup in 1981/82 and in 82/83 they lost 4-1 to Southend United in the 2nd round of the ESC. They played the Shrimpers again that season in the Essex Thames Side Trophy, two late goals by the football league side broke Rainham's resistance with the final result being 3-2 to the Roots Hall team.
1993/94 was the last season played for Rainham Town in the Second Divsion of the Isthmian League where they finished bottom with a playing record of 4 wins, 2 draws and 36 losses out of 42 games. Shipping 116 goals and scoring only 24. The season was an immense struggle with the club leading a nomadic existance after leaving Deri Park playing firstly at Purfleet and then at Aveley's Mill Field. With no prospect of moving back to their home town the club sadly folded.
Vistors to Deri Park will inform you of a rickety old main stand with a leaky roof that moved if their was a gust of wind. This is what made characteristic old grounds like this one on Wennington Road so brilliant to visit. A far cry from the modern all seated stadia of the FA Premier League but all the more endering with it.
CLICK ON THE PHOTOS TO ENLARGE IN ORDER TO READ THE TEXT | <urn:uuid:b0c208c1-e091-4dff-bd7c-0a9404de7e47> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 3,644 |
AdDirecto MOD APK 3.2.1 [Premium Unlocked] DownloadCyberlink Corp
|Category||Video Players & Editors|
|MOD Features||Premium Unlocked|
|Update On||November 24, 2021|
AdDirector MOD APK is one of the best video creation tools on the mobile platform. This application offers many outstanding video editing features, along with options from simple to complex. This will certainly help users unleash their creativity according to their own preferences. In this article, let’s find out some more advantages of this application.
Introduce about AdDirector
AdDirector – Provides everything available for you to create the best videos
When using AdDirector, everything related to video editing is in the palm of your hand in no time. You can choose a set of tools to cut, merge and correct video colors as you like with just a few basic operations. Including font selection, font color, video timing structure, display content, etc. Moreover, this application has a relatively small download size so it will be compatible with most current mobile devices.
After the success of previous products, the publisher Cyberlink Corp decided to launch the AdDirector application. And it did not disappoint users when it became one of the best video editing apps of 2020 recommended by Google Play. Whether directed to slideshows, commercials, or any other genre, this application will meet your needs quickly.
Ready to create quality videos
Since it is an application whose main function is to edit videos, it will not take you too long to get used to what is available in AdDirector. The main features of the application revolve around editing tools from simple to complex. There are a number of customizations such as colors, palette parameters, matching frames, and more. Of course, you can use your own footage or choose from the library of resources provided in the app. This makes the video creation process much faster and more convenient.
Using AdDirector is simpler than ever, thanks to the state-of-the-art controls available. All operations are optimized for mobile devices so that users can easily use any feature they want. Basically, you just need to touch the screen to choose your requirements and watch the video change on the main screen.
After completing the editing process, click on the save icon or share through popular social networking sites. That is also all the operations that you will have to do when creating videos through this application. Everything is done and the response is quick thanks to the optimization algorithms available. If you have any questions, please contact us to get answers as soon as possible.
Customize the right frame
AdDirector not only offers general features but also specific needs of each user object. For example, you can customize the frame to suit the social networking sites you want to share the video on. Because each platform will have different length and width dimensions when posting videos. This inadvertently causes many users to encounter the error of displaying video scale after posting on social networking sites. Realizing the above problem, this application allows you to format your video for any social networking platform with just a few basic tips.
The number of diverse designs
The design pattern is one of the attractions of video editing apps on mobile platforms. Because not all users have their own design ideas available when using editing applications. If there are design templates available, everything will become much simpler and more convenient. Fortunately, AdDirector offers many designs with a variety of content.
As a result, you can easily find the right templates for your design needs in the shortest possible time. There are quite a few themes available such as fashion, medical, travel, auto, sports, etc. When clicking on a topic, a series of suitable designs will be displayed on the screen for you to use. use immediately. Moreover, these contents are constantly updated from time to time and allow users to access them unlimitedly. Therefore, we firmly believe that your experience will always be at the highest level for a long time.
How to install AdDirecto
Before starting to download the app, you need to ensure that your device does not appear in any version of AdDirector at the moment.
Step 1: You need to download the AdDirector (MOD Premium Unlocked) version exclusively released by Modded-1.com.
Step 2: Proceed to unlock unknown settings on mobile. Then allow the AdDirector app to access.
Step 3: Click the Install button after the download is complete.
Step 4: The app icon will appear right after the installation has finished. Finally, just tap it to start using the app right away.
Download AdDirecto MOD APK for Android
AdDirecto is not simply an ordinary video editing application, but it also meets the needs of many users around the world. Through this application, you can customize various video templates according to your personal preferences. It can be for personal purposes, study, or work purposes. Besides, a paid version of this app is also available to give you more advanced experiences. If interested, please download the AdDirecto MOD file below this article to save money for yourself.
- Premium Unlocked | <urn:uuid:04cb5869-b8ca-4a44-b0a2-5fdf04494f34> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 5,228 |
Today began the Little League softball season for our family. It was the first practice and the first of many hours watching 4th and 5th graders learn the art of fielding and batting. Growing children takes a lot of time. Time that could be spent doing something else… ANYTHING else. Alas, Rosy the robot hasn’t been invented yet and I’m content being present for my children to keep up the facade of a caring parent to reduce future therapy costs. I keed, I keed. About Lester:
I like Pina Coladas and taking long walks off of short piers… Whoops, here is the real one.
I have lived in Hampden with my fabulous family for 10 years. After much time and effort, I received my interdisciplinary Ph.D. in Sensors from the University of Maine in August 2011. In September, I start my new job as a Lecturer in Mathematics at the University of Maine in Augusta with a focus on Math Education. | <urn:uuid:e5d0c7cf-54fb-48de-80cd-e3ebd803d890> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 886 |
Sonja Morgan wants to tell you she has a hangover this morning…
The reality of being a reality drunk.
Oops. Seems Sonja slipped a few too many martinis in her purse this weekend and as a consequence ran over a few red lights before NY’s finest pulled the seasoned reality drunk of Unbearable Housewives of NY out of her car. Needless to say, Sonja failed the part where they asked her to walk the straight double yellow lines, and as for taking the breathalyzer test, Sonja politely declined. She having manners and all.
Anyway she now has a fantastic hangover to deal with and this terrific mugshot that Bravo must be seriously considering in this season’d finale episode.
Money can’t buy you class, but it can always buy you another martini. | <urn:uuid:03515e00-441c-4fab-b99d-2006312d7909> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 743 |
Gold mining equipment indonesia exodusminingmachine. Portable Gold Mining Equipment Indonesia. Portable gold mining equipment indonesiaour company is a largescale heavy enterprise that taking heavy mining machinery manufactory as main products and integrated with scientific research production and marketing we are concentrating on producing and selling machines such as jaw.Gold Ore Mining Equipment Companies In Indonesia. Gold Ore Mining Equipment Companies In Indonesia We are a large-scale manufacturer specializing in producing various mining machines including different types of sand and gravel equipment, milling equipment, mineral processing equipment and building materials equipment.Qingzhou Keda Mining Machine -Shandong Magnetic Equipment Research Institution is a modern formal company which has been re-registered after the integration of the company. We professionally produce, process and sale than a dozen of series equipments such as gold mining equipments, sand producing and mining equipments, sieving.Jul 02, 2013 crusher machines in indonesia. Posted on July 2, 2013 by shuijing. Crushing Machine, You Can Buy Various High Quality Crushing Machine Products from Global Crushing Machine Suppliers and Crushing Machine Manufacturers at Alibaba.com. Gold Mining Equipment.
Mar 23, 2018 China Gold Mining Machine supplier, Gold Dredger, Gold Machine Manufacturers Suppliers - Qingzhou Lusheng Sand Mining Mchinery.Coal Mining Equipment Supplier Indonesia - , gold mining equipment manufacturers indonesia, mining , Gold Mining Equipment For Sale in South Africa, Gold Mining. gold mining equipment suppliers in indonesia. Mining news and commentary from around the globe Daily updates on gold and commodity prices, exploration, mine development and.200m3 hour bucket chain gold dredger for sales in Indonesia. 1. Company Information . Qingzhou Yongli Mining And Dredging Machinery , is one of China leading company of sand gold diamond mining equipments, which has than 25 years' experience in producing cutter suction dredgers,jet suction dredgers,bucket chain dredger, diamond gold selection dredger, sand washing plant, gold.Quality Manufacturer of Commercial Gold Mining Equipment. Minequip’s gold mining equipment is manufactured for commercial use in small to medium sized gold recovery operations, and our gold mining equipment is used successfully in production gold mines in New Zealand, Mongolia, Papua New Guinea, Bolivia, Ghana and Cameroon.
Founded in 1997, Shandong Xinhai Mining Technology Equipment Inc, (Stock Code 836079) under Xinhai is a stockholding high and new technology enterprise to provide the Turn-key Solution for Mineral Processing Plant including design and research, machine manufacturing, equipment procurement, management service, mine operation, mine materials procurement management as well as industry.Gold refining machine suppliers,Centrifugal gold concentrator . Gulin™ is a leading manufacturer supplier of gold refining machine in China, south Africa, India, USA, Pakistan, UK, UAE and other countries. detailed.Jiangxi Province County Mining Machinery Factory is specialized in researching, manufacturing, sales and door tracking service as one of the metallurgical mineral processing machinery enterprise, our company is engaged in the mineral processing equipment product design and production for several years history, has accumulated rich experience in design and production.Separation processing machine machine Central America. Supplier and Manufacturer of Separation Machines, Vapor Liquid Separation For Supplier and Manufacturer of Liquid Gold Mining ECO Friendly Green . Click.
Qingzhou Jinzun Mining Machinery Co.,Ltd. Is large gold mining service company,Specialized in designing, manufacturing,installing and debugging of gold mining equipment as well as providing flow sheet design and course of training of mining. Our company was founded in 2015 year as one of the best manufacturer of gold mining equipment in China.Used gold mining equipment price in Indonesia - crusher machine for sale. You are here Mineral Crusher › Beneficiation plant › Used gold mining equipment price in Indonesia.Shanghai XSM is a professional mining equipment manufacturing company, we produce all types of ore mineral crusher, mill, sand making machine, mobile crushing plant, mineral processing and other.Gold Mining Equipment, Gold Washing Trommel, Centrifugal Gold Concentrator manufacturer supplier in China, offering Alluvial Black Iron Sand Heavy Mine Process Equipment, High Tension 4 Roll Electrostatic Separator for Zircon Ore Upgrading, 1200 Gauss Wet Low Intensity Magnetic Drum Separator and so on.Gold mining equipment in indonesia Stone crusher, mobile. gold equipment supplier in indonesia - quarry plant and.Zenith is a professional manufacturer and exporter of gold mining equipment indonesia, such as crushing Impact Mining Equipment supplies mining equipment. | <urn:uuid:34192c5b-2b7b-4116-95a0-706d9d9f5989> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 4,938 |
If you are a parent or an educator of a child with Childhood Apraxia of Speech (CAS), the journey to help them find their voice may often feel overwhelming and challenging. But do not be disheartened! There are various proven strategies and techniques to support their speech growth. In this blog post, we will explore the essentials of CAS and specifically discuss the power of music.
What is childhood apraxia of speech (CAS)?
Children with CAS have a speech disorder that affects how they plan the movements required for speech. What appears to be an easy task for most kids can be impossible for others. Children with CAS need practice combining sounds to say words and phrases. One site that may be helpful to you is Apraxia-Kids. Another approach to treatment of apraxia is called PROMPT. You can find information here about that approach. https://promptinstitute.com/
As a speech-language pathologist who worked with very young children for years, diagnosing apraxia with children who are not yet speaking can be difficult. There can be so many possible reasons why a child is not speaking. I hesitate attaching the label of apraxia of speech to children who are not imitating or who cannot use words to communicate. But there are some children who attempt to imitate who struggle to produce vowel sounds and vowel combinations and to move from vowels to consonants, consonants to vowels, all with the purpose of shaping words. Motor planning is affected. Even if a diagnosis of apraxia is not given, these suggestions can be helpful for you.
How can I help my child with apraxia of speech?
Your child will benefit from lots of verbal practice. I am guessing that you have tried many things, but getting a child to practice something that is difficult is often easier said than done. Speech and language therapy will be helpful, and I encourage you to locate a speech-language pathologist (SLP) in your area who can guide you.
From the research I have read and from experience, I have created a little poem of important components to speech and language therapy for children with apraxia.
Keep sounds moving.
Keep them slow with
Intonation and rhythmic flow.
Core words, Cues to
Feel and see.
Repetition, Chains of three.
These 7 tips are more fully explained in the blog articles focused specifically for children with apraxia. Go here to read those articles. The suggestions below focus on using music to enhance the speech and language therapy for children with apraxia.
Use intonation and rhythmic flow to assist with sound blending.
There are many ways to create a joy for vocalizing, but one excellent tool for children is music. Practicing intonation and rhythm will help a child understand the normal inflectional flow of speech. Our Talk It Rock It songs can provide verbal practice that is enjoyable and that focuses on sound blending from vowels and vowel combinations to consonant-vowels (CV), CVCV structures, words, and phrases. You can listen to song samples, see the visuals that illustrate the songs, and watch a video that describes our songs. Go to our songs to find out more. Our songs are great, but there are many other ways to incorporate music into your day.
- Sing your own songs throughout the day.
More than anything, we encourage you to make a song out of every moment. We believe that “Every moment is a note, every situation is a song, and every person is a player.” When you go to the park, drive in the car, go to the store, tuck your child in at night, eat together, etc., sing about what you are doing. Sing at the level your child can understand and handle verbally. When a child is actively involved in music, it activates his/her whole brain. You will do nothing but good things for a child if you present things musically.
