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Cardiac rhythm management devices are devices that either pace or otherwise excite selected chambers of the heart by electrical stimulation. A pacemaker, for example, is a cardiac rhythm management device that enforces a particular heart rate by delivering pacing pulses to the heart in response to lapsed time intervals and sensed cardiac electrical activity (i.e., intrinsic heart beats). Cardiac rhythm management devices, either in addition to or instead of pacing the heart, may also deliver stimulation pulses in order to excite a particular chamber or region of a chamber in synchrony with sensed intrinsic cardiac activity occurring elsewhere. Such devices are typically implanted subcutaneously on a patient's chest and have leads threaded intravenously into the heart to connect the device to the electrodes used for sensing and stimulation.
In order to cause a contraction in the absence of intrinsic activity (referred to herein as excitation), the stimulus pulses delivered to the heart by the device must achieve “capture,” which refers to causing sufficient depolarization of the myocardium that a propagating wave of excitation and contraction result (i.e., a heart beat). A stimulus pulse that does not capture the heart is thus an ineffective pulse. This not only wastes energy from the battery of the device, but can have deleterious physiological effects as well. For example, a pacemaker that is not achieving capture is not performing its function in enforcing a minimum heart rate. For a particular implanted lead, a capture threshold exists which is the lowest energy pulse that will achieve capture when a stimulus pulse is output through the lead. (The energy of a stimulus pulse is determined by the voltage and duration of the pulse.) A common technique used to determine if capture is present during a given cardiac cycle is to look for an “evoked response” immediately following a stimulus pulse. The evoked response is the wave of depolarization that results from the stimulus pulse and evidences that the stimulated chamber has responded appropriately and contracted. In the case of ventricular stimulation, by detecting the evoked R-wave, the device is able to detect whether the stimulus pulse was effective in capturing the heart, that is, causing a ventricular contraction. Capture verification can be performed by a clinician using an external programmer to adjust operating parameters and monitor sensing data to ensure that the heart is reliably paced and/or otherwise excited. Alternatively, a cardiac rhythm management device may be programmed to perform capture verification tests automatically, either at periodic intervals or upon a command from an external programmer.
Stimulation/sensing leads are generally of two types, bipolar and unipolar. A unipolar lead has one electrode at its distal end connected to a conductor within the lead which is covered by insulation. A bipolar lead has two conductors which are respectively connected to a distal and proximal electrode. The distal electrode is usually a tip electrode which may be fixed into the myocardium, and the proximal electrode is a ring electrode around the body of the lead. In bipolar stimulation, a stimulus pulse is output between two electrodes, and in bipolar sensing, the voltage difference between the two electrodes is sensed. A bipolar stimulus pulse may be output with a polarity such that one electrode is the cathode (electrically negative) and the other electrode is the anode (electrically positive). In unipolar sensing/stimulation, the electrode at the end of the lead is used as either a cathode or anode, and the housing of the device or an electrode on another lead is used as an electrode of the opposite polarity, referred to as a reference. Cathodal stimulation of the myocardium is generally preferred because it has a lower and more stable capture threshold. Cardiac rhythm management devices with bipolar leads may typically be programmed to deliver either bipolar or unipolar stimulus pulses through a lead. Bipolar stimulation is preferred by some clinicians, however, because it more precisely delivers energy to the heart with less risk of causing contractions of overlying skin or skeletal muscle.
Once a cardiac rhythm management device has been implanted, a clinician typically sets up the configuration of the device using an external programmer. Among the parameters that can be adjusted during this process, is the stimulus pulse energy for a given lead, which is normally set to a value corresponding to the capture threshold determined for that lead. For example, the stimulus pulse energy may be set to the value of the capture threshold plus some specified safety margin. The present invention is directed toward an improved method and apparatus for adjusting the stimulation parameters of a cardiac rhythm management device employing bipolar stimulation. |
Q:
How to get total number of bytes/sectors/blocks written to disk since booting?
I'm considering and update from HDD to SSD. But since Flash cells can only sustain limited writes. I want to know how much data my computer write during normal operation. So I can determine how long lifetime I can expect from the SSD.
Is it possible to get (rough) numbers somehow?
A:
The first idea I found is the vmstat -d command.
It tells you the number of sectors written since booting.
fdisk -l will tell you the sector size.
By multiplying the two you can get the number of bytes touched.
It seems my computer does roughly 1 gigabytes worth of writing in two hours. By doing a quick calculation a 128G SSD with 3000 write cycles would last 90 years... Nothing to worry about.
A:
Look at this page http://linuxpoison.blogspot.com.au/2009/02/how-to-measure-and-read-disk-activity.html
# cat /sys/block/sda/stat
11836508 1974427 276764974 242202738 13703385 18793696 597760590 2010426698 135 76333414 2253542452
Field 3 -- # of sectors read
Field 7 -- # of sectors written
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At AllianceHealth Medical Group , our goal is to provide our patients with education and resources to enable them to make lifestyle and health care decisions. Please contact your health care team for information relative to your individual needs.
Cancellations
Please contact us as soon as possible if you are going to reschedule your appointment. Our policy requires 24 hours’ notice for cancellations. A fee may be assessed for a missed appointment.Prescription Refill Requests
If you are in need of a prescription refill, please contact your pharmacy and they will provide our office with the necessary forms to expedite that process. If it is a new prescription, please contact our office so that we may consult with your provider.Privacy Laws
HIPAA regulations limit the people who have access to your private and protected health information. In your patient packet, you will find a form that will allow you to list the people with whom you allow us to discuss your care.
Helpful DefinitionsBeneficiary: A person who receives benefits of any insurance plan or policy.Claim: A request for payment for services submitted by the provider.Coinsurance: A specified percentage of covered expenses which the insurance carrier requires the beneficiary to pay toward eligible medical bills.Co-pay or Co-payment: A specific set dollar amount contracted between the insurance company and the beneficiary to be paid prior to any services rendered.Covered Services: Services for which an insurance policy will pay.Deductible: A specified dollar amount of medical expenses which the beneficiary must pay before an insurance policy will pay.Explanation of Benefits (EOB): A statement from an insurance company showing the processing of a claim.Medically Necessary: Treatments or services that insurance policies will pay for as defined in the contract.Non-Covered Services: Services for which an insurance policy will not provide payment. These services are to be paid by the patient at the time of service.Pre-Certification/Authorization: A service-specific requirement that your insurance company’s approval be obtained before a medical service is provided.Provider: A person or organization that provides medical services. |
Q:
Display email address field next to author in wp_dropdown_users
the post_author_meta_box uses wp_dropdown_users showing the user name of authors.
How do I display the email address in brackets next the author's name?
Can one filter the wp_dropdown users do to this?
A:
the only filter hook called in wp_dropdown_users() function is wp_dropdown_users which pass a string of the dropdown in an html form so you can manipulate this dropdown at that hook with some major REGEX.
A better solution would be to use get_users() and create the dropdown your self, something like this:
$selected = 1; //just for example, you can get that by get_post_meta()
$siteusers = get_users(); // you can pass filters and option
$re = '';
if (count($siteusers) > 0){
$re = '<select name="users_with_email">';
foreach ($siteusers as $user) {
$re .= '<option value="' . $user->ID . '">'.$user->user_nicename . ' ('.$user->user_email .')</option>';
}
$re .= '</select>';
$re = str_replace('value="' . $selected . '"','value="' . $selected . '" selected="selected"', $re );
}
echo $re;
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Carol’s Cool Cats
Carol Babel has loved cats since she got her first one at age 2. Her husband Bob Weller was also a cat lover. Now they have a cattery, breeding and competing the mysterious (even mystical, some believe) Maus that date back to Egyptian times. With their cheetah-like back legs, Maus can run at 30 mph and jump six feet in the air. They’re strong swimmers, too — strong enough to retrieve ducks, as they once did for the pharaohs. Oh, and they make perfect pets — if you like cats with lots of energy.Did your husband think it odd you wanted to go to a cat show on your second date?No, because we both loved cats. It was at that show that we saw a silver Egyptian Mau for the first time. Both of us fell in love. Do you think they are, as some say, mystical?I don’t know, but once you look into their pale green eyes, you’ll never be the same. We say they melt your heart and capture your soul. That’s what happened to us. A Mau was featured in the movie “Catwoman” with Halle Berry. It breathed life back into her and gave her special powers ...The Egyptians certainly revered these cats. If one died in a household, the family would go into mourning and shave their eyebrows. Hieroglyphics show them riding the shoulders of pharaohs. Mummified remains of Maus have been found — we saw cat mummies with the signature spotted fur in the Cairo Museum. And look at the similarities between Egyptian women like Cleopatra and the cats. They outlined their eyes in black like the Maus’ and they wore multiple bracelets to mimic their striping. How rare are they?There are fewer than 5,000 in the world.What are they like as house pets?Maus are very intelligent and very high energy. On a scale of 1 to 10 for energy, they’re a nine — it may not be for everyone. They’re also very social and want to be with you all the time. They’re very dog-like. They come when you call their name. They’re self-taught fetchers; they’ll bring toys to you. It no doubt is a throwback to the duck hunting they did with the pharaohs. I bet they have a good life at your house ...They do. We give them a lot of attention, especially the kittens. We love playing with them, sometimes until midnight. They sleep in our bed. In the morning they have classical music and in the afternoon they watch TV.What do they watch?They really do love “Animal Planet,” especially if they can hear and see birds. |
We rolled up to the Yeti Tribe gathering. There was a little check in table, a waiver to sign, a T shirt to be gotten, etc. And a personalized sticker for your bike, a nice memento and a way to keep everybody's bikes straight (it can get complicated when there are hundreds of Yetis laying around). This was my first trip to the Tribe, but I had seen these stickers on customers bikes, and was looking forward to getting one of my own.
The check in table was being ran by children, girls in the 10 to 12 year old range if I had to guess. We already had these girls a little flustered, because there were four of us talking over each other, and asking them questions they weren't there to answer.
"So what's your name"
"Dan Lucero"
"Hmm, I don't see that sticker here. Do you have a nick name?"
"Errr, no."
"There's a Lucille sticker, is that you?"
"No, thats not me."
Then the girl proceeds to look through all the stickers, looking for Dan, or Lucero, with no luck.
"Are you sure its not Lucille"
"Yeah"
The oldest girl at the table jumps in, asks my name again, cross references a different list, and shouts out "Dan Lucero- yeah, Lucille is his sticker"
Thats when I remember that Swinton signed me up. Well played sir. I believe he had been watching a bit of Arrested Development at the time. Is he saying I'm a grumpy alcoholic matriarch?
Charlie also discovered that he was signed up as Chuck Fresh, but that makes sense, because that is his actual name.*
(*not his actual name)
The Tribe Gathering is basically a big bike riding weekend party that Yeti has been throwing for 15 years. Reportedly it started impromptu, with 10 people the first year. Last year they had 350. This year was a little down, at 250, presumably due to the remote location of the Uncompahgre Plateau, outside of Montrose CO. Everyone is invited, as long as you ride Yeti. They put it on as an appreciation event. This was the first year of our crew going, although we had a number of customers and friends there that are regulars.
The drive to Montrose takes about six hours. It is both a beautiful and boring drive, at times. If you have never been on the passes between Durango and Silverton and Ouray, you should check it out, unless you find tight and twisty roads with no guard rails and sheer cliffs scary, in which case you should maybe avoid it. It is a little surprising to have such a seemingly dangerous stretch of road open to the public in America, the lawyers and safety police haven't taken all the fun away yet. But I doubt it will be long before somebody goes sailing off the cliff while texting, and somebody will declare the road unsafe.
The Tribe gathering was another 30 minutes or so outside of Montrose up on the Uncompahgre plateau. So by the time Dave, Charlie, my Dad (aka Lee), and I pulled up to the party we were a little road weary and excited. After we were finished making the poor 10 year old volunteers stressed out, we found a nice little spot to camp.
The setting was beautiful forest up on the plateau, with the big tent headquarters in a big clearing and dispersed camping all around it.
The event was catered, and the food was amazing. The beer was supplied by Oscar Blues, and there was enough on hand to kill every last attendee with alcohol poisoning.
Friday was pretty mellow, as there was a big day of riding ahead on Saturday. We didn't have enough time to ride Friday, but lots of people had been out exploring the area that day.
So if you happen to own a school bus, you should totally build a deck on the roof, and then get a 3 man water balloon launcher, because it is hilarious.
You can really take some people by surprise when you hit them with a water balloon from 100 yards away.
Saturdays ride was dubbed "The Whole Uncalada", the local equivalent to Moabs Whole Enchilada. It was 27 miles, with a shuttle at both ends, and way way more descending than climbing.
Loading up 3 moving trucks and two school busses with riders was an impressive sight.
And the stretch of bikes laying along the side of the road at the start of the ride was awesome. It was a seriously impressive collection of nice bikes.
It was a great ride. We didn't stop for too many photo ops, we were having too much fun pedaling.
But feeling thoroughly jazzed on the bus ride home (with a couple quick beers in me), there was plenty of time for photos.
We got back and stuffed ourselves on an amazing dinner.
Danny doesn't appear to trust his meal.
And once everyone was thoroughly fed and beered up, Yeti started their traditional stupid human tricks.
Mini bike racing...
Mini bike tossing...
And foot down....
There was some talking on the mike, a little video to watch, and eventually a booze fueled dance party broke out. I may or may not boogie down when the right number of beers have been drank and the music is good.
We did another ride on Sunday morning before heading out of town. It was a beautiful ride through the trees on really nice loamy soil, undulating along the plateau, with a few great views thrown in.
Then we packed it up and hauled tail back to 'Burque. A quick 12 hours at home and here I was opening shop Monday morning, bleary eyed and smiling. I can definitely think of worse ways to spend 72 hours.
We will definitely go again next year. I hope we can bring even more friends with us then. If you're lucky, you'll get to watch me dance (and maybe even get an "I love you man" hug from me).
Firstly, as of right.....NOW!....we will be open for bizness on Mondays. We will do our normal weekday hours of 10 to 6. Our reasoning for this is two fold:
Fold 1) It will allow us to make even more money than we already are, I mean, we are getting pretty rich, but my wealth hasn't exceeded my wildest dreams yet, which is precisely what I was promised would happen when opening my own bike shop. And..
Fold 2) This will give us more time to crank out the repairs, because it is riding season, you know, and everybody would like their bike done yesterday, thanks. And we get it, and while I'm fairly sure our turn around is the fastest in town (and our work is the best, but you already knew that), we want to keep it that way all through the summer.
So there is that.
Secondly, The 24 Hours of Enchanted forest is this weekend, June 18th and 19th. So we will be closed for the weekend, so HA! No bike repairs for you!
As per always, the infamous Bikeworks Bacon Station will be serving up gross amounts of cooked pig flesh. It is always a good time, and this year promises to be better than ever. Why you ask? Because normally we just provide all the provisions for the Bacon Station, and the awesome volunteers run it. But this year we will be bringing home the bacon, and cooking the bacon, and heckling the racers about eating the bacon, and drinking the beer from the keg which we may or may not bring, and we will be partying and not racing and its going to be awesome.
That along with a new course which sounds amazing, and perfect weather (I haven't checked the forecast, but I'm just going to declare it), this should be the bestest Enchanted Forest ever.
So... if you didn't sign up to race but don't want to miss the fun, come on out and camp with us (we will be camping down a random dirt road, in the trees, where the race course passes by, so I'm told). Get a hold of us at the shop, and we will give you directions. And maybe bring an extra pound of bacon, because we normally go through 40 or 50 pounds of it, but normally I'm not there drunkenly eating it the whole time. And I'm bringing my kids, and the little one can seriously put away some bacon.
Thats about it. To summarize:
1) Bikeworks ABQ, now 100% more open on Mondays
2) Bikeworks ABQ, 100% less open this Saturday than normal.
3) Bikes, Beer, Bacon (in whichever order you prefer).
So what has everybody got planned for the weekend? Have you heard about the Bike & Brew fest in Santa Fe? Its got like, bikes, and beer, and music, and food, and stuff. Seems like you could definitely find a worse way to kill some time.http://outsidesantafe.com/
Here's a random picture of my two dogs, nicely stacked, because I like to put a picture near the top of each post.
I checked it out last year, it was a pretty cool scene. Unfortunately last year it was really cold and rainy during the event. Hopefully this year will be nicer weather. Also they moved it from the Railyard area over to Fort Marcy park, which is an awesome park. So I think the vibe will be more festival-y.
There are numerous organized rides that you can sign up for, so if there are trails in the area you haven't done before, this might be a good way to learn them.
There is also the Poker Ride put on by our bro-hams at BTI. You ride around La Tierra and pick up playing cards, and then you can win prizes and get beer. It costs $20 but it's a fund raiser for trail building, so quit being cheap. http://outsidesantafe.com/event/poker-ride/
I will be most likely toiling away at the Bikeworks sweatshop on Saturday, but perhaps the boss will let me off early enough to catch some of the fun. Then on Sunday I will be partaking in the Santa Fe Century, with my beautiful and lovely wife on our school bus yellow tandem.http://santafecentury.com/
(my wife is short, but the children's stoker cranks are for the kid, not her)
We haven't exactly put many miles in on the bike, so we're going to do the 50 mile option, assuring we all make it home alive and in good spirits.
Shortly after we acquired this lovely tandem, I hooked up the trail-a-bike to it, and rode with my 8 year old on the back, and my 5 year old in the middle. It was about all I could do to keep upright when my boy started rocking side to side on the trail-a-bike. That experiment only happened once.
Anyway, also in Santa Fe on Sunday is the Big Mountain Enduro series race at Glorietta Camps.
The BME series is pretty big, and you should expect to see some pro level riders hauling ass, which makes for good spectating. I plan on cruising over there to do some watching after the century.
I raced the Enduro at Glorietta last year (it wasn't part of the BME then) and there was a newly built trail called Chilidog. That trail had some pretty cool technical spots, with A and B lines, that were a short hike up from the start/finish. So I'm thinking this will be a good place to head to with a backpack full of beers on Sunday afternoon.
(I got so rad at the enduro last year!)
So thats about the gist of it. If anybody is planning on being up there this weekend, let me know, maybe we can meet up, and high-five, and be all like "hey Bro, we normally high-five in Albuquerque, but now we are in Santa Fe!" And then we will slam our beers and go get another.
And if you pass us during the Century, say Hi! We should be easy enough to spot, the bike is literally (like, literally, you guys) school bus yellow.
Hey there internet website readers. Long time no see. I blame myself, really. I mean, you could write me stories, but its cool, I'll do the stories, don't worry.
So, stories huh? Want to hear a story about me crashing in a great big painful stupid way, but where I don't get seriously injured so we can all have a laugh and not feel guilty. Yeah you do.
It all started way back around lunch time today, when a group of us headed out for a few hours of pedaling in Otero, in a civilized, friendly style. It was one of those rides that turned into an impromptu big group, because everybody happened to be free at 1pm on Sunday. At least all the beautiful people happened to be free.
(I only associate myself with the beautiful people.)
I don't know if you know this, but mountain biking on a warm spring day with a bunch of your friends is a pretty awesome thing to do. As a result, spirits were high. Also, I was riding a new Yeti, the SB45c to be exact, which was resulting in high spirits as well.
It's a real fine bicycle, and it makes you feel confident going very fast over the big rocks and drops and jumps and stuff. But the problem is, I'm not so good at the jumps part. So descending Otero Canyon I got a little over zealous and took one of the larger rock-pile jumps. You know, the type that spits you straight up into the air, with a completely flat landing, and it takes everything you got not to land completely on your front wheel.
Well, I didn't quite get it done.
The interesting part is trying to decipher all my bruises. I managed to hit/bruise my right ankle, knee, thigh, hip, shoulder, and palm. But I have that long scrape running down the length of my left forearm, and I can't figure out how, or what I scraped against.
I pretty much rode my front wheel until it hit a granite slab, which I then splatted onto, best as I can recall. Quite the rookie jumping mistake.
Disappointingly, I only took the jump because Charlie took it right in front of me, and he made it look easy. Stupid Charlie, he should have crashed for my sake.
As for my fancy pants new Yeti, it came away relatively unscathed.
The only part of the bike that hit the rocks is the driveside seat stay, as shown. But mostly what you see there is a frame protector sticker that has done its job, and is now peeling up. The frame protector is from a small company called Invisiframe out of the UK.
These are full frame clear sticker kits, from 3M. They are made specific to the bike model and even size. They come in gloss or matte finish. They are a wet application, and they are quite tricky to put on nicely (at least for me they are). I haven't pulled the damaged piece off yet, and I can tell that the carbon did get a little scratched underneath, but I'm pretty sure that the Invisiframe just paid for itself, and I would have been very sad with a very scratched bike without it.
The kits go for about $115 once we get them here to the US, depending on the exchange rate at the moment. I have been doing them installed for around $200, maybe more depending on how dirty the bike is and how many cables/hoses have to be removed first. So, if you like keeping your shiny new expensive toy shiny and new looking, give it a thought, it seems to work.
This wasn't my first time riding the new Yeti. I built it last Thursday, and then took off Friday morning for a weekend in Flagstaff and Sedona with (stupid no-crash) Charlie and some Flagstaff friends. It was a silly good time, we got 3 days of riding in, about 20 miles each day of singletrack, and I broke the SB45 in real good.
Some things that happened along that trip were....
Charlie and I achieved Ninja tire-plugging status, with this 1/4" long slice right at the rim successfully repaired using a Panaracer plug kit on the trail. He probably has 75 miles on the tire since we plugged it, and no problems.
I have mostly been using a more simple kit made by Genuine Innovations, and I have become very fond of those little booger looking strips. If you haven't checked them out yet, you should stop by and grab some, it's $6 very well spent.
Charlie and I posed for a stereotypical Sedona pic, which I then shared on the internet, which caused quite a stir, since we are so shockingly handsome.
My bike got nice and muddy, as it snowed 3 inches Friday evening in Flagstaff, and we rode there on Sunday. People are often worried that the Switch Infinity link on Yeti's is delicate. But it's not, and I took a bad upside photo of my muddy bike to prove it. Boom, problem solved, end of discussion.
Charlie was also riding a brand new SB45c, it was totes adorable, we were both riding brand new Yetis of the same model.
I talk to a lot of people that have never ridden in Flagstaff, but have been to Sedona numerous times. Flag is a ton of fun to ride in, there is some really challenging stuff, and I highly recommend it. I also like the town quite a bit more than hanging out in Sedona, which is often overwhelmingly touristy. And if you are in Flag and need bike stuff or trail info, you should go to Flag Bike Revolution, because they are rad. So there, one more of my opinions shared with the world even though nobody asked.
24 Hours in the Old Pueblo is the kind of fun that takes some time to recover from. Typically you get home wiped out, filthy, and disheveled. And you spend a little time telling yourself that you won't be doing that again. But like anything, the exhaustion fades from memory while the stories of hijinks and glory grow. Six months later you're scheming on next year, and before you know it you're bumping along in the back of a Westy for seven hours, staring at dog ass and drinking banquet beers.
(little Neptune surfed his way to AZ, while I contemplated the upholstery and trucker bombs)
I have been attending Old Pueblo intermittently over the past 13 years. My last two efforts were duo races with Danny, stories of which I am sure can be found elsewhere on this here website. This year we were on a 4 person singlespeed team, consisting of myself (Lucero), Danny, Anona, and Ryan Travelsnacks.
Danny, Anona and I drove out together on Friday in their Eurovan camper, while Travelsnacks and our friend Maggie showed up like rockstars at about 10am on Saturday (race starts at noon). Preparations were quickly made and the race was off before we knew it.
One of the "things" about Old Pueblo is the LeMans style start. With such a massive field, the very long LeMans start provides a way to thin the crowd out a bit. Serious racers run hard, soloists and partiers take their time. I even saw a table stationed along the run full of half filled cups for beer handups.
(here is Ryan, flying the colors, lined up near the front waiting to run)
One of the other "things" about Old Pueblo is the sheer size.
After I handed Ryan's bike off, I stood and filmed the start for a bit. It just goes on like that for several minutes, while the horde files in and grabs their rides.
Our race got off to a good start, with our whole team putting in big efforts. I managed to get a flat, and managed to bungle the fix with a too-short valve on my spare and a broken co2 inflator. As I realized I needed bailing out, a guy wearing a 2 Wheel Jones jersey rolled up and offered help. He gave me a tube and a co2 and chilled out while I got sorted. When I offered to give him something for payback, he laughed and said "nah man, It's cool. My brother owns this shop (points at jersey), I'm pretty styled out." To this I could only reply, in my embarrassment, "awesome, thanks!" I didn't feel like explaining that I also own a bike shop, but couldn't manage to fix my own flat.
(out of context sunset pic)
The size of the "camping" rigs out at the race is always a little shocking. It seems that an unofficial competition is played amongst many to set up the most elaborate base camp. Massive RV's and 5th wheels, multiple EZ Ups, giant backyard grills and gourmet meals, movie screen projectors, couches, you will see it all out there.
Generally the crazy setups just add to the spectacle of the race, and help make everything quite exciting. But the constant running of generators gets pretty old, and the race day morning traffic within 24 Hour Town was completely ridiculous. At one point it actually felt a little dangerous trying to weave my way down to the exchange tent through the incoming trucks . I'm assuming most of the traffic was friends and family showing up to watch the race start, and it seems that most of them could have parked down the street and walked to their camps.
So, if by some chance the powers that be at Epic Rides are reading this (the aren't) my one suggestion to improve an otherwise perfectly ran race is to make a parking lot, possibly with a shuttle service, to handle the Saturday morning visitor traffic.
Our team's camp was pretty minimal, hiding under the Eurovan awning for shade, with a couple of tents and a cooler. Maggie went even more minimalist and blew off setting up her tent..
As I returned from my 5am lap, and saw the mat on the ground with tipped over cans of pringles and beer, I couldn't help but laugh at the contrast to the luxo RV's all snug with their sleeping inhabitants.
Which brings me back to our race. So I headed out for a 5am lap, after trying to back out of it. I was suffering from allergies a couple days before the race, and I came down with a head cold during Saturday. When I woke up at 4:30am Sunday morning to go out for my 4th lap, just drinking water made my throat hurt. I didn't think I could do another lap, as I was going into coughing fits and breathing was difficult.