- When you sing songs, sing them in a manner that is within your child’s verbal ability.
My motto is, “Sing a song that your child can simply sing.” If that means vowel sounds, sing vowels, blending them together. You may want to sing consonant-vowels like “ba ba ba,” or “na na na” to typical children’s songs like The Wheels on the Bus. Classical pieces like Vivaldi’s Four Seasons or Handel’s Water Music are also excellent for singing vowels and consonants blended together. Or perhaps try our instrumental-only tracks on our song sets. Sing whatever sounds your child can say.
- Make noises!
Your child may benefit from hearing you make noises like sneezing, coughing, and kissing as modeled in our song, Noisy, Noisy, Noisy (Imitation Exploration Set 1). Animal noises such as the songs, Puppy, Puppy, Puppy, Animals (Imitation Exploration Set 1), Yee Haw (Imitation Exploration Set 1), or many of the animal sound songs in Animals Movin’ and Groovin’ Set 5 are also great to practice. You could also use our Animal Faces to encourage your child to imitate animal sounds. You can watch a video and read descriptions of the animal faces at our Animal Faces shop.
- Be a rock star!
If your child is able to produce some simple consonant-vowel sounds such as mama, dada, or baba, you may want to lose yourself in singing some Beach Boy songs, pretending you are the background singer. Those songs are filled with vowels and consonant-vowel structures. We have used this concept of consonant-vowel practice and our songs are packed with them. Some examples are The New BMW, Tongue Tip Time,(Imitation Exploration Set 1), I Dressed Myself (Rock & Roll with a Language Goal Set 2), Singing a Song (Rock & Roll with a Language Goal Set 2), and many of the songs in Drills for Sounds Set 3.
- Check out our speech practice goals featured in our songs sets. Specific Speech Sound Practice and Imitation of Sounds, Words, and Phrases is heavily emphasized in our song sets. Many of our songs vary in complexity from single sound productions to simple phrases all within the same song. Our songs also often incorporate “chains of three.” This technique repeats the same word three times sequentially to help children with imitation of sounds in running speech without the complexity of using phrases. The abbreviated titles of the song sets below are: IE-Imitation Exploration Set 1, RR- Rock and Roll with a Language Goal Set 2, DS – Drills for Sounds Set 3, AMG- Animals Movin’ and Groovin’. The songs listed below are excellent for children with apraxia of speech.
Noises and Animal sounds IE1 – Animals; Noisy, Noisy, Noisy; Puppy, Puppy, Puppy IE2 – Yee Haw DS1– Ha, Ha, Ha; Howls and Hoots AMG – Hooray!, On the Farm, Ah Choo!, Who Are You?, Animal Jive
Vowels and Vowel + Vowel combinations- IE1 – Monkey Song; Go in My Car RR1– Bananas DS1– Vowels; Howls and Hoots; Wheels DS2 – Ride the Horsie
CV words and nonsense sounds, CVC words, and Chains of Three
B, P, and M sounds IE1– Bye Bye; Baby Blowing Bubbles; Puppy, Puppy, Puppy IE2 – The New BMW RR2 – Ball, Ball, Ball DS1 – A Monkey, A Moose, A Mouse DS2 – Bus, Boat, Bike
W and Y sounds IE2 – The New BMW DS1 – Wheels DS2 – Ride the Horsie
N, T, and D sounds IE2 – Tongue Tip Time RR1 – I Dressed Myself; Uh-Oh RR2 – Singing a Song DS1 – No, No, Nigh, Night
K and G sounds IE1 – Go in My Car IE2– Yee Haw RR1 – Go DS1 – Happy Birthday Cake and Cookies
H sound DS1 – Ha, Ha, Ha; Howls and Hoots RR2 – Ha Ha Hiding; Help Me Mama
F and SH sounds DS1 – Fish, Sharks, and Shells
CH and J sounds IE1 – Express Train DS1 – Jump on the Choo Choo L sound RR1 – I Love
S sound DS1 – Hissing Snake
Final Consonants in words IE1 – Put the Sound on the End DS2 – Bus, Boat, Bike; I See a Bug
VCV productions – IE2– Gonna Get You C1V1C2V2 –
B, G, CH combinations IE2 – Booga Choo Choo
CH+W combinations IE1 – Express Train
T +N and D + Y combinations DS1 – Tiny Tony
G+N combinations– RR2– Ha Ha Hiding
W+R combinations- RR2 – Where Did My Shoes Go?
H+G combinations- DS2 – I See a Bug
Multiple consonant combinations DS2 – Let Me Hear You Say
Isolated sounds, Single word repetition – CVC and CVCV, and Chains of 3- IE1– Milk and Juice; Baby Blowing Bubbles; Put the Sound on the End IE2 – Hi; Let’s Eat RR1 – I Love DS1 – Jump on the Choo Choo; Happy Birthday Cake and Cookies; A Monkey, A Moose, A Mouse; Tiny Tony; Fish, Sharks, and Shells DS2 – Bus, Boat, Bike; Hippopotamus; Talk and Look; I See a Bug
2-word phrase repetition and 2-4 syllable words- IE1 – Puppy, Puppy, Puppy; Barefoot Toes; Bye Bye IE2 – Hi RR1 – Cheese and Macaroni; Bananas; No Way RR2 – Where Did My Shoes Go?; Snowman; Alphabeat DS1 – Happy Birthday Cake and Cookies; A Monkey, A Moose, A Mouse; Wheels DS2 – Bus, Boat, Bike; I See a Bug; Let Me Hear You Say; Talk and Look; In, Out, Up, Down AMG – Animal School, Walking Elephants Consonant sound blending DS1 – A Monkey, A Moose, A Mouse.
Teaching a child with apraxia to talk is undoubtedly a challenging task, but with persistence, patience, and the right support, significant progress can be achieved. Incorporating tools such as music and providing ample opportunities for repetition and practice are essential to success. Additionally, working closely with SLPs and other professionals can help create a comprehensive and effective therapy plan tailored to the child’s unique needs. Remember that every child’s journey with CAS is different, and their progress may take time. Celebrating small milestones and maintaining a positive attitude will go a long way in helping the child improve their speech and language abilities. | <urn:uuid:a36bb1e2-c0e9-4216-b858-56b730e38574> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 9,373 |
Spectacular animations exhibiting lightning storms throughout the Earth have been put along with knowledge from a brand new satellite tv for pc challenge that can make it simpler for forecasters to foretell extreme storms.
The European climate company, Eumetsat, and the European Area Company (ESA) launched the primary animations utilizing knowledge captured by the Leonardo Lightning Imager, which was launched on the Meteosat Third Era satellite tv for pc system above Africa final December.
Described by the ESA because the « first European lightning hunter », the system has cameras overlaying Europe, Africa, the Center East and elements of South America and might detect a single bolt « quicker than the blink of an eye fixed ».
Undertaking supervisor for the imager, Guia Pastorini, stated: « The Lightning Imager has 4 cameras and every one can seize 1,000 photographs per second, day and evening, detecting even a single lightning bolt quicker than the blink of an eye fixed.
« Because of particular algorithms, knowledge is processed on board to ship solely helpful info to Earth, supporting the event of extra correct climate forecasts, in addition to contributing to the research of climate phenomena and air transport security.
« Along with ESA and Eumetsat, and coordinating a world industrial group, Leonardo has been engaged on this excellent know-how for 10 years, and immediately we’re very proud to current the pictures of the primary European lightning hunter, the one on this planet with these distinctive performances. »
Animations of the storms have been created utilizing a sequence of photographs and uncooked knowledge from lightning measurements captured throughout a time of 1 minute.
Knowledge from the Meteosat satellite tv for pc’s different primary Earth statement instrument, the Versatile Mixed Imager, may also be used to assist forecasters and climate specialists monitor future storms.
Eumetsat director-general, Phil Evans, stated: « Extreme storms are sometimes preceded by abrupt adjustments in lightning exercise.
Learn extra on Sky Information:
How will El Nino affect the UK’s climate?
Tropical storms type in Atlantic in June for first time
« By observing these adjustments in exercise, Lightning Imager knowledge will give climate forecasters extra confidence of their forecasts of extreme storms.
« When these knowledge are used at the side of the high-resolution knowledge from the Versatile Mixed Imager, climate forecasters might be higher capable of monitor the event of extreme storms and have an extended lead-in time to warn authorities and communities. »
WEEZYTECH – Copyrights © All rights reserved | <urn:uuid:78f78f11-8244-4fe6-9b19-822d8347c3a0> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 2,654 |
The National Centers for Environmental Information (NCEI), a National Oceanic and Atmospheric Administration (NOAA) organization, has recently announced that 2017 was the costliest year on record for the U.S. when it came to severe weather. In 2017, the U.S. experienced 16 separate weather and climate disasters that resulted in $1 billion dollars of damage or more. This year ties 2011 for total number of $1 billion-or-more disasters, and includes three hurricanes, two flooding events, three major tornado outbreaks, five major storm events, the freeze in Georgia, a drought in North Dakota, and Western firestorms.
Even though 2017 is tied with 2011 for the number of $1 billion-or-more events, the total monetary damage for the 2017 season has set a new-record of $306 billion. This beats 2005, which set a record of $214.8 billion, due largely to hurricanes Dennis, Katrina, Rita, and Wilma.
Of this year’s hurricane and other natural disasters, the insurance industry will be paying for about $135 billion worth of damage, a new record. According to a press release from Munich RE, a major reinsurer, the total cost of natural disasters worldwide for 2017 was $330 billion. 2011 holds the record for highest global cost, at $354 billion, due mostly to earthquakes that year in Japan.
Last year was certainly a year of extreme weather events, and while not a new baseline for the following year, there does seem to be an increase in the average amount of fiscal damage caused by natural disasters every year, even when adjusted for inflation.
The NCEI is often called upon to give predictions of future weather patterns, and they have compiled a list of all $1 billion-or-more events from 1980 to 2017. Since 1980, there have been 219 weather events that cost at least $1 billion (adjusted for inflation). For the years between 1980 and 2017, the annual
average was 5.8 events. In the last five years, 2013 to 2017, the average was double, at 11.6 events. This indicates that the number of very destructive weather events has gone up and will continue to go up.
The rising global average temperature could be a key driver in this change, as warmer air holds more rain, warmer waters create stronger hurricanes, and rising ocean waters cause more flooding, which all leads to stronger storms. Data from NOAA shows that the U.S. had its third warmest year on record, and Asian countries that experienced strong flooding also had above average temperatures. If curious, the announcement and accompanying data is available online at ncdc.noaa.gov/billions. | <urn:uuid:8500df6a-75e0-4a10-b3c9-8324e92526c4> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 2,559 |
Megami Magazine volume 155 (April 2013) came right at the end of the winter 2013 season so there are a number of posters for completed series, but there are a few for series that are still airing. The cover features Akane from Vividred Operation in her transformed state. Her smile and pose really help to showcase her cheerful side and brighten the magazine’s cover. Before getting into the posters, just remember that any super ecchi content isn’t shown directly on this page, you’ll have to click on the links to view them.
This is the first time I’ve seen something like this from Megami. The cover actually folds out to show Rei on the opposite side of Akane. What’s even cooler is that the text in the background is mirrored on Rei’s side, helping to contrast the two characters.
The next interesting thing about this volume is that the first poster isn’t actually a poster, but a large fold-out consisting of the girls from Idolmaster in recognition of their upcoming movie. This fold-out is twice the size of a regular poster so I had to take a few shots and stitch them together, but it’s great to see them fit all of the girls into one illustration even if it can’t be taken out of the magazine.
The first regular poster has Kobato and Yukimura changing on a bed. It’s not particularly impressive when compared to the previous volume’s Boku wa Tomodachi ga Sukunai NEXT poster, but still cute.
For once Megami actually has a Love Live poster where the characters, outfits, and background all flow together to create something that looks flawless.
Kud seems to get the most attention out of all of the Little Busters girls, but on the bright side she’s never alone so it gives characters like Rin to make an appearance. I like how this illustration has supplemented the plain bed scene with some pillows and ribbons. The folds in their clothes and the way Rin’s hair spreads out also helps to enhance the appeal of this poster.
With the Index movie coming up as well, characters from that series are also getting some of the spotlight in Megami. I honestly think the illustrations used so far (this one included) could’ve been much better.
I don’t really have much to say about this poster, it’s the perfect example of an average Megami poster: not too impressive, but nothing is wrong with it.
Aoi and Charles from Da Capo III seem to be playing dirty by going with the naked apron trick.
This poster is an example of how you can take something plain like a bikini shot at the beach and make it more impressive. To start, rather than use a single tone for the skin, it’s actually different shades depending on its exposure to the sun, which is clearly shown by the light rays to be in the top right. Next, having some sand on Katsu’s bottom makes it seem more like they’re at the beach. Having an actual background also helps.
I can’t say I was too happy about this Kotoura-san poster. Except for the detail in the fishnet stockings there isn’t really much that stands out.
As far as Star Plus One posters go, this one is actually not as eye-catching, but it still looks pretty.
It feels a bit weird to see two samurai dressed up as maids doing a heart pose, but then again, I’m not watching Hyakka Ryouran.
Despite the ecchi level, I actually thought this poster was nice. The lines were done smoothly, giving the characters nice curves.
Personally I find things like camera settings in an illustration to be distracting, but besides that, this Robotics;Notes poster is quite detailed with al of the snacks lying around. It’s also fun to see the characters in nekomimi maid outfits.
I think this Henneko poster of Tsukiko is by far the most detailed in this volume. Not only does Tsukiko simply look adorable, but the amount of effort put into making the pockets of light shining on her as well as the different shades of moss behind her is amazing, making for one stunning illustration.
The Minami sisters always seem to have fun together, especially when they go out to places like the beach.
The Chikaoka Sunao poster in this volume has the characters indoors for a change. I didn’t get the same calming feeling from this one as I did from the others, but maybe it’s because studying isn’t exactly a calming activity. I wonder if they’re at a WcDonald’s.
One anime last season that seems to have slipped under my radar is Kick Start Generation. It appears to be a one episode OVA based on a visual novel. I’m not too sure what it’s about, but if I find it I’ll certainly watch it.
The Anime Character Catch Up section covers some of the series that are coming this year. Of course, number one is the highly anticipated Prism Nana anime. Many of the others like Nyaruko and Oreimo have already started airing.
Another interesting unaired series to note is Choujigen Game Neptune, which is a spin-off of the Neptunia PS3 game. The characters look a lot cuter.
As with the past several volumes, the back cover again features a full Puchimas ad.
There were no freebies with this volume, but as usual there was a B2 sized poster. The first side has an illustration of some of the Girls and Panzer girls playing at the beach. I think the character designs more than anything make this poster worth looking at.
The reverse side keeps up with the beach theme by featuring Rei in a black bikini. Attractive? yes, plain? a little bit. The illustrations on both sides of the B2 poster are nice, but I know Megami can do better.
Taking into account all of the posters though, this was an above average volume. Except for the Kotoura-san and Index posters, there was really nothing that looked terrible. As you can probably guess, my favourite was the Henneko poster of Tsukiko and I also liked the Idolmaster fold-out. While I didn’t mention it earlier, you should definitely get this volume if you’re an Idolmaster fan because there is a lot of content on the series, or if you’re a Vividred fan for the cover and poster. | <urn:uuid:ddf37448-989e-4b2b-9a4d-a7d09cb2e1fc> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 5,924 |
We love to bring you data mine info because it’s fun and interesting to speculate about what might make it into the game. As always, remember that this might contains spoilers, this is not official SWTOR news and we don’t actually know if any of this info will end up live in the game. With that said, let’s check it out!
Here is some new info about 2.3 PTS data mined files a well as some corrections:
Well it’s that time again.
Going through the files I found artwork for new companion customizations for Qyzen, Skadge, Sgt. Rusk, Gault, Xalek, Ashara, and Yuun. Can’t really show them to you, as I haven’t had time to play around with character/npc models. They don’t have associated item entries, so they’re probably a little ways out. Apparently these went live with 2.2.2, and were body skins for existing customizations. Yay, for small fixes!
Treek on the other hand has 3 new customization item entries and artwork in addition to the currently known ones. A quick search of the usual vendors on the PTS did not turn them up.
Special Note: Treek’s Legacy unlock logic APPEARS to require the completion of her introductory quest once, before her Cartel Coin unlock option is available (a la HK-51). Which means only Legacy 40+ characters could have her, and all the uproar was over nothing.
Additional Note: Some have linked to the Eric Musco forum post stating that Treek will not have a Legacy requirement when purchased with CC. This is not how it appears to function on the PTS, and given this information. It’s possible that this will be changed. Personally I’m betting on a miscommunication, and Treek functioning as currently implemented.
Could someone please test this on the PTS with an account that hasn’t already done Treek’s introductory quest? Please provide a screenshot of the Character Perks and Global Unlock>Other legacy windows for verification.
Now that’s out of the way. There’s this:
- Tauntaun Redfur – Unlocks the Tauntaun Redfur mount. Movement speed increases based on the rank of your Speeder Piloting skill.
It looks like the work on the Tauntaun mount is progressing. I hope it’s not more than a patch or two out.
As for PvP, there was one little tidbit I ran across last time that I didn’t include in my other 2.3PTS post. The locations of the new “arenas” they mentioned are Corellia, Makeb, and Tatooine. There’s also no complicated WZ game state scripts, or anything more complex than spawn/respawn shield and multiple round coding for them. They could be honest to goodness small group PvP Arenas. Or, they could just be an early test, unused code, or misinformation. Take it as you will.
Everything else has been pretty much covered by Dulfy. Though I did sign up for some of the special F2P promotions awhile back, and my PTS character received an in-game mail for the pets. So maybe they are finally rolling out the fix for that promo. | <urn:uuid:f307a6cf-6b15-4b72-8746-09e3e631d8bc> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 2,878 |
If the following headline grabbed your individual awareness, after this you probably got word of this innovative device. Maybe you have regarded about it intended for a extended time, or it could be the outbreak has spurred your interest in such program.
Some providers choose present day business gear for not any reason. Normally, they really want to match the circumstances to be able definitely not to provide a chance that will more advanced resistance. Others are skeptical of switch and are generally for this reason practical. Covid-19 possesses created unique conditions for all areas about all of our everyday living. Educational institutions, universities or colleges, company give good results distantly. It would not have access to been attainable without better technology. That can be why institutions around the very world happen to be actively embracing board of directors portal guru services.
Questions Related to Board of Directors Portal
Is It Safe?
We are unable to question the case of safety since that was the major process regarding the web developers. They recognize that online hackers work night and day and establish their expertise. This program is possibly not some basic record web hosting service support. There are actually safety mechanisms here which are more than the strength of attackers. Like to be able to exploit cloned data, an authorized needs decryption keys. Of course , they carry out not unique them. This exceptional camera is not necessarily the actual basic safety option, however it is definitely reliable.
are always on shield, so customers have not any factor that will worry concerning your trickle out.
How many years Does indeed It Consider To turn into a Positive Person of the Platform?
If a person choose a quality product, then that process will not likely take very long. The should often be user-friendly and uncomplicated plus obtainable with any sort of device. Typically the intuitive user interface is definitely a little research for paperwork and day to day staying for contact together with acquaintances. Certain of you may be unlikely to require help out of your provider to get going. Still, a new team of experts is ready to be able to guide. Typically the training training course is possibly not extended. Later on, every single end user, if at all possible, possesses the opportunity to contact technical support to mend the condition or to have option to an issue.
Can Board Portal Software Develop Productivity?
Certainly yes, your own team will work in considerably more relaxed circumstances. What’s more, these no longer experience to complete the particular labor intensive contracts. One other very important factor is certainly company meetings without the need to journey scattered. Negotiators present your high quality with involvement without becoming overpowered through company journeys. Can be it possible to collaborate in more comfortable cases than your professional with free board portal software gives you? You can be just about anywhere in addition to make use of any kind of out there gadget. With the occasion of pressure majeure, your current team can certainly discuss crucial issues at any time, having often the mandatory files currently happening. If perhaps you own several encounter running a business, then simply you already have answered this specific question.
How To Choose a Card issuer?
Managers ought to determine just what their business demands together with what options will allow these people find elements completed. It will probably create it better to find the main right company. Your likely provider, therefore, will fully understand everything that assistance to offer to help meet your online business needs.
Make time to browse reviews of board management software. Perhaps you actually have an opportunity to talk using you regarding this software package. That is usually the fastest way to learn about concerning key facts of your application and also its particular pros. First hand information is obviously the actual most trustworthy. | <urn:uuid:2d8f3ee3-2dbf-49ab-80aa-75d750a1ed13> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 4,070 |
This has been a busy week, I am gearing up for my LTS lecture
on the 30th. Its free for everyone and I hope you all tune in to watch it!
The subject matter should be interesting to all Java developers and its essentially how you build a cross platform solution implementation, you don't need any knowledge of Codename One since I won't be discussing it much. Its about device issues and how these work with the JVM. So feel free to distribute this to your friends who aren't necessarily Codename one developers.
But this in't why I've been busy, we had a major server failure this week which is rare since our architecture is highly redundant and should be resistant to failure. To understand what failed one needs to understand how Codename One servers actually work. When you send a build to the cloud you aren't sending it to a build server. You are sending it to our cloud server which is based on Google's App engine for Java.
App engine is highly redundant and pretty stable so its very unlikely that it will fail, a failure in app engine would mean that our web console (where you see the build results appear) would stop working and you would be unable to send builds. Even if a build server fails only a specific build will fail, since we have redundancy all servers would need to fail for service to stop entirely.
The first failure included an in-ability to send a build while the console itself and everything else worked as expected, to make matters worse on the server side we got no error whatsoever and no indication that something was going wrong. Investigating something like this is naturally remarkably difficult! App engine uses a tool called the blob store to perform uploads, so when data is submitted to app engine it really reaches a Google
internal service after which it arrives at our Servlet where it is added to the database and delegated to a build server. Unfortunately, we weren't getting to the servlet! The failure occured within the Google upload process which is effectively seamless to us. So we started looking at whether upload or the blob store service were down, they were not. We were able to upload (e.g. device logs etc.).
Since the blob store uses a Google internal URL the upload process consists of two distinct stages, the user needs to "request" an upload URL from google and then upload to that URL (after which he is redirected to the servlet). That was the culprit, when we requested a URL we passed the user credentials. The idea was to save blob store space/upload time in the case of a user who ran out of credits. Google extracted the arguments that we passed to the servlet (notice that these arguments are never explicitly passed to the blob store which doesn't get the request context)! These arguments were then appended to the URL returned (which is naturally a post URL) creating an illegal URL that can't be fixed. We made several attempts at patching this such as editing the URL dynamically (using substring, url encoding etc.) all of which produced cases such as uploads getting "swallowed" with no redirect to the actual build servlet. Eventually, we just redirected without the arguments and this worked around the issue. This was the second time this year where we had a failure of this type (the first was due to Google App Engine being down for a couple of hours). This still puts us at a 99.999
% uptime on an annual basis which is pretty good.
Notice: This post was automatically converted using a script from an older blogging system. Some elements might not have come out as intended.... If that is the case please let us know via the comments section below. | <urn:uuid:39b65d2e-e8c9-47fc-a73c-126151bd518b> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 3,634 |
Received Date: June 12, 2015; Accepted Date: June 25, 2015; Published Date: July 25, 2015
Citation: Shamsuzzaman MM, Rashid AHA, Mamun MAA, Mazumder SK, Haque MA (2015) Present Status of Marine Puffer Fishes in Bangladesh. J Aquac Res Development 6:370. doi:10.4172/2155-9546.1000370
Copyright: © 2015 Shamsuzzaman MM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at Journal of Aquaculture Research & Development
The study was conducted to create a checklist of available species of marine puffer fishes of Bangladesh. Cox’s Bazar was selected as the study area as common marine fish landing stations are situated there. The study was conducted for a period of one year form July 2011 to June 2012. Puffers were sampled form the fishing vessels on landing stations after return from the sea and also form the local fish markets in four seasons viz. winter, pre-monsoon, monsoon and post monsoon. Most of the fishes were much abundant in the winter season than that of other seasons. After the completion of the study, a total of nine marine puffer fish species were found as- Takifugu poecilonotus, Chelonodon laticeps, Takifugu oblongus, Arothron stellatus, Lagocephalus lunaris, Takifugu vermicularis, Arothron Leopardus, Lagocephalus sceleratus and Arothron immaculatus. The most abundant species was Takifugu vermicularis followed by Lagocephalus lunaris while the lowest abundance was observed for Takifugu poecilonotus.
Puffer fish; Cox’s bazar; Seasons; Bangladesh
Puffer fishes belong to the family Tetraodontidae . The family includes many familiar species, which are variously called puffer fish, puffers, balloon fish, blowfish, bubble fish, globefish, swellfish, toadfish, toadies, honey toads, sugar toads, sea squab etc. They are called puffer fish because of their ability to inflate themselves with water or air when they feel threatened. They use air to expand its body to look intimidating to predators. Tetradotoxin, the puffer fish’s toxin, is usually present in the liver, gall bladder, intestine, gonads (ovaries and testes), eggs, and skin of the fish in sufficient amounts to cause intoxication among people who eat the fish. These toxins are 1,200 times more deadly than the poison cyanide and can affect a person’s central nervous system of human . Mild intoxication includes light-headedness, numbness of the lips etc. Tetradotoxin poisoning deadens the tongue and lips, and induces dizziness and vomiting, followed by numbness and prickling over the body, rapid heart rate, decreased blood pressure, and muscle paralysis. The toxin paralyzes diaphragm muscles and eventually stops breathing . They are often cheaper than other fishes, and because they contain inconsistent levels of toxins between seasons, there is little awareness or monitoring on its danger. Actually the puffers do not produce toxins themselves. Tetrodotoxin is assumed to be a metabolic product of the host. This toxin is produced by microorganisms, mainly algae engulfed by the puffer which is a subject related to season and this toxin is then bioaccumulated in their body. This puffer fish poisoning is relatively common in some Asian countries, particularly in Japan, Thailand, China and also in Bangladesh . This toxin is both heat and acid stable , so are not destroyed by cooking, freezing or by digestion process. Tetrodotoxin poisoning has no specific antidote, but immediate supportive treatment and judicious administration of neostigmine, along with atropine, can minimize fatalities .
In Bangladesh, puffer poisoning attributed to ingestion of puffers as a rising health problem over the last 10-15 years in the country. These incidences occurred due to ingestion of puffers, mainly the freshwater forms . Perhaps, in many cases in the ancient times puffer intoxication could not be identified due to the lack of research and proper examination. The most frustrating case is even during this age of science, people are dying after eating puffer. In addition, there is no exact information of when and where, for the first time the incident of death occurred in Bangladesh after eating this fish. Between 1994 and 1996, seven poising incidents involving 43 patients with 16 deaths due to consumption of freshwater puffer fish were reported . In 1998, a serious food poisoning incident involving 8 people with 5 deaths occurred in Cox’s Bazar due to ingestion of roe of a marine puffer Takifugu oblongus and, the panic has spread all over the country. In 2008, in South Bateshwar village of the Belabo Upzaila, Narshingdi, 95 people who had consumed puffer fish; 79 developed toxicity characterized by tingling sensation in the body, perioral numbness, dizziness, and weakness, 16 of them died. A total of 36 victims, including seven deaths incident resulting from the ingestion of the marine puffer Takifugu oblongus occurred at Degholia in the Khulna district of Bangladesh on 18 May 2002.