Ryan was up, and told me not to worry, skip my lap, we were just there to have fun. But I had been watching Ryan watch the results, and we had been bouncing between 3rd and 4th all night. Danny was out on course, and Anona was sleeping. After fantasizing about not riding, I realized that nobody was ready to take my lap and I would be tanking our race if I didn't go out.
So I suited up and headed out, promising to my team that I was going to go nice and slow.
I got through my lap, but it was about 30 minutes slower than Danny and Ryan's laps (1:05 vs 1:35, approximately).
(sparkly gold temporary tattoo war paint)
I was allowed to skip my last lap. Which was fine, because by that time Danny and Ryan had finally gotten warmed up and really started flying. They went back to back for our last 4 team laps, securing our 3rd place position by about 40 minutes and finishing just 30 minutes off 2nd place.
(here is my view from the podium)
(the 4 Person Single Speed category isn't "co-ed", and Anona was the only Woman on the podium)
Getting on the podium was pretty exciting at such a big race. As I mentioned, I first did this race in 2003. And that was the last time I had been on the podium as well, in the 4 Man Open category. It was pretty exciting, and the prize table was ample, I scored a sweet Maxxis hoody and an Ardent Race tire.
After podium pics and high 5's, I jumped in with Ryan and Maggie and we boogied back to ABQ, getting in around 11pm. It was a long drive. It was one of those drives that had you questioning what you choose to do for fun.
Old Pueblo is pretty much a guaranteed good time, if the weather cooperates. The organizers are on point, the goody bag is amply stocked, yummy food vendors, beer flowing everywhere, and of course a screamingly fast and fun 17 miles of singletrack. And this year, the weather was perfect. It was a fantastic episode of Old Pueblo, and I'm recharged and ready to do it again.
Hi there! Did everybody have a lovely holiday season? Are you a little fatter than normal, and your liver hurts? Yeah, us too.
Well, enough chit chat, lets talk about bikes.
Since it's the off season, we finally got around to putting price tags on all our bikes. And in the process, we have marked down every bike in the store that isn't a 2016 model. That means that most of the bikes in the shop are at least 15% off right now. We are also selling off a few of our demo bikes.
I wrote some lovely sales tags using my fine penmanship skills, which I will present to you now, so you can get an idea of what we have around....
See! Bargains!!!! And that's just some of them. Speaking of bargains, we have a funny story behind us yelling "BARGAINS" in the shop all the time. Come by and I'll tell it to you.
Nextly, we've got a couple nice used bikes to move along. Such as a nearly new Surly Karate Monkey singlespeed, a Trek Madone 5.9 with Ultegra Di2, and a Volagi Viaje XL. We will talk about the Volagi, since that's the one I have pictures of at the moment.
Remember Volagi? They were the ones that the big red S sued when they first came out. Anyway, we took this Viaje XL in on trade recently. It hasn't been ridden much, has a few upgraded parts, and we've dialed it in so it's ready to roll. Originally it probably sold for close to $3,000. We're asking $1750.
Yup, we're finally putting a phone booth in our shop.
Actually, we're taking the useless dead corner of the shop and trying to make it useful. There will be some storage space inside for clothing, and some much needed slatwall space for retailing our fine wares.
And that's about all for now. We have a few more bikes going up on the "Sales!" page soon remember the Sales! page? You know, the one I was just talking about? Seriously, pay more attention. |
"Previously on Z Nation." "Those are zombie bites." "Eight of them." "You're looking at the only human known to have survived being bitten by a zombie." "If we can get him to the lab in California they can use his blood and make more of the vaccine." "Is that what I think?" "!" "They ain't sharks!" "You still think about him?" "Antoine?" "I try not to." "Antoine?" "Is that him?" "No." "Even if I never know for sure what happened to Antoine" "I'm okay with being here now with you." "I'm good with that too." "This is a national emergency." "I've decided to catalog all the theories about where the Z virus came from." "There's more than a few." "Is it what the Zoroastrians would call Frashokereti?" "Or are we contaminated with Amazon brain rot?" "Or maybe we passed through the tail of a comet that sprinkled the earth with zombie dust." "Or was it a defense department weaponized virus that escaped the lab?" "Or how about self fulfilling prophecy." "Public fascination with all things zombie just willed it into existence." "As things went south the theories got weirder." "Good times for religions with an end of the world scenario." "The crazier the better." "The Apocalypse business was booming." "At least while there still was business to boom." "It reminds me of a poem by Yeats." ""And what rough beast, its hour come round at last, slouches toward Bethlehem to be born?"" "There is no cure." "What rough beast indeed." "Father, we ask that watch over our brothers and sisters as they leave our congregation for a greater journey." "Amen." "And although we will not see them again in this life, they will live on through their sacrifice." "Now I ask you all to rise." "Brother Eli, Brother Matthew, please help with the Resurrected" "Let us pray." "For today is a day of joy." "I ask now for the anointed to please step forward." "These brothers and sisters will soon know the true meaning of peace that only belief and resurrection can bring." "May these keep you safe on your journey and serve as the instrument of your salvation." "I envy you, brothers." "Sister." "Let us ring the bell and joyously call out for more of the resurrected to join our flock." "Brother Eli." "Brother Matthew." "Please prepare to greet them." "No Zs in sight." "Anybody else worried about Mr. Sunshine out there?" "I know." "He's looking worse." "Yeah, he was pretty creepy to start with." "Come on, guys." "Give him a break." "It's the Apocalypse." "None of us look our best." "It's like one long bad hair day." "Speaking of hair, what's with all the bald patches?" "Maybe that vaccine is like zombie chemo." "Or maybe that vaccine isn't working." "What do you think, Doc?" "I've seen Zs look better than him." "Will he make it to California?" "If we haul ass." "If he goes zombie, we might have to put him down." "Dibs on piking him." "If he turns, piking him's the least of our problems." "What?" "Pit stop's over." "Let's get moving." "I have a ginormous bladder." "Sue me." "Man, I sure could use some of them Kansas City barbecue ribs about now." "How bout you, darlin'." "You're a big rib eater, aren't you?" "You know I was almost starting to feel sorry for you." "You look pretty happy for someone who hasn't eaten in two days." "Could be worse." "Really?" "We're still alive, aren't we?" "You were always a glass half full kinda guy." "It's what I love about you." "Actually I'm looking forward to getting some food and a hot shower at Province Town." "Well don't get your hopes up." "We don't even know if this place still exists." "Hammond had it marked on his map as a resupply place." "And if his contact there is the same Major Williams from my National Guard days, we might actually get some help." "So we're relying on the map of a dead guy?" "In case you forgot that dead guy was a hero who died protecting you." "Just because he's dead doesn't make him a hero." "Well I hope Province Town does exist because we're out of just about everything but hope." "One thousand five hundred and fifty four." "Surrender all weapons?" "Are they serious?" "Looks like." "What do you wanna do?" "Their town, their rules." "Looks like we don't have much of a choice." "Stop right there!" "This is a private compound." "I'm gonna have to ask you to turn around and go back the way you came." "I'm looking for Major Wiliams." "Joe Williams." "And who are you?" "I'm Sergeant Charles Garnett, Georgia National Guard." "We've known each other going back pre-z." "Wait there." "Your crew stays in the truck." "They try to get out or we see a weapon, we'll fire." "Easy everyone." "Charlie's got it under control." "So you're calling him Charlie now?" "Yeah, and I'm gonna start calling you my bitch if you don't shut up." "Well holy shit." "It's the ghost of Charlie Garnett." "Never expected to see you again." "At least not alive." "Hey, Joe." "Didn't expect to see you again either." "Looks like we're both still standing." "Looks like." "Last time I saw you, you were pulling my ass out of a ditch full of Zs." "Just returning the favor." "How many Zs we kill that day?" "Not enough." "Do you mind?" "Stand down." "You're the first person I've seen from before." "How the hell you end up here?" "I'm actually on a mission for the government, if you can believe that." "If it was anybody but you," "I wouldn't." "We've come from New York." "Haven't eaten in a few days." "New York?" "Haven't seen anyone east of the Mississippi for over a year." "How many of you are there?" "Eight." "Including a doctor." "Real doctor?" "Sort of." "He's watched a lot of E.R." "All right." "Come inside and tell me your story." "We'll get you some food." "But the truck stays outside." "Let them in." "And of course you'll have to check your weapons." "Just make sure we get these back." "Why is this not making me feel any safer?" "Looks like it's seen a little action." "Ex prison guard?" "TSA." "Just like Dodge City." "We have our reasons." "Makes sense." "Strong on the outside." "Safe on the inside." "Major, you're not gonna believe this." "Three of Jacob's flock are back." "Major Williams?" "We'd like to come back." "We were wrong to leave." "Jacob turned out to be just some crazy cult leader." " We brought food." " What do you want us to do?" "If they're clean, let 'em back in." "Probably won't be the last of his sheep to wander back." "?" "Have mercy... ?" "Oh, have mercy ?" "I feel so much lighter without that damn hammer." "Yeah, I feel naked, and not in a good way." "When we started out, everyone was armed." "Then one day a guy decided to shoot his wife's boyfriend." "He turned, and we lost five people." "So we made a rule." "Only guards could carry inside." "Then a trading group came in." "Took a gun off a guard." "Seven dead that time." "We were lucky it wasn't worse." "We have a strong perimeter." "Never been breached." "All our problems happened inside." "So we removed the threats." "No weapons inside the walls, period." "It's a better way to live." "Safer." "Being armed all the time has an effect on people." "Maybe I'm naïve, but this gives me hope." "Is this a zombie cage?" "Doesn't seem much use these days." "We patrol the surrounding area for Zs twice a day, so they aren't really a problem." "It's the people we have to worry about." "Since going weapon-free, we've gone over a year without a fatality." "Think about that." "You've been out in the world." "How many deaths have you seen in the last year?" "Enough for a lifetime." "What if someone, you know, dies of natural causes?" "Sure, that could happen." "All the doors and gates close automatically, sealing off each section of the compound." "Like on a submarine." "Can't be opened by Zs." "Everything's been zombie-proofed." "You ever hear of the Titanic?" "You're welcome to wait outside in your vehicle." "You'll have to forgive my friend." "He's been through a lot." "We all have." "Nothing's perfect, but this is as close as it gets." "After a while, most people find they can actually sleep through the night." "Really?" "I can't imagine that." "We grow all our own fruits and vegetables." "The scraps and our waste all go into a biomass generator." "We're up to four hours of electricity a day." "Really?" "That's cool." "What's their story?" "We had a little trouble a while back with a preacher we took in." "He drank his own kool-aid." "Decided the Zompocalypse was actually The Second Coming and we needed to save the Zs, not kill them." "Calls them "The Resurrected." Real whack-job." "I'm not an expert on the Bible, but I'm pretty sure there's nothing in there about zombies." "We had to kick him out, along with his followers." "I've seen this kind of thing before." "Crazy spreads fast." "So why would you let them back in?" "They all had family still here." "I knew once they were out a while, they'd get hungry or scared and some would come back." "Like clockwork these three turned up today." "Not true believers, huh?" "Hard to believe on an empty stomach." "Speaking of which, let's get you people something to eat." "First meal is on me." "The rest you trade for." "No meat of course." "Hope you're vegetarian." "Oh yeah." "We're headed to a CDC lab in California." "You're never gonna make it to California." "Yeah, that's what I've been told." "No, seriously." "The Zs are swarming out west." "Millions of them." "Been hearing about it second and third hand." "Nothing left to eat in the city, so they're pouring into open country, forming mega herds." "Rumor has it the whole west coast is a no-go zone." "Well we still got to try." "The guy's a pain in the ass, but he's our only chance for a cure." "Getting yourself killed won't cure anything." "I could use you here." "I need experienced soldiers and a doctor." "That's a tempting offer, Joe." "But we got to keep going." "Clock's ticking on our guy." "In fact, I could use your help." "We could use an old school ass kicker like you out on the road." "I don't know." "I've seen so much hope come to nothing." "This is the first thing I've been a part of that might actually work." "These folks rely on me." "I know." "I get it." "I've got a spare room two or three of you can use." "The rest can grab a bunk in the community room." "Let me think about what you said." "We'll talk more tomorrow." "In the meantime, get some rest." "Thanks." "Thank you." "Dude." "Dude, slow down." "They're not gonna take it from you." "So..." "We got the lowdown on the sleeping situation." "There's a room that two or three of us can share, and there's a communal bunk." "Dibs on the room." "What?" "Be less risk of anyone figuring out who I am." "I think we should give it to those two." "What, no, no, no." "We're not a..." "Yeah, you guys take it." "Yeah." "Is it that obvious?" "Well..." "If we're gonna do the time, we may as well do the crime." " Are you serious?" " Yes." "Well that was funny." "It's not exactly what I was..." "It's perfect." "Roberta, ummm..." "Yeah?" "I mean, come on." "This room, it's like you know here's the bed." "It's... cozy." "Cozy." "Yeah." "I don't know what to say." "Don't say anything." "Hey, ummm, I don't have any..." "We'll think of something." "I went to Catholic school." "Oh." "Chair." "All right." "What are you worried about the nuns?" "Never know." "For indeed we have had good news preached to us, just as the unbelievers." "But the word they heard did not profit them, for their hearts were closed to the truth." "So then we shall open their eyes." "That fella seems pretty popular for a guy who just got kicked out of here." "It was a lot harder than we expected it." "Thought we'd be better off back here." "Lucky for you the Major was willing to take you in again." "Yes, it was lucky for us all." "Hey, Luke." "Glad to see you back, man." "I knew you were too smart to fall for that Jacob clown." "Yeah." "It wasn't at all what I thought it was gonna be." "Glad to be back." "I think I left some meds in my ammo bag." "Do you mind checking for me?" "Sure, hang on." "Hey, are you all right?" "Listen to me, all of you, for I have good news." "The major didn't believe in the word of Jacob." "But he will." "All of you will be given another chance to hear his word and join the Resurrection Church." "What are you doing?" "Get down from there." "He's got a weapon!" "For as the Father raises the dead and gives them life, so also the Son gives life to whom he will." "He's gonna turn." "Damn it." "Oh God!" "Luke!" "Help me secure these doors!" "We have to contain this!" "Are you sure you didn't go to Catholic school?" "Uh-uh." "Go away!" "Hey!" "This is a very bad time to bother us." "Oh, terrible time." "Who's there?" "Zombies?" "It can't be." "Come on." "Murphy!" "Murphy!" "Murphy!" "Come on!" "Come on!" " Come on!" "Let's go!" " Hurry!" "I would give my left nut for that z-whacker right now!" "Come on, you guys!" "Let's go!" "Oh, that was a bad one." "Where's Murphy?" "The last we saw, he ran out some other door." "We need a leash for that guy." "Someone wedged that door open for the zombies." "What?" "We can barely face these guys one at a time." "This outbreak spreads, they'll be coming at us 50 at a time." "What about Murphy and the others?" "I don't know." "We need weapons." "Joe." "What the hell happened?" "Jacob and his cult." "The ones we let back in slit their throats." "Goddamn suicide zombies." "They sabotaged the doors." "Insane bastards." "Everything we've worked for, it's gone." "All gone." "We need weapons." "The armory's full of Zs." "We can't get in there." "Well you got to have some hidden somewhere." "No." "They're all in the cage." "All of them?" "!" "How are we supposed to defend ourselves?" "!" "I thought we were zombie-proofed!" "Hey, Joe." "You got to pull yourself together, man." "There's got to be a way out of here." "Garnett!" "Thank God you're okay." "Where's Murphy?" "Got separated." "Zombies everywhere." "10K?" "He's out there somewhere." "If anyone can make it he can." "If only he had his gun." "You have to get to the emergency exit before we're completely overrun." "Where is it?" "Through those doors." "There's a long hallway ending in a reinforced door." "It leads outside the perimeter." "Don't stop till you hit the woods, then you can double back around to your truck." "What about you?" "I've got to stay and try to save as many as I can." "Ready?" "Yeah." "Yeah." "Indeed." "All right, let's go!" "Die you freakin' Z!" "Human!" "Human." "Human." "Sorry." "You look like one of them." "You don't look so good yourself, sweetheart." "Look, I need some help." "Okay." "We'll stick together." "Two of us might have a chance." "Why didn't you help?" "Why didn't it attack you?" "Are you part of this?" "!" "No!" "No." "Help me!" "For God's sake!" "Come, brothers and sisters!" "It is as I foretold!" "Our Second Coming is here!" "Behold the Resurrected!" "It's time to take what is rightfully ours." "Bring me the Blasphemers alive." "It's jammed!" "It won't open!" "Turn around!" "Turn around!" "Back up!" "The door's blocked!" "Guys, we're not gonna make it." "We have to turn around!" "Go back!" "Go back!" "Go back!" "Come on!" "Charlie, I'm scared." "Push those Zs back!" "I can't even turn around." "Push!" "Addy!" "Addy!" "Addy!" "Stay with me!" "Addy!" "Come here." "Hey, hey." "It's okay." "We're not gonna last much longer." "10K!" "Come on." "Come on." "How do we get out of here?" "I've been using the roofs to move." "The cult freaks are in the compound." "Armed." "Murphy?" "Haven't seen him." "We need weapons." "Then we'll find Murphy." "Let's go." "Greetings brothers and sisters." "The Resurrection Church welcomes you." "Please raise your hands to the heavens or I will resurrect you where you stand." "Let them go." "The Resurrected will take care of them." "The rest of you, come with us." "The last of the Resurrected have been secured." "And those who died today have the honor of entering into grace ahead of us." "Blessed is the path before them." "Blessed will their journey be." "Brothers and sisters," "I know you have hate in your hearts right now and do not come willingly to this test of faith." "But today each of you will become part of the New Resurrection Church." "You must choose how you are served." "You may join the living flock and spend your days serving the Resurrected." "Or your souls taking the next step on their journey to eternal life." "The time has come for you to choose." "Join me and walk among the living or follow this blasphemer who thought he could oppose the righteous and now walks among the dead." "Now don't feel sorrow for the Major, brothers and sisters." "Although we stood against the man he was, we take joy in his choice to join the Resurrected!" "Blessed is the path before him!" "What choice?" "To live with you lunatics or die and become a zombie?" "I don't know your name, brother." "But I welcome you to the resurrection church." "With us you will know everlasting joy and peace." "There was peace here." "Joe Williams, the man you killed, gave you peace." "This was a good place." "This was a safe place." "And it can be again." "It's not too late." "Put down your weapons." "Let's live the way that people are supposed to." "Helping one another, working together." "It's not too late." "Put down your weapons." "Let us free." "We'll help you." "The Resurrected aren't any closer to God than you and I are." "I envy you, brother." "The time for you to walk among the Resurrected is near." "Charlie." "I'm gonna kill you, you psychotic bastard." "Don't you worry, sister." "You won't be far behind your Charlie." "Shoot him." "I can't get a shot." "I need to get on the roof." "You get the truck." "Rejoice as both of you will walk before me the on road to every lasting life." "Listen, Jacob." "Kill me, resurrect me, but spare the others." "Don't be afraid, brother." "I send you to a better place." "Blessed is the path before him!" "I am the new resurrection and the life." "Whoever believes in me, though he die, yet shall he live." "Stop!" "If you think the Resurrected are one step closer to heaven then prepare to meet your new god." "Come, brother." "Step away from the Resurrected." "That's no place for a mortal human." "Come join our flock." "All are welcome." "I am not one of the Resurrected." "I'm your messiah." "That's blasphemy, brother." "We can all see you're one of the living." "Eight times!" "I was bitten and did not turn!" "Eight times I was infected by their bloody saliva." "And yet here I stand before you." "And I am here to tell you that he is a false prophet!" "For I am the true incarnation of the Resurrected!" "What the hell is he doing?" "I have no idea." "Kill the blasphemer." "But the bites, Jacob." "He's a false prophet!" "I can prove it!" "I can prove that my words are true." "Tell us, blasphemer." "How can you possibly prove this outrageous lie?" "I'll show you." "Observe Ye of little faith." "Jesus." "No." "Just Murphy." "Okay, that's enough of that." "The Resurrected will not attack me because they love and fear me." "Behold my flock." "There's your proof, brothers and sisters!" "Now let us go, Jacob, before my flock resurrects all of you!" "Jacob, what if he's speaking the truth?" "He's no messiah." "I'll prove it." "There's one last test for you to pass, blasphemer." "Damn it." "A bullet to the heart will reveal the truth!" "No!" "Charlie." "Charlie." "You'll be ok." "Go get..." "Go get Murphy." "No." "I'm not leaving you." "I love you." "I love you too." "Then go." "Live." "No." "Don't." "Don't go." "Come on!" "Warren, we have to go." " No." " We have to go now!" "We can't let him turn!" "No!" "We have to give him mercy!" "There's no time!" "No!" "Let me go!" "No!" "Wait a minute!" "There's no time." "No." "No." "Wait!" "Wait!" "Come on." "Come on." "Come on." "We have to go, 10K!" "What is she doing?" "Charles Garnett," "I give you mercy." "Let's go." "Someday maybe we'll find out the real reason the Zombie Apocalypse happened." "All this death and destruction." "All the pain and heartache." "Who do we blame?" "Maybe it was a government virus that escaped the lab." "Maybe it was voodoo." "Or maybe God just doesn't like us." "Some days though" "I wonder if we brought this on ourselves." "We had a chance to do this whole planet earth thing right, and... and we blew it." "We got the Apocalypse we deserved." "But if we're lucky, some day this will all be over." "I hope so." "And next time, I hope we get it right." |
Q:
Understanding Do While Loop with nested if else statement
My professor made us do this in class and I am super confused looking at those outputs.
Does this(x + " " + y + " " + z) mean add all 3 variables if (y > z) ? The output doesn't make any sense to me at all.
public class Practice
{
public static void main (String[] args)
{
int x=10, y=11, z=3;
do
{
System.out.println(x + " " + y + " " + z);
if (y > z)
{
y = y-5;
}
else
{
y = y + 3;
}
x = x - 2;
} while (x > 0);
System.out.println("Bye");
}
}
OUTPUT:
10 11 3
8 6 3
6 1 3
4 4 3
2 -1 3
Bye
A:
System.out.println(x + " " + y + " " + z);
This is not adding x,y and z. Its just appending values in string for printing
your numbers are converted to strings
|
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Adrenocortical carcinoma (ACC) is a rare and aggressive tumor. ACC may be associated with different syndromes of hormone excess, most frequently Cushing's syndrome with or without hypersecretion of androgens. Recent data suggest that cortisol excess is a negative prognostic factor in advanced and localized ACC. Surgery with radical intent, when feasible, is the most effective treatment for ACC with hypercortisolism. Mitotane is the medical treatment of choice, both postoperatively and in inoperable or metastatic cases. Because of its slow onset of action, combination with other antisecretory agents (ie, metyrapone) is helpful to achieve more rapid and effective control of hypercortisolism. |
You’ve dusted off the cyclocross bike after a long few months in storage. You’ve inspected it once, replaced what needed to be replaced, and now … you’re finally riding it again! Well, make sure it stays in that almost-new condition by checking out our article on Daily Maintenance and Inspection.
Good habits just after you finish a ride or race will guarantee fewer mechanical issues out on the course and better longevity from your components. Here’s Dave’s daily routine, well-honed after thousands of applications in the pits.
This is the ninth installment in our series of from-the-crew-pits tips. Some will be straight-forward, others more involved, but they’ll all help you to keep your cyclocross bike humming smoothly along. Catch up on the last article about a quick and dirty power-wash.
by Dave Drumm
The key to having a mechanical-free race starts as soon as you have finished your last training ride or race. A habit that you should get into is cleaning your bike as soon as possible, before the mud and grime have a chance to set in. If you have a workstand, wash the bike with the wheels removed and handle them as a separate entity. Once your bike has been washed with soap and water and all visible muck is removed, wipe your bike down with a clean, soft rag. Use this time to inspect the bike as you go along, starting from the top and moving to the bottom as you inspect the frame and fork for any visible damage, such as nicks in the carbon, cracks or dents.
Once done with the frame, inspect your shifters and brake levers. Squeeze the levers and look inside–mud will often work it’s way into the junction between the lever and the body. Clean it out to the best of your ability. Wipe and inspect the cable housing look for any cracks or wear areas–if it looks suspect, it’s time to change it. Inspect the brakes making sure that they move freely and check the pads for debris. If it looks like there is metal or particles in the pads themselves use a flat file to remove a thin layer of the contact patch. When doing this be sure to use quick light strokes keeping the file flat against the pad. If filing does not remove the embedded debris, replace the pads. This debris will damage the braking surface of your rim.
Next check that your crank spins freely without a lot of drag or noise. Grab the driveside crankarm and check for play in the bottom bracket. If there is place or excessive noise or drag it should be replaced. Check that your chainring bolts and crank arms are tight. Inspect the front derailleur for wear and excessive play. If you are using a single chain ring setup check the guides to insure that they are not making contact with the chain and are within tolerance to prevent your chain from falling off. Inspect your pedals–they should move freely and with out noise.
Now inspect the chain. Make sure it’s clean and that all links move freely. The best way to do this is to grasp the chain lightly in a rag and back pedal the crank slowly with your free hand. If there is a stiff link, it will be evident. If you have a chain checker, use it to check the wear. If it is greater than 75% replace it. Inspect the rear derailleur, making sure it operates freely. Shift your bike in to it’s easiest gear. Now grasp the rear derailleur with one hand and shift quickly into the hardest gear. The cable should become slack. While slack, slide the housing out of the cable stops. The inner wire should now be exposed. Wipe the cable with a clean rag. If the cable is bent or frayed, replace it. If it looks fine, use a light lube, like Boeshield T-9, and apply to the piece of cable that will be inside the housing. Wipe off the excess lube and reinsert the housing into the cable stops. Check that everything is back in place correctly by shifting through the gears. It should move easily.
Next, inspect the jockey wheels on the derailleur. They should be clean and spin freely–if they don’t, they’ll need to be overhauled or replaced or you risk breaking your derailleur off the next time it gets caked with mud. Move back up to the rear brake. With the wheel removed, you should be able to slide the brake cable housing from the cable stops with little effort. Wipe and lube the cable in the same fashion as you did with the derailleur cable. Reinsert the housing and squeeze the brake lever to make sure it is seated correctly. It’s much more difficult to do this to the front brake cable, but most of the time the front brake will be fine. If your front brake does not move smoothly, replace the housing and cable.