In Bangladesh, only 3 species of freshwater puffer fish (Tetradon cutcutia, Chelonodon patoca and Tetradon fluviatilis) are available but we do not have any published research information regarding the species numbers of marine puffer. Marine puffers are mainly distributed in the Bay of Bengal. Coastal fishermen reported that some local businessmen distributed the fresh puffers to non-coastal parts of the country , where people were fully unfamiliar with those larger varieties, to make a quick profit. Lack of knowledge about marine puffer toxicity contributed to the outbreaks. Moreover, the researchers found some large dried marine puffer fishes to be sold in the local market of Sylhet, where those are sold by attributing new names as nontoxic marine fishes and no publication is yet observed on this important matter. In this context, the study was undertaken as an emergent issue. The objective of the study was to make a checklist of marine puffer fish available in the country which will be helpful in awareness making among the people regarding the puffer fish and their intoxication.
Study area and period of investigation
The field investigations were conducted for a period of one year from July 2011 to June 2012. Fish samples were collected from two stations of Cox's Bazar Sadar Upazila, Bangladesh in four different seasons. The fish collection stations were Fishery Ghat Bazar and Nazirar tek Artisanal Fish Landing Center (Figure 1). The seasons were- (1) the dry winter season, from December to February; (2) the transition period, from March to May (pre-monsoon); (3) the rainy season, from June to September (Monsoon); and (4) the second transition period, between October and November (post-monsoon) (Figure 1).
Collection of fish sample
Puffers were sorted from the catch were directly collected from the fish baskets when the fishing boats came to the landing center and immediately preserved with 10% formaldehyde solution in plastic jar and brought back to the laboratory of the Fisheries Faculty, Sylhet Agricultural University.
Collected samples were washed gently with tap water and then the morphometric meristic characters were pointed out. Taxonomic studies were done on the basis of the physical features of the collected specimens. The fishes were identified following the works of Holthuis, George, Hossain, Jhingran, Howladar, Shafi and Quddus, Day, George et al., Huda and Hoque and Fischer and Bianchi [12-23]. To establish the views concerning taxonomy of a species, several specimens of different sizes were examined. Attempts have been made to provide valid scientific name of all the genera and species and were listed in accordance with the rules and principles as set forth in the international code.
Catch composition analysis
The weights of each group of species were taken and their percentages of composition were determined. The total numbers of fish in each taxon were also recorded.
This project was undertaken as an emergent issue and research were conducted only for one year. During this period a total of 9 (Nine) species were found from the marine habitat, which are described as follows:
1. Species: Takifugu poecilonotus; Synonyms: Fugu poecilonotus, Fugu poecilonotus, Tetraodon poecilonotus; English names: Fine patterned Puffer, Pufferfish; Local name: Potka; Maximum Size: 20 cm (TL); Meristic: D. 12-15; A.10-13; P1. 11-14; P2. Absent
It's ovary and liver are violently toxic, gonad and skin strongly toxic and flesh is weakly toxic (Figure 2).
2. Species: Chelonodon laticeps; Synonyms: Fugu laticeps, Tetraodon laticeps; English names: Blow Puffer, Pufferfish, swellfish; Local name: Potka; Maximum size: 25 cm (TL); Meristic: D. 11-15; A. 11-15, P1. 10-13; P2. Absent
Toxic part of this puffer is skin and viscera (Figure 3).
3. Species: Takifugu oblongus; Synonyms: Tetrodon oblongus Bloch, 1786, Ausland . Fische, 2: 6; Sphoeroides oblongus Hora, 1924, Mem. Asiat. Soc. Bengal, 6:498; Torguigener oblongus Munro, 1955, Marine and Freshwater Fishes of Ceylon, p. 280; English names: Lattice Blaasop, Oblong Blow Fish; Local name: Dora Potka; Maximum size: 40 cm.
Description: Body fairly elongate. Head broad. Top of head, front part of back and belly with spinules. Eye with a free orbital rim except above. A pair of nasal organ before eye. Upper lateral line running along back anteriorly, gently sloping down to caudal peduncle posteriorly. Lower lateral line, slightly undulating line from chin to caudal base. Head and body covered with long spines.
Distribution: Indo-West Pacific region from South Africa to Indonesia and Japan including India, Sri Lanka and Bangladesh. Several specimens were collected from St. Martin’s Island.
Status and conservation: Not considered as a Threatened fish in the Red List of IUCN (2006).
Remarks: The fish contains poison called tetradotoxin in the internal organs, especially in liver and ovaries. There had been reports of death by eating the fish. Skin, gonad and viscera of this puffer are toxic (Figure 4).
4. Species: Arothron stellatus;
Synonyms: Tetrodon lagocephalus stellatus Bloch and Schneider, 1801, Systerna lchthyol., p. 503; Tetrodon stellatus Day, 1878, The Fishes of India, p. 705; Diodon asper Cuvier, 1818, Mern. Mtis. Hist. Nat. Paris, 4: 138; Tetraodon calamara Ruppell, 1829, Fische Rot hen Meeres, p. 64; Kanduka michiei Hora. 1925, Rec. indian Mus., 26: 579; English names: Starry Puffer Fish, Starry Blowfish; Local name: Badami Potka; Maximum size: 120 cm .
Description: Body oblong. Dorsal profile arched, upper profile of snout slightly concave. Interorbital space broad and flat. Eye high, above level of mouth, but not interfering with upper profile of head. Carries 2 nasal tentacles on each side. A suture dividing both the jaws; Jaws modified to form a beak of 4 heavy, powerful teeth, 2 above and 2 below. Back and sides to below level of pectorals covered with brown spots. Pectoral yellowish with brown spots. Meristic: D 10-11; P1 17- 19; P2 absent; A 10-12.
Status and conservation: Not in the Red List of IUCN Bangladesh (2000).
Distribution: Indo-Pacific region from Red Sea throughout South- East Asia to Pacific Ocean including the Bay of Bengal and Bangladesh. Reported from Bangladesh by Shafi and Quddus . Also reported from the Sundarbans area of Bangladesh .
Remarks: All species of the group have the ability to inflate their body with air. Considered as the giant among puffers reaching a total length well in excess of a meter. The ovary of this species is violently toxic while the flesh is nontoxic (Figure 5).
5. Species: Lagocephalus lunaris
Synonyms: Tetrodon lunaris Bloch and Schneider, 1801, Systema Ichthyol., p. 505; Tetraodon lunaris Bleeker, 1852, Verh. Bat. Gen., 24: 12; Spheroides lunaris Jordan and Seale, 1907, Proc. Day. Acad. Sci., 10: 14; Gastrophysus lunaris Munro, 1955, Marine and Freshwater Fishes of Ceylon, p. 280; Sphoeroides lunaris Weber and de Beaufort, 1960, Fishes of the Indo-Australian Archipelago, p. 378. English names: Green Pufferfish, Blowfish, Green Rough-backed Puffer; Local name: Photka
Description: Body elongate with a rounded back. Head broad; bony interorbital space flat. Eyes high, above level mouth. A pair of nostrils before each eye. Two lateral lines, lower line is straight ridge from chin to caudal peduncle. A yellowish line from eye to middle of caudal.
Largest recorded size: 45 cm standard length. Meristic: D XII-XIV; P1 16-19; P2 absent; A 11-12.
Distribution: Indo-West Pacific region including India, Bangladesh, Thailand, Malaysia, Indonesia, the Philippines, Hong Kong and China. Status and conservation: The status of the species has not been assessed in the Red List of IUCN Bangladesh (2000) (Figure 6).
6. Species: Takifugu vermicularis
Synonyms: Fugu vermicularis, Spheroides abbotti, Tetraodon vermicularis:English names: Pear puffer, Purple puffer, Purple Pufferfish; Local Name: Potka; Maximum size: 30 cm (TL); Meristic: D.12-15; A.10-13; ; P1. 16-19; P2. Absent.
Toxic part of this puffer is skin and viscera (Figure 7).
7. Species: Arothron Leopardus
Synonym: Tetrodon leopardus Day, 1878, Fishes of India, p. 706; English name: Banded Leopard Blowfish; Local name: Bagha Potka
Description: Body elongated. Dorsal profile slightly arched. Eyes high, above level of mouth, 1½ diameter apart. Spines extend from front edge of eyes to dorsal fin. Below they are close together and reach the vent. A single lateral line on side of body. Nasal organ with 2 bifid tentacles. Dorsal situated in the last third of the body. Reticulated narrow black interspaces between large white spots on caudal and dorsal. Meristic: D 1l; P1 18; P2absent; A8-9.
Distribution: Indian Ocean including India, Sri Lanka and Bangladesh.
Status and conservation: The status of the species has not been assessed in the Red List of IUCN Bangladesh (2000).
Remarks: Its overy is violenty toxic, liver and skin also toxic while flesh is nontoxic (Figure 8).
8. Species: Lagocephalus sceleratus
Synonyms: Tetraodon sceleratus Gmelin, 1789, Sys. Nat. Linnaeus, p. 1444; Gastrophysus argenteus Bleeker, 1855, Verh. Akad. Amsterdam, 2: 16; Tetrodon sceleratus Day, 1878, Fishes of India, p. 701; Gastrophysus sceleratus Munro, 1955, The Marine and Fresh Water Fishes of Ceylon, p. 280; Spheroides sceleratus Jordon and Snyder, 1901, Proc. U.S. Nat. Mus., 24: 234; English names: Spotted Rough-backed Blowfish, Silver Toadfish; Local name: Photka
Description: Body elongated with a rounded back. Head broad; bony interorbital space flat. Eyes high, above level of mouth. Whole body spinous except the sides. A pair of nostrils before the eye. Sensory canals on head surrounding the eyes. Two lateral lines, lower line running from the chin in a straight line to base of caudal. Dorsal and anal pointed, somewhat falcate. Pectorals pointed. Caudal forked. Olive green above with numerous brown or black spots. Whitish laterally and below with a silvery longitudinal band. A triangular white spot in front of the eye. Fins pinkish. Largest recorded size is 110 cm in standard length. Meristic: D. 10-12; A. 9-11; P1. 16-17, P2. Absent
Distribution: Indo-West ‘Pacific region from Southern Africa to Australia including India, Sri Lanka and Bangladesh.
Remarks: Its liver and ovary are strongly toxic while skin and flesh are weakly toxic. The poisonous organs are removed by specialist cooks on the day fish is caught (Figure 9).
9. Species: Arothron immaculatus
Synonyms: Tetrodon immaculatus Bloch and Schneider, 1801, Syst. lchth., p. 507; Tetraodon sordidus Ruppell, 1829, Fische Rothen Meeres, p. 64; Tetraodon aspilos Bleeker, 1851, Nat. Tijds. Ned. Indie, 2: 495; Tetrodon irninaculatus Day, 1878, Fishes of India, p. 703; Tetraodon iinrnaculatus Fowler, 1903, Proc. Acad. Nat. Sd. Philadelphia, 55: 165; English names: Immaculate Puffer, Immaculate Blowfish; Local name: Potka; Maximum size: 30 cm .
Distribution: Indo-West Pacific region from Red Sea and East Africa (including the south coast of South Africa) to Indonesia, north to Southern Japan including India, Bangladesh, Sri Lanka, Malaysia, Maldives, the Philippines, Thailand.
Status and conservation: Not in the Red List of IUCN Bangladesh (2000) (Figure 10).
Frequency of fish species presence
During the study period nine puffer fish species was found in the observed area. Among them the highest presence were observed for Takifugu vermicularis (20.2%) followed by Lagocephalus lunaris while the lowest were observed for Takifugu poecilonotus (Table 1).
|Fish Species||Percentage (%) by presence (number)|
Table 1: Frequency of fish species presence in the research areas
Seasonal variation of fish species
The species were usually abundant in the winter seasons. On the other hand in the monsoon they were found to be least abundant in the catch (Table 2).
|Winter Season (December to February)||Pre-monsoon period (March to May)||Rainy season (June to September)||Post-monsoon (October to November)|
++=More present, +=Less present, -=Absent
Table 2: Seasonal variation of fish species between two study area
This study provides information regarding the occurrence of puffer fish in Cox’s Bazar Sadar representing Bay of Bengal. There is no published research data on marine puffers availability in Bangladesh. Moreover, catching of fish is largely dependent upon seasons, types of trawl nets used and location of fishing spots. So, from this short period of research, only 9 species were collected and observed. Most marine puffer fishes are not attractive looking and have very lower value as table fish in context of Bangladesh; so most of those are discarded in the sea from catch after sorting on trawl board which hampers its easy collection from landings.
The project was funded by Sylhet Agricultural University Research System (SAURES) under the University Grant Commission (UGC) of Bangladesh. We would also like to acknowledge the use of the universities research grant while preparing this publication. | <urn:uuid:8264bcf2-6dc1-4652-912c-735c966913ec> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 18,128 |
Browse by author
Lookup NU author(s): Professor Steve BullORCiD
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
Conventional methods for analysing nanoindentation load-displacement curves to obtain mechanical properties, such as Young's modulus or hardness, require careful calibration of the indenter tip end shape and can overestimate hardness in cases where significant pile-up occurs. This paper introduces alternative methods for analysis, which are not so susceptible to such problems. Results from TiN and nickel suggest that the slopes method recently introduced by Oliver is an improvement on the other existing analysis methods.