Now it’s time for the wheels. Inspect the cassette of the rear wheel. It should be clean and free of debris. Spin it by hand. It should spin easily. Check the forward motion–there shouldn’t be any movement once the pawls of the freehub body have engaged. Wipe down your rims’ braking surface with a clean rag and check that the surface is still flat. If it’s excessively concave, it’s time to start thinking about new rims.
Reinsert the rear wheel and run the bike through the gears. Hook up the brake cable. Test the brake and then spin the wheel. Does the brake make contact with the wheel without applying the brake? It shouldn’t. If it does, the wheel needs to be trued. When applying the brakes, make sure that they make contact with the rim at the same time on each side. If they don’t, you’ll have to adjust the brakes until they do. Before doing this, double check that the wheel is in the drops completely. Inspect the tires for any cuts, holes, abrasions or abnormalities. Replace as needed. If you are running tubulars, with the tire inflated, try to push the tire off the rim with your thumbs. Check this around the entire tire. You should not be able to do this. If you can, they need to be reglued and this process just saved your next race and maybe your collarbone. Now lube your chain, hang up your bike and go grab a beer. You’ve earned it.
This whole process doesn’t take very long and you should make this part of your cleaning routine. As a mechanic for a Pro Cycling team I have found that this routine is one of the best ways to ensure a mechanical free race. It is the only way to find problems before they become an issue.
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Cyclocross MagazineAbout Us
Cyclocross Magazine is a print and digital magazine and website for the cyclocross community by cyclocross racers. We’re based on community-contributed content, which means we welcome content submissions from anyone and prioritize representing all aspects of the sport of cyclocross, from the most grass-roots scene to the highest professional level of the sport. |
Poll: Favorite Dustin Hoffman Movie
He 'graduated' in 1967, dustin' off Hollywood's leading man standards. In 1969, he was 'walking here' and in 1976, he was actually running. Whether "Rain", "Marathon" "Little Big" or one "of the President's", Dustin Hoff... was the MAN (though in 1982, he admitted he was a better man with a woman, as a woman... than he ever was as a man). And on the 8th day of the 8th month, beloved star and iconic method actor Dustin Hoffman celebrated his 80th birthday. On this occasion, or celebrating the 50th anniversary of his breakthrough role, or the 20th anniversary of his last Oscar-nominated performance, let's have a look at his leading, co-leading or scene-stealing supporting roles in movies. Which of these movies starring Dustin Hoffman is your personal favorite? Mr. Voter, you're trying to make a choice. Aren't you? Well, once you're done, you're discussing here, you're discussing here! |
News Releases
TWENTIETH CENTURY FOX CONSUMER PRODUCTS - BLE 2016 PREVIEW STATEMENT
Twentieth Century Fox Consumer Products (FCP) enters Brand Licensing Europe 2016 (BLE 2016) with new developments from within its expanding portfolio of world-class entertainment brands. FCP will highlight new upcoming TV and movie properties in addition to its vast archive of classic properties available for multi category licensing.
FCP’s new TV content includes the award-winning animated series Bob’s Burgers and the unique comedy Son of Zorn which mixes live action & animation plus new reboots from Prison Break and 24: Legacy. The enduringly popular Family Guy features highly on the bill alongside The Simpsons, a powerful franchise that continues to evolve. A complete lifestyle proposition, visitors to the show will see first-hand how The Simpsons brand is perfectly positioned to capitalize upon the trend for gender neutral properties and demand amongst teen girls and young women for design led products across all categories.
FCP will showcase Ice Age, officially the biggest animated franchise globally as well as upcoming movies for 2017 including Ferdinand the new Blue Sky Studios animation, War for the Planet of the Apes and Alien: Covenant plus The Greatest Showman. New for 2018 comes the highly anticipated Alita: Battle Angel and the first of four AVATAR sequels is planned for release later in that year; Blue Sky’s new family animation Pigeon Impossible is scheduled for 2019.
In addition FCP brings to BLE the studio’s vast archive including Hollywood classics such as the Fox Marilyn Monroe movies Gentlemen Prefer Blondes and How To Marry A Millionaire, plus iconic titles ranging from Titanic and Romeo & Juliet to Edward Scissorhands, Home Alone and Buffy the Vampire Slayer. |
Voices - Tony Hazell says the four UK countries can learn from each other.
When I took on the role of chair of the Nursing and Midwifery Council (NMC) in January, I became aware very quickly of the challenge of being a four-country regulator. |
from __future__ import division
import numpy as np
import pytest
import mock
from six import iteritems
from six.moves import xrange
from allensdk.internal.mouse_connectivity.interval_unionize\
.tissuecyte_unionize_record import TissuecyteBaseUnionize, \
TissuecyteInjectionUnionize,TissuecyteProjectionUnionize
@pytest.fixture(scope='function')
def data_arrays():
fq = np.ones(100)
fq[25:] = 0
lq = np.ones(100)
lq[:75] = 0
top = np.ones(100)
top[:70] = 0
return {'injection_fraction': fq,
'aav_exclusion_fraction': top,
'projection_density': np.arange(100),
'projection_energy': np.arange(100) * 2,
'injection_density': np.multiply(np.arange(100), fq),
'injection_energy': np.multiply(np.arange(100) * 2, fq),
'sum_pixels': np.ones(100) * 900,
'sum_pixel_intensities': np.ones(100),
'injection_sum_pixel_intensities': np.ones(100)[:50]
}
def test_base_init():
tbu = TissuecyteBaseUnionize()
for item in TissuecyteBaseUnionize.__slots__:
assert( getattr(tbu, item) == 0 )
@pytest.mark.parametrize('anc_mvd', [0, 1])
def test_base_propagate(anc_mvd):
an = TissuecyteBaseUnionize()
an.sum_pixels = 12
an.max_voxel_index = 100
an.max_voxel_density = anc_mvd
ch = TissuecyteBaseUnionize()
ch.sum_pixels = 5
ch.max_voxel_index = 50
ch.max_voxel_density = 0.5
ch.propagate(an)
assert( an.sum_pixels == 17 )
if an.max_voxel_density == 1:
assert( an.max_voxel_index == 100 )
else:
assert( an.max_voxel_index == 50 )
@pytest.mark.parametrize('spp', [0, 1])
def test_base_set_max_voxel(spp):
darr = np.arange(25) / 24
darr[15:] = 0
low = 12
tbu = TissuecyteBaseUnionize()
tbu.sum_projection_pixels = spp
tbu.set_max_voxel(darr, low)
if spp == 1:
assert( tbu.max_voxel_index == 26 )
assert( tbu.max_voxel_density == 14 / 24 )
else:
assert( tbu.max_voxel_index == 0 )
assert( tbu.max_voxel_density == 0 )
def test_base_slice_arrays():
arrays = {ii: np.arange(10) + ii for ii in xrange(20)}
low = 5
high = 8
tbu = TissuecyteBaseUnionize()
sl = tbu.slice_arrays(low, high, arrays)
for k, v in iteritems(sl):
assert( len(v) == 3 )
assert( v.sum() == k * 3 + 18 )
@pytest.mark.parametrize('sum_pixels,sum_projection_pixels', [(0, 2), (0, 2)])
def test_base_output(sum_pixels, sum_projection_pixels):
tbu = TissuecyteBaseUnionize()
tbu.sum_pixels = sum_pixels
tbu.direct_sum_projection_pixels = sum_projection_pixels / 2
tbu.sum_projection_pixels = sum_projection_pixels
tbu.sum_projection_pixel_intensity = 100
tbu.max_voxel_index = 999
tbu.max_voxel_density = 1
out = tbu.output(10, 900, (10, 10, 10), np.arange(1000))
assert( out['volume'] == sum_pixels * 900 )
assert( out['direct_projection_volume'] == sum_projection_pixels * 450 )
assert( out['projection_volume'] == sum_projection_pixels * 900 )
if sum_pixels > 0:
assert( out['projection_density'] == sum_projection_pixels / sum_pixels )
else:
assert( out['projection_density'] == 0 )
if sum_pixels > 0:
assert( out['projection_energy'] == 100 / sum_pixels )
else:
assert( out['projection_energy'] == 0 )
if sum_projection_pixels > 0:
assert( out['projection_intensity'] == 100 / sum_projection_pixels )
else:
assert( out['projection_intensity'] == 0 )
assert( out['max_voxel_x'] == 90 )
assert( out['max_voxel_y'] == 90 )
assert( out['max_voxel_z'] == 90 )
def test_injection_calculate(data_arrays):
tiu = TissuecyteInjectionUnionize()
tiu.calculate(20, 80, data_arrays)
assert( tiu.sum_pixels == 4500 )
assert( tiu.sum_projection_pixels == 900 * np.arange(20, 25).sum() )
assert( tiu.sum_projection_pixel_intensity == 1800 * np.arange(20, 25).sum() )
assert( tiu.max_voxel_index == 24 )
assert( tiu.max_voxel_density == 24 )
def test_projection_calculate(data_arrays):
tiu = mock.MagicMock()
tiu.sum_pixels = 1
tiu.sum_projection_pixels = 2
tiu.sum_projection_pixel_intensity = 3
tpu = TissuecyteProjectionUnionize()
tpu.calculate(20, 80, data_arrays, tiu)
assert( tpu.sum_pixels == 900 * 50 - 1 )
assert( tpu.sum_projection_pixels == 900 * np.arange(20, 70).sum() - 2 )
assert( tpu.sum_projection_pixel_intensity == 1800 * np.arange(20, 70).sum() - 3 )
assert( tpu.max_voxel_index == 69 )
assert( tpu.max_voxel_density == 69 )
|
"Classroom expenses": Pawlenty's latest education shenanigans
Not so very long ago, theoretically serious people were making theoretically serious remarks about Tim Pawlenty running for President. Now Minnesota's governor is on a press conference per day pace out of fear that he won't even win reelection.
In between last week's multi-point program to beat back the hordes of illegal immigrants diluting the Scandinavian heritage of our state, and Tuesday's proposal to toss $123 million in bonding at our state prison system so that we can "lock up sex offenders," Pawlenty spent his Monday confab with the press meddling in the spending patterns of local school districts. According to his official website, he "proposes requiring 70 percent of education spending be in the classroom."
"After dramatically increasing K-12 funding last legislative session, we want to ensure that those dollars are well spent," Pawlenty announced, calling his plan "common sense" because state funding would be "targeted on children, not bureaucracies."
As campaign positions go, declaring that you'll spend education dollars on cherubic children instead of faceless bureaucrats is fairly foolproof. The reality behind the rhetoric, however, isn't quite that simple.
Take that part about "dramatically increasing K-12 funding," for instance. Because of the actions in the last legislative session, the basic school funding formula will indeed rise by 4 percent in 2006. But the Minnesota Department of Finance has subsequently announced that they expect Minnesota's inflation rate to be 3.5 percent this year. Because Pawlenty and the other lawmakers at the Capitol haven't budgeted for inflation since 2001, that leaves a measly half-percent real-dollar increase in the formula for 2006. And that amounts to less than the $159 million in local property taxes Pawlenty tapped to make his education budget look good.
Tim Pawlenty has never accepted responsibility for the rise in local property taxes resulting from his policies. Without that local property tax hike, the state's commitment to education wouldn't even be able to keep pace with inflation. Yet Pawlenty has the gall to cite the state's generous education budget as justification for telling local school districts how to spend their money.
Move on to the part of the statement where Pawlenty wants to spend the money "on children, not bureaucracies." No politician has ever lost an election bashing bureaucracies, but they exist to administer, monitor, and implement programs. And few programs churn out as much red tape as the federal No Child Left Behind initiative that Pawlenty has steadfastly supported. First NCLB set up an obstacle course of measurements and impossibly high standards, practically guaranteeing that all public schools would sooner or later fail. When that began happening and the inevitable backlash ensued, the feds began granting waivers and exceptions to the rules all over the place.
Local school administrators have also had to devote significant bureaucratic resources to cope with the numerous changes in state education standards over the past ten years. (Remember Profile of Learning?) Funding sources have also fluctuated in that time, with the state picking up the lion's share of education funding during the Ventura Administration (part of Jesse's "Big Fix") only to see it inexorably swinging back to the local level under Pawlenty. Meanwhile, the state has delayed its payments to local districts for five years in a row, an accounting trick that helps Pawlenty and company balance the budget while adding to the need for capable, and expensive, administrators in the school districts.
Finally, there is the question of what does and doesn't qualify as "classroom expenses." The various answers only occasionally stray into the realm of "common sense."
For example, it is good and appropriate that special education programs are regarded as classroom expenses. However, this appears to be a change in policy for the Governor, who, when confronted with a $4 billion deficit in 2003, pledged that education in the classroom would be "held harmless." Then he froze special education funding despite increased enrollments and enormous increases in costs that, because they were federally mandated, had to be paid. Yet Pawlenty's bio over the next two years stubbornly included the notion that he solved the deficit without raising taxes or harming the funding for classroom education. If he believed what he was saying, then he didn't regard special education as part of classroom expenses.
Monday's press briefing gave a clearer indication of what does and doesn't qualify as classroom expenses. Teacher salaries and benefits, special education, vocational education, and instructional supplies comprise the major items that made the cut. But money spent on guidance counselors, school nurses, media centers and libraries, principals and superintendents, athletics, maintenance workers, and teacher training are all not considered to be classroom expenses.
"Not counting libraries, media centers, computer labs; it is ridiculous to assert that those things are not related to classroom learning and classroom instruction," says Scott Croonquist, executive director of the Association of Metropolitan School Districts. "Do we really think that parents and students consider these learning aids nonessential and not related to what happens in the classroom?"
To demonstrate how specious these criteria can be, a district that buys hundreds of power saws and other "instructional supplies" for "vocational education," theoretically could turn all the voc-ed students loose razing the libaries, media centers, computer labs and they would actually improve their spending percentage on what Pawlenty is defining as "classroom expenses." But in this age of soundbyte journalism, the fallout from all this is probably a more widespread public peception that Tim Pawlenty believes in greater accountability of our education resources. Go figure. |
The Story of Vernon and Irene Castle
The Story of Vernon and Irene Castle is a 1939 American biographical musical comedy directed by H.C. Potter. The film stars Fred Astaire, Ginger Rogers, Edna May Oliver, and Walter Brennan. The film is based on the stories My Husband and My Memories of Vernon Castle, by Irene Castle. The movie was adapted by Oscar Hammerstein II, Dorothy Yost and Richard Sherman.
Plot
The film tells of novice American dancer Irene Foote (Ginger Rogers) who convinces New York-based British vaudeville comic Vernon Castle (Fred Astaire) to give up slapstick comedy in favor of sophisticated ballroom dancing.
Their big break comes when they are stranded in Paris, along with their friend Walter Ashe (Walter Brennan), with no money. They catch the eye of influential agent Maggie Sutton (Edna May Oliver), who arranges a tryout for them at the prestigious Café de Paris, where they become an overnight sensation. After taking Europe by storm, the Castles return to the United States and become just as big a sensation. Their fame and fortune rises to unprecedented heights in the immediate pre-World War I years.
When World War I starts, Vernon returns to Britain and joins the Royal Flying Corps, while Irene makes patriotic movie serials to aid the war effort. However, Vernon is killed in a training accident, leaving Irene to carry on alone.
Cast
Fred Astaire as Vernon Castle
Ginger Rogers as Irene Castle (née Foote)
Edna May Oliver as Maggie Sutton
Walter Brennan as Walter Ash
Lew Fields as Himself
Etienne Girardot as Papa Aubel
Janet Beecher as Mrs. Foote
Rolfe Sedan as Emile Aubel
Leonid Kinskey as Artist
Robert Strange as Dr. Hubert Foote
Douglas Walton as Student Pilot
Clarence Derwent as Papa Louis
Sonny Lamont as Charlie, Tap Dancer
Frances Mercer as Claire Ford
Victor Varconi as Grand Duke
Donald MacBride as Hotel Manager
Leyland Hodgson as British Sergeant
Production
Irene Castle acted as advisor to this film, and constantly disagreed with the director as to details of costuming and liberties taken. When informed that white actor Walter Brennan was to play the part of faithful servant Walter, she was dumbfounded: the real Walter was black.
The film marks several "firsts": the characters in it are more realistic than usual in an Astaire-Rogers film, there is none of the usual "screwball comedy" relief provided by such actors as Edward Everett Horton, Victor Moore, or Helen Broderick, it is the only Astaire-Rogers musical biography, the only one on which Oscar Hammerstein II worked, the only one of their musicals with a tragic ending, and the only one in which Astaire's character dies.
Reception
The film was popular in the US, making $1,120,000 and it also earned $705,000 elsewhere. However, due to high costs RKO accounts recorded the film as losing $50,000.
Footnotes
External links
The Story of Vernon and Irene Castle at the Reel Classics web site; contains plot detail.
Category:1939 films
Category:1930s biographical films
Category:1930s musical comedy films
Category:American films
Category:American aviation films
Category:American biographical films
Category:American black-and-white films
Category:American musical comedy films
Category:Biographical films about entertainers
Category:English-language films
Category:Films directed by H. C. Potter
Category:Films set in the 1910s
Category:Films set in Paris
Category:Films set in Westchester County, New York
Category:Films with screenplays by Dorothy Yost
Category:Musical films based on actual events
Category:RKO Pictures films
Category:World War I films |
Rudy Giuliani stepped in it on Sunday. On Monday, he tried to clean it up.
The President’s personal lawyer tweeted that when he said “truth isn’t truth” on NBC’s “Meet the Press,” it was “not meant as a pontification on moral theology but one referring to the situation where two people make precisely contradictory statements, the classic ‘he said,she said’ puzzle.”
My statement was not meant as a pontification on moral theology but one referring to the situation where two people make precisely contradictory statements, the classic “he said,she said” puzzle. Sometimes further inquiry can reveal the truth other times it doesn’t. — Rudy Giuliani (@RudyGiuliani) August 20, 2018
Giuliani made the original comment in the context of whether President Trump should sit for an interview with special counsel Robert Mueller. |
Blood glucose overestimation in diabetic patients on continuous ambulatory peritoneal dialysis for end-stage renal disease.
Diabetic patients on continuous ambulatory peritoneal dialysis (CAPD) for renal failure depend on glucose analysers for regular monitoring of glycaemic control. We aim to inform health professionals of the potentially dangerous overestimation of blood glucose values by some analysers in patients using Icodextrin for dialysis. Twenty-five patients on continuous ambulatory peritoneal dialysis (10 patients on an 8-12-h nocturnal exchange of Icodextrin) had random glucose analysis performed on venous blood using standardized reference laboratory (lab) technique (glucose oxidase GOD-PAP), and simultaneously on capillary blood using the Precision Q.I.D System (glucose oxidase method) and the Advantage meter (glucose dehydrogenase method). The Precision Q.I.D System agreed with the lab results in both the Icodextrin group and the non-Icodextrin group (80-90% of values fell within 20% of the corresponding lab result). In contrast, the Advantage meter agreed with the lab results only in the non-Icodextrin group (95% of values within 20% of the corresponding lab value), and not in the Icodextrin group, where only 5% of the analyser values fell within 20% of the corresponding lab value. The Precision Q.I.D System, which utilizes glucose oxidase reaction, is safe for use in diabetic patients treated with Icodextrin. All analysers must be cross-checked with the laboratory reference method before use in these patients. |
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About Me
Hi, my name is Wanda J. Baker and I am a researcher . Learning new stuff and writing about the latest topics is my hobby. Sharing my thoughts with you guys is totally fun, so stay tuned and share as much information as you want. |
# サーバー用の Git の取得
Git サーバーを立ち上げるには、既存のリポジトリをエクスポートして新たなベアリポジトリ (作業ディレクトリを持たないリポジトリ) を作らなければなりません。これは簡単にできます。リポジトリをクローンして新たにベアリポジトリを作成するには、clone コマンドでオプション `--bare` を指定します。慣例により、ベアリポジトリのディレクトリ名の最後は `.git` とすることになっています。
$ git clone --bare my_project my_project.git
Cloning into bare repository 'my_project.git'...
done.
このコマンドを実行したときの出力はちょっとわかりにくいかもしれません。`clone` は基本的に `git init` をしてから `git fetch` をするのと同じことなので、`git init` の部分の出力も見ることになります。そのメッセージは「空のディレクトリを作成しました」というものです。実際にどんなオブジェクトの転送が行われたのかは何も表示されませんが、きちんと転送は行われています。これで、`my_project.git` ディレクトリに Git リポジトリのデータができあがりました。
これは、おおざっぱに言うと次の操作と同じようなことです。
$ cp -Rf my_project/.git my_project.git
設定ファイルにはちょっとした違いもありますが、ほぼこんなものです。作業ディレクトリなしで Git リポジトリを受け取り、それ単体のディレクトリを作成しました。
## ベアリポジトリのサーバー上への設置
ベアリポジトリを取得できたので、あとはそれをサーバー上においてプロトコルを準備するだけです。ここでは、`git.example.com` というサーバーがあってそこに SSH でアクセスできるものと仮定しましょう。Git リポジトリはサーバー上の `/opt/git` ディレクトリに置く予定です。新しいリポジトリを作成するには、ベアリポジトリを次のようにコピーします。
$ scp -r my_project.git user@git.example.com:/opt/git
この時点で、同じサーバーに SSH でアクセスできてかつ `/opt/git` ディレクトリへの読み込みアクセス権限がある人なら、次のようにしてこのリポジトリをクローンできるようになりました。
$ git clone user@git.example.com:/opt/git/my_project.git
ユーザーが SSH でアクセスでき、かつ `/opt/git/my_project.git` ディレクトリへの書き込みアクセス権限があれば、すでにプッシュもできる状態になっています。`git init` コマンドで `--shared` オプションを指定すると、リポジトリに対するグループ書き込みパーミッションを自動的に追加することができます。
$ ssh user@git.example.com
$ cd /opt/git/my_project.git
$ git init --bare --shared
既存の Git リポジトリからベアリポジトリを作成し、メンバーが SSH でアクセスできるサーバーにそれを配置するだけ。簡単ですね。これで、そのプロジェクトでの共同作業ができるようになりました。
複数名が使用する Git サーバーをたったこれだけの作業で用意できるというのは特筆すべきことです。サーバー SSH アクセス可能なアカウントを作成し、ベアリポジトリをサーバーのどこかに置き、そこに読み書き可能なアクセス権を設定する。これで準備OK。他には何もいりません。
次のいくつかのセクションでは、より洗練された環境を作るための方法を説明します。いちいちユーザーごとにアカウントを作らなくて済む方法、一般向けにリポジトリへの読み込みアクセスを開放する方法、ウェブ UI の設定、Gitosis の使い方などです。しかし、数名のメンバーで閉じたプロジェクトでの作業なら、SSH サーバーとベアリポジトリ _さえ_ あれば十分なことは覚えておきましょう。
## ちょっとしたセットアップ
小規模なグループ、あるいは数名の開発者しかいない組織で Git を使うなら、すべてはシンプルに進められます。Git サーバーを準備する上でもっとも複雑なことのひとつは、ユーザー管理です。同一リポジトリに対して「このユーザーは読み込みのみが可能、あのユーザーは読み書きともに可能」などと設定したければ、アクセス権とパーミッションの設定は多少難しくなります。
### SSH アクセス
開発者全員が SSH でアクセスできるサーバーがすでにあるのなら、リポジトリを用意するのは簡単です。先ほど説明したように、ほとんど何もする必要はないでしょう。より複雑なアクセス制御をリポジトリ上で行いたい場合は、そのサーバーの OS 上でファイルシステムのパーミッションを設定するとよいでしょう。
リポジトリに対する書き込みアクセスをさせたいメンバーの中にサーバーのアカウントを持っていない人がいる場合は、新たに SSH アカウントを作成しなければなりません。あなたがサーバーにアクセスできているということは、すでに SSH サーバーはインストールされているということです。
その状態で、チームの全員にアクセス権限を与えるにはいくつかの方法があります。ひとつは全員分のアカウントを作成すること。直感的ですがすこし面倒です。ひとりひとりに対して `adduser` を実行して初期パスワードを設定するという作業をしなければなりません。
もうひとつの方法は、'git' ユーザーをサーバー上に作成し、書き込みアクセスが必要なユーザーには SSH 公開鍵を用意してもらってそれを 'git' ユーザーの `~/.ssh/authorized_keys` に追加します。これで、全員が 'git' ユーザーでそのマシンにアクセスできるようになりました。これがコミットデータに影響を及ぼすことはありません。SSH で接続したときのユーザーとコミットするときに記録されるユーザーとは別のものだからです。
あるいは、SSH サーバーの認証を LDAP サーバーやその他の中央管理形式の仕組みなど既に用意されているものにするとこもできます。各ユーザーがサーバー上でシェルへのアクセスができさえすれば、どんな仕組みの SSH 認証であっても動作します。
|
Fight erupts at Newark anti-violence rally
An anti-violence protest in Newark, New Jersey turned violent after rival activist groups clashed on city hall steps. The protest was related to the mayor’s policies to curb violent crime in the predominantly African-American community.
There have been 104 murders in Newark this year, 11 more than in 2014, according to local media. As part of reforms proposed to address Newark’s rising levels of violent crime, the city is unifying the police, fire department, and emergency management under a new department of public safety.
Wednesday’s event was organized by anti-violence activists Salaam Ismial of the New Jersey Study Commission on Violence, and Abdul Muhammad. They called on Newark Mayor Ras Baraka to “unleash his quality of life plan in addressing ongoing violence facing Newark residents.”
Reacting to the incident, Baraka said that Ismial’s group should have held the rally in its home community of Elizabeth.
“While we appreciate their concern for the citizens of Newark, it would have been more appropriate for Mr. Salaam Ismial, the coordinator of this event, to bring to light the issue of violence in their town, by doing so in their town,” he said.
“It was also disheartening to learn that a former Newark municipal employee, Mr. Abdul Muhammad, was the instigator in a confrontation with another well-known Newark community activist and was allegedly pivotal in the ensuing melee,” Baraka added.
Minister Thomas Ellis, who heads the Newark-based 'Enough is Enough Coalition', joined Ismail and Muhammad at the event. After the incident, he said he was disappointed that the stand against violence had turned into a political feud, the Newark Star-Ledger reported.