Author(s): Bull SJ
Publication type: Article
Publication status: Published
Journal: Zeitschrift Fur Metallkunde
ISSN (print): 0044-3093
Publisher: Carl Hanser Verlag | <urn:uuid:bd55fcfb-4404-49f8-991c-b46a7966702a> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 887 |
Rated 3.7 out of 5 by 3
Rated 4 out of 5 by Yoyoartiste I now wake up in the morning without body aches.
This has been a very satisfactory product. I only wish it had a way to wrap around the mattress. I had to find clips to attach it to the mattress cover.
August 4, 2014
Rated 2 out of 5 by Soozamagooz Not What I expected
I bought this topper for a guest bed that has a thinner, older but still very gently used mattress on it. I wanted to add a little more oomph and luxury to the bed as I am re-furbishing the room. The whole reason I chose this topper was because it shows elastic straps to hold it on. The item came with no elastic. So now it is held on by a mattress cover which is not that snug and there is alot of shifting going on. All the other toppers fit deep mattresses which would not work for me. Also, The topper stays depressed wherever anything lays on it. And unless I completely unmake the bed including mattress cover, I can't pouf it or smooth with my hands. Now I have a lumpy looking, but soft mattress. P.S. I also think this topper may be too cushy for some, but that remains to be seen. I kept the item anyway, since return shipping would have broken the bank ($20 extra shipping involved to get here).
May 21, 2014
Rated 5 out of 5 by nanc411 great comfort
I haven't slept on it very long but it is soft and cuddly. I like that!
July 5, 2013 | <urn:uuid:09fbcabc-05e8-47fd-b3bf-161af93e41f9> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,372 |
The fact that we refer to the different ways chinese people speak as dialects is a little confusing. Actually, the chinese dialects are different languages just as much as, say, English, Dutch, German, French, Spanish, Italian, Portuguese, etc.. So no, they are not mutually intelligible, though they may contain many similarities.
The situation with the writing is a bit different. In fact, only Mandarin has a standard writing system, so no matter which part of China a person comes from, or which dialect is their mother tongue, local publications will be in Mandarin. Therefore, to be able read this material, one must be literate in Mandarin, even if one cannot speak it! Most official publications in Hong Kong are also in Mandarin. However, chinese characters have been adapted in order to write Cantonese, and so some things may be writting in Cantonese. However, under these circumstances, cantonese grammar and vocabulary is used, and therefore may make as much sense to a Mandarin speaker, as say reading spanish would to a french speaker (in other words, they may be able to understand the general meaning if not every word). | <urn:uuid:7caf69ab-44f1-488a-ac15-88096b6a7af3> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,137 |
Perry, FL Groundwater project
During the fall of 1993 the Florida Department of Environmental Protection (FDEP) determined that an experimental and computational study was needed to assess the furthest lateral distance that contaminants, dumped in the Fenholloway river by a paper mill just outside the town of Perry Florida , could penetrate. This study was prompted after complaints from local residents, during the winter of 1989-1990, regarding the color, smell and taste of their well water. At the time chemical analyses were conducted on the surrounding wells where trace amounts of an unidentified inorganic material were found in a small number of wells tested. Proctor and Gamble (owners of the paper mill) paid for the installation of deeper wells for the cases that tested positive for the inorganic substance.
In 1995 the study was completed and its results released to the public. This report contained information on worst case scenarios for both the wet and dry seasons. The motivation for this study was prompted by fears that contamination from the paper mill had traversed through the surface water into the surrounding aquifer; contaminating the wells of nearby inhabitants. Prior to the paper mill being built the Fenholloway river acted as a gaining stream which means that as the river progresses downstream water is constantly added to the flow. The paper mill disrupted this natural process leading to a discontinuity of sorts above and below the wells drilled by the paper mill.
Using data from 1993 the FDEP combined their research, simulations, and knowledge to determine whether the paper mill was in fact contaminating the water. In light of their work Buckeye Technologies Inc., owner of the paper mill, made an agreement with the FDEP, approved by the EPA in 1995, where they agreed to a comprehensive plan to attain Class III (fishable/swimmable) status for the Fenholloway River under applicable Florida law (the Fenholloway Agreement). (annual report 2011)
We're presenting a re-visit to the original study conducted, using current data. With similar computational tools and improved computational power we will be able to see how the region has changed since the initial investigation and to explore the effects that the Fenholloway Agreement has had on the Fenholloway river, the town of Perry's water, and the surrounding area.
We will be using the data from the 2011 Buckeye Technologies annual report and information gathered from an interview with their Corporate Environmental Health and Safety Manager, Ray Andreu. This data will be used to simulate the groundwater movement in the region around the paper mill and the Fenholloway River. We will be simplifying the work that was done in 1993, in particular we will only be studying the wet season of 2011, from June to September.
If you would like to look through the results and methodology of our work, you can download the tar-zipped folder here. This work was done with a fellow graduate student in our department, Nathan Crock, whose website can be found here. | <urn:uuid:98a3e72d-2250-49de-8f2c-d44e7d77aca1> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 3,058 |
Summary: Setting (Timeframe): 27th & 28th centuries
Brief Plot: It's the end of the world as we know it. Can a small group of military boys & girls save the human race?
Categories: Original, Other, Resident Evil, Final Fantasy VI Characters: Kefka
Chapters: 4 Table of Contents
Word count: 3282 Read Count: 594
Other Results: 1 Challenges | <urn:uuid:a7f09441-7657-4409-84ea-2743f8eeb611> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 338 |
Messaging to Motivate Consumers
Longevity and health messaging are unlikely to sell more produce by themselves. According to the Food Marketing Institute’s Power of Produce, produce often is an impulse buy, with top drivers of unplanned purchases being eye-catching displays, hot deals, sampling, recipe and serving ideas and nutrition callouts.
Appearance ranks far ahead of price and nutrition in the produce purchase decision tree. Shoppers also express a strong desire for expanded assortments in locally grown, seasonal, organic, sustainably grown and fair wage/living wage produce items. They do associate fresh produce with digestive health, heart health, healthy weight and having essential nutrients in the diet, and it’s these specific benefits rather than longevity that may be effective in callouts and in-store signage.
Industry veterans remain skeptical. “The nutrition story doesn’t fly,” says Dick Spezzano, produce industry consultant, Monrovia, CA. “People know they can live healthier and maybe longer if they eat fresh fruits and vegetables. That’s not what sells. We need to make it easier to eat fresh produce by taking the mystery out of selection and cooking, ramping up in-store marketing, and enhancing store websites.”
“I would never make a claim regarding eating nuts to live longer,” says Chad Hartman, director of marketing, Tropical Foods, Charlotte, NC. “We don’t do that type of messaging. Health is part of a bigger package.”
“We conduct a lot of research on the health effects of berries on diabetes, metabolic syndrome, cancer and heart disease but we can’t make a claim for longevity,” says Mary Ann Lila, Ph.D., director, Plants for Human Health Institute, North Carolina State University, Raleigh. “I suggest marketing color for health — colors are the beacons for benefits.”
“So many factors contribute to longevity, including genetics, lifestyle, personal habits, exercise, risk behavior and diet,” says Steve Muro, president, Fusion Marketing, Chatsworth CA. “Can we encourage a healthy diet that is rich in produce? Yes. Can we offer promises of increased life spans? No. I suggest that produce managers arm themselves with information on quick and easy preparation and new usage ideas instead. Emotional messaging related to parenting may also have an impact. Feelings are powerful human drivers that can change behavior more than logic can.”
“Consumers are scrutinizing everything, and we need to get them not to second-guess that fruits and vegetables are healthy,” says Lisa Hansen, vice president, McDill Associates, Soquel, CA. “It’s a given that produce helps people live longer and healthier. How do we help consumers make produce part of every meal? It requires the retailer, marketer and grower to work together on innovations like single serve items in a car cup or veggies cut into fun shapes. Healthy is fun, and it doesn’t have to be complicated. If going with a health message, make it compelling and relevant. Consider co-branded content for retailers. Partner with others for co-branded content that includes infographics, tip sheets, website templates and digital campaigns. But maybe health isn’t the most important message; usage is.”
Social Media Speaks
Social media continues to provide a vehicle for engaging consumers and creating pull for produce. The Produce for Better Health Foundation’s (PBH’s) consumer-focused Fruits and Veggies — More Matters Facebook page recently reached its 1 million “Likes” milestone, emphasizing its leadership position as a trusted source for information, health research and tips on fruits and vegetables. PBH produced its first Facebook Live segment in fall 2017 and manages Twitter, Pinterest and Instagram pages.
Personal and in-store technology simplifies communications with customers. Shoppers in general and Millennials in particular will use smartphone apps to scan labels and research items before buying. Food Marketing Institute’s RD, chief health and wellness officer Sue Borra predicts a rise in cooking videos and other ways to marry in-store and digital experiences. “Retailers can create in-store apps with information and answers so that shoppers don’t have to search for department personnel,” says Dick Spezzano, produce industry consultant, Monrovia, CA. “They also can access training videos for staff.”
“Additionally, personalized nutrition solutions open up a very different area,” says Borra. “Consumers today are less interested in, say, heart health and more in my health profile and what meals are right for me.”
A Sampling of Links to Long-Term Health
Reduced risk of diabetes, blood glucose management, reduced inflammation, weight management
Healthy body weight, nutrient adequacy, reduced risk of chronic diseases such as Type 2 diabetes and heart disease; may benefit cognition and working memory
Reduced risk of mortality, heart health, neuroprotective benefits, cancer chemoprevention, antidiabetic properties
Cardiovascular health, improved insulin response, brain health, anticancer properties, gut health; longevity in animals
Urinary tract health, heart health, improved blood pressure, healthy immune system functioning, oral health, anti-inflammatory nutrients that may lower risk of heart disease and certain cancers
Reduced cancer risk, lower risk of heart disease
Reduced overall mortality and mortality from some types of cancer, coronary heart disease, cardiovascular disease, diabetes and respiratory disease. Lower risk of being overweight and metabolic syndrome.
Health and longevity
Reduced risk of mortality, obesity, Type 2 diabetes, cognition
Heart health, cognitive health, reduced cancer risk, gut health, lower mortality rates
News regarding fruits and vegetables continues to get better around the world. A review of studies on 12 different food groups found a positive association between eating vegetables, fruits, or nuts and lower death rates. In the UK, consumption of fruit and particularly vegetables has been associated with lower death rates from cancer and heart disease. Among older adults in two Chinese studies, fruit and vegetable intake correlated with a lower risk of dying. A Taiwanese study showed older adults who spent the most money on fruits and vegetables lived the longest. A French study found that risk of death was significantly lower among people who ate the most produce (and also ate fish regularly). Finnish men who ate the most berries, fruits and vegetables were least likely to die from heart disease or other causes.
Research conducted by Harvard University scientists overwhelmingly supports a relationship between fruits and vegetables, health and longevity. “Our studies are based on three large cohorts: the Nurses Health Study, Nurses Health Study 2, and Health Professionals Follow-up Study,” explains Vasanti Malik, PhD, research scientist, Harvard School of Public Health, Boston. “We look at healthy aging as it relates to intake of fruits and vegetables within the context of a healthy dietary pattern. Over and over, fruits and vegetables have an inverse relationship with diabetes and cardiovascular disease, meaning people who eat the most produce have the lowest risk of disease.” Dr. Malik cautions that one can’t draw conclusions about fruits and vegetables alone because they are eaten within the context of a dietary pattern.
National Geographic fellow Dan Buettner, who coined the term Blue Zones for communities characterized by longevity, asserts, “All of the diets of the Blue Zone centenarians have a “plant slant,” with cornerstones of beans and lentils, greens, local and seasonal vegetables, fruits and nuts.”
“The common denominator in Blue Zone diets is fruits and vegetables. The diets otherwise are incredibly diverse, for example, higher fat in the Mediterranean, lower fat in Asia, and vegetarian and vegan in Loma Linda, CA,” says David L. Katz, MD, director, Yale University Prevention Research Center, Griffin Hospital, Derby, CT. “Any good diet is high in fruits and vegetables; they’re the remedy to everything that ails us.”
It would be naive to think fruits and vegetables, or even diet alone, enhance longevity. A research group in London looked at the relationship between a combination of healthy behaviors and aging without disability, mental health problems or diseases such as heart disease, stroke, cancer or diabetes. The group found the more healthy behaviors, the greater the likelihood of successful aging.
Blue Zones Project
Several years ago, researchers teamed up with National Geographic to identify communities around the world with the highest life expectancy. Five communities — Barbagia region of Sardinia; Ikaria, Greece; Nicoya Peninsula, Costa Rica; Seventh Day Adventists (concentrated in Loma Linda, CA); Okinawa, Japan — stand out for their habits associated with longevity, including a diet rich in fruits and vegetables. Leveraging these learnings, the Blue Zones Project® is helping transform 41 communities across the U.S. into areas where the healthy choice is easy and people live longer with a higher quality of life. The 41 communities are:
Florida: Naples, Bonita Springs, Estero, Immokalee
Iowa: Fairfield, Harlan, Woodbine, Algona, Spirit Lake, Waterloo, Spencer, Sioux City, Oskaloosa, Muscatine, Mason City, Marion, Iowa City, Cedar Rapids, Cedar Falls
California: Redondo Beach, Manhattan Beach, Hermosa Beach
Hawaii: Central Maui, Wahiawa, Manoa/Makiki/McCully/Moiliili, Kapolei/Ewa, West Hawaii, North Hawaii, East Hawaii, Koolaupoko
Minnesota: Albert Lea
Oklahoma: Pottawatomie County
Oregon: The Dalles, Grants Pass, Umpqua, Klamath Falls
Texas: Fort Worth
Wisconsin: Horicon, Juneau, Mayville, Beaver Dam | <urn:uuid:ce847a8a-b5b9-49c9-b42e-15eb07dd2c4a> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 9,678 |
PDF is a familiar file format for most people. Adobe first introduced it in 1993, and later standardized it in 2008 to allow anyone to create PDF files and the tools necessary to do so.