“Today we stood on the steps of City Hall to show that black lives matter in Newark, and it turned out ugly.” |
Demography and the Palestine Question (II)
The Palestinians who remained after the 1948 Palestine War in the new State of Israel (often as internal refugees) started to experience phenomenal population growth: on 1 January 2015 there were close to 1.4 million Palestinians in Israel (excluding annexed East Jerusalem), a ninefold increase since the Nakba. However, this growth must be put in perspective: the population of Jewish Israelis increased just as much, reaching about 6 million people in 2015, also a ninefold increase during the period 1948–2015. More than 3 million Jews from all around the globe arrived in Israel, though this refers to the gross (not net) number of immigrants, of which a large part did not settle permanently in Israel. It is estimated that the Israeli diaspora totals well over 700,000, if not close to a million.
The Palestinians of Israel tried to counter or resist this extraordinary flood of immigration by maintaining a demographic balance at the cost of one of the highest birth and natural population growth rates in the world (Table 5). They currently constitute 18 percent of the Israeli population (and not 20 percent, as is often claimed, because Israeli statistics include the Palestinians of East Jerusalem after annexation by Israel in 1967).
The population growth of Palestinians should not be seen as the result of a well structured, pro-natalist policy. During the British Mandate and after 1948, the high birth rate of Palestinians was more due to their collective unconscious telling them that they needed numbers in order to persevere on their land. Of course there was no government structure to encourage this trend through pro-natalist policies. For Jews, on the other hand, the State of Israel implemented a whole series of measures (both explicit and implicit) that were necessary for maintaining a high Jewish fertility rate and even to increase it.
The Palestinians of Israel reached their highest fertility rate during 1960–65, with an average of 8.1 children per woman (9.2 for Muslims, 4.7 for Christians, and 7.5 for Druze). Since then it has declined steadily, except during the period of the first intifada when, in unison with the Palestinians of the occupied territories, population growth once again became a means for a minority to persevere and to affirm itself. Today, for the Palestinians of Israel, the notion of bringing many children into the world as an act of militancy to support the struggle has become a relic of the past. After several years, when Palestinians changed the ways they “negotiate their reproductive decisions,”[1] babies were no longer being seen as a national instrument and the fertility rate for Palestinian women in Israel was to plunge irremediably from 4.67 children at the end of the last century to 3.35 in 2013. At the same time, the fertility rate of Israeli Jews strongly continued its upward trend, although already high for a developed country, increasing from 2.62 children in 1995–99 to 3.05 in 2013. This rate is double that of any developed European country or an Arab country like Lebanon, and 50 percent higher than that of Morocco or Tunisia. At present, Palestinian and Jewish fertility rates differ only slightly; within three years at the most, the rates are expected to become identical (Diagram 1).
In the occupied territories, the fertility rate has been maintained at a high level for a long time. During the first intifada, it was particularly strong among the most educated – and the most politicized – Palestinian women, and higher than that of illiterate women, who were also less aware politically. During the second intifada, however, this trend was inversed, bringing about a sharp decline of the fertility rate. While it remained high until 2000, with 6 children per woman, it then dropped to 4 children according to MICS3 (the 2010 UNICEF-developed Multiple Indicator Cluster Survey). From then on, pro-natalist watchwords fell on deaf ears in the face of economic difficulties, with the territories sealed off, unemployment rising, and the standard of living falling. Demographically there appeared a divergence between individual and social values, with couples wanting smaller families in the hope of ensuring a better future for their children, rather than having larger families in order to support the national cause.
In areas of friction between Israeli Jews and Palestinians, the demographic superiority of the Jews is indisputable. While the fertility rate was still high for Palestinians in Jerusalem in 2013 with 3.35 children per woman, it was considerably higher for Jews throughout the Holy City, reaching 4.20; for Jewish settlers alone in East Jerusalem this rate was almost 5.5 children. The same is true for Jewish colonies in the West Bank, where the fertility rate in 2010 was 5.02, compared to 4.0 for Palestinians (MICS3 survey of the Palestinian Central Bureau of Statistics). The exceptionally high fertility rate of the Jewish settlers is of course due to a nationalistic and religious expansionist ideology, supported by colossal subsidies provided by the Israeli state or by parastatal organizations in the form of either direct or disguised aid. The Palestinians thus find themselves facing an expansionist and militant Jewish demography at a time when they are no longer inclined to counter it by having many children themselves. Only in Gaza is the Palestinian fertility rate still very high, but no higher than that of the Israeli settlers.
Table 6 provides projections for the population of historical Palestine (Israel and the occupied territories of the West Bank and Gaza) covering the period 2015–48. In 2048, the total population of Jews and Palestinians living in Mandate Palestine is expected to reach almost 20 million, an impressive figure when considering the small total land area. The Jews, who have a relative majority at present, are expected to become a minority by 2048 (mostly due to the strong population growth of Palestinians in Gaza), with their population totaling 9.2 million compared to 10.7 million Palestinians. However, the most significant lessons can be drawn from the demographic shifts within each population group.
First should be noted the systematic conquest of the West Bank and East Jerusalem by Israeli settlers. Numbering more than 650,000 today, their population could grow to 1.7 million by 2048 with their high fertility rate and exuberant immigration; if they do, they could represent more than a fourth of the population of the West Bank. In addition to the evident threat that this colonization poses for Palestinians, the steep increase in the proportion of settlers within the Jewish population of Israel – from 9 percent to 19 percent by 2048 – is likely to have serious consequences for Israel due to the economic and political cost this demographic shift entails: the strengthening of the demographic base of the political right wing, and in particular of the extreme right, in public opinion and in the Knesset is an example.
Palestinians are also expected to experience a demographic change loaded with strong political connotations: the shifting of the center of gravity of the Palestinian population from the West Bank to Gaza, from 39 percent at present to parity by 2048: 48 percent compared to 52 percent in the West Bank including East Jerusalem, but 51 percent compared to 49 percent without East Jerusalem. The distinctiveness of Gaza, in particular in the domain of elections, could thus be strengthened. It is necessary to note also that the demographic center of gravity for Palestinians could shift to historical Palestine as compared to the Palestinian diaspora (see Tables 6 and 7). |
1. Introduction {#sec1-materials-11-00008}
===============
Organic thin film transistors (OTFTs) are fundamental components of organic electronic devices, such as flexible large-area displays, radio frequency identification tags, and integrated circuits \[[@B1-materials-11-00008],[@B2-materials-11-00008],[@B3-materials-11-00008],[@B4-materials-11-00008],[@B5-materials-11-00008]\]. Incorporation of organic semiconductors as active materials in electronics allows for the use of facile solution-based fabrication techniques \[[@B6-materials-11-00008]\]. This has the potential to decrease device fabrication costs by facilitating high-throughput manufacturing techniques. OTFTs also enable the production of electronic devices with increased mechanical flexibility through integration onto substrates with various rigidities. Finally, versatile chemical synthetic methodologies allows for the engineering of a plethora of soluble organic semiconductors, in which both the electronic properties and nanoscale morphology can be tuned.
Designing organic semiconductors with performance and stability that are on par with more traditional silicon-based semiconductors remains challenging \[[@B7-materials-11-00008],[@B8-materials-11-00008],[@B9-materials-11-00008],[@B10-materials-11-00008],[@B11-materials-11-00008],[@B12-materials-11-00008],[@B13-materials-11-00008]\]. Two-dimensional (2D) thienoacenes, such as tetrathienoanthracene (TTA), combine two important strategies toward solving these drawbacks: The incorporation of sulphur atoms and a rigid structure. The presence of sulphur heteroatoms can strengthen electronic communication between molecules due to larger π-orbitals \[[@B14-materials-11-00008],[@B15-materials-11-00008]\]. The rigid star-shaped structure of 2D TTAs can encourage these molecules to aggregate into columnar formations, promoting microstructural control over the morphology of the active layer \[[@B2-materials-11-00008],[@B16-materials-11-00008],[@B17-materials-11-00008]\]. Additionally, conjugated structures containing electronegative heteroatoms also possess superior stability towards oxygen and light when compared to their fully-carbon analogues \[[@B18-materials-11-00008],[@B19-materials-11-00008],[@B20-materials-11-00008]\].
There are a few examples in the literature of the synthesis and incorporation of 2D thienoacenes into organic electronic devices \[[@B21-materials-11-00008]\]; however, there are limited examples of fused thieno\[3,2-*b*\]thiophene (TT) motifs, despite the fact that these few derivatives rank among the highest performing 2D thienoacenes. Zhang et al. synthesized a small molecule comprised of a dithieno\[3,2-*b*:2′,3′-*d*\]thiophene core with nine fused rings and seven sulphur atoms \[[@B22-materials-11-00008]\]. This molecule displayed a forty-fold improvement in charge mobility in OTFTs compared to the parent TTA due to its increased affinity for self-assembly into crystalline nanoribbons in solution. A cyclized thienothiophene core with benzothiophene arms has shown excellent hole mobility in the single-crystal state compared to its shorter thiophene analogue, owing to strong intermolecular contacts and increased effective π-conjugated surface \[[@B23-materials-11-00008]\]. Finally, a rigid dibenzosexithiophene unit has been copolymerized with bithiophene to afford a wide band-gap polymer for photovoltaic applications, albeit with modest performance due to the disordered polymer network \[[@B24-materials-11-00008]\]. While OTFTs prepared from these TT-based 2D thienoacenes displayed excellent mobilities, the devices were fabricated from single crystals or nanoribbons using a mask method, which is not easily amenable to large-scale high-throughput fabrication techniques. Achieving similar devices performances from OTFTs produced using simple solution-based methodologies would therefore be advantageous.
Previous work from the Brusso group has focused on the synthesis of derivatives of TTA and their nitrogen-containing counterpart tetrathienoacridine \[[@B25-materials-11-00008],[@B26-materials-11-00008],[@B27-materials-11-00008],[@B28-materials-11-00008]\]. To improve upon their performance, the conjugation of these systems was extended in two dimensions with oligothienyls of increasing lengths, as it was anticipated that such an approach would enhance the degree of intermolecular communication. Of these derivatives, OTFTs were fabricated using both mono- and bi-thienyl TTA molecules through simple solution-based methodologies. Moderate device performance was observed, with the best mobilities on the order of 10^−4^--10^−3^ cm^2^/Vs. Little improvement in OTFT performance was observed upon expanding the conjugation, likely as a result of increased disorder in the solution-processed thin films. In an effort to overcome this limitation, TT moieties were incorporated into the construction of 2D thienoacenes. The rigid structure of TTs should lead to increased intermolecular interactions in the solid-state, better π-electron delocalization and enhanced light absorptivity and charge conductivity, while simultaneously tuning the energy levels on the molecular orbitals by virtue of the electron-rich nature of the TT core \[[@B29-materials-11-00008],[@B30-materials-11-00008]\].
The Brusso group recently reported the synthesis of four novel rigid 2D thienoacenes and thienoacridines that incorporate the TT motif in the arms and/or the core of star-shaped frameworks \[[@B31-materials-11-00008]\]. Star-shaped architectures were chosen so that the π-framework could be extended in 2D, allowing for the potential for enhanced stability and intramolecular interactions. Here, we report the first successful incorporation of these novel molecules into OTFTs and identify routes to improve device performance through solution process engineering. Unlike previous studies that focused on one compound, this study investigates several derivatives with the TT moiety in different locations.
2. Results {#sec2-materials-11-00008}
==========
[Figure 1](#materials-11-00008-f001){ref-type="fig"}a depicts the structures of the four TT-containing molecules used in this study. Tetra(5-hexyl)thieno(\[3,2-*b*\]thieno)anthracene (**1**) and tetra(5-hexylthieno\[3,2-*b*\]thieno)acridine (**2**) contain TT moieties fused to an anthracene or acridine core, respectively. Tetra(5-hexylthieno)benzothieno\[3,2-*b*\]benzothiophene (**3**) possesses a TT core with thienyl arms, while tetra(5-hexylthieno\[3,2-*b*\]thieno)benzothieno\[3,2-*b*\]benzothiophene (**4**) contains both a TT core and four TT arms. All four of the star-shaped molecules are functionalized with four alkyl chains to promote solubility. The synthesis, optical and electrochemical properties of compounds **1**--**4** has been reported previously \[[@B31-materials-11-00008]\].
Bottom-gate bottom-contact (BGBC) OTFTs ([Figure 1](#materials-11-00008-f001){ref-type="fig"}b,c) were constructed using pre-fabricated chips purchased from Fraunhofer IPMS (Dresden, Germany). The gate electrode was n-doped Si, with a 230 nm thick SiO~2~ dielectric and Au electrodes. Each chip contained 16 devices ([Figure 1](#materials-11-00008-f001){ref-type="fig"}b), four sets of four different channel lengths (2.5, 5, 10 and 20 µm); all devices had a channel width of 2000 µm, allowing for a range of W/L ratios to be investigated. Device fabrication involved cleaning the chips with acetone and oxygen plasma before treatment with an octyltrichlorosilane (OTS) toluene solution to form a self-assembled monolayer on the surface of the chips \[[@B32-materials-11-00008]\]. The organic semiconductor layers were prepared by spin coating a thin film of each of the four thienoacene derivatives onto the chips. All devices were characterized first in vacuum (pressure less than 0.1 Pa) then in air, using the same experimental parameters for both sets of experiments.
The first devices were prepared using chlorobenzene as a solvent, as this was the solvent used in the literature to investigate oligothienyl TTA molecules \[[@B26-materials-11-00008]\]. The devices prepared with the four TT-containing molecules shown in [Figure 1](#materials-11-00008-f001){ref-type="fig"} all demonstrated p-type behavior in both vacuum and air, which is consistent with other reported TT derivatives. The hole mobility versus device channel length is reported in [Figure 2](#materials-11-00008-f002){ref-type="fig"}. Some of the molecules, in particular **1**, were poorly soluble in chlorobenzene, hindering the formation of a consistent thin film across the entire chip. This inhomogeneity resulted in poor organic semiconductor film quality, which led to low mobilities and inconsistent device performance; this was particularly noticeable for the larger-channel devices ([Figure 2](#materials-11-00008-f002){ref-type="fig"}).
Molecules **1**--**4** all displayed good to excellent solubility in CS~2~, which was chosen as the solvent for the next round of experiments. Solutions with concentrations of 5 mg/mL were made for each of the molecules, and devices were prepared again by spin coating. As can be observed in [Figure 2](#materials-11-00008-f002){ref-type="fig"} for molecule **1**, hole mobilities increased by an order of magnitude for all channel lengths compared to devices prepared using chlorobenzene as the spin-casting solvent. This increase in device performance was attributed to the enhanced solubility, which allowed for more even film formation. While the performance improvements were impressive, uneven film coverage and pooling was still observed, which is problematic for large area fabrication.
In an effort to further improve device performance, molecules **1**--**4** were each blended with poly(styrene) (PS). Several reports in the literature demonstrate that blending organic semiconductor small molecules with insulating polymers can be an advantageous route towards the fabrication of stable, high-performance OTFTs \[[@B33-materials-11-00008],[@B34-materials-11-00008]\]. Blending allows for an amalgamation of the excellent semiconducting properties of the small molecule with the ease of processing and film uniformity afforded by using polymers. The two-component films will phase segregate during the deposition process, with the small molecules accumulating at either the air-thin film or thin film-dielectric interface. Microstructural control of this vertical phase separation has been demonstrated to be dependent on a wide range of processing conditions, including blend ratio, concentrations, solvent, polymer molecular weight and post-thermal treatment. For BGBC OTFT devices, it is essential that the small molecules segregate to the dielectric interface to facilitate efficient charge transport. Yoon and coworkers demonstrated that the utilization of a high-molecular weight polymer allows for the small molecules to accumulate adjacent to the dielectric, whereas a combination of a smaller-molecular weight polymer and thermal annealing promoted segregation of the small molecules to the air-thin film interface \[[@B35-materials-11-00008]\].
For our experiments, a high-molecular weight PS (M~n~ = 194 kDa) was used to assist in the formation of the semiconducting layer at the dielectric interface. Samples were prepared with each of the thienoacenes such that there was a 1:1 wt/wt ratio of PS to small molecule, with CS~2~ again employed as the solvent. As shown in [Figure 2](#materials-11-00008-f002){ref-type="fig"}, blending with PS resulted in further improvement in our OTFTs. The hole mobilities increased by an additional order of magnitude for the larger channel devices, corresponding to an increase of over 1000% for the 10 and 20 µm channel lengths. Additionally, it was observed that device variability decreased significantly and that the devices were more robust when tested in air. This increased reliability is likely due to the improved film forming characteristics of the polymer-small molecule blend.
Example output and transfer curves for the **4**/PS blend in both vacuum and air are shown in [Figure 3](#materials-11-00008-f003){ref-type="fig"} for a channel length of 5 µm. The output data in [Figure 3](#materials-11-00008-f003){ref-type="fig"}a exhibits the typical linear-saturation behavior expected for OTFTs. Device parameters, including both average and highest mobilities (*µ*), on-off ratios (*I~on/off~*) and threshold voltages (*V~T~*) can be found in [Table 1](#materials-11-00008-t001){ref-type="table"} (for a channel length of 5 µm) or in [Tables S1--S3 in the Supplementary Materials](#app1-materials-11-00008){ref-type="app"} (for the remaining three channel lengths).
[Figure 4](#materials-11-00008-f004){ref-type="fig"} plots the average mobilities for all four thienoacene blends in both air and vacuum with respect to channel length. Interestingly, slightly different trends were observed for the four small molecules when comparing performance in air to vacuum or between the different channel lengths. In general, devices prepared with **4**/PS blend demonstrated superior performance in air compared to vacuum for all channel lengths, with a 20--125% increase in mobility observed. The highest mobility of all the devices tested was obtained for a **4**/PS device in air, with a maximum mobility of 9.2 × 10^−3^ cm^2^/Vs for a channel length of 5 µm. These mobilities are not as high as the values reported for TT-based OTFTs prepared using deposition or nanoribbon mask methodologies, but a direct comparison with our solution-processed devices is not completely valid due to the drastically different semiconducting films that can be obtained. A more logical comparison would be to compare OTFTs prepared with our anthracene and acridine derivatives (molecules **1** and **2,** respectively) with previously reported anthracene molecules. The highest mobility obtained for molecule **1** represents a 1740% increase over previously-reported solution-processable anthracene molecules. For molecule **2**, the highest mobility of 6.2 × 10^−3^ cm^2^/Vs represents a 2380% increase in mobility \[[@B28-materials-11-00008]\].
The hole mobilities of the **1**/PS devices in vacuum and air were relatively equivalent and consistent for the four device channel lengths (on the order of 5 × 10^−4^ cm^2^/Vs). A slightly higher average mobility was achieved in vacuum compared to air for all but the devices with a channel length of 10 μm. The most dramatic change in mobilities when comparing data obtained in vacuum to air occurred for **2**/PS devices. A 400--700% increase in mobility was achieved for the devices when characterized in air, leading to an average mobility of 1.6 × 10^−3^ cm^2^/Vs for the 10 µm channel devices in air. We surmise the enhanced performance for the **2** devices is attributed to the presence of the nitrogen atom in the acridine core, which makes this molecule more stable in air compared to derivatives with an anthracene core \[[@B18-materials-11-00008],[@B19-materials-11-00008]\].
Out of the four compounds investigated in this study, devices prepared using **3**/PS were consistently the least performing at all channel lengths, for both vacuum and air experiments. The average mobilities for these devices were two orders of magnitude lower compared to **4**/PS at channel lengths of 2.5 and 5 µm, resulting in a 2300--3600% decrease in average mobility at these two channel lengths ([Table 1](#materials-11-00008-t001){ref-type="table"}). Interestingly, the best performance for the **3**/PS devices was achieved at the largest channel length, with average mobilities reaching 2.6 × 10^−4^ cm^2^/Vs in air. This value was still two orders of magnitude lower than the average mobilities for **2**/PS devices (1.3 × 10^−3^ cm^2^/Vs) for the same channel length.
Ranking the OTFT performance of the four thienoacenes in terms of mobilities makes sense when the conjugation length of the four molecules is considered. Molecule **3** has the shortest conjugation path, and, consequently, devices prepared with this molecule consistently underperformed compared to the others, under all studied processing conditions. The conjugation length for **1** is equivalent to **2**; consequently, these two molecules show average mobilities that are roughly on the same order of magnitude in vacuum. However, in air, the increased stability of **2** compared to **1** enables devices containing the former to outperform those prepared with the latter. For the shortest channel lengths, the highest mobilities were obtained for **4**, which also possesses the longest conjugation path. With the larger channels characterized in air, the mobility of the **2**/PS devices surpassed that of the **4**/PS devices. This could be attributed to a favorable doping of **2** in air, or better long-order film morphology for **2** compared to **4**.
Threshold voltages (*V~T~*) for the different molecules varied between −7 and −37 V in vacuum, and between −1 and −21 V in air ([Figure S1, Supplementary Materials](#app1-materials-11-00008){ref-type="app"}). However, notable increases in current often occur close to 0 V, with the threshold voltage appearing high in some cases due to deviation from ideal saturation-regime current-voltage behavior Equation (1) (see [Supplementary Materials](#app1-materials-11-00008){ref-type="app"} in the measurements). [Figure S2](#app1-materials-11-00008){ref-type="app"} shows how the mobility and *V~T~* of the **4**/PS blend varies for one device as a function of gate voltage. Noticeable charge mobilization begins just below 0 V in air and just below −20 V for vacuum. The presence of oxygen in the air modifies the electronic environment in the film, facilitating hole transport at lower gate voltages without causing an excessive increase in current at 0 V as in some polymers like poly(3-hexylthiophene) (P3HT). Thus, **4** could operate at a relatively low operating voltage in air but not vacuum, despite the apparently high threshold voltage for some samples. On the other hand, devices made with **1** have an average threshold voltage of around −1 V. In air, they demonstrate higher off currents and therefore lower on/off current ratios (*I~on/off~*) of 10^1^ to 10^2^ due to induced charge carriers (doping) at 0 V.
3. Conclusions {#sec3-materials-11-00008}
==============
In conclusion, we have reported for the first time the incorporation of four novel star-shaped 2D thienoacenes, which contain a TT moiety in the core and/or arms of the molecule, into OTFTs. All four organic semiconductors were incorporated into p-type devices and tested in both a vacuum and air. The best field-effect mobilities approached 10^−2^ cm^2^/Vs for devices using **4** or **2** when characterized in air. This represents an increase in performance of 160% over devices with 2D thienoacenes previously reported by the Brusso group. Among the few reports using solution processed molecules containing similar functional groups, our average mobilities are comparable to the best mobilities. Blending the small molecules with poly(styrene) resulted in improved performance as well as improved consistency in devices. The stability and enhanced performance of these molecules means that strict air-free fabrication techniques are not required for device manufacturing. We have therefore identified a robust method for obtaining consistent films and ultimately consistent OTFT characteristics using solution processable TT containing molecules. This novel class of materials is worthy of further investigation, with the possibility of improved device performance through molecular design and device engineering; in particular, improving the solubility of the TT derivatives or substituting the insulating polymer could further improve OTFT performance from this class of molecules. Overall, these results represent a useful starting point for the development of solution-processed devices containing TT moieties.
The authors are very grateful for financial support from the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant to Jaclyn L. Brusso and Benoît H. Lessard, and the postdoctoral fellowship to Nicole A. Rice Infrastructure used to complete this work was acquired using Canada Foundation for Innovation's John R. Evans Leaders Fund (CFI-JELF) and NSERC Research Tools and Instruments (RTI) grant program.
######
Click here for additional data file.
The following materials are available online at [www.mdpi.com/1996-1944/11/1/8/s1](www.mdpi.com/1996-1944/11/1/8/s1). Tables S1--S3 provides device data for all molecules (tested in vacuum and air) for channel lengths of 2.5, 10 and 20 µm, respectively. Figure S1 compares the average threshold voltages for molecules **1**--**4** in vacuum and air, while Figure S2 depicts device mobility and threshold voltage as a function of gate voltage.
All authors contributed equally to this work.
The authors declare no conflict of interest.
{#materials-11-00008-f001}
{#materials-11-00008-f002}
{#materials-11-00008-f003}
{#materials-11-00008-f004}
materials-11-00008-t001_Table 1
######
Properties of devices tested in vacuum and air for a channel length of 5 µm.
Name Vacuum Air
------ ------------- -------------- -------------- ----------- ------------- -------------- -------------- -----------
1 7.7 ± 1.6 2.3 × 10^−3^ 10--10^3^ −8 ± 2 6.7 ± 1.1 1.4 × 10^−3^ 10--10^2^ −0.96 ± 4
2 3.0 ± 0.82 2.5 × 10^−3^ 10^2^--10^4^ −23 ± 0.9 15 ± 1.5 3.9 × 10^−3^ 10^2^--10^3^ −16 ± 0.6
3 0.73 ± 0.16 2.2 × 10^−4^ 10--10^3^ −16 ± 2 0.54 ± 0.14 2.4 × 10^−4^ 10--10^3^ −13 ± 3
4 12 ± 1.7 3.1 × 10^−3^ 10^3^--10^4^ −32 ± 0.6 20 ± 3.8 9.2 × 10^−3^ 10^3^--10^4^ −28 ± 1
|
Transgender teenage couple in love. He used to be a her and...
It seems transgender teenage couple Arin Andrews and Katie Hill could be any couple in swimming trunks frolicking during the summer heat, except what makes their love unique is the fact that Arin Andrews used to be a she and Katie Hill used to be a he before receiving full gender reassignment operations.
According to Katie, she was finally able to make the full switch over thanks to an anonymous donation to the tune of $35 000 after her story appeared in the local paper. Whilst Arin, who is still at school was able to undergo an operation to remove both of his breasts allowing him to fully show off his new male physique.
Tells Arin: ‘Now I can wear a tank top, which I couldn’t before, I can go swimming shirtless, I can walk outside, I can just be a regular guy now.
‘I hated my breasts, I always felt like they didn’t belong – now I can finally be comfortable in my own body.’
‘Now when I’m out in a public pool, or lifting weights, no-one raises an eyebrow, they just think I’m a guy – just a skinny dude in the gym trying to build some muscle.”
‘My family have really surprised me with how supportive they have been throughout the surgery. I’m so lucky to have them and Katie to rely on.’
According to the couple, they first met nearly two years ago at a support group for transgender teenagers and bonded through shared experiences.
Tells Katie: ‘To me, Arin’s just my Arin, he’s always looked manly to me. But now he’s had the surgery he’s much more confident and comfortable with himself.’