These days there are too many PDF editors to choose from, and they all seem to do the same task. Most of them aren’t worth your time, but it’s also quite difficult to get much done for free.
So here are our top picks for editing and creating PDFs on your Mac.
How to Print to PDF in macOS
Your Mac can create PDFs natively, which means just about any desktop publishing app can become a PDF editor. You’ll miss out on features like interactive forms, but there’s no quicker way to share a document or web page as a PDF.
To export as a PDF in macOS:
- Click File > Print in your editor, browser, or other relevant application.
- Find the PDF drop-down at the bottom of the Print dialog. Click it and choose Save as PDF.
- Give your file a name, specify a password if required under Security Options, then click Save.
Editing PDFs With Preview
In short: Part of macOS. Fine for markup, signing documents, and simple PDF management; not a “true” PDF editor or creator.
Preview is an app that comes pre-installed as part of macOS. It’s a barebones document viewer, but it also includes a few handy PDF tools. Unfortunately, it’s not a PDF creator. You can’t design interactive documents or forms from scratch using Preview, but you can make rudimentary edits to existing ones.
Its best features are its markup and annotation tools. Preview also allows you to rearrange page order, delete pages, import new pages, and export individual pages as separate documents. You can’t edit existing PDF elements or create new ones, which means you can’t “edit” the PDF so much as annotate it.
Preview functions as a better PDF viewer than an editor. You can sign forms using its in-built signature feature, enter text into forms and save the input, and mark up a PDF with shapes, arrows, custom text, and your own scribble. These tools are easy to use and look great on the page, but it’s a far cry from a proper editor.
Some users report that Preview does not display its changes correctly in other editors, though I’ve had no problems arise from this when using the app to sign and return forms.
Editing PDFs With LibreOffice Draw
In short: Proper free PDF editing and creation with an open source look and feel, warts and all.
There’s a lot to love about the open-source office suite LibreOffice, not least the Draw app’s ability to edit PDF files. We’re not talking simple markup a la Preview, but full-blown PDF editing. To get started, launch Draw and point it at the PDF file you want to edit.
Once Draw opens your file, it converts shape elements into fixed images which you can resize and move. You can also move or fill text boxes, though any pre-filled data will be lost upon import. You can add your own shapes and boxes, form elements, charts, tables, and so on.
The biggest problem with LibreOffice Draw is its interpretation of certain PDF files. The formatting can appear slightly off, with weird text kerning and style interpretation. It’s also a fairly limited PDF creator. Form creation tools are hidden away under View > Toolbars > Form Controls. These can even create working interactive forms, but the tools are far from advanced.
Download: LibreOffice (Free)
Editing PDFs With Adobe Acrobat Pro DC
In short: Pricey but complete, perfect for editing and creating PDF files from scratch. It’s also the only app on this list to include optical character recognition (OCR).
Adobe created the PDF, and it’s still providing one of the best solutions for PDF editing, creation, and all the basic tasks in between. DC stands for “Document Cloud” which should give you an idea of what Adobe is going for: a cloud-reliant subscription-based all-in-one solution. At $15 per month, the biggest barrier to entry is the price, though you can try for free before you buy.
For your money, you get one of the best tools of its kind. Acrobat allows you to take the standard “desktop publishing” blank page route, but it’s also a master of conversion. This means you can design your document in Pages, Word, or even an app like Illustrator, then convert with Acrobat, add some PDF jazz, and keep it all handy in the cloud. You can even snap a picture with your camera, then turn it into an interactive document.
Every time you open a PDF, Acrobat will scan it and make text searchable using OCR. Editing tools are second to none, and you won’t have to worry about the weird formatting issues seen in free solutions like LibreOffice. A clear differentiation between edit and view mode means you won’t accidentally screw up formatting while trying to fill out a form. If you can afford it, you won’t be disappointed.
Download: Adobe Acrobat Pro DC (Free trial, subscription required)
Editing PDFs With PDF Expert
In short: An affordable single-license premium PDF editor that lacks some creative tools, but plays nicely with most PDF files.
Readdle’s PDF Expert is a premium tool, but it’s a one-off purchase. For $60 you’ll get a competent editor that allows for proper PDF document editing that’s a step above what Preview offers. Unfortunately PDF creation from scratch isn’t an option here, and a few of the editing tools leave something to be desired.
The app is a competent editor for basic text, markup, and image-related duties. You can fix typos, add a new photo to your resume, or add hyperlinks, but there are no tools for adding new shapes and form fields. However, it does include tools for merging, annotation, signing documents, and a fast search.
If you need a good editor and can’t commit to a Creative Cloud subscription, PDF Expert might just fit the bill. There’s a seven-day free trial upon downloading, so you can test out the features and decide if the app goes far enough with its limited tools. It’s worth noting that the app enjoys positive reviews and a 4.5/5 star rating on the Mac App Store.
Download: PDF Expert ($60)
Forget the Other PDF Editors
I tried a fair few PDF editors while coming up with this list, and Adobe Acrobat Pro DC was probably the best solution. Windows users can use apps like Nitro and Foxit for common PDF tasks, but the scene is a little more limited on a Mac. In particular, look out for fake landing pages masquerading as official websites, especially if they suggest using a third party “installer” app for downloads. | <urn:uuid:bb49a514-fde4-4daf-952e-4c3a032dfe12> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 6,448 |
In the novel, “The Adventures of Huckleberry Finn” the main character Huck Finn learns how to make better decisions. He realizes how his decisions will affect other people, specifically, his best friend Jim. Huck begins the novel with no direction or guidance, living with his drunk and abusive father. Miss Watson and the Widow Douglas struggle to try to teach Huck how to have good judgement and how to be a good person. Huck is also guided and taught by the runaway slave, and Huck’s best friend, Jim.
Starting from a young age, everyone loves to go on adventures and have fun, just like Huck Finn. Growing up in St. Petersburg, Missouri, he is a white 12 year old boy and the son of a drunken father. In the beginning of the book, Huck is seen as a little innocent boy. Until he enters the world with his friend, Tom Sawyer, as they go on adventures, which creates problems and controversy through the history of the North and South, civilization, and racism and slavery. In The Adventures of Huckleberry Finn by Mark Twain, Huck has many controversial experiences that are still a problem in today’s society, which is why we should keep teaching the book in school.
The novel, The Adventures of Huckleberry Finn, was written by Samuel Clemens, also known by his pen name Mark Twain. This novel is about a young boy named Huckleberry Finn who narrates his journey along the Mississippi River. Huck meets many characters along the way and his relationships with each individual character are very unique. However, the relationship he has with Jim, the runaway slave, is ever changing. In The Adventures of Huckleberry Finn, Mark Twain embellishes the bond formed between Huck and Jim and how Huck views Jim as a slave, friend, and father-figure.
Huck describes the abusive and cruel relationship he has with Pap when he says, “He used to always whale me when he was sober and could get his hands on me; though I used to take to the woods most of the time when he was around”(Twain 9). The fact that Huck had to run “to the woods most of the time when he was around,” shows the kind of unsafe environment a young boy should not be raised in. Once Huck realizes that his own father may be a threat to his life, he deviously fakes his own death and begins his new adventures, setting sail on a raft with the company of a runaway slave named
The incongruity displayed through Tom Sawyer and the Grangerford family creates schemes that showed their character's immaturity. Huck followed Tom’s plan to save Jim and if Huck didn’t follow through with the plan, it saved Jim from a lot of pain. Tom’s irrational thoughts concluded "[the plan] was for us to run him down the river, on the raft, and have adventures plumb to the mouth of the river, and tell him about his being free, and take him back home on a steamboat, in style, and pay him for his lost time... and then he would be a hero, and so would we". This reveals how immature and greedy Tom is and how he would risk a black man’s life you prove he is a hero.
The historical novel, Adventures of Huckleberry Finn, written by Mark Twain in 1884, has many literary elements to generate a good plot and compose a good story. Twain introduces the characters, the major ones being Huck Finn and Tom Sawyer, as well as Jim. Finn was a white, poor child, who unlike Sawyer was not very dramatic in his way of life. Tom Sawyer read a lot and knew how to make any situation thrilling. Jim, a very mature black child, tags along with Finn (as well as the King and the Duke) to run away, and ultimately needs to get rescued in the end as he is forced into slavery by Ms. Watson.
Huckleberry Finn is a story about a rambunctious young boy who adventures off down the Mississippi River. “The Adventure of Huckleberry Finn” by Mark Twain demonstrates a situation where a Huck tries to find the balance between what is right and what is wrong. Huck faces many challenges in which his maturity will play a part in making the correct decision for himself and his friend Jim. Huck becomes more mature by the end of the novel by showing that he can make the correct decisions to lead Jim to the freedom he deserves. One major factor where Huck matures throughout the novel is through his experience.
Huckleberry Finn is a significant character in Twain’s novel Adventures of Huckleberry Finn. Typically anyone who reads this novel gains a sense of knowledge of what it was like to live in such times. In this book, Huck undergoes many types of occurrences ranging from manufacturing a gang with his friends to dressing up as a girl. Huck also is involved in more serious and controversial events that mentally force Huck to think like an adult. Readers get to experience Huck’s way of thinking throughout the whole book.
In the very first chapter, Huck reminds the reader that they were introduced to Tom Sawyer and himself in the previous novel stating that they were best friends (Twain 13). Although they may be friends the reader sees that they don’t always see eye to eye. Instead of finding new friends Huck chooses not to find another friend because he looks up to Tom. He desperately wants someone to look up to him thus he goes along with Tom’s ridiculous plans. At the end of the novel when Huck asks, “What would he do if the evasion worked all right?…he said he had planned in his head from the start” (Twain 275).
Huck and Tom have been friends for a while as hinted at in the beginning by Mark Twain with the preceding novel, the Adventures of Tom Sawyer. Tom idolizes the life of a robber and convinces his friends to play along in his games of stealing and murdering. As the novel plays on Tom reappears towards the end as the nephew of the Phelps family. Here we learn that Tom is still the same and doesn’t really care about the well-being of Jim nor Huck with his stupid
Authors of classic American literature often utilize a character’s development to establish a worldview or opinion. In The Adventures of Huckleberry Finn and The Great Gatsby, Mark Twain and F. Scott Fitzgerald use their narrators, Huck Finn and Nick Carraway, to suggest an argument about American society. Seeking adventure, both characters embark on a journey, but their encounters with society leave them appalled. While they each have personal motives for abandoning their past, both end up interacting with different cultures that lead them to a similar decision about society and their futures. Ultimately, they stray from the dominant culture in order to escape the influence of society. Therefore, Twain and Fitzgerald claim that American society
Comparison: My Life to Huck Finn’s Throughout my life, there have been numerous occasions in which I haven’t felt completely free to do what it is I want. Much like Huck, I would often try to sneak away from my house to explore. I can’t remember a time that I actually got away with it, but I would always try nonetheless. However, it never felt like I was being forced into a way of life like Huck was. Huck had it much harder, and grew up in a more harsh condition than what I was put into.
Huck Finn hates living in the home of the Widow Douglas because she is always “pecking” at him and attempting to “sivilize” him, she, imposes rules and regulations (“Don’t put your feet up there, Huckleberry,” “Don’t scrunch up like that,” “Set up straight”) . With new clothes to wear, and extreme ways to govern his daily life including and bells to order him, Huck finds domestic life with the Widow and her sister Miss Watson with restricting rules Huck, “felt so lonesome I most wished I was dead.” Then when Huck stayed with his drunken father Pap he also is provided with no real home. Huck is in an isolated cabin in the woods and Pap locks Huck inside and poses a threat with his rifle. Huck also hates Tom Sawyer’s gang of robbers that pretends
Huck once again compares himself to Tom and furthers the conclusion that Huck must holds jealousy toward what Tom can do. In conclusion, Mark Twain does an amazing job of showing some of the extremes of pride, greed, and envy in ‘The Adventures of Huckleberry Finn’. Nobody ever wants to show their dark side to anybody, but sometimes its just brought out of them and sooner or later consumes
During the 1840s in Missouri, a young boy name Huckleberry Finn runs away from home. At his first destination, he meets Jim, a run away slaves. The story goes along with the adventure of Huck and Jim. Along the way floating in Mississippi river, Huck and Jim meet many people. The most significant character they met was the King and Duck, the con artists, who help to show the growth in Huck 's moral while creating sorts of problems. | <urn:uuid:b9d043d7-f807-466c-83ab-fae58349c4fd> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 8,658 |
What Big Data Means To Us
By: Brian Boyko – April 4, 2013
You ever get the feeling that people are using the same words and talking about completely different things?
For example, when I talk to my dad about Cloud Computing, he often asks “But what happens if it rains?"
Defining Big Data
One of the more confusing buzzwords, according to this report by Omar Gallaga at the Austin American Statesman, is “Big Data.” With good reason: How big does the data have to be to be Big Data? Can you use Big Data tools on smaller data that’s still pretty big? How does Big Data relate to data mining? Is Big Data all video and stuff? Is “’Big’ Data” data that’s influential enough to lobby Congress?
The problem with “Big Data” is not that the term itself is overused, but that it is very, very broad. As a general rule, Big Data consists of datasets that are just too big to be analyzed, monitored, manipulated, or accessed by standard tools. Big Data, therefore, requires specialized tools and methods to make the most of, tools that are only now being developed. So, really, it should be called “Too Big Data.” But too big for what? Well – it all depends on context. When we put on our “Drupal Developer” hats, we tend to think of Big Data as data beyond what Drupal is designed to handle effectively on its own. And while Drupal is a very extensible framework, solving “Big Data” problems takes quite a bit of know-how.
Standard solutions and caching
There’s the brute-force method of throwing more memory, bandwidth, and processing power to the database server itself, but we typically don’t find this method to be cost-effective or future friendly. A step up from brute-force is caching. And by caching, we mean caching everything – from using Varnish to cache individual pages before serving them up to the visitor, to all the various caching solutions out there. Good for some things, but not really an elegant solution.
Drupal’s Big Data problems: bootstrapping and relational databases
In order to solve the problem of Big Data on Drupal, we have to look at the specific issues that bottleneck data on Drupal. First is Bootstrapping. As Drupal initializes every pageload – it asks every module if it has something to contribute to each part of the pageload process. In many if not most cases, this is a redundancy of effort. The more modules it has to ask, the slower the bootstrap. This is not bad design – it’s one of the reasons Drupal is so extensible. But it does compound the problem. Underneath the hood, Drupal is storing everything in a normalized, relational database (usually MySQL). There’s no duplication of data – everything is stored in different tables, and tables refer to each other in order to access the correct data. As soon as you have to query data, you’re pulling from multiple tables using the SQL keyword “JOIN.” While this ability to “join” makes makes MySQL powerful, JOIN commands are resource expensive, can be extremely slow, reduce the maintainability of code, and increase complexity.
NoSQL and “front end-gineering” to the rescue
We use a combination of technologies, including (but not limited to) MongoDB, Node, and Ember to get past some of the specific problems with Big Data by bypassing bootstrapping whenever possible, and by using more efficient data access methods. MongoDB is a NoSQL database; and NoSQL is designed for better horizontal scaling and higher availability, as well as optimized for retrieval and appending operations. The data is de-normalized – meaning, you’ll have duplicate data. So, if you have the available disk space, the performance tradeoff makes it worth it.
Why implement Drupal if we’re just going to bypass it?
You may ask that if the goal in all this is to bypass Drupal, well… why use Drupal at all? By all means, if you don’t need Drupal – don’t use it! But, there are some things, like content management and user permissions, which Drupal does exceptionally well. Getting back to our main point, Big Data for Drupal really just means increasing Drupal’s capacity to scale. As specialized solutions become less necessary, we’ll have to redefine how big Big Data is. Or we could just say any dataset that requires a Mack truck full of hard drives to move is Big Data.
You know what, it’s simple, it’s direct… I like that one better. Let’s go with that.
Find out how we use assistive technologies to help Drupal manage large data sets smoothly... | <urn:uuid:1d0e0eec-3d06-403b-9afe-2729b5cd2730> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 4,420 |
Is your young one looking for a totally radical way to show off their inner turtle? If so, look no further than these officially licensed Teenage Mutant Ninja Turtles t-shirts! Whether you've got a fan of Michelangelo, Donatello, Leonardo or Raphael, these TMNT shirts are a great way to rock the half shell. Featuring the design of Nickelodeon's new Teenage Mutant Ninja Turtles series, these awesome Ninja Turtles t-shirts will have your kids saying “Booyakasha!”
- 100% Cotton
- Boys Fit
- Officially Licensed
More Teenage Mutant Ninja Turtles Items: Teenage Mutant Ninja Turtles Merchandise
My son loved the shirt and it fit perfect!
Payment & Security
Your payment information is processed securely. We do not store credit card details nor have access to your credit card information. | <urn:uuid:6f17e640-ed9c-4f7e-b0d5-9446243f1ed8> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 789 |
Table of Contents
For many truck drivers and trucking companies, securing no down payment commercial truck insurance can feel like navigating a winding mountain road full of unexpected turns and potential hazards. One of the biggest hurdles can be the initial financial obstacle, the down payment. This upfront cost can be a significant burden, especially for owner-operators and small fleets operating on tight margins.
However, there’s a glimmer of hope for those seeking to get their rigs rolling without breaking the bank no down payment commercial truck insurance. This option allows qualified drivers and companies to obtain essential coverage without the immediate financial pinch of a down payment.
Understanding No Down Payment Commercial Truck Insurance
Before diving into the specifics, let’s clarify what no down payment commercial truck insurance actually entails. no down payment commercial truck insurance not a magic trick that eliminates all costs associated with your policy. Instead, it’s a financing arrangement where the insurance premium is spread out over the policy term, typically in monthly installments. This means you can get the coverage you need now and pay for it gradually over time.
Benefits of No Down Payment Commercial Truck Insurance
The advantages of this approach are undeniable:
- Reduced upfront costs: This is the most significant benefit, allowing you to prioritize other business needs or investments while still securing vital insurance coverage.
- Flexibility: Monthly payments make budgeting easier and provide greater control over your cash flow.
- Faster coverage: No down payment can expedite the insurance process, getting you covered and on the road quicker.
- Peace of mind: Knowing your truck is protected can give you the confidence to focus on your business and deliveries.
Things to Consider Before You Roll
While no down payment commercial truck insurance offers clear advantages, it’s crucial to approach it with caution and awareness.
- Potentially higher premiums: The convenience of no down payment may come at the cost of slightly higher monthly premiums compared to a traditional pay-in-full approach.
- Interest charges: Financing arrangements often involve interest charges, adding to the overall cost of your policy.
- Creditworthiness: Qualifying for no-down payment options may depend on your credit score and financial history.
- Policy terms and conditions: Carefully review the terms and conditions of your policy, including cancellation clauses and renewal options.
Finding the Right No Down Payment Commercial Truck Insurance Provider
With the benefits and considerations in mind, the next step is finding the right no down payment commercial truck insurance provider. Here are some tips:
- Shop around: Compare quotes from multiple insurers to find the best combination of coverage, price, and financing terms.
- Ask questions: Don’t hesitate to ask your insurance agent about the specific details of the no-down payment option, including interest rates, cancellation policies, and potential fees.
- Read the fine print: Thoroughly review the policy documents before signing to ensure you understand all the terms and conditions.
Beyond No Down Payment: Additional Strategies for Affordable Truck Insurance
While no down payment commercial truck insurance can be a valuable tool, it’s not the only way to make commercial truck insurance more affordable. Consider these additional strategies:
- Maintaining a good driving record: A clean driving history can significantly reduce your premiums.
- Bundling your insurance: Combining your commercial truck insurance with other business policies, like liability insurance, can offer discounts.
- Increasing your deductible: Choosing a higher deductible can lower your monthly premiums, but remember you’ll be responsible for a larger amount out-of-pocket in case of a claim.
- Negotiating your rates: Don’t be afraid to negotiate with insurance providers, especially if you have a good driving record or a strong business relationship.
Commercial truck insurance with no down payment
Unfortunately, finding commercial truck insurance with absolutely no down payment is quite rare. Insurance companies typically require some form of upfront payment to mitigate risk and ensure you’re invested in the policy. However, there are a few options that can help minimize your initial out-of-pocket expenses:
- Monthly payment plans: Most insurance companies offer monthly payment options, which can spread the cost of your premium over the policy term. This can make your insurance more manageable and avoid a large upfront payment.
- Deferred down payment: Some insurers, especially those specializing in trucking insurance, may offer a deferred down payment option. This means you would only pay a portion of the down payment upfront, with the remaining amount due later.
- Factoring: Factoring companies can advance you a portion of your upcoming invoices in exchange for a fee. You can then use this money to cover the down payment on your insurance policy. However, factoring typically comes with high fees, so it’s important to weigh the costs carefully before using this option.
- Consider alternative coverage: If you’re a low-risk driver with a good safety record, you may be eligible for discounts on your insurance premium. Additionally, you may be able to reduce your coverage amount to lower your upfront costs. However, be sure to carefully consider your needs before reducing your coverage, as you don’t want to be underinsured in case of an accident.
Here are some resources that can help you find low down payment commercial truck insurance:
- Premier Truck: They offer a no-down-payment option for commercial truck insurance, with the caveat that the full premium must be paid upfront at the end of the policy term.
- Empire Company: They offer a variety of commercial truck insurance products, including some with low-down payment options.
- Texas Insurance Agency: They are an independent insurance agency that can help you compare quotes from different insurers to find the best deal on commercial truck insurance.
Remember, when shopping for commercial truck insurance, it’s important to compare quotes from different insurers to get the best coverage for the price. Be sure to ask about all of your options for down payments and monthly payment plans. And finally, don’t sacrifice coverage to save money on your down payment. Getting the right insurance is essential for protecting your business.
No down payment commercial truck insurance costs
While the idea of “no down payment commercial truck insurance” costs might sound appealing, it’s important to understand that insurance policies are not typically structured like loans with down payments. You may come across offers for monthly payment plans, financing options, or installment payment schedules, but these still involve paying your premium (the total cost of your coverage) over time rather than upfront.
Unfortunately, there isn’t a straightforward answer to “no down payment commercial truck insurance costs” because it’s not a common offering in the industry. However, there are ways to minimize your upfront costs and make commercial truck insurance more manageable. Here’s what you need to know:
No down payment Commercial Truck Insurance Costs:
- Premium: The actual cost of your insurance is a premium calculated based on various factors, like:
- Type of truck: flatbed, tanker, refrigerated, etc.
- Cargo: What you haul and its value.
- Mileage and routes: distance and risk factors.
- Driver experience and record: age, CDL, and driving history.
- Coverage level: liability, physical damage, cargo, etc.
- Credit history: financial stability.
- Location: Risk factors based on area.
- Payment Options: You typically have different payment options for your premium, like:
- Annual: Pay the entire premium upfront.
- Semi-annual: Two payments per year.
- Monthly: Divide the premium into monthly installments.
No Down Payment Misconception:
- No literal “down payment” exists: You won’t pay a large chunk upfront, followed by installments.
- Payment options include installments. Monthly, semi-annual, or annual payments are your way to spread out the cost.
- Focus on overall cost: Consider the total annual premium rather than the monthly payment.
Finding the Best Rates:
- Compare quotes: Get quotes from different reputable insurance companies to compare premiums and coverage options.
- Shop around. Don’t just rely on your first quote.
- Work with an agent: An experienced insurance agent can help navigate the complexities and find the best coverage for your needs at a competitive price.
Remember, there’s no magic formula for no down payment commercial truck insurance. Focus on finding the best coverage at an affordable price, considering the total annual cost and payment options that work for your budget.
I hope this clarifies the concept of commercial truck insurance costs and the misconception of a “down payment” .
No down payment commercial truck insurance in Texas
While finding commercial truck insurance in Texas with no down payment might seem tempting, it’s crucial to understand the nuances and be aware of potential drawbacks before jumping in. Here’s what you need to know:
Finding Policies with No Down Payment Commercial Truck Insurance in texas:
- Limited Options: While some niche agencies or specialized truck insurance providers might offer zero-down options, they’re not standard in the market. You’ll likely have fewer choices and potentially higher premiums compared to traditional policies.
- Alternative Payment Structures: Instead of no down payment, some companies offer monthly payment plans or installments, spreading the initial cost over a period. This can ease the upfront burden while still requiring regular payments.
Drawbacks of No Down Payment Commercial Truck Insurance in texas:
- Higher Overall Cost: Policies with no down payment often have higher monthly premiums or interest rates compared to traditional options. The total cost over the policy term might be significantly higher.
- Potential Cancellation: If you miss payments or default on the agreement, your policy could be canceled, leaving you vulnerable without coverage.
- Coverage Limitations: No-down options might come with limited coverage or higher deductibles to balance the lack of upfront payment. Ensure you understand the covered perils and exclusions before agreeing.
Finding no down payment commercial truck insurance in Texas can be tricky, but there are options available. Here’s what you need to know:
Challenges with No Down Payment Commercial Truck Insurance in texas:
- Risk for insurers: Offering no down payment increases the risk for insurance companies, as they receive no upfront payment to cover potential losses. This can lead to higher premiums or stricter eligibility requirements.
- Limited options: Not all insurance companies offer no-down payment options for commercial truck insurance. You may need to shop around and compare quotes from different providers.
- Finance options: Some insurance companies may partner with lenders to offer financing options for insurance premiums. This allows you to spread out the cost of your policy over a period of time.
- Payment plans: Some insurers may offer flexible payment plans, allowing you to make monthly payments on your premium instead of a single upfront payment.
- Discounts: Look for discounts that could lower your premium, such as good driving record discounts, multi-policy discounts, or discounts for installing safety features in your truck.
Alternatives to consider:
- Shop Around: Compare quotes from various insurance providers, both traditional and specialized, to find the best combination of coverage, price, and payment terms. Negotiate for discounts based on your driving record, safety initiatives, or bundling your truck insurance with other business policies.
- Finance the Down Payment: Explore financing options from banks or lenders to cover the initial payment. This allows you to spread the cost while securing full coverage from the outset.
- Focus on Coverage: Prioritize finding a policy with adequate coverage for your specific needs and risks, not just the payment structure.
- Read the fine print: Carefully review the policy terms and conditions, including cancellation policies, deductibles, and limitations, before signing.
- Seek Professional Advice: Consulting with an independent insurance agent specializing in commercial truck insurance can help you navigate the options and find the best policy for your budget and needs.
By understanding the implications and exploring alternatives, you can make an informed decision about no down payment commercial truck insurance in Texas. Prioritize finding the right coverage to protect your investment and operate your business with peace of mind.
No down payment commercial truck insurance can be a game changer for drivers and companies struggling with upfront costs. By understanding its benefits, limitations, and available options, you can make informed decisions and secure the coverage you need to keep your business moving forward. Remember, responsible driving, proactive risk management, and exploring cost-saving strategies can further enhance your journey towards affordable and comprehensive truck insurance. | <urn:uuid:87fd8d01-635c-42c2-89b2-b7c345e9da0f> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 13,397 |
The root word from which this term is drawn means to “swarm” or “teem.” The noun appears to apply to small creatures to be found in large numbers. (Ex. 8:3; Ps. 105:30; compare Exodus 1:7.) It first occurs at Genesis 1:20 with the initial appearance of living souls on the fifth creative day when the waters began to swarm with living souls. The Flood destroyed earthly ‘swarming things’ outside the ark.—Gen. 7:21.