With both teens’ physical appearance matching their gender, both are excited to be able to go swimming, boating and sunbathe like other couples.
Reflects Katie: ‘Being transgender myself, I understand Arin probably better than anybody else, how good he feels and how complete he feels.’
In the future, Arin might consider having genital surgery, but acknowledges this too can be complicated, and for now he’s delighted with his new body.
Both the couple’s families are supportive of their relationship and say the way the way the teenagers have supported each other has helped in their transition.
Tells Arin’s mum Denise Andrews: ‘Seeing Katie go through her surgery was helpful to Arin.
‘It was being around it and seeing her getting to transform. And being a couple at the time was I think just the cherry on the cake.
‘Every transgender person would love to have the transformation physically because it just completes them as a person.’
The last two years have been very difficult for the teenagers.
Katie was bullied at school, and Arin had to change to a different high school when he revealed he was transgender, and has lost friends in the process.
‘I lost one of my best friends through the transition,’ said Arin. ‘We used to go on vacations together and were like sisters.
‘But I got the chance to open her eyes and show her I’m still a good person. I’m still the person I was, I just look different.
‘She was gone for a while but then she came back.
‘It taught me that the people who really love you need some time, but they’ll always come back around.’
After he began dressing as a boy, Arin also lost a new male friend who learned about his past as a girl.
‘He said: ”I pictured you as a girl, and I can’t do it anymore,”’ said Arin, adding: ‘You can’t just force people to be your friends.’
Katie goes on to tell about the difficulties of assimilation at her new university in Oklahoma where she has struggled to make new friends because of prejudices against transgender people in the traditional Southern state.
‘I had quite a lot of friends in college that were really close to me and then all of a sudden they just stopped talking to me.
‘I think what happened is they found out I was trans through a story or word of mouth and they decided that was too much for them.’
The last two years have also gone on to be difficult for the teenager’s families after having to come to terms with losing their son and daughter, and also some of their own friends.
Reflects Arin’s mum Denise: ‘There are still a group of people we don’t interact with any more. I know that they questioned me as a parent, they’re not comfortable with it.’
‘A lot of people worry about losing the gender of their child. But as you look through albums and realise your babies are growing up, we also watched them grow up and turn into somebody different.
‘Whether they stay the same gender or not, they become independent.’
Now their outward transformation is complete, the teenagers hope people will accept them as their new genders, and their difficulties will become a thing of the past.
Reflects Arin: “I’ve learned what really matters when it comes to being transgender is who I feel I am on the inside and not necessarily how I look like on the outside…”
via the UK’s dailymail |
Q:
Cross Dependent Cascading Dropdowns in MS Access
My concept is this: There are three columns relating to a definite hierarchy. I would like our users to be able to input into the combo boxes in whichever order they'd like and have the information pulled in the other two combo boxes be reactive to this.
Example: Country / State / (County/Region/District/City) in a tracker; The sql referenced table with source info would be Country_Name, State_Name, County_Name
If one were to put in "Vienna" into County, one would have options for Georgia, Missiouri, etc. under state, and United States and Austria as options for Country (I have no idea the larger provincial structure for Austria to add them to a state field--this is meant as an analogous example).
If one were to put in "Virginia" under state one would get United States as an option for Country, and Various counties as options for County.
The hierarchy would be relatively normal for inputting a country, as that's the natural drill down.
I do understand how to do a cascading (one-way) combo-box. The problem lies with being unable to use a nested Iif in the control source, or being unable to temporarily amend the control source through _AfterUpdate cases--please excuse the pseudocode:
Private Sub State_AfterUpdate()
If Country = "" And County = "" Then
Me.Country.ControlSource = "SELECT Country_Name FROM Natl_Structure WHERE State_Name = " & Forms![Postal]![State]
Me.County.ControlSource = "Select County_Name FROM Natl_Structure WHERE State_Name = " & Forms![Postal]![State] & ";"
Elseif Country <> "" And County = "" Then
Me.County ControlSource = "Select County_Name FROM Natl_Structure WHERE (State_Name = " & Forms![Postal]![State]) AND (Country_Name = " & Forms![Postal]![Country] & ";"
...and flip it for the opposite case. And set up the opposite of the first case for if both were setup (not that it would be necessary at that point, but just to account for all cases). Then apply the same sort of measure to the other two combo boxes.
Any and all help would be appreciated.
A:
You have to use IIF in your control sources to check if there is already a value in the other combo boxes or not.
Me.County.ControlSource = "Select County_Name FROM Natl_Structure WHERE 1=1" &
IIf(IsNull(Forms![Postal]![State]),"", " AND State_Name = " & Forms![Postal]![State]) &
IIf(IsNull(Forms![Postal]![Country]),""," AND Country = " & Forms![Postal]![Country])
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from splinter import Browser
b = Browser()
b.visit('http://selenium.dunossauro.live/aula_07.html')
b.find_by_css('input')[3].click() # slice
# lazy
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The Essential Properties of Yoga Questionnaire: Development and Methods.
Yoga interventions have considerable heterogeneity, are multi-dimensional, and may impact health in different ways. However, most research reports regarding the effects of yoga on health and wellbeing do not adequately describe the components of the yoga interventions being used. Thus, drawing comparisons across studies or understanding the relative effects of specific aspects of a yoga intervention are rarely possible. To address this problem, we created the Essential Properties of Yoga Questionnaire (EPYQ) Project, an NCCAM-funded set of studies to develop a translational tool for yoga researchers. Here we describe the methods and developmental processes used in the EPYQ Project in detail. The project consists of four main phases. Phase I was designed to gain a comprehensive understanding of the relevant aspects of yoga by conducting a comprehensive systematic literature review and conducting focus groups with stakeholders including a wide variety of yoga teachers and students. In Phase II, a pool of potential questionnaire items was developed for the prototypic questionnaire using information from Phase I. Cognitive interviews were conducted with the preliminary EPYQ items to assess the perceived clarity, meaning, and importance of each item. In Phase III, the prototypic questionnaire was administered to two large samples of yoga students and instructors. Military personnel and veterans who practiced or taught yoga (n = 329) were recruited to participate. Factor analysis and item response theory were used to identify factors and select the final questionnaire items. Phase IV is ongoing and will collect reliability and validity data on the final instrument. Results are expected to be available in 2016. The EPYQ will provide an objective tool for describing the amount of various components of yoga interventions, eventually allowing researchers to link specific yoga components to health benefits, and facilitating the design of yoga interventions for specific health conditions. |
363 F.Supp. 574 (1973)
Thomas J. REEDER et al., Plaintiffs,
v.
MASTERCRAFT ELECTRONICS CORPORATION et al., Defendants.
No. 68 Civ. 5007.
United States District Court, S. D. New York.
August 22, 1973.
*575 Silverman & Harnes, New York City, for plaintiffs; Sidney B. Silverman, New York City, of counsel.
Charles Sutton, for Mastercraft Electronics Corp. and Al Dayon.
H. John Gluskin, New York City, pro se.
OPINION
ROBERT J. WARD, District Judge.
In 1968 plaintiffs each purchased common stock of defendant Mastercraft Electronics Corporation ("Mastercraft"), which was then selling at between five and six dollars per share. This action arises from plaintiffs' allegations that the individual defendants and Mastercraft manipulated the price of the stock by disseminating to the public false and misleading information concerning the business prospects of the corporation. Plaintiffs seek to recoup their losses, basing their theory of recovery on Sections 10(b) and 27 of the *576 Securities Exchange Act of 1934, 15 U. S.C. §§ 78j(b) and 78aa (1971), and Securities Exchange Commission Rule 10b-5 (17 C.F.R. 240.10b-5) thereunder.
I. Mastercraft, a Delaware corporation, was formerly known as First Standard Corporation ("First Standard"), a public corporation whose stock was being traded over-the-counter. Defendant Dayon was chairman of the board of directors of Mastercraft and was its largest stockholder. Defendant Gluskin, an attorney, was the secretary of Mastercraft and was also a director.
In January, 1968, First Standard acquired the assets of Mastercraft Electronics Corporation, a private family-owned New York corporation ("Mastercraft, N. Y."). First Standard then changed its name to Mastercraft.
In order to raise capital for Mastercraft, defendants issued over 200,000 shares of common stock of Mastercraft to its employees, who were formerly employees of Mastercraft, N. Y., and who had each owned a small percentage of the private corporation.[1] Although this stock was not registered with the Securities and Exchange Commission as required by Section 5 of the Securities Act of 1933, 15 U.S.C. § 77e (1971), and it bore a legend restricting its resale without compliance with that Act, Gluskin wrote a letter advising Mastercraft's transfer agent that the stock could be reissued to the employees without the legend, and it was so reissued. The employees endorsed the reissued stock certificates in blank and surrendered control of them to Gluskin, who delivered them to broker dealers. A substantial number of these unregistered shares were then sold to the public.
The proceeds of these sales were placed in a bank account in Gluskin's name. The employee record holders received an amount sufficient to pay the taxes assessed against them on the sale. Gluskin kept a portion of the money himself, and the rest of the proceeds were turned over to Mastercraft.
At trial Gluskin asserted that the employees were at all times the beneficial owners of the stock and that the sales were exempted from the Securities Act's requirement of registration. Nevertheless, in connection with these transactions Gluskin and Dayon were indicted in January, 1971 (71 Cr. 57). Subsequently, Gluskin pleaded guilty to an information, and before Judge Frankel on December 23, 1971, the following colloquy transpired:
The Court: In other words, the new company was taking this money and then using it for its corporate purposes, and would it be fair to say that the naming of these receiving and shipping people was a fake?
The Defendant: Yes
. . . . . .
The Court: It wasn't really their stock?
The Defendant: That's right.
In addition, Dayon pleaded guilty to Count One of the indictment.[2] At the time of the taking of his plea on October 1, 1971, he stated: "I knew that by giving stock to these nominees that I was doing wrong."[3]
In order to facilitate the sale of the unregistered Mastercraft stock defendants prepared and sent a letter to shareholders *577 ("the shareholder letter").[4] This letter was misleading and was sent for the express purpose of "making a market" for the stock. The misrepresentations *578 and omissions in this letter were legion.
James Farnell, who signed the shareholder letter, was the president and sales manager of Mastercraft. He testified that the orders booked for the first quarter of 1968 as represented in the letter were grossly overstated. He indicated that the orders for January were added to those of February and the sum was listed as February's orders. The same procedure, adding the previous month's total to the orders for the current month, was used again in March. Thus, the first quarter total was inaccurate and misleading. Although Dayon contends that this "error" in calculation was attributable only to a mathematical mistake by Farnell, and that he was unaware of the miscalculation, the argument is not persuasive. It is inconceivable that Dayon, the chairman of the board of directors, did not know, or should not have known, of this error.
In addition, the letter falsely represents the imminency of the marketing of a video-recording system. First, the written commitments for the system were only $358,000, not $1,500,000 as stated. Second, the system had not been adequately tested. Third, mass production of the system had not been ordered. Fourth, Mastercraft was able to obtain a letter of credit for only twenty units. These were the only units received in 1968.
The result of these misrepresentations and omissions was to distort the prospects of marketing the video-recording system by Mastercraft in 1968, thereby making the prospective purchase of Mastercraft stock appear more attractive than it actually was.
At trial defendants did not seriously contest the nature of these untruths; rather, their defense was that plaintiffs did not prove that the letter was mailed to shareholders. Defendants did not offer proof that the letter was not mailed, but testified that they could not "recall" having seen the letter themselves and did not know whether such a letter was ever mailed.
It is at best unusual that the chairman of the board of directors and secretary of a corporation were not familiar with whether a shareholder letter was prepared and mailed. Nevertheless, defendants' frequent lapses of memory during the course of this trial can only be termed convenient.[5] After hearing *579 defendants' testimony and observing their demeanor at this trial and comparing their testimony with their statements at previous Court appearances,[6] the Court concludes that the testimony given by defendants in their own behalf can be afforded little weight.
On the other hand, Farnell testified that he knew the letter went out to the shareholders. In addition certain of the plaintiffs and one of the plaintiffs' witnesses testified to having seen and discussed the letter.[7] Also, defendants did make comments which indicate that the letter was prepared and sent out. For example, Dayon recognized that "something like" the letter was being prepared by Farnell and Gluskin, and Gluskin knew that the letter was to be used to inform the shareholders of Mastercraft of the operation of Mastercraft's business. Under these circumstances, I find that the letter was mailed, was received by the shareholders, and contained numerous misrepresentations.
The shareholder letter also caused the market in Mastercraft to be artificially inflated. Plaintiffs produced Martin Whitman, who is associated with a member firm of the New York Stock Exchange, and is the author of numerous articles on securities and corporate problems. Whitman also has given lectures in these areas and is presently giving lectures at Yale University. He also has acted as a consultant to the SEC. Finally, Whitman was qualified as an expert witness in this Court on previous occasions. I find him fully qualified as an expert in this action.
Whitman examined a financial statement of Mastercraft for the fiscal year ending February 20, 1968.[8] Based on his examination of this statement, Whitman testified that the market value of Mastercraft was "nil or nominal." He observed that Mastercraft's current liabilities exceeded its current assets, its working capital position "was negative and consisted almost entirely" of factored inventories, it had only "nominal" sales for the year ending February 28, 1968, and had reported a deficit of over $109,000.
Whitman believed that the shareholder letter had an important impact on the market price of Mastercraft because the letter gave the impression that Mastercraft was in a growth trend, had a "hot new product," and could enter new areas "on an attractive competitive basis." In fact, Whitman believed that "virtually all of the market value of Mastercraft in 1968" was due to the shareholder letter.
On the basis of Whitman's testimony, and in the light of defendants' guilty pleas to the market manipulation charges,[9] the Court finds that the Mastercraft *580 shares in 1968 were virtually worthless.
II. The Court has determined that all of the elements necessary for liability under Rule 10b-5 are present here. The Rule provides that it shall be "unlawful for any person, directly or indirectly," (1) "To employ any device, scheme, or artifice to defraud," (2) "To make any untrue statement of a material fact" or to omit to state a material fact so that the statements made "in the light of the circumstances," are misleading, and (3) "To engage in any act, practice, or course of business which operates or would operate as a fraud or deceit upon any person." Affiliated Ute Citizens v. United States, 406 U.S. 128, 92 S.Ct. 1456, 31 L.Ed.2d 741, rehearing denied, 407 U.S. 916, 92 S.Ct. 2430, 32 L.Ed.2d 692, rehearing denied, 408 U.S. 931, 92 S.Ct. 2478, 33 L.Ed.2d 345 (1972). The purpose of the rule is "to achieve a high standard of business ethics in the securities industry." SEC v. Capital Gains Research Bureau, 375 U.S. 180, 186, 84 S.Ct. 275, 280, 11 L.Ed.2d 237 (1963).
A. Defendants Gluskin and Dayon have violated Rule 10b-5 in all three of its enumerated provisions. Defendants' activities, discussed previously, constituted a "course of business" or a "device, scheme, or artifice" which operated as a fraud upon these plaintiffs. Affiliated Ute Citizens, supra. The evidence is clear that defendants willfully misrepresented the truth in creating a market for their stock. See Lanza v. Drexel & Co., 479 F.2d 1277 (2d Cir. 1973). Their activities were calculated to influence the investing public to purchase shares. Cf. Heit v. Weitzen, 402 F.2d 909, 913 (2d Cir. 1968), cert. denied, 395 U.S. 903, 89 S.Ct. 1740, 23 L.Ed.2d 217 (1969); S.E.C. v. Texas Gulf Sulphur Co., 401 F.2d 833 (2d Cir. 1968), cert. denied, 394 U.S. 976, 89 S.Ct. 1454, 22 L.Ed.2d 756 (1968), 404 U.S. 1005, 92 S.Ct. 561, 30 L.Ed.2d 558 (1971), rehearing denied, 404 U.S. 1064, 92 S.Ct. 733, 30 L.Ed.2d 753 (1972).
In addition, investors such as plaintiffs, were entitled to full disclosure of the business prospects of Mastercraft which would be material to a decision whether to purchase Mastercraft shares. See, Republic Technology v. Lionel Corp., 483 F.2d 540 (2d Cir. 1973). Defendants were also under a duty to disclose accurately and honestly those prospects in the shareholder letter. The misrepresentations and omissions were material because a reasonable investor might have considered them important in the making of his decision. Cf. Mills v. Electric Auto-Lite Co., 396 U.S. 375, 384, 90 S.Ct. 616, 24 L.Ed.2d 593 (1970). The failure to disclose material information accurately which defendants were under a duty to disclose establishes the requisite element of causation in fact. Affiliated Ute Citizens, supra, 406 U.S. at 154, 92 S.Ct. 1456.
Defendants contend that privity between buyer and seller is necessary under 10b-5. This is simply not the law. In New Park Mining Co. v. Cranmer, 225 F.Supp. 261, 266 (S.D.N.Y.1963), the Court stated,
A purchaser or seller of stock is not limited under Section 10(b) and Rule 10b-5 to an action against the other party to the purchase or sale; he can sue a third person if in connection with the purchase or sale that person defrauded him.
See also, Fischman v. Raytheon Mfg. Co., 188 F.2d 783 (2d Cir. 1951); Kuehnert v. Texstar Corp., 286 F.Supp. 340, 345 (S.D.Tex.1968), aff'd, 412 F.2d 700 (5th Cir. 1969).[10]
Defendants also contend that reliance on the misrepresentations and omissions is necessary and that plaintiffs did not establish this element of their cause of action at trial.
*581 It is not clear to what extent reliance is still an element in 10b-5 actions. Although some cases have talked in terms of reliance, List v. Fashion Park, 340 F.2d 457 (2d Cir. 1965), cert. denied, 382 U.S. 811, 86 S.Ct. 23, 15 L. Ed.2d 60 (1965); Heit v. Weitzen, supra, 402 F.2d at 913; at least in cases concerning a failure to disclose, affirmative reliance no longer must be demonstrated. Affiliated Ute Citizens, supra, 406 U.S. at 153, 92 S.Ct. 1456; Lanza v. Drexel & Co., supra, 479 F.2d at 1320. This is based on the now accepted view that reliance has little rational role in non-disclosure cases. See 2 Bromberg, Securities LawFraud: SEC Rule 10b-5 at 209 (1967). "The proper test is whether the plaintiff would have been influenced to act differently than he did act if the defendant had disclosed to him the undisclosed fact." List v. Fashion Park, supra, 340 F.2d at 463.
In addition, some decisions in "misrepresentation" cases indicate that reliance may be inferred "from the totality of circumstances." Janigan v. Taylor, 344 F.2d 781 (1st Cir.), cert. denied, 382 U.S. 879, 86 S.Ct. 163, 15 L. Ed.2d 120 (1965); Kahan v. Rosenstiel, 424 F.2d 161 (1st Cir. 1970); Gerstle v. Gamble-Skogmo, Inc., 298 F.Supp. 66, 98 (E.D.N.Y.1969). Nevertheless, reliance is still generally required in misrepresentation cases.
Although the shareholder letter here primarily consisted of misrepresentations, plaintiffs bought shares of Mastercraft on the open market. The reliance requirement also appears to have little relevance under these circumstances. Plaintiffs argue, and this Court accepts the view, that had defendants not engaged in "making a market" for Mastercraft stock, plaintiffs certainly would not have purchased the stock at the artificially inflated price.
One commentator considers the reliance requirement unfair to investors:
It would . . . be unfair (to demand reliance in open market trades) since an investor who trades with reference to market price and conditions may be affected by the misstatement although he never hears it. This difficulty might be overcome by saying that he has relied indirectly. 2 A. Bromberg, Securities LawFraud: SEC Rule 10b-5 at 212 (1967).
The Court concurs in this view. Demonstrating reliance in open market situations such as here should not be necessary. Plaintiffs should be required only to demonstrate a material misstatement by defendants. See, Note, Reliance Under Rule 10b-5: Is the "Reasonable Investor" Reasonable? 72 Col.L.Rev. 562, 576 (1972).
To the extent that demonstrating reliance is still required under present law, there is sufficient evidence that it exists here. Plaintiffs' witness Salvatore Nicolosi, a New York City detective, testified that upon his recommendation his parents purchased Mastercraft shares. He testified that he first learned of Mastercraft in the latter part of May, 1968, after having been given a letter by an ex-partner which described Mastercraft and its financial status. Nicolosi identified the shareholder letter as being "very similar" to the letter he saw in 1968. In addition, he discussed the letter with approximately twelve to fifteen other persons. In fact, almost all of the plaintiffs testified that they learned of Mastercraft through Nicolosi.
The evidence presented satisfies the Court that the primary impetus behind the purchase of Mastercraft shares by these plaintiffs was the misleading shareholder letter circulated by defendants.
B. The liability of the corporation is co-extensive with that of Gluskin and Dayon. Affiliated Ute Citizens, supra, 406 U.S. at 154, 92 S.Ct. 1456, 31 L.Ed.2d 741.
C. The proper measure of damages to plaintiffs who have not sold their stock is the purchase price of the stock. See 2 A. Bromberg, supra at 226 (1967). Thus, plaintiffs may recover their entire purchase price and interest *582 from the date of purchase. Plaintiffs who sold their stock may recover the difference between their purchase price and the price at which they sold their shares. Chasins v. Smith, Barney & Co., 305 F.Supp. 489 (S.D.N.Y.1969), aff'd, 438 F.2d 1167 (2d Cir. 1970). They may recover interest on the entire purchase price from the date of purchase until the date of sale, and interest on the difference from the date of sale.
The foregoing constitutes the findings of fact and conclusions of law of the Court for the purposes of Rule 52, Fed. R.Civ.P.
Settle judgment on note.
NOTES
[1] Each employee owned between ¼ and 1 share out of 100 total shares.
[2] Count One alleged that defendants committed the previously discussed acts as well as the substance of a 10b-5 violation as described, infra.
[3] The Securities and Exchange Commission also commenced a civil action against defendants for the above-described conduct, 68 Civ. 3279, and for creating a market in the Mastercraft shares. See, infra. Defendants consented to a final judgment of permanent injunction without admitting or denying the allegations contained in the complaint.
[4] The shareholder letter which is dated April 24, 1968 reads as follows:
Dear Shareholder:
As you know, First Standard Corp. (Delaware) acquired the assets of Master-Craft Electronics Corp. (New York) in January, 1968 and changed its name from First Standard Corp. to MasterCraft Electronics Corp. Business is being conducted from the above premises under MasterCraft's new management and personnel.
Our fiscal period is from March 1st to February 28th and the annual report is now being prepared and will be forwarded to you when completed. Pending the issuance of this report, and in order to answer the many requests for information, we would like to give you an idea of what has transpired since January, 1968.
MasterCraft Electronics Corp. (New York) was a manufacturer and developer of electronic consumer products (about 65 in number), such as television, radios, phonographs, walkie-talkies, tape-recorders, and inter-coms. In 1967 we did a volume of $1,685,000.00.
Our 1968 line has been upgraded and includes several new items such as a solid state 8 track stereo tape cartridge portable ($29.95 retail), a capstan tape-recorder with a built-in AM-FM radio capable of recording any broadcast by the press of a button ($99.00 retail) and an 8 track car stereo unit ($39.95 retail).
Since the introduction of our new product line, our first quarter sales promotion and the expansion of our marketing areas, the following comparisons are noted:
ORDERS BOOKED *
+
1967 1968 - %
JANUARY $137,000.00 $151,000.00 +10%
FEBRUARY 123,000.00 300,000.00 +144%
MARCH 177,000.00 453,000.00 +155%
___________ ___________
FIRST QUARTER $437,000.00 $904,000.00
* Excluding Video Recording System orders
The reason for Master-Craft's decision to sell its assets to First Standard Corp. was the fact that we wanted to broaden our field to encompass the Video Recording System that First Standard Corp. had developed, using ordinary audio tape. Mr. Al Dayon, the Chairman of our Board of Directors made a trip to Japan with a prototype of this Video-Recording System for the purpose of resolving production performance. After a full and detailed investigation he came to the conclusion that Maruwa Electronics & Chemical Co. Ltd., one of Japan's well-known electronic manufacturers, was capable of producing the Video-Recording System developed by First Standard in reasonable volume at a cost that would enable us to retail the Camera, Monitor and Tape-Recorder for less than $700.00, which is about half the cost of competitive models.
Maruwa has indicated to us that it has tooled up and is prepared to produce 500 units in the month of May, 1968 and expects that subsequent production will be substantially greater but cannot at the present time be specific in regard thereto.
Since Mr. Dayon's return from Japan our engineers have increased the proficiency of the Video-Recording System, which will be reflected in the first deliveries to be made.
For the past three months we have invited members of the trade to view the performance of the Video-Recording System at our premises and we have also undertaken to demonstrate same in many parts of the country. We have received written commitments for our Video-Recording System in excess of $1,500,000.00 to be shipped as received from Japan. An unusual delay in delivery from Japan can result in some cancellations.
We have expanded our sales force nationally to include the west coast area, southwest area and midwest area, none of which was heretofore covered by us.
Our 1968 line of consumer-products will begin to arrive in May and should steadily grow for the balance of the year.
Under the aegis of a dedicated and progressive management team, we look forward to a favorable 1968.
Very truly yours,
JAMES S. FARNELL,
President.
[5] The following are only examples of what occurred throughout the trial:
When asked if he had ever seen Mastercraft's financial statement for the fiscal year ending in February, 1968, Gluskin stated, "I never said that I had never seen it. I just don't have any recollection of having seen it. I have seen so many papers."
Gluskin also testified to checking the "English language employed, to see that the flow of language was reasonably intelligent and understandable" in the shareholder letter.
However, when asked for identification purposes whether he had ever seen the letter, he stated, "I can't say that this specific exhibit was seen by me but I am familiar with the fact that we were talking about the substance of it." When asked by plaintiffs' counsel whether he had seen the financial statement, Dayon said that he recalled seeing it and that it was a report prepared by Mastercraft's accountants for Mastercraft. However, after a recess, on voir dire, Dayon was unable to "recall" if his accountants prepared balance sheets for Mastercraft, he "wasn't sure" if Mastercraft had other accountants, and did not "recall" seeing the financial statement "before today".
Both defendants also did not "recall" relating the nature of the wrongful acts they committed to Judge Frankel, who took their guilty pleas.