The law regarding clean and unclean things shows that the term may apply to aquatic creatures (Lev. 11:10), winged creatures, including bats and insects (Lev. 11:19-23; Deut. 14:19), land creatures, including rodents, lizards, chameleons (Lev. 11:29-31), and creatures traveling on their “belly” and multi-legged creatures (vss. 41-44). Many, but not all, of these were “unclean” as food under that Law. | <urn:uuid:f72c464d-d4be-4bc4-a56f-9584e92ffff6> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 819 |
It has sparked a revolution in the way we communicate, work, learn, shop, connect with our friends, travel, engage with politics and raise money for charity.
We use it for entertainment, to listen to music and to watch films, but it has also powered campaigns that have changed the world and sparked revolutions that toppled governments. And it is all down to one man, who not only invented the World Wide Web, but gave his creation to the world for free.
It is 25 years since Sir Tim Berners-Lee devised plans for the Web while working at the European physics laboratory CERN. He was frustrated that scientists would come to the Swiss centre to take part in experiments, but once they returned to their own laboratories across the globe, it was difficult to swap results and data.
Also researchers used dozens of different computers, each with different software, which meant none could communicate with each other.
Sir Tim, who was working at CERN as a software engineer, says: “I found it frustrating that in those days there was different information on different computers. You had to log on to different computers to get at it.
“Also, sometimes you had to learn a different program on each computer. So finding out how things worked was really difficult. Often it was just easier to go and ask people when they were having coffee.”
Sir Tim became focused on the challenge of finding an easier way to swap information. He wrote a paper titled Information Management: A Proposal, which outlined the initial idea of the Web as “a universal linked information system”. His boss wrote, “Vague but exciting” on the cover, and Sir Tim went away to work on his plans.
Working with colleagues at CERN, he tried different programs and tested his work, and, by October 1990, he had created the three fundamental technologies that remain the foundation of today’s Web – HTML, URI and HTTP.
The first website , with links that users could click on with a mouse, was launched in December of that year.
At that stage, the technology was known as The Mesh, but Sir Tim coined the term World Wide Web and by 1991 people outside CERN started to access and connect to it.
In 1993, CERN announced the technology would be available to everyone for free, and the biggest communications revolution since the printing press was under way.
Sir Tim says:
Some people point out that the Web can be used for all the wrong things. For downloading pictures of horrible, gruesome, violent or obscene things, or ways of making bombs which terrorists could use.
Other people say how their lives have been saved because they found out about the disease they had on the Web, and figured out how to cure it.
The thing to remember is that any really powerful thing can be used for good or evil. Dynamite can be used to build tunnels or to make missiles.
So what is made of the Web is up to us. You, me, and everyone else. | <urn:uuid:68adbe81-02aa-4a4e-a4f7-79836daf3689> | HuggingFaceTB/smollm-corpus/tree/main/fineweb-edu-dedup | smollm-corpus | eng_Latn | 2,890 |
Get Saatva Pillow Warranty…
The very word this brand name is unidentified to numerous people. I’ve likewise had lots of people ask me this concern when they go to purchase a brand-new bed mattress.
Of all, let me explain why it’s not a good mattress. Mattresses are primarily used to supply comfortable sleeping. You might call it a kind of bed; however, this is really a misnomer because mattresses can not give you a good night’s sleep. Because of the springs that help you sleep, this is.
It’s true that most mattresses are made with good quality coils. What many people do not understand, nevertheless, is that coil springs inside a lot of bed mattress are prone to getting bent out of shape. You can picture just how much this will impact your sleep. How bending out of shape coils like supra’s must take place is by natural wear and tear. The coils just get extended and can no longer support the weight of your body.
You get an excellent mattress by buying an old sutera foam mattress or by taking benefit of great sale uses on sutera mattresses in Web shops. Another excellent method to get a great mattress is by asking professional bed mattress contractors for guidance and tips on the finest type of mattress to get for your requirements.
The mattress is in fact composed of numerous layers and the innermost layer is called the “air layer”. There is the “memory foam” which “breathes” so that all these layers support each other, thus supplying for an extremely comfy sleeping condition. Saatva Pillow Warranty
It does have some good mattresses. It is nevertheless a bit pricey. If your money is not really a problem, then the sutera is a good alternative. However, if your main function of getting a good mattress is for back assistance, then an incredibly flat top bed mattress would be a better option. | <urn:uuid:0366dc88-ac72-4422-be92-6223d26d2d70> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,817 |
Elephone has launched its latest 3G smartphone, the MT6572W Dual Core 3G GPS Mini Phone. This phone is an improvement of its predecessor such as Kitkat 4.4 OS, stronger body, longer battery life, high resolution screen, and so on. The white color body gives the phone an executive look.
The Elephone MT6572W comes with a strong body with smooth rounded corners and edges. The finishing is matte finish with non-grease coating. The volume control is located on left hand side and the power button is located on the right side of the phone for easy operation. It also has a 3.5mm audio out port, through which you can enjoy listening to your favorite songs. The phone is light weight and slim and features a 2.45 inch TFT display with capacitive touch screen and 240 x 432 pixels. On the rear side, you have the 2.0 MP camera with LED flash light, capable of taking clear photographs even at low lights. The front side has 0.3 MP camera for taking selfies. You can also take excellent quality videos through the cameras.
Elephone MT6572W comes with the dual core processor MTK6572W which can clock speed more than 1.0GHz, thereby enabling you do multitasking at the same time without any lagging. The inbuilt 512 MB RAM in combination with the dual core processor makes the experience of using this smart phone a pleasure. This comes with an inbuilt 4 GB inbuilt ROM, for storing lots and lots of data. The phone also comes with an extended storage slot, which can house a 32 GB micro SD card. It also features 802.11 b/g/n WiFi, Bluetooth 4.0 and GPS.
Elephone MT6572W comes with inbuilt 50 languages, so the phone is ready to be shipped worldwide. The battery that comes with this Elephone MT6572W, is powerful 550mAh battery, which has enough juice to make the phone usage for long periods without charging. | <urn:uuid:72d46320-8106-48a7-8aa9-c205b075f961> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 1,808 |
Many people enjoy observing wild birds, and Oregon has a rich variety of birds to see! We see many birds at the farm, and in this post (and follow-up comments) we’ll list our observations.
If you’re interested in birding, visit the Audubon Society of Portland‘s home page to find more resources. For this post, we are using their 2013 Species Checklist as the starting point for our bird list.
Okay, let’s get started. On August 16, 2013, we observed:
- Barn Swallow
- Pine Siskin
- American Goldfinch
- Northern Flicker
- Steller’s Jay
- Great Blue Heron
After dusk, we heard a pair of nighthawk’s crying over the field, but it was too dark to identify them.
Previously, we observed a barn owl in the century-old barn. | <urn:uuid:3714b2c7-8b3b-4b84-9040-525642792861> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 719 |
Latest Team Rankings
Free Text Alerts
|ShopMobileRadio RSSRivals.com Yahoo! Sports|
|College Teams||High Schools|
October 29, 2010
Locksley, 40, understands there's a sense of urgency to win. He arrived at New Mexico amid much anticipation came after a successful stint as offensive coordinator at Illinois under Ron Zook. Locksley's recruiting prowess also was enticing.
But his New Mexico tenure has been extremely rocky. He debuted last season with a 1-11 record, going 1-7 in the Mountain West. This season, the Lobos are 0-7 and one of just two winless teams (Akron is the other) in the nation.
Locksley's tenure has been marked by an age/sexual discrimination lawsuit, a confrontation with an assistant and lots of losing. He also has had to navigate through probation brought on by the previous regime.
The probation has featured scholarship limitations. New Mexico hasn't been able to sign more than 20 players in either of the past two classes, and 20 is the limit in this cycle, as well. While the NCAA allows for FBS teams to have 85 players on scholarships, New Mexico can't exceed 80 because of the probation.
The probation also has led to just six coaches on the road recruiting instead of seven and 48 official visits per cycle as opposed to 56.
The Lobos' struggles this season have been exacerbated by injuries. End Johnathan Rainey, who had 9.5 sacks and 15.5 tackles for loss last season, has been lost for the season with a broken neck. Projected starting quarterback B.R. Holbrook has played in just three games because of a knee injury.
For now, Locksley has the support of New Mexico athletic director Paul Krebs. Rivals.com recently spoke to Locksley about his tenure at New Mexico, which plays at Colorado State -- the only team the Lobos beat last season -- on Saturday.
How difficult has this season been?
"This has been a difficult process but you have to stay focused. It's almost like d? vu of 2006 at Illinois. It was our second year at Illinois. We lost to Ohio University at home. We won two games that year [2-10]. We were a young team that still was growing. The next year, we went to the Rose Bowl."
How do you deal with the losing? It has to wear on you.
"If it weren't for my experiences at Illinois (2005-08) and Maryland (1997-2002), those programs I played a role in turning around as an assistant, I would say 'yes,' the losing is difficult. But I have insulated myself from the negativity. I don't read the paper, I don't go online, I don't look at the news. I definitely lean on the experience of those rough Maryland years and Illinois years."
What has been the biggest hurdle for you at New Mexico?
"Lack of depth. If you look at the 2006 signing class, which is my senior class now, they signed 26 players and only six are still here. In 2007, they signed 26 and there are only 10 left. So, there aren't that many juniors and seniors on the roster.
"Part of the issue was they recruited multiple junior college players during the last couple of years. When you get into the JC business, you have to recruit them every year or you are going to have some gaps in your recruiting classes. We decided not to go heavy on JCs my first two years here. For any program to be successful, you have to have solid recruiting classes every year and a foundation of players. We have tried to fill the gaps as best we could with the high school recruits and break the junior college cycle."
Will you get heavily into recruiting the junior-college ranks for this upcoming class?
"We didn't go the JC route my first couple of years because we wanted to build the program the right way. We can now go JC to fill some of our needs because I have a foundation of young players that we have redshirted and are coming along. Now, I can kind of fill some gaps with some JCs. We will take five to six junior college players in this class."
Were you ready to be a head coach?
"Oh, sure. There's no doubt about it. The football part of it, no doubt I was ready. My two biggest issues have been HR [human resource] related. [An EEOC claim by an administrative assistant and the altercation with an assistant.] The adversity helped me develop as a head coach and as a person.
"I will tell you this: I could have controlled the J.B. Gerald situation and maybe won a few more games. [Gerald was the Lobos' assistant who alleged that Locksley punched him during a meeting in September 2009. While an investigation didn't corroborate Gerald's story, Locksley was reprimanded by the university and suspended for 10 days.]"
What would you have done differently in the handling of the situation?
"As the head coach, I have to make decisions that are right for my program and that includes personnel. I could have handled the Gerald situation earlier, when there were signs of insubordination. When you take a chance and hire a friend, it's difficult to cut ties. There is a thin line when you hire friends and you have to make sure you keep things professional."
Have used anyone as a sounding board during your development as a head coach?
"I talk to [Houston coach Kevin] Sumlin, [Southern Miss coach Larry] Fedora and [Oklahoma State coach Mike] Gundy. Tony Dungy and I have talked about changing cultures and exchanged text messages. I have read all his books. We've talked about management of people, handling of situations, just everything.
"I do a lot of reading, too. I recently read Bill Belichick's book, 'The Education of a Coach.' His situation as head coach of the Cleveland Browns was similar to mine here at New Mexico. It has benefited me to read that."
What was appealing about the New Mexico job?
"I was pursuing multiple jobs throughout the country when I decided to take the New Mexico job. The enticement was it would give me a chance to learn how to be a head coach at place that has had success. I knew I could come in here and recruit because of the location. Southwest Airlines has a major hub here [in Albuquerque]; you can get direct flights from almost anywhere in the country. And we have been able to do that.
"We have been able to attract talent. On our roster, we have [wide receiver] Deon Long, a transfer from West Virginia. [Linebacker] Javarie Johnson was a Miami commitment who transferred from Maryland. Both have four years of eligibility and were big-time recruits. [Wide receiver] Lamaar Thomas was a four-star player who played his first two years at Ohio State. We went and got [four-star defensive tackle] Calvin Smith out of Florida. We have been able to sell New Mexico in two years even with limited scholarships."
Amid the losing and the human resources issues, what have been some of the biggest positives for you?
"I love coaching and having an influence on the lives of young men. It's about mentoring them and preparing them for life after UNM. Successes can be judged in a variety of ways. Although we are disappointed in our lack of wins, we still have a lot to be grateful for. The football will continue to get better. We are on track to have one of the highest APR's we've ever had. We have had consecutive semesters of 2.72 GPA, which is the second-highest team GPA they ever have had. The team GPA was over 3.0 over this summer. And since June of 2009, we have had little to no off-field incidents with our players. We have also spent countless hours in the Albuquerque community."
Will you be back for a third year?
"I expect to be. I have four years remaining on my current contract after this season. The administration has been very supportive of what we are trying to do and get accomplished. We have set goals that we plan on obtaining, but it takes time.
"I have tried to maintain my focus on my vision of where I see us going, grind through it ,and we continue to recruit, recruit, recruit. We have to continue to develop players and get better. We are improving, and our future looks bright." | <urn:uuid:ea335879-d795-4972-8712-b8961296b704> | HuggingFaceFW/fineweb/tree/main/sample/350BT | fineweb | eng_Latn | 7,872 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.