[6] For example, at the taking of Gluskin's guilty plea on October 4, 1971, Gluskin related the events of the scheme in great detail. Judge Frankel termed his statements a "fairly lucid account". However, at trial, less than two years later, Gluskin said he had no recollection of the nature of the charges to which he pleaded guilty.
[7] See Section IIA, infra, relating to reliance.
[8] Dayon identified this statement as being authentic. See note 4, supra.
[9] At the taking of his plea, Dayon stated that another named defendant in the indictment, not a party to this proceeding, was paying off brokers "to make a market" for the Mastercraft stock.
Defendants contend that the indictment and information and the judgments of conviction by plea of guilty are not competent evidence in this proceeding. The prevailing view is otherwise. See 1B Moore's Federal Practice ¶ .418 at 2706 (1965). The Court considers the pleas of guilty as admissions which are fully admissible in this proceeding.
At any rate, the Court has determined that sufficient evidence was presented to find that defendants are liable to plaintiffs fully apart from any consideration of the guilty pleas.
[10] Plaintiffs have not pressed Count I of their complaint based on Section 5 of the Securities Act of 1933, 15 U.S.C. § 77e, because of their inability to demonstrate that the shares they purchased were those which were illegally sold by defendants.
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Q:
Async-Await Not Executing On Expected Thread
In an attempt to understand async/await I made a little sample WPF application that has one button. When clicked it will do some 'work' :
private async void goButtonClicked(object sender, EventArgs e)
{
WhatThreadAmI();
var task = populateRawData().ConfigureAwait(false);
WhatThreadAmI();
BusyIndicator.IsBusy = true;
await task;
WhatThreadAmI(); //this isnt on the main thread - why??
BusyIndicator.IsBusy = false;
Console.WriteLine("fin");
}
The "WhatThreadAmI" simply compares the current thread to the UI thread which I save on initialization.
public bool IsMainThread => uiThread == Thread.CurrentThread;
I expected the output of this to be True - True - True, with the "WhatThreadAmI" call in the populate raw data method to return false.
What actually happens is True - True - False, with the ""WhatThreadAmI" call in the populate raw data method returning true.
I know I must be missing something very fundamental here, but can someone please help me understand what is going on?
A:
var task = populateRawData().ConfigureAwait(false);
ConfigureAwait(false) returns a configured task awaiter that does not resume on a captured context. I explain how await captures and resumes on context in detail on my blog; the usage of ConfigureAwait(false) means to not capture and resume on the context. In this case, the "context" is the UI thread. So, the await doesn't resume of the UI thread because the ConfigureAwait(false) is explicitly telling the await that it doesn't need to.
On a side note, the task variable in that code does not contain a Task. It's extremely unusual to have the result of ConfigureAwait in a variable instead of with its await. The following example is equivalent and - I think - expresses more clearly what's going on:
WhatThreadAmI();
var task = populateRawData();
WhatThreadAmI();
BusyIndicator.IsBusy = true;
await task.ConfigureAwait(false);
WhatThreadAmI(); //this isnt on the main thread - why??
BusyIndicator.IsBusy = false;
Put another way: it's ConfigureAwait, not ConfigureTask. It doesn't change the task at all; ConfigureAwait only makes sense to use with await.
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I’d had difficulties finding a place in Atlético’s team. In those days, the 4-4-2 formation prevailed in football, but in that system there was only one position I could play. One of the two central midfielders traditionally had a more defensive profile, whereas the other was more technical; more of an organiser. That second role is where I fitted in. My only position.
Cruyff arrived, and I saw that his plan was to play with a diamond in midfield, with four men playing inside. I thought that I could play in any one of those four positions, which opened up the options for me to fit into his team.
Then I saw the way he planned to incorporate that diamond, with three defenders behind and three forwards. From the position I took in the middle of the pitch that offered many possibilities for a pass. That was my main asset – choosing the best pass available and having the technique to deliver it.
As a result, from the very first pre-season matches I played for Barcelona in the Netherlands, I could see that there was a huge new range of possibilities for me as a player. It was a joy to see the footballing idea that Cruyff brought, and to see so soon how it worked so well.
“I wanted to enjoy every day of my life as a footballer; now, here was a manager who proposed an idea in which I could”
Training was very different to what I was used to. Before, the players’ physical condition had always been the most important element. Under Cruyff, technique took precedence.
Technique; tactics; positioning exercises; short games. Everything was always with the ball. It was like when I was a kid and played with my friends in the streets in my hometown.
Then there were the practice games. Short, competitive matches with teams of three players. It felt like we were having fun every day. Football was the profession I had chosen because I loved it so much, and I wanted to enjoy every single day of my professional life. Now, here was a manager who proposed an idea – a training methodology in which all of us had a good time.
There is no point having a good time if it doesn’t help you win. You know that can’t continue. But Cruyff’s way helped us get results too. It felt ideal. |
Price search results for Cocoon Insect Shield Mosquito Head Net
For extra protection from flying, biting insects, wear the Cocoon Insect Shield Mosquito Head Net over your hat. It secures at the bottom with a drawstring, to keep you covered. Built in insect protection with Insect Shield protection invisible, odorless, does not change the feel of the fabric. Long lasting gear treatment on Insect Shield model lasts through 6 months of constant exposure to sun and rain. Protects against mosquitoes, ticks, ants, flies, fleas, chiggers and no see ums. Wear over a hat. Drawstring at the bottom secures the fit. Mesh size: 324 holessquare inch for great protection. Size: 19x17. Weight 1.3 oz. Pack size 2.8x2. |
Q:
Python's generators similar in Java
I have python background so please allow me have my code in python.
In Java (Android) have an arrayList<customObject>. In each customObject corresponds a boolean (for visibility).
I want to perform operations as more efficient as possible to check the visibility boolean. In python I would create a generator.
Assuming my schema is :
list = [{"item": customObject, "visible": boolean}, {...}, {...}]
visible_matches = [x for x in list if x['visible']]
for match in visible_matches:
dosomething(match)
or an alternative schema:
list = [[ customObject, boolean], [...], [...]]
visible_matches = [x for x in list if x[1]]
How could I perform the same in Java?
arrayList<arrayList<boolean,customObject>> or
arrayList< SimpleEntry<"item",customObject>, SimpleEntry<"visible",boolean> >
look a really dirty solutions to me. Is there any simpler way to achieve this?
A:
Java doesn't have generators in the same sense that Python does (iterators are not exactly the same thing). Creating custom objects on the fly like you did in Python doesn't work either. Because Java is strongly typed, you must define your custom object before you can use it. Python is not strongly typed.
In a separate file, try this starting code. I named mine class MyCustomObject because it's inside MyCustomObject.java. The names have to match.
public class MyCustomObject {
public boolean visible;
// Constructor
public MyCustomClass(boolean visible) {
this.visible = visible;
}
}
Now that you have a custom object, you can instantiate and manipulate it like this in your main class. I called mine class Main because again, it's in Main.java.
public class Main {
public static void main(String[] args) {
ArrayList<MyCustomObject> list = new ArrayList<>();
list.Add(new MyCustomObject(true));
list.Add(new MyCustomObject(false));
list.Add(new MyCustomObject(true));
list.Add(new MyCustomObject(true));
....
for (MyCustomObject potentialMatch: list) {
if(obj.visible)
doSomething(potentialMatch);
}
}
}
|
/*
Copyright (c) 2012, Broadcom Europe Ltd
All rights reserved.
Redistribution and use in source and binary forms, with or without
modification, are permitted provided that the following conditions are met:
* Redistributions of source code must retain the above copyright
notice, this list of conditions and the following disclaimer.
* Redistributions in binary form must reproduce the above copyright
notice, this list of conditions and the following disclaimer in the
documentation and/or other materials provided with the distribution.
* Neither the name of the copyright holder nor the
names of its contributors may be used to endorse or promote products
derived from this software without specific prior written permission.
THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS "AS IS" AND
ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED
WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE ARE
DISCLAIMED. IN NO EVENT SHALL THE COPYRIGHT HOLDER OR CONTRIBUTORS BE LIABLE FOR ANY
DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES
(INCLUDING, BUT NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES;
LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND
ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT
(INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE OF THIS
SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.
*/
#include "interface/khronos/include/EGL/egl.h"
#include "interface/khronos/include/EGL/eglext.h"
extern int eglIntOpenMAXILDoneMarker (void* component_handle, EGLImageKHR egl_image);
|
Jason Moralee, "For Salvation's Sake": Provincial Loyalty, Personal Religion, and Epigraphic Production in the Roman and Late Antique Near East. New York and London: Routledge, 2004. Pp. xviii, 244. ISBN 0-415-96778-3. $65.00.
This book, 'a substantially revised version' of the author's 2002 doctoral dissertation at the University of California, Los Angeles (xvii), is a case study of the Greek epigraphic formula 'hyper soterias' and its Latin equivalent 'pro salute' in the ancient Near East, here defined as the area corresponding to the modern states of Israel, Jordan, Lebanon, and Syria. This formula occurs in some 400 inscriptions from this region, ranging in date from the first century BCE to the eighth century CE, and Moralee has to all appearances done an excellent job in gathering and analyzing them. His chief interest lies in the social functions of these inscriptions, the way they worked to structure relationships both within local communities and between local communities and the empire, and his observations on this topic are intelligent and show an admirable sensitivity to nuance. In all these respects the book constitutes a useful contribution to the study of dedicatory inscriptions in the Roman empire. At the same time, however, there is a hesitation in engaging with larger issues that in the end somewhat limits its significance.
The book consists of six chapters, a brief conclusion, and a lengthy appendix of inscriptions (121-182), followed by notes, bibliography, and a general index. In Chapter One, 'Introduction' (1-22), Moralee provides an overview of his material, which falls into two main classes: dedications for the salvation of the emperor and dedications for the salvation of the dedicator and/or other private individuals, which he calls dedications for 'personal salvation'. The former are almost entirely restricted to the first three and a half centuries CE, when they constitute the vast majority of dedications erected 'for salvation'. The latter begin earlier (the earliest datable example is from 69 BCE) and continue later; in late antiquity, when dedications for the emperor's salvation come to an end, they become the norm. Here and throughout the book, Moralee provides numerous charts and graphs that analyze his data according to a variety of criteria: geographical location, date, formula, and the like. He concludes the introduction with a brief discussion of earlier research, in which he sees a tendency to focus on dedications for the emperor's salvation to the neglect of those erected for personal salvation. He argues that an examination of both types together is needed to correct some of the false deductions that follow from this bias.
In Chapter Two, 'The Salutary Ideology' (23-38), Moralee examines the assumptions that underlay dedications for the emperor's salvation: that the empire and its inhabitants depended on the well-being of the emperor, that the emperor in turn depended on the favor of the gods, and that it was consequently important for the inhabitants of the empire to ask the gods for the emperor's salvation. Moralee terms this nexus of mutual dependence 'the salutary ideology', and uses literary evidence to trace its development, spread, and transformation in the imperial period. But in order to understand why people expressed this ideology in the form of permanent inscriptions, he argues, we must examine the inscription themselves.
This he does in the third chapter, 'The Reception of the Salutary Ideology in the Near East' (39-58). Here he provides more specific analysis of the data found in dedications for the emperor's salvation: the names of the dedicators (Greek, Roman, Semitic), their status, the deities invoked, the context, and so forth. As I noted above, Moralee's chief concern here is with the work these inscriptions did, and his premise is eminently sensible: 'inscriptions affirming loyalty became a vehicle for elites in the provinces to fashion individual and collective identity' (40). Because 'the underlying impetus to affirm the salutary ideology involved obligations that emanated from local affairs', these inscriptions served both to craft 'an imperial identity that transcended race, social status, and political clout' and at the same time 'to affirm social distinctions at the local level' (57-8).
Chapter Four provides a succinct discussion of 'The Demise and Transformation of the Salutary Ideology' (59-68). Dedications for the emperor's salvation start to become more scarce in the third century CE, and virtually disappear by the mid-fourth century. Yet the salutary ideology itself did not die out, but came to be expressed orally in the context of the Christian liturgy rather than epigraphically in a civic context. Moralee analyzes a mosaic representation of Salus as an example of this ideological shift 'from public inscriptions on city gates and theaters to strictly personal and religious contexts in churches and synagogues' (68).
In the fifth chapter, Moralee examines 'Pagan, Christian, and Jewish Dedications for Personal Salvation' (69-94). He again analyzes the number and distribution of these dedications, quantifying the information about the names, deities, and personal relationships attested in them. He also considers their physical context, and provides some evocative sketches of what would have been involved in erecting and reading them. His main thesis here is that Christian dedications for personal salvation did not grow out of dedications for the emperors, as earlier scholars supposed, but derived instead from the pagan tradition of erecting dedications for personal salvation, which as he indicates in Chapter One predated those on behalf of emperors. Among pagans and Christians alike, these dedications served to inscribe the dedicators' social identity in the public record and to structure their relationships with other people, either demonstrating their loyalty and subservience (in dedications erected by an inferior on behalf of a superior) or their authority and patronage (in those erected by a superior on behalf of an inferior). We find these functions in Jewish dedications as well, indicating that Jews partook of the same social and cultural forms as their Christian neighbors.
The final chapter, 'Localizing Provincial Loyalty and Personal Religion: Three Case Studies' (95-114), provides a closer look at the inscriptions from Heliopolis and the Bekaa valley, Dura Europos, and Gerasa. Here Moralee brings together conclusions from the previous chapters in short studies that are both more specific and more synoptic; Gerasa, which has yielded fifty-five dedications for the emperor's salvation, receives particular attention. The brief Conclusion (115-120) summarizes his findings, especially with regard to dedications on behalf of the emperor.
There is much of value in this book. Moralee clearly worked hard to amass his database, which draws on a wide range of publications and gives every appearance of being comprehensive. His approach is sensible and sensitive to nuance, and he consistently demonstrates good judgment in his discussion of particular questions. To take one example more or less at random, he argues that when Christians erected dedications for personal salvation, they did so for the same reasons as the pagans from whom they inherited the practice: to ask their God for physical well-being in exchange for votive offerings. That is, they did not use the term 'salvation' in the specifically Christian sense of the eternal salvation of the soul. At the same time, he suggests that recent arguments to exclude entirely any theological significance go too far: 'available in homilies, public readings, and liturgical performance, the specifically Christian understanding of sôtêria as a future event would not have been too obscure to readers, especially given that the vast majority of the dedications were made in a specifically Christian context -- the church' (89). As this suggests, Moralee rejects simplistic either/or interpretations and instead highlights the multi-faceted nature of these inscriptions and the complexity of the social and cultural world that they reveal to us.
Inevitably, I have some criticisms. There are a few errors that escaped the notice of the copy-editor, although nothing too serious; the book is on the whole well produced.1 But the complete lack of maps is a little frustrating. Although it was no doubt impractical to chart the location of every site mentioned, one or two maps showing the major regions and more important settlements would have been very helpful; all we get, however, is the suggestion that 'those interested in locating the places mentioned in the following pages will want to consult The Barrington Atlas' (183, n. 5). As excellent a resource as that atlas is, however, it is not terribly convenient to keep at one's side while reading a book.
More seriously, however, there is a failure to answer or even to ask some key questions that seems to me in part to undermine Moralee's entire project. First of all, what do the terms 'soteria' and 'salus' really mean in these inscriptions? Moralee very briefly comments in his introduction that 'salvation did not last a lifetime, much less for eternity, for this salvation pertained to specific moments of anxiety, sickness, disorder and dislocation' (1), and he briefly reiterates this view at later points (e.g., 87: 'the dedicators desired to be snatched from death, cured of terrible illnesses, the restoration, in short, of the wholeness of the body in the present'). Given that the entire book centers on this concept, however, these brief and scattered remarks do not strike me as a sufficient examination of what people meant when they asked the gods for 'soteria' or 'salus', and why we should regard this request as particularly significant. Moreover, in the absence of any such discussion, the translation of these terms by 'salvation' seems to me questionable. The English word 'salvation' has strong and specific connotations that are surely to some extent misleading in the context of these inscriptions. Moralee does not explain his choice of translation, which is by no means inevitable: 'preservation', 'safety', and 'well-being' are obvious options. I can imagine various advantages to the translation 'salvation': it perhaps was equally appropriate to both the Greek and the Latin words; perhaps its semantic range was wide enough to cover connotations of 'soteria' and 'salus' in pagan, Christian, and Jewish contexts. It is not so much the translation of 'soteria' and 'salus' as 'salvation' that bothers me, as the complete absence of any attempt to explain or justify it. As I indicated above, Moralee does at times address the question of what these words would have meant to different groups. But the general lack of interest in the meaning of these words gave me the feeling that in a fundamental respect I did not know what the book was actually about.
A closely related question is whether dedications 'for salvation' constitute a significant and distinctive category. Moralee notes that he did not include in his database inscriptions 'that contain words related to sôtêria' or 'dedications in Aramaic that ask for the similar quality of "life"' (4). We are apparently meant to assume that this exclusion had no significant effect on his conclusions, but some indication of this would have been welcome. More importantly, it seems to me, there is no discussion of similar dedicatory formulas that happen not to include the specific terms 'soteria' and 'salus', such as dedications for the health or the safety or simply 'for' ('hyper' or 'pro') someone. Do dedications for 'salvation' differ from these in any significant way? Or are they all merely verbal variations on a common idea? If the latter, then the decision to examine only dedications for 'salvation' seems somewhat arbitrary, and I cannot help but wonder how different the results might have looked if the net had been cast more widely. Obviously, there are practical limits to the amount of material someone can cover in a study of this sort. But there should be at least an attempt to place this particular selection of material in a wider context so that we can better evaluate its distinctive or typical qualities.
For these reasons it is somewhat difficult to avoid the impression that what we have here is not so much a topic as a database. Moralee tabulates all the dedications from a certain region that employ a certain formula, but never really explains in what way this particular group of inscriptions is significant: the database serves to justify itself. Now, I like a good database as much as the next person, and I find few things more entertaining than trawling through a solid collection of dedicatory inscriptions (I mean this entirely seriously). The thorough presentation of all the inscriptions in Moralee's database, with text, translation, and annotations, would have been a valuable resource and would on its own have made up for any unresolved questions in the main text. Unfortunately, the appendix of inscriptions is disappointing in this respect. Moralee provides neither texts nor translations of the inscriptions, but simply describes them. Moreover, he has chosen a principle of organization that I found frankly bewildering: first, according to specific formula (so that dedications 'for the salvation of the Lords, Emperors', for example, form a separate category from those 'for the salvation of our Lords, Caesars'), then within formula according to region, and lastly within region according to date or lack thereof. Not only does this organization make the collection difficult to search, but it also seems to insist on the significance of something (i.e., the details of the formula) which, since it receives no discussion in the text, seems not to be significant after all. In fact, as far as I could detect, Moralee never once refers to this appendix either in the body of his book or in the notes. It would have been useful, for example, when reading about a particular inscription, to be able to refer to it in the appendix. But Moralee, ignoring the appendix altogether, refers instead only to the inscription's main publication. Given that the descriptions in the appendix often add little to the descriptions he provides in the text, this is perhaps not too great a loss. But then what was the purpose of including the appendix at all? It may of course be that for reasons of economy a full presentation of the inscriptions was simply not feasible. In that case, however, it was surely the responsibility of someone from the press to help the author work out a more satisfactory solution.
These problems seem to me to weaken an otherwise valuable study. Yet it would be wrong to end on a negative note, since this book is full of useful material and intelligent analysis. Moralee is clearly a promising scholar, and I look forward to seeing more work from him.
Notes:
1. The graphs on pp. 12-15 appear to be printed upside down. Very occasionally a sentence seems to be garbled (e.g., in the first line of p. 71: 'and they continued to do so they the Roman occupation of the city'), and there are a few misspellings (p. 49, 'Sybilline'; 'Liebescheutz' for 'Liebeschuetz' throughout). |
Media playback is unsupported on your device Media caption Defence Secretary Philip Hammond: "We're very determined that the rules of engagement will be followed"
Five Royal Marines have been charged with murder over an incident in Afghanistan in 2011, the MoD has said.
It says nine marines were arrested over the incident, involving an insurgent. Four have been released without charge.
The five charged remain in custody, and the next stage of the process is likely to be trial by court martial.
The marines were arrested by the Royal Military Police after suspicious video footage was found on a serviceman's laptop by civilian police in the UK.
The charges are related to an incident in Afghanistan last year, when Royal Marine 3 Commando Brigade was based in Helmand.
The MoD previously said the incident followed an "engagement with an insurgent" and no civilians were involved.
Analysis The first concern for military commanders is how will these allegations impact the war on the ground? That is why the Ministry of Defence has not made clear exactly where this incident took place. How will Afghans respond and how will the Taliban use this for their own purposes? Though it's important to say that it's hard for the Taliban to take the moral high ground when they do not abide by any rules of war. The second concern is the impact on the wider mission. The chancellor was recently reported to have asked why do British troops need to remain in Afghanistan for another two years. We were told George Osborne was only playing devil's advocate. But there are many others who seriously question why British service personnel are still fighting and dying in a war that's already lasted more than a decade. This incident will only add fuel to that debate. British military forces had hoped to leave Afghanistan with their heads held high. These allegations threaten to undermine their reputation - not just for the five Royal Marines who have been charged with murder, but for everyone in uniform. That is why the MoD is taking these allegations so seriously.
It is believed to be the first time UK servicemen have been arrested and charged with such charges during the Afghanistan conflict.
The Service Prosecuting Authority (SPA), an independent body that conducts prosecutions on behalf of the military, decided the five should face murder charges.
Bruce Houlder QC, the director of service prosecutions, will oversee the next stage of the process.
Speaking on the BBC's Andrew Marr Show, Defence Secretary Philip Hammond did not comment on the specifics of the case but insisted the MoD was "determined that rules of engagement" be followed.
He added: "Everybody serving in theatre knows the rules of engagement, they carry cards in their uniforms with the rules on them in case they should need to remind themselves."
During a six-month tour of duty, which lasted from April to October last year, seven servicemen from 3 Commando Brigade were killed in action, all from 42 Commando.
A court martial is a public court with similar powers to a crown court. It can impose prison sentences, fines or other forms of justice depending upon the nature of the crime.
They are presided over by a judge advocate and a board of up to seven lay members, individuals with no legal training much like a jury in civilian courts.
Colonel Richard Kemp, a former commander of British forces in Afghanistan, said: "The case against the troops concerned needs to be set out quickly because there's no question that these kind of allegations will undermine the morale of troops serving in Afghanistan today."
The MoD said it would be inappropriate to comment further on the ongoing investigation. |
Human monoclonal antibodies: the residual challenge of antibody immunogenicity.
One of the major reasons for seeking human monoclonal antibodies has been to eliminate immunogenicity seen with rodent antibodies. Thus far, there has yet been no approach which absolutely abolishes that risk for cell-binding antibodies. In this short article, I draw attention to classical work which shows that monomeric immunoglobulins are intrinsically tolerogenic if they can be prevented from creating aggregates or immune complexes. Based on these classical studies two approaches for active tolerization to therapeutic antibodies are described. |
Background {#Sec1}
==========
The human skin is the most exposed organ to the external environment and represents the first line of defense against external chemical and microbial threats. It harbors a microbial habitat that is person-specific and varies considerably across the body surface \[[@CR1]--[@CR4]\]. Recent findings suggested an association between the use of antiperspirants or make-up and skin microbiota composition \[[@CR5]--[@CR7]\]. However, these studies were performed for a short period (7--10 days) and/or without washing out the volunteers original personal care products, leading to incomplete evaluation of microbial alterations because the process of skin turnover takes 21--28 days \[[@CR5]--[@CR9]\]. It is well-established that without intervention, most adult human microbiomes, skin or other microbiomes, remain stable compared to the differences between individuals \[[@CR3], [@CR10]--[@CR16]\].
Although the skin microbiome is stable for years \[[@CR10]\], little is known about the molecules that reside on the skin surface or how skin care products influence this chemistry \[[@CR17], [@CR18]\]. Mass spectrometry can be used to detect host molecules, personalized lifestyles including diet, medications, and personal care products \[[@CR18], [@CR19]\]. However, although the impact of short-term dietary interventions on the gut microbiome has been assessed \[[@CR20], [@CR21]\], no study has yet tested how susceptible the skin chemistry and Microbiome are to alterations in the subjects' personal care product routine.
In our recent metabolomic/microbiome 3D cartography study \[[@CR18]\], we observed altered microbial communities where specific skin care products were present. Therefore, we hypothesized that these products might shape specific skin microbial communities by changing their chemical environment. Some beauty product ingredients likely promote or inhibit the growth of specific bacteria: for example, lipid components of moisturizers could provide nutrients and promote the growth of lipophilic bacteria such as *Staphylococcus* and *Propionibacterium* \[[@CR18], [@CR22], [@CR23]\]. Understanding both temporal variations of the skin microbiome and chemistry is crucial for testing whether alterations in personal habits can influence the human skin ecosystem and, perhaps, host health. To evaluate these variations, we used a multi-omics approach integrating metabolomics and microbiome data from skin samples of 11 healthy human individuals. Here, we show that many compounds from beauty products persist on the skin for weeks following their use, suggesting a long-term contribution to the chemical environment where skin microbes live. Metabolomics analysis reveals temporal trends correlated to discontinuing and resuming the use of beauty products and characteristic of variations in molecular composition of the skin. Although highly personalized, as seen with the microbiome, the chemistry, including hormones and pheromones such as androstenone and androsterone, were dramatically altered. Similarly, by experimentally manipulating the personal care regime of participants, bacterial and molecular diversity and structure are altered, particularly for the armpits and feet. Interestingly, a high person-to-person molecular and bacterial variability is maintained over time even though personal care regimes were modified in exactly the same way for all participants.
Results {#Sec2}
=======
Skin care and hygiene products persist on the skin {#Sec3}
--------------------------------------------------
Systematic strategies to influence both the skin chemistry and microbiome have not yet been investigated. The outermost layer of the skin turns over every 3 to 4 weeks \[[@CR8], [@CR9]\]. How the microbiome and chemistry are influenced by altering personal care and how long the chemicals of personal care products persist on the skin are essentially uncharacterized. In this study, we collected samples from skin of 12 healthy individuals---six males and six females---over 9 weeks. One female volunteer had withdrawn due to skin irritations that developed, and therefore, we describe the remaining 11 volunteers. Samples were collected from each arm, armpit, foot, and face, including both the right and left sides of the body (Fig. [1](#Fig1){ref-type="fig"}a). All participants were asked to adhere to the same daily personal care routine during the first 6 weeks of this study (Fig. [1](#Fig1){ref-type="fig"}b). The volunteers were asked to refrain from using any personal care product for weeks 1--3 except a mild body wash (Fig. [1](#Fig1){ref-type="fig"}b). During weeks 4--6, in addition to the body wash, participants were asked to apply selected commercial skin care products at specific body parts: a moisturizer on the arm, a sunscreen on the face, an antiperspirant on the armpits, and a soothing powder on the foot (Fig. [1](#Fig1){ref-type="fig"}b). To monitor adherence of participants to the study protocol, molecular features found in the antiperspirant, facial lotion, moisturizer, and foot powder were directly tracked with mass spectrometry from the skin samples. For all participants, the mass spectrometry data revealed the accumulation of specific beauty product ingredients during weeks 4--6 (Additional file [1](#MOESM1){ref-type="media"}: Figure S1A-I, Fig. [2](#Fig2){ref-type="fig"}a orange arrows). Examples of compounds that were highly abundant during T4--T6 in skin samples are avobenzone (Additional file [1](#MOESM1){ref-type="media"}: Figure S1A), dexpanthenol (Additional file [1](#MOESM1){ref-type="media"}: Figure S1B), and benzalkonium chloride (Additional file [1](#MOESM1){ref-type="media"}: Figure S1C) from the facial sunscreen; trehalose 6-phosphate (Additional file [1](#MOESM1){ref-type="media"}: Figure S1D) and glycerol stearate (Additional file [1](#MOESM1){ref-type="media"}: Figure S1E) from the moisturizer applied on arms; indolin (Additional file [1](#MOESM1){ref-type="media"}: Figure S1F) and an unannotated compound (*m/z* 233.9, rt 183.29 s) (Additional file [1](#MOESM1){ref-type="media"}: Figure S1G) from the foot powder; and decapropylene glycol (Additional file [1](#MOESM1){ref-type="media"}: Figure S1H) and nonapropylene glycol (Additional file [1](#MOESM1){ref-type="media"}: Figure S1I) from the antiperspirant. These results suggest that there is likely a compliance of all individuals to study requirements and even if all participants confirmed using each product every day, the amount of product applied by each individual may vary. Finally, for weeks 7--9, the participants were asked to return to their normal routine by using the same personal care products they used prior to the study. In total, excluding all blanks and personal care products themselves, we analyzed 2192 skin samples for both metabolomics and microbiome analyses.Fig. 1Study design and representation of changes in personal care regime over the course of 9 weeks. **a** Six males and six females were recruited and sampled using swabs on two locations from each body part (face, armpits, front forearms, and between toes) on the right and left side. The locations sampled were the face---upper cheek bone and lower jaw, armpit---upper and lower area, arm---front of elbow (antecubitis) and forearm (antebrachium), and feet---in between the first and second toe and third and fourth toe. Volunteers were asked to follow specific instructions for the use of skin care products. **b** Following the use of their personal skin care products (brown circles), all volunteers used only the same head to toe shampoo during the first 3 weeks (week 1--week 3) and no other beauty product was applied (solid blue circle). The following 3 weeks (week 4--week 6), four selected commercial beauty products were applied daily by all volunteers on the specific body part (deodorant antiperspirant for the armpits, soothing foot powder for the feet between toes, sunscreen for the face, and moisturizer for the front forearm) (triangles) and continued to use the same shampoo. During the last 3 weeks (week 7--week 9), all volunteers went back to their normal routine and used their personal beauty products (circles). Samples were collected once a week (from day 0 to day 68---10 timepoints from T0 to T9) for volunteers 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, and 12, and on day 0 and day 6 for volunteer 8, who withdraw from the study after day 6. For 3 individuals (volunteers 4, 9, 10), samples were collected twice a week (19 timepoints total). Samples collected for 11 volunteers during 10 timepoints: 11 volunteers × 10 timepoints × 4 samples × 4 body sites = 1760. Samples collected from 3 selected volunteers during 9 additional timepoints: 3 volunteers × 9 timepoints × 4 samples × 4 body sites = 432. See also the "[Subject recruitment and sample collection](#Sec10){ref-type="sec"}" section in the "[Methods](#Sec10){ref-type="sec"}" sectionFig. 2Monitoring the persistence of personal care product ingredients in the armpits over a 9-week period. **a** Heatmap representation of the most abundant molecular features detected in the armpits of all individuals during the four phases (0: initial, 1--3: no beauty products, 4--6: common products, and 7--9: personal products). Green color in the heatmap represents the highest molecular abundance and blue color the lowest one. Orange boxes with plain lines represent enlargement of cluster of molecules that persist on the armpits of volunteer 1 (**b**) and volunteer 3 (**c**, **d**). Orange clusters with dotted lines represent same clusters of molecules found on the armpits of other volunteers. Orange arrows represent the cluster of compounds characteristic of the antiperspirant used during T4--T6. **b** Polyethylene glycol (PEG) molecular clusters that persist on the armpits of individual 1. The molecular subnetwork, representing molecular families \[[@CR24]\], is part of a molecular network (<http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=f5325c3b278a46b29e8860ec5791d5ad>) generated from MS/MS data collected from the armpits of volunteer 1 (T0--T3) MSV000081582 and MS/MS data collected from the deodorant used by volunteer 1 before the study started (T0) MSV000081580. **c**, **d** Polypropylene glycol (PPG) molecular families that persist on the armpits of individual 3, along with the corresponding molecular subnetwork that is part of the molecular network accessible here <http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=aaa1af68099d4c1a87e9a09f398fe253>. Subnetworks were generated from MS/MS data collected from the armpits of volunteer 3 (T0--T3) MSV000081582 and MS/MS data collected from the deodorant used by volunteer 3 at T0 MSV000081580. The network nodes were annotated with colors. Nodes represent MS/MS spectra found in armpit samples of individual 1 collected during T0, T1, T2, and T3 and in personal deodorant used by individual 1 (orange nodes); armpit samples of individual 1 collected during T0, T2, and T3 and personal deodorant used by individual 1 (green nodes); armpit samples of individual 3 collected during T0, T1, T2, and T3 and in personal deodorant used by individual 3 (red nodes); armpit samples of individual 3 collected during T0 and in personal deodorant used by individual 3 (blue nodes); and armpit samples of individual 3 collected during T0 and T2 and in personal deodorant used by individual 3 (purple nodes). Gray nodes represent everything else. Error bars represent standard error of the mean calculated at each timepoint from four armpit samples collected from the right and left side of each individual separately. See also Additional file [1](#MOESM1){ref-type="media"}: Figure S1
To understand how long beauty products persist on the skin, we monitored compounds found in deodorants used by two volunteers---female 1 and female 3---before the study (T0), over the first 3 weeks (T1--T3) (Fig. [1](#Fig1){ref-type="fig"}b). During this phase, all participants used exclusively the same body wash during showering, making it easier to track ingredients of their personal care products. The data in the first 3 weeks (T1--T3) revealed that many ingredients of deodorants used on armpits (Fig. [2](#Fig2){ref-type="fig"}a) persist on the skin during this time and were still detected during the first 3 weeks or at least during the first week following the last day of use. Each of the compounds detected in the armpits of individuals exhibited its own unique half-life. For example, the polyethylene glycol (PEG)-derived compounds *m/z* 344.227, rt 143 s (Fig. [2](#Fig2){ref-type="fig"}b, S1J); *m/z* 432.279, rt 158 s (Fig. [2](#Fig2){ref-type="fig"}b, S1K); and *m/z* 388.253, rt 151 s (Fig. [2](#Fig2){ref-type="fig"}b, S1L) detected on armpits of volunteer 1 have a calculated half-life of 0.5 weeks (Additional file [1](#MOESM1){ref-type="media"}: Figure S1J-L, all *p* values \< 1.81e−07), while polypropylene glycol (PPG)-derived molecules *m/z* 481.87, rt 501 s (Fig. [2](#Fig2){ref-type="fig"}c, S1M); *m/z* 560.420, rt 538 s (Fig. [2](#Fig2){ref-type="fig"}c, S1N); *m/z* 788.608, rt 459 s (Fig. [2](#Fig2){ref-type="fig"}d, S1O); *m/z* 846.650, rt 473 s (Fig. [2](#Fig2){ref-type="fig"}d, S1P); and *m/z* 444.338, rt 486 s (Fig. [2](#Fig2){ref-type="fig"}d, S1Q) found on armpits of volunteers 3 and 1 (Fig. [2](#Fig2){ref-type="fig"}a) have a calculated half-life ranging from 0.7 to 1.9 weeks (Additional file [1](#MOESM1){ref-type="media"}: Figure S1M-Q, all *p* values \< 0.02), even though they originate from the same deodorant used by each individual. For some ingredients of deodorant used by volunteer 3 on time 0 (Additional file [1](#MOESM1){ref-type="media"}: Figure S1M, N), a decline was observed during the first week, then little to no traces of these ingredients were detected during weeks 4--6 (T4--T6), then finally these ingredients reappear again during the last 3 weeks of personal product use (T7--T9). This suggests that these ingredients are present exclusively in the personal deodorant used by volunteer 3 before the study. Because a similar deodorant (Additional file [1](#MOESM1){ref-type="media"}: Figure S1O-Q) and a face lotion (Additional file [1](#MOESM1){ref-type="media"}: Figure S1R) was used by volunteer 3 and volunteer 2, respectively, prior to the study, there was no decline or absence of their ingredients during weeks 4--6 (T4--T6).
Polyethylene glycol compounds (Additional file [1](#MOESM1){ref-type="media"}: Figure S1J-L) wash out faster from the skin than polypropylene glycol (Additional file [1](#MOESM1){ref-type="media"}: Figure S1M-Q)(HL \~ 0.5 weeks vs \~ 1.9 weeks) and faster than fatty acids used in lotions (HL \~ 1.2 weeks) (Additional file [1](#MOESM1){ref-type="media"}: Figure S1R), consistent with their hydrophilic (PEG) and hydrophobic properties (PPG and fatty acids) \[[@CR25], [@CR26]\]. This difference in hydrophobicity is also reflected in the retention time as detected by mass spectrometry. Following the linear decrease of two PPG compounds from T0 to T1, they accumulated noticeably during weeks 2 and 3 (Additional file [1](#MOESM1){ref-type="media"}: Figure S1M, N). This accumulation might be due to other sources of PPG such as the body wash used during this period or the clothes worn by person 3. Although PPG compounds were not listed in the ingredient list of the shampoo, we manually inspected the LC-MS data collected from this product and confirmed the absence of PPG compounds in the shampoo. The data suggest that this trend is characteristic of accumulation of PPG from additional sources. These could be clothes, beds, or sheets, in agreement with the observation of these molecules found in human habitats \[[@CR27]\] but also in the public GNPS mass spectrometry dataset MSV000079274 that investigated the chemicals from dust collected from 1053 mattresses of children.
Temporal molecular and bacterial diversity in response to personal care use {#Sec4}
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To assess the effect of discontinuing and resuming the use of skin care products on molecular and microbiota dynamics, we first evaluated their temporal diversity. Skin sites varied markedly in their initial level (T0) of molecular and bacterial diversity, with higher molecular diversity at all sites for female participants compared to males (Fig. [3](#Fig3){ref-type="fig"}a, b, Wilcoxon rank-sum-WR test, *p* values ranging from 0.01 to 0.0001, from foot to arm) and higher bacterial diversity in face (WR test, *p* = 0.0009) and armpits (WR test, *p* = 0.002) for females (Fig. [3](#Fig3){ref-type="fig"}c, d). Temporal diversity was similar across the right and left sides of each body site of all individuals (WR test, molecular diversity: all *p* values \> 0.05; bacterial diversity: all *p* values \> 0.20). The data show that refraining from using beauty products (T1--T3) leads to a significant decrease in molecular diversity at all sites (Fig. [3](#Fig3){ref-type="fig"}a, b, WR test, face: *p* = 8.29e−07, arm: *p* = 7.08e−09, armpit: *p* = 1.13e−05, foot: *p* = 0.002) and bacterial diversity mainly in armpits (WR test, *p* = 0.03) and feet (WR test, *p* = 0.04) (Fig. [3](#Fig3){ref-type="fig"}c, d). While molecular diversity declined (Fig. [3](#Fig3){ref-type="fig"}a, b) for arms and face, bacterial diversity (Fig. [3](#Fig3){ref-type="fig"}c, d) was less affected in the face and arms when participants did not use skin care products (T1--T3). The molecular diversity remained stable in the arms and face of female participants during common beauty products use (T4--T6) to immediately increase as soon as the volunteers went back to their normal routines (T7--T9) (WR test, *p* = 0.006 for the arms and face)(Fig. [3](#Fig3){ref-type="fig"}a, b). A higher molecular (Additional file [1](#MOESM1){ref-type="media"}: Figure S2A) and community (Additional file [1](#MOESM1){ref-type="media"}: Figure S2B) diversity was observed for armpits and feet of all individuals during the use of antiperspirant and foot powder (T4--T6) (WR test, molecular diversity: armpit *p* = 8.9e−33, foot *p* = 1.03e−11; bacterial diversity: armpit *p* = 2.14e−28, foot *p* = 1.26e−11), followed by a molecular and bacterial diversity decrease in the armpits when their regular personal beauty product use was resumed (T7--T9) (bacterial diversity: WR test, *p* = 4.780e−21, molecular diversity: WR test, *p* = 2.159e−21). Overall, our data show that refraining from using beauty products leads to lower molecular and bacterial diversity, while resuming the use increases their diversity. Distinct variations between male and female molecular and community richness were perceived at distinct body parts (Fig. [3](#Fig3){ref-type="fig"}a--d). Although the chemical diversity of personal beauty products does not explain these variations (Additional file [1](#MOESM1){ref-type="media"}: Figure S2C), differences observed between males and females may be attributed to many environmental and lifestyle factors including different original skin care and different frequency of use of beauty products (Additional file [2](#MOESM2){ref-type="media"}: Table S1), washing routines, and diet.Fig. 3Molecular and bacterial diversity over a 9-week period, comparing samples based on their molecular (UPLC-Q-TOF-MS) or bacterial (16S rRNA amplicon) profiles. Molecular and bacterial diversity using the Shannon index was calculated from samples collected from each body part at each timepoint, separately for female (*n* = 5) and male (*n* = 6) individuals. Error bars represent standard error of the mean calculated at each timepoint, from up to four samples collected from the right and left side of each body part, of females (*n* = 5) and males (*n* = 6) separately. **a**, **b** Molecular alpha diversity measured using the Shannon index from five females (left panel) and six males (right panel), over 9 weeks, from four distinct body parts (armpits, face, arms, feet). **c**, **d** Bacterial alpha diversity measured using the Shannon index, from skin samples collected from five female (left panel) and six male individuals (right panel), over 9 weeks, from four distinct body parts (armpits, face, arms, feet). See also Additional file [1](#MOESM1){ref-type="media"}: Figure S2
Longitudinal variation of skin metabolomics signatures {#Sec5}
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To gain insights into temporal metabolomics variation associated with beauty product use, chemical inventories collected over 9 weeks were subjected to multivariate analysis using the widely used Bray--Curtis dissimilarity metric (Fig. [4](#Fig4){ref-type="fig"}a--c, S3A). Throughout the 9-week period, distinct molecular signatures were associated to each specific body site: arm, armpit, face, and foot (Additional file [1](#MOESM1){ref-type="media"}: Figure S3A, Adonis test, *p* \< 0.001, *R*^2^ 0.12391). Mass spectrometric signatures displayed distinct individual trends at each specific body site (arm, armpit, face, and foot) over time, supported by their distinct locations in PCoA (principal coordinate analysis) space (Fig. [4](#Fig4){ref-type="fig"}a, b) and based on the Bray--Curtis distances between molecular profiles (Additional file [1](#MOESM1){ref-type="media"}: Figure S3B, WR test, all *p* values \< 0.0001 from T0 through T9). This suggests a high molecular inter-individual variability over time despite similar changes in personal care routines. Significant differences in molecular patterns associated to ceasing (T1--T3) (Fig. [4](#Fig4){ref-type="fig"}b, Additional file [1](#MOESM1){ref-type="media"}: Figure S3C, WR test, T0 vs T1--T3 *p* \< 0.001) and resuming the use of common beauty products (T4--T6) (Additional file [1](#MOESM1){ref-type="media"}: Figure S3C) were observed in the arm, face, and foot (Fig. [4](#Fig4){ref-type="fig"}b), although the armpit exhibited the most pronounced changes (Fig. [4](#Fig4){ref-type="fig"}b, Additional file [1](#MOESM1){ref-type="media"}: Figure S3D, E, random forest highlighting that 100% of samples from each phase were correctly predicted). Therefore, we focused our analysis on this region. Molecular changes were noticeable starting the first week (T1) of discontinuing beauty product use. As shown for armpits in Fig. [4](#Fig4){ref-type="fig"}c, these changes at the chemical level are specific to each individual, possibly due to the extremely personalized lifestyles before the study and match their original use of deodorant. Based on the initial use of underarm products (T0) (Additional file [2](#MOESM2){ref-type="media"}: Table S1), two groups of participants can be distinguished: a group of five volunteers who used stick deodorant as evidenced by the mass spectrometry data and another group of volunteers where we found few or no traces suggesting they never or infrequently used stick deodorants (Additional file [2](#MOESM2){ref-type="media"}: Table S1). Based on this criterion, the chemical trends shown in Fig. [4](#Fig4){ref-type="fig"}c highlight that individuals who used stick deodorant before the beginning of the study (volunteers 1, 2, 3, 9, and 12) displayed a more pronounced shift in their armpits' chemistries as soon as they stopped using deodorant (T1--T3), compared to individuals who had low detectable levels of stick deodorant use (volunteers 4, 6, 7, and 10), or "rarely-to-never" (volunteers 5 and 11) use stick deodorants as confirmed by the volunteers (Additional file [1](#MOESM1){ref-type="media"}: Figure S3F, WR test, T0 vs T1--T3 all *p* values \< 0.0001, with greater distance for the group of volunteers 1, 2, 3, 9, and 12, compared to volunteers 4, 5, 6, 7, 10, and 11). The most drastic shift in chemical profiles was observed during the transition period, when all participants applied the common antiperspirant on a daily basis (T4--T6) (Additional file [1](#MOESM1){ref-type="media"}: Figure S3D, E). Finally, the molecular profiles became gradually more similar to those collected before the experiment (T0) as soon as the participants resumed using their personal beauty products (T7--T9) (Additional file [1](#MOESM1){ref-type="media"}: Figure S3C), although traces of skin care products did last through the entire T7--T9 period in people who do not routinely apply these products (Fig. [4](#Fig4){ref-type="fig"}c).Fig. 4Individualized influence of beauty product application on skin metabolomics profiles over time. **a** Multivariate statistical analysis (principal coordinate analysis (PCoA)) comparing mass spectrometry data collected over 9 weeks from the skin of 11 individuals, all body parts, combined (first plot from the left) and then displayed separately (arm, armpits, face, feet). Color scale represents volunteer ID. The PCoA was calculated on all samples together, and subsets of the data are shown in this shared space and the other panels. **b** The molecular profiles collected over 9 weeks from all body parts, combined then separately (arm, armpits, face, feet). **c** Representative molecular profiles collected over 9 weeks from armpits of 11 individuals (volunteers 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12). Color gradient in **b** and **c** represents timepoints (time 0 to time 9), ranging from the lightest orange color to the darkest one that represent the earliest (time 0) to the latest (time 9) timepoint, respectively. 0.5 timepoints represent additional timepoints where three selected volunteers were samples (volunteers 4, 9, and 10). PCoA plots were generated using the Bray--Curtis dissimilarity matrix and visualized in Emperor \[[@CR28]\]. See also Additional file [1](#MOESM1){ref-type="media"}: Figure S3
Comparing chemistries detected in armpits at the end timepoints---when no products were used (T3) and during product use (T6)---revealed distinct molecular signatures characteristic of each phase (random forest highlighting that 100% of samples from each group were correctly predicted, see Additional file [1](#MOESM1){ref-type="media"}: Figure S3D, E). Because volunteers used the same antiperspirant during T4--T6, molecular profiles converged during that time despite individual patterns at T3 (Fig. [4](#Fig4){ref-type="fig"}b, c, Additional file [1](#MOESM1){ref-type="media"}: Figure S3D). These distinct chemical patterns reflect the significant impact of beauty products on skin molecular composition. Although these differences may in part be driven by beauty product ingredients detected on the skin (Additional file [1](#MOESM1){ref-type="media"}: Figure S1), we anticipated that additional host- and microbe-derived molecules may also be involved in these molecular changes.
To characterize the chemistries that vary over time, we used molecular networking, a MS visualization approach that evaluates the relationship between MS/MS spectra and compares them to reference MS/MS spectral libraries of known compounds \[[@CR29], [@CR30]\]. We recently showed that molecular networking can successfully organize large-scale mass spectrometry data collected from the human skin surface \[[@CR18], [@CR19]\]. Briefly, molecular networking uses the MScluster algorithm \[[@CR31]\] to merge all identical spectra and then compares and aligns all unique pairs of MS/MS spectra based on their similarities where 1.0 indicates a perfect match. Similarities between MS/MS spectra are calculated using a similarity score, and are interpreted as molecular families \[[@CR19], [@CR24], [@CR32]--[@CR34]\]. Here, we used this method to compare and characterize chemistries found in armpits, arms, face, and foot of 11 participants. Based on MS/MS spectral similarities, chemistries highlighted through molecular networking (Additional file [1](#MOESM1){ref-type="media"}: Figure S4A) were associated with each body region with 8% of spectra found exclusively in the arms, 12% in the face, 14% in the armpits, and 2% in the foot, while 18% of the nodes were shared between all four body parts and the rest of spectra were shared between two body sites or more (Additional file [1](#MOESM1){ref-type="media"}: Figure S4B). Greater spectral similarities were highlighted between armpits, face, and arm (12%) followed by the arm and face (9%) (Additional file [1](#MOESM1){ref-type="media"}: Figure S4B).
Molecules were annotated with Global Natural Products Social Molecular Networking (GNPS) libraries \[[@CR29]\], using accurate parent mass and MS/MS fragmentation patterns, according to level 2 or 3 of annotation defined by the 2007 metabolomics standards initiative \[[@CR35]\]. Through annotations, molecular networking revealed that many compounds derived from steroids (Fig. [5](#Fig5){ref-type="fig"}a--d), bile acids (Additional file [1](#MOESM1){ref-type="media"}: Figure S5A-D), and acylcarnitines (Additional file [1](#MOESM1){ref-type="media"}: Figure S5E-F) were exclusively detected in the armpits. Using authentic standards, the identity of some pheromones and bile acids were validated to a level 1 identification with matched retention times (Additional file [1](#MOESM1){ref-type="media"}: Figure S6B, S7A, C, D). Other steroids and bile acids were either annotated using standards with identical MS/MS spectra but slightly different retention times (Additional file [1](#MOESM1){ref-type="media"}: Figure S6A) or annotated with MS/MS spectra match with reference MS/MS library spectra (Additional file [1](#MOESM1){ref-type="media"}: Figure S6C, D, S7B, S6E-G). These compounds were therefore classified as level 3 \[[@CR35]\]. Acylcarnitines were annotated to a family of possible acylcarnitines (we therefore classify as level 3), as the positions of double bonds or *cis* vs *trans* configurations are unknown (Additional file [1](#MOESM1){ref-type="media"}: Figure S8A, B).Fig. 5Underarm steroids and their longitudinal abundance. **a**--**d** Steroid molecular families in the armpits and their relative abundance over a 9-week period. Molecular networking was applied to characterize chemistries from the skin of 11 healthy individuals. The full network is shown in Additional file [1](#MOESM1){ref-type="media"}: Figure S4A, and networking parameters can be found here <http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=284fc383e4c44c4db48912f01905f9c5> for MS/MS datasets MSV000081582. Each node represents a consensus of a minimum of 3 identical MS/MS spectra. Yellow nodes represent MS/MS spectra detected in armpits samples. Hexagonal shape represents MS/MS spectra match between skin samples and chemical standards. Plots are representative of the relative abundance of each compound over time, calculated separately from LC-MS1 data collected from the armpits of each individual. Steroids detected in armpits are **a**, dehydroisoandrosterone sulfate (*m/z* 369.190, rt 247 s), **b** androsterone sulfate (*m/z* 371.189, rt 261 s), **c** 1-dehydroandrostenedione (*m/z* 285.185, rt 273 s), and **d** dehydroandrosterone (*m/z* 289.216, rt 303 s). Relative abundance over time of each steroid compound is represented. Error bars represent the standard error of the mean calculated at each timepoint from four armpit samples from the right and left side of each individual separately. See also Additional file [1](#MOESM1){ref-type="media"}: Figures S4-S8
Among the steroid compounds, several molecular families were characterized: androsterone (Fig. [5](#Fig5){ref-type="fig"}a, b, d), androstadienedione (Fig. [5](#Fig5){ref-type="fig"}c), androstanedione (Additional file [1](#MOESM1){ref-type="media"}: Figure S6E), androstanolone (Additional file [1](#MOESM1){ref-type="media"}: Figure S6F), and androstenedione (Additional file [1](#MOESM1){ref-type="media"}: Figure S6G). While some steroids were detected in the armpits of several individuals, such as dehydroisoandrosterone sulfate (*m/z* 369.19, rt 247 s) (9 individuals) (Fig. [5](#Fig5){ref-type="fig"}a, Additional file [1](#MOESM1){ref-type="media"}: Figure S6A), androsterone sulfate (*m/z* 371.189, rt 261 s) (9 individuals) (Fig. [5](#Fig5){ref-type="fig"}b, Additional file [1](#MOESM1){ref-type="media"}: Figure S6C), and 5-alpha-androstane-3,17-dione (*m/z* 271.205, rt 249 s) (9 individuals) (Additional file [1](#MOESM1){ref-type="media"}: Figure S6E), other steroids including 1-dehydroandrostenedione (*m/z* 285.185, rt 273 s) (Fig. [5](#Fig5){ref-type="fig"}c, Additional file [1](#MOESM1){ref-type="media"}: Figure S6B), dehydroandrosterone (*m/z* 289.216, rt 303 s) (Fig. [5](#Fig5){ref-type="fig"}d, Additional file [1](#MOESM1){ref-type="media"}: Figure S6D), and 5-alpha-androstan-17.beta-ol-3-one (*m/z* 291.231, rt 318 s) (Additional file [1](#MOESM1){ref-type="media"}: Figure S6F) were only found in the armpits of volunteer 11 and 4-androstene-3,17-dione (*m/z* 287.200, rt 293 s) in the armpits of volunteer 11 and volunteer 5, both are male that never applied stick deodorants (Additional file [1](#MOESM1){ref-type="media"}: Figure S6G). Each molecular species exhibited a unique pattern over the 9-week period. The abundance of dehydroisoandrosterone sulfate (Fig. [5](#Fig5){ref-type="fig"}a, WR test, *p* \< 0.01 for 7 individuals) and dehydroandrosterone (Fig. [5](#Fig5){ref-type="fig"}a, WR test, *p* = 0.00025) significantly increased during the use of antiperspirant (T4--T6), while androsterone sulfate (Fig. [5](#Fig5){ref-type="fig"}b) and 5-alpha-androstane-3,17-dione (Additional file [1](#MOESM1){ref-type="media"}: Figure S6E) display little variation over time. Unlike dehydroisoandrosterone sulfate (Fig. [5](#Fig5){ref-type="fig"}a) and dehydroandrosterone (Fig. [5](#Fig5){ref-type="fig"}d), steroids including 1-dehydroandrostenedione (Fig. [5](#Fig5){ref-type="fig"}c, WR test, *p* = 0.00024) and 4-androstene-3,17-dione (Additional file [1](#MOESM1){ref-type="media"}: Figure S6G, WR test, *p* = 0.00012) decreased in abundance during the 3 weeks of antiperspirant application (T4--T6) in armpits of male 11, and their abundance increased again when resuming the use of his normal skin care routines (T7--T9). Interestingly, even within the same individual 11, steroids were differently impacted by antiperspirant use as seen for 1-dehydroandrostenedione that decreased in abundance during T4--T6 (Fig. [5](#Fig5){ref-type="fig"}c, WR test, *p* = 0.00024), while dehydroandrosterone increased in abundance (Fig. [5](#Fig5){ref-type="fig"}d, WR test, *p* = 0.00025), and this increase was maintained during the last 3 weeks of the study (T7--T9).
In addition to steroids, many bile acids (Additional file [1](#MOESM1){ref-type="media"}: Figure S5A-D) and acylcarnitines (Additional file [1](#MOESM1){ref-type="media"}: Figure S5E-F) were detected on the skin of several individuals through the 9-week period. Unlike taurocholic acid found only on the face (Additional file [1](#MOESM1){ref-type="media"}: Figures S5A, S7A) and tauroursodeoxycholic acid detected in both armpits and arm samples (Additional file [1](#MOESM1){ref-type="media"}: Figures S5B, S7B), other primary bile acids such as glycocholic (Additional file [1](#MOESM1){ref-type="media"}: Figures S5C, S7C) and chenodeoxyglycocholic acid (Additional file [1](#MOESM1){ref-type="media"}: Figures S5D, S7D) were exclusively detected in the armpits. Similarly, acylcarnitines were also found either exclusively in the armpits (hexadecanoyl carnitines) (Additional file [1](#MOESM1){ref-type="media"}: Figures S5E, S8A) or in the armpits and face (tetradecenoyl carnitine) (Additional file [1](#MOESM1){ref-type="media"}: Figures S5F, S8B) and, just like the bile acids, they were also stably detected during the whole 9-week period.
Bacterial communities and their variation over time {#Sec6}
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Having demonstrated the impact of beauty products on the chemical makeup of the skin, we next tested the extent to which skin microbes are affected by personal care products. We assessed temporal variation of bacterial communities detected on the skin of healthy individuals by evaluating dissimilarities of bacterial collections over time using unweighted UniFrac distance \[[@CR36]\] and community variation at each body site in association to beauty product use \[[@CR3], [@CR15], [@CR37]\]. Unweighted metrics are used for beta diversity calculations because we are primarily concerned with changes in community membership rather than relative abundance. The reason for this is that skin microbiomes can fluctuate dramatically in relative abundance on shorter timescales than that assessed here. Longitudinal variations were revealed for the armpits (Fig. [6](#Fig6){ref-type="fig"}a) and feet microbiome by their overall trend in the PCoA plots (Fig. [6](#Fig6){ref-type="fig"}b), while the arm (Fig. [6](#Fig6){ref-type="fig"}c) and face (Fig. [6](#Fig6){ref-type="fig"}d) displayed relatively stable bacterial profiles over time. As shown in Fig. [6](#Fig6){ref-type="fig"}a--d, although the microbiome was site-specific, it varied more between individuals and this inter-individual variability was maintained over time despite same changes in personal care routine (WR test, all *p* values at all timepoints \< 0.05, T5 *p* = 0.07), in agreement with previous findings that individual differences in the microbiome are large and stable over time \[[@CR3], [@CR4], [@CR10], [@CR37]\]. However, we show that shifts in the microbiome can be induced by changing hygiene routine and therefore skin chemistry. Changes associated with using beauty products (T4--T6) were more pronounced for the armpits (Fig. [6](#Fig6){ref-type="fig"}a, WR test, *p* = 1.61e−52) and feet (Fig. [6](#Fig6){ref-type="fig"}b, WR test, *p* = 6.15e−09), while little variations were observed for the face (Fig. [6](#Fig6){ref-type="fig"}d, WR test, *p* = 1.402.e−83) and none for the arms (Fig. [6](#Fig6){ref-type="fig"}c, WR test, *p* = 0.296).Fig. 6Longitudinal variation of skin bacterial communities in association with beauty product use. **a**-**d** Bacterial profiles collected from skin samples of 11 individuals, over 9 weeks, from four distinct body parts a) armpits, b) feet, c) arms and d) face, using multivariate statistical analysis (Principal Coordinates Analysis PCoA) and unweighted Unifrac metric. Each color represents bacterial samples collected from an individual. PCoA were calculated separately for each body part. **e**, **f** Representative Gram-negative (Gram -) bacteria collected from arms, armpits, face and feet of e) female and f) male participants. See also Additional file [1](#MOESM1){ref-type="media"}: Figure S9A, B showing Gram-negative bacterial communities represented at the genus level
A significant increase in abundance of Gram-negative bacteria including the phyla *Proteobacteria* and *Bacteroidetes* was noticeable for the armpits and feet of both females (Fig. [6](#Fig6){ref-type="fig"}e; Mann--Whitney *U*, *p* = 8.458e−07) and males (Fig. [6](#Fig6){ref-type="fig"}f; Mann--Whitney *U*, *p* = 0.0004) during the use of antiperspirant (T4--T6), while their abundance remained stable for the arms and face during that time (Fig. [6](#Fig6){ref-type="fig"}e, f; female arm *p* = 0.231; female face *p* value = 0.475; male arm *p*= 0.523;male face *p* = 6.848751e−07). These Gram-negative bacteria include *Acinetobacter* and *Paracoccus* genera that increased in abundance in both armpits and feet of females (Additional file [1](#MOESM1){ref-type="media"}: Figure S9A), while a decrease in abundance of *Enhydrobacter* was observed in the armpits of males (Additional file [1](#MOESM1){ref-type="media"}: Figure S9B). Cyanobacteria, potentially originating from plant material (Additional file [1](#MOESM1){ref-type="media"}: Figure S9C) also increased during beauty product use (T4--T6) especially in males, in the armpits and face of females (Fig. [6](#Fig6){ref-type="fig"}e) and males (Fig. [6](#Fig6){ref-type="fig"}f). Interestingly, although chloroplast sequences (which group phylogenetically within the cyanobacteria \[[@CR38]\]) were only found in the facial cream (Additional file [1](#MOESM1){ref-type="media"}: Figure S9D), they were detected in other locations as well (Fig. [6](#Fig6){ref-type="fig"}e, f. S9E, F), highlighting that the application of a product in one region will likely affect other regions of the body. For example, when showering, a face lotion will drip down along the body and may be detected on the feet. Indeed, not only did the plant material from the cream reveal this but also the shampoo used for the study for which molecular signatures were readily detected on the feet as well (Additional file [1](#MOESM1){ref-type="media"}: Figure S10A). Minimal average changes were observed for Gram-positive organisms (Additional file [1](#MOESM1){ref-type="media"}: Figure S10B, C), although in some individuals the variation was greater than others (Additional file [1](#MOESM1){ref-type="media"}: Figure S10D, E) as discussed for specific Gram-positive taxa below.
At T0, the armpit's microflora was dominated by *Staphylococcus* (26.24%, 25.11% of sequencing reads for females and 27.36% for males) and *Corynebacterium* genera (26.06%, 17.89% for females and 34.22% for males) (Fig. [7](#Fig7){ref-type="fig"}a---first plot from left and Additional file [1](#MOESM1){ref-type="media"}: Figure S10D, E). They are generally known as the dominant armpit microbiota and make up to 80% of the armpit microbiome \[[@CR39], [@CR40]\]. When no deodorants were used (T1--T3), an overall increase in relative abundance of *Staphylococcus* (37.71%, 46.78% for females and 30.47% for males) and *Corynebacterium* (31.88%, 16.50% for females and 44.15% for males) genera was noticeable (WR test, *p* \< 3.071e−05) (Fig. [7](#Fig7){ref-type="fig"}a---first plot from left), while the genera *Anaerococcus* and *Peptoniphilus* decreased in relative abundance (WR test, *p* \< 0.03644) (Fig. [7](#Fig7){ref-type="fig"}a---first plot from left and Additional file [1](#MOESM1){ref-type="media"}: Figure S10D, E). When volunteers started using antiperspirants (T4--T6), the relative abundance of *Staphylococcus* (37.71%, 46.78% females and 30.47% males, to 21.71%, 25.02% females and 19.25% males) and *Corynebacterium* (31.88%, 16.50% females and 44.15% males, to 15.83%, 10.76% females and 19.60% males) decreased (WR test, *p* \< 3.071e−05) (Fig. [7](#Fig7){ref-type="fig"}a, Additional file [1](#MOESM1){ref-type="media"}: Figure S10D, E) and at the same time, the overall alpha diversity increased significantly (WR test, *p* = 3.47e−11) (Fig. [3](#Fig3){ref-type="fig"}c, d). The microbiota *Anaerococcus* (WR test, *p* = 0.0006018)*, Peptoniphilus* (WR test, *p* = 0.008639), and *Micrococcus* (WR test, *p* = 0.0377) increased significantly in relative abundance, together with a lot of additional low-abundant species that lead to an increase in Shannon alpha diversity (Fig. [3](#Fig3){ref-type="fig"}c, d). When participants went back to normal personal care products (T7--T9), the underarm microbiome resembled the original underarm community of T0 (WR test, *p* = 0.7274) (Fig. [7](#Fig7){ref-type="fig"}a). Because armpit bacterial communities are person-specific (inter-individual variability: WR test, all *p* values at all timepoints \< 0.05, besides T5 *p* n.s), variation in bacterial abundance upon antiperspirant use (T4--T6) differ between individuals and during the whole 9-week period (Fig. [7a](#Fig7){ref-type="fig"}---taxonomic plots per individual). For example, the underarm microbiome of male 5 exhibited a unique pattern, where *Corynebacterium* abundance decreased drastically during the use of antiperspirant (82.74 to 11.71%, WR test, *p* = 3.518e−05) while in the armpits of female 9 a huge decrease in *Staphylococcus* abundance was observed (Fig. [7](#Fig7){ref-type="fig"}a) (65.19 to 14.85%, WR test, *p* = 0.000113). Unlike other participants, during T0--T3, the armpits of individual 11 were uniquely characterized by the dominance of a sequence that matched most closely to the *Enhydrobacter* genera*.* The transition to antiperspirant use (T4--T6) induces the absence of *Enhydrobacter* (30.77 to 0.48%, WR test, *p* = 0.01528) along with an increase of *Corynebacterium* abundance (26.87 to 49.74%, WR test, *p* = 0.1123) (Fig. [7](#Fig7){ref-type="fig"}a---male 11).Fig. 7Person-to-person bacterial variabilities over time in the armpits and feet. **a** Armpit microbiome changes when stopping personal care product use, then resuming. Armpit bacterial composition of the 11 volunteers combined, then separately, (female 1, female 2, female 3, male 4, male 5, male 6, male 7, female 9, male 10, male 11, female 12) according to the four periods within the experiment. **b** Feet bacterial variation over time of the 12 volunteers combined, then separately (female 1, female 2, female 3, male 4, male 5, male 6, male 7, female 9, male 10, male 11, female 12) according to the four periods within the experiment. See also Additional file [1](#MOESM1){ref-type="media"}: Figure S9-S13
In addition to the armpits, a decline in abundance of *Staphylococcus* and *Corynebacterium* was perceived during the use of the foot powder (46.93% and 17.36%, respectively) compared to when no beauty product was used (58.35% and 22.99%, respectively) (WR test, *p* = 9.653e−06 and *p* = 0.02032, respectively), while the abundance of low-abundant foot bacteria significantly increased such as *Micrococcus* (WR test, *p* = 1.552e−08), *Anaerococcus* (WR test, *p* = 3.522e−13), *Streptococcus* (WR test, *p* = 1.463e−06), *Brevibacterium* (WR test, *p* = 6.561e−05), Moraxellaceae (WR test, *p* = 0.0006719), and *Acinetobacter* (WR test, *p* = 0.001487), leading to a greater bacterial diversity compared to other phases of the study (Fig. [7](#Fig7){ref-type="fig"}b first plot from left, Additional file [1](#MOESM1){ref-type="media"}: Figure S10D, E, Fig. [3](#Fig3){ref-type="fig"}c, d).
We further evaluated the relationship between the two omics datasets by superimposing the principal coordinates calculated from metabolome and microbiome data (Procrustes analysis) (Additional file [1](#MOESM1){ref-type="media"}: Figure S11) \[[@CR34], [@CR41], [@CR42]\]. Metabolomics data were more correlated with patterns observed in microbiome data in individual 3 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11C, Mantel test, *r* = 0.23, *p* \< 0.001), individual 5 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11E, *r* = 0.42, *p* \< 0.001), individual 9 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11H, *r* = 0.24, *p* \< 0.001), individual 10 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11I, *r* = 0.38, *p* \< 0.001), and individual 11 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11J, *r* = 0.35, *p* \< 0.001) when compared to other individuals 1, 2, 4, 6, 7, and 12 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11A, B, D, F, G, K, respectively) (Mantel test, all *r* \< 0.2, all *p* values \< 0.002, for volunteer 2 *p* n.s). Furthermore, these correlations were individually affected by ceasing (T1--T3) or resuming the use of beauty products (T4--T6 and T7--T9) (Additional file [1](#MOESM1){ref-type="media"}: Figure S11A-K).
Overall, metabolomics--microbiome correlations were consistent over time for the arms, face, and feet although alterations were observed in the arms of volunteers 7 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11G) and 10 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11I) and the face of volunteer 7 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11G) during product use (T4--T6). Molecular--bacterial correlations were mostly affected in the armpits during antiperspirant use (T4--T6), as seen for volunteers male 7 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11G) and 11 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11J) and females 2 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11B), 9 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11H), and 12 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11K). This perturbation either persisted during the last 3 weeks (Additional file [1](#MOESM1){ref-type="media"}: Figure S11D, E, H, I, K) when individuals went back to their normal routine (T7--T9) or resembled the initial molecular--microbial correlation observed in T0 (Additional file [1](#MOESM1){ref-type="media"}: Figure S11C, G, J). These alterations in molecular--bacterial correlation are driven by metabolomics changes during antiperspirant use as revealed by metabolomics shifts on the PCoA space (Additional file [1](#MOESM1){ref-type="media"}: Figure S11), partially due to the deodorant's chemicals (Additional file [1](#MOESM1){ref-type="media"}: Figure S1J, K) but also to changes observed in steroid levels in the armpits (Fig. [5A, C, D](#Fig5){ref-type="fig"}, Additional file [1](#MOESM1){ref-type="media"}: Figure S6G), suggesting metabolome-dependant changes of the skin microbiome. In agreement with previous findings that showed efficient biotransformation of steroids by *Corynebacterium* \[[@CR43], [@CR44]\], our correlation analysis associates specific steroids that were affected by antiperspirant use in the armpits of volunteer 11 (Fig. [5](#Fig5){ref-type="fig"}c, d, Additional file [1](#MOESM1){ref-type="media"}: Figure S6G) with microbes that may produce or process them: 1-dehydroandrostenedione, androstenedione, and dehydrosterone with *Corynebacterium* (*r* = − 0.674, *p* = 6e−05; *r* = 0.671, *p* = 7e−05; *r* = 0.834, *p* \< 1e−05, respectively) (Additional file [1](#MOESM1){ref-type="media"}: Figure S12A, B, C, respectively) and *Enhydrobacter* (*r* = 0.683, *p* = 4e−05; *r* = 0.581, *p* = 0.00095; *r* = 0.755, *p* \< 1e−05 respectively) (Additional file [1](#MOESM1){ref-type="media"}: Figure S12D, E, F, respectively).
Discussion {#Sec7}
==========
Despite the widespread use of skin care and hygiene products, their impact on the molecular and microbial composition of the skin is poorly studied. We established a workflow that examines individuals to systematically study the impact of such lifestyle characteristics on the skin by taking a broad look at temporal molecular and bacterial inventories and linking them to personal skin care product use. Our study reveals that when the hygiene routine is modified, the skin metabolome and microbiome can be altered, but that this alteration depends on product use and location on the body. We also show that like gut microbiome responses to dietary changes \[[@CR20], [@CR21]\], the responses are individual-specific.
We recently reported that traces of our lifestyle molecules can be detected on the skin days and months after the original application \[[@CR18], [@CR19]\]. Here, we show that many of the molecules associated with our personal skin and hygiene products had a half-life of 0.5 to 1.9 weeks even though the volunteers regularly showered, swam, or spent time in the ocean. Thus, a single application of some of these products has the potential to alter the microbiome and skin chemistry for extensive periods of time. Our data suggests that although host genetics and diet may play a role, a significant part of the resilience of the microbiome that has been reported \[[@CR10], [@CR45]\] is due to the resilience of the skin chemistry associated with personal skin and hygiene routines, or perhaps even continuous re-exposure to chemicals from our personal care routines that are found on mattresses, furniture, and other personal objects \[[@CR19], [@CR27], [@CR46]\] that are in constant contact. Consistent with this observation is that individuals in tribal regions and remote villages that are infrequently exposed to the types of products used in this study have very different skin microbial communities \[[@CR47], [@CR48]\] and that the individuals in this study who rarely apply personal care products had a different starting metabolome. We observed that both the microbiome and skin chemistry of these individuals were most significantly affected by these products. This effect by the use of products at T4--T6 on the volunteers that infrequently used them lasted to the end phase of the study even though they went back to infrequent use of personal care products. What was notable and opposite to what the authors originally hypothesized is that the use of the foot powder and antiperspirant increased the diversity of microbes and that some of this diversity continued in the T7--T9 phase when people went back to their normal skin and hygiene routines. It is likely that this is due to the alteration in the nutrient availability such as fatty acids and moisture requirements, or alteration of microbes that control the colonization via secreted small molecules, including antibiotics made by microbes commonly found on the skin \[[@CR49], [@CR50]\].
We detected specific molecules on the skin that originated from personal care products or from the host. One ingredient that lasts on the skin is propylene glycol, which is commonly used in deodorants and antiperspirants and added in relatively large amounts as a humectant to create a soft and sleek consistency \[[@CR51]\]. As shown, daily use of personal care products is leading to high levels of exposure to these polymers. Such polymers cause contact dermatitis in a subset of the population \[[@CR51], [@CR52]\]. Our data reveal a lasting accumulation of these compounds on the skin, suggesting that it may be possible to reduce their dose in deodorants or frequency of application and consequently decrease the degree of exposure to such compounds. Formulation design of personal care products may be influenced by performing detailed outcome studies. In addition, longer term impact studies are needed, perhaps in multiple year follow-up studies, to assess if the changes we observed are permanent or if they will recover to the original state.
Some of the host- and microbiome-modified molecules were also detected consistently, such as acylcarnitines, bile acids, and certain steroids. This means that a portion of the molecular composition of a person's skin is not influenced by the beauty products applied to the skin, perhaps reflecting the level of exercise for acylcarnitines \[[@CR53], [@CR54]\] or the liver (dominant location where they are made) or gallbladder (where they are stored) function for bile acids. The bile acid levels are not related to sex and do not change in amount during the course of this study. While bile acids are typically associated with the human gut microbiome \[[@CR34], [@CR55]--[@CR58]\], it is unclear what their role is on the skin and how they get there. One hypothesis is that they are present in the sweat that is excreted through the skin, as this is the case for several food-derived molecules such as caffeine or drugs and medications that have been previously reported on the human skin \[[@CR19]\] or that microbes synthesize them de novo \[[@CR55]\]. The only reports we could find on bile acids being associated with the skin describe cholestasis and pruritus diseases. Cholestasis and pruritus in hepatobiliary disease have symptoms of skin bile acid accumulation that are thought to be responsible for severe skin itching \[[@CR59], [@CR60]\]. However, since bile acids were found in over 50% of the healthy volunteers, their detection on the skin is likely a common phenotype among the general population and not only reflective of disease, consistent with recent reports challenging these molecules as biomarkers of disease \[[@CR59]\]. Other molecules that were detected consistently came from personal care products.
Aside from molecules that are person-specific and those that do not vary, there are others that can be modified via personal care routines. Most striking is how the personal care routines influenced changes in hormones and pheromones in a personalized manner. This suggests that there may be personalized recipes that make it possible to make someone more or less attractive to others via adjustments of hormonal and pheromonal levels through alterations in skin care.
Conclusion {#Sec8}
==========
Here, we describe the utilization of an approach that combines metabolomics and microbiome analysis to assess the effect of modifying personal care regime on skin chemistry and microbes. The key findings are as follows: (1) Compounds from beauty products last on the skin for weeks after their first use despite daily showering. (2) Beauty products alter molecular and bacterial diversity as well as the dynamic and structure of molecules and bacteria on the skin. (3) Molecular and bacterial temporal variability is product-, site-, and person-specific, and changes are observed starting the first week of beauty product use. This study provides a framework for future investigations to understand how lifestyle characteristics such as diet, outdoor activities, exercise, and medications shape the molecular and microbial composition of the skin. These factors have been studied far more in their impact on the gut microbiome and chemistry than in the skin. Revealing how such factors can affect skin microbes and their associated metabolites may be essential to define long-term skin health by restoring the appropriate microbes particularly in the context of skin aging \[[@CR61]\] and skin diseases \[[@CR49]\] as has shown to be necessary for amphibian health \[[@CR62], [@CR63]\], or perhaps even create a precision skin care approach that utilizes the proper care ingredients based on the microbial and chemical signatures that could act as key players in host defense \[[@CR49], [@CR64], [@CR65]\].
Methods {#Sec9}
=======
Subject recruitment and sample collection {#Sec10}
-----------------------------------------
Twelve individuals between 25 and 40 years old were recruited to participate in this study, six females and six males. Female volunteer 8 dropped out of the study as she developed a skin irritation during the T1--T3 phase. All volunteers signed a written informed consent in accordance with the sampling procedure approved by the UCSD Institutional Review Board (Approval Number 161730). Volunteers were required to follow specific instructions during 9 weeks. They were asked to bring in samples of their personal care products they used prior to T0 so they could be sampled as well. Following the initial timepoint time 0 and during the first 3 weeks (week 1--week 3), volunteers were asked not to use any beauty products (Fig. [1](#Fig1){ref-type="fig"}b). During the next 3 weeks (week 4--week 6), four selected commercial beauty products provided to all volunteers were applied once a day at specific body part (deodorant for the armpits, soothing foot powder between the toes, sunscreen for the face, and moisturizer for front forearms) (Fig. [1](#Fig1){ref-type="fig"}b, Additional file [3](#MOESM3){ref-type="media"}: Table S2 Ingredient list of beauty products). During the first 6 weeks, volunteers were asked to shower with a head to toe shampoo. During the last 3 weeks (week 7--week 9), all volunteers went back to their normal routine and used the personal care products used before the beginning of the study (Fig. [1](#Fig1){ref-type="fig"}b). Volunteers were asked not to shower the day before sampling. Samples were collected by the same three researchers to ensure consistency in sampling and the area sampled. Researchers examined every subject together and collected metabolomics and microbiome samples from each location together. Samples were collected once a week (from day 0 to day 68---10 timepoints total) for volunteers 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, and 12, and on day 0 and day 6 for volunteer 8. For individuals 4, 9, and 10, samples were collected twice a week. Samples collected for 11 volunteers during 10 timepoints: 11 volunteers × 10 timepoints × 4 samples × 4 body sites = 1760. Samples collected from 3 selected volunteers during 9 additional timepoints: 3 volunteers × 9 timepoints × 4 samples × 4 body sites = 432. All samples were collected following the same protocol described in \[[@CR18]\]. Briefly, samples were collected over an area of 2 × 2 cm, using pre-moistened swabs in 50:50 ethanol/water solution for metabolomics analysis or in Tris-EDTA buffer for 16S rRNA sequencing. Four samples were collected from each body part right and left side. The locations sampled were the face---upper cheek bone and lower jaw, armpit---upper and lower area, arm---front of the elbow (antecubitis) and forearm (antebrachium), and feet---in between the first and second toe and third and fourth toe. Including personal care product references, a total of 2275 samples were collected over 9 weeks and were submitted to both metabolomics and microbial inventories.
Metabolite extraction and UPLC-Q-TOF mass spectrometry analysis {#Sec11}
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Skin swabs were extracted and analyzed using a previously validated workflow described in \[[@CR18], [@CR19]\]. All samples were extracted in 200 μl of 50:50 ethanol/water solution for 2 h on ice then overnight at − 20 °C. Swab sample extractions were dried down in a centrifugal evaporator then resuspended by vortexing and sonication in a 100 μl 50:50 ethanol/water solution containing two internal standards (fluconazole 1 μM and amitriptyline 1 μM). The ethanol/water extracts were then analyzed using a previously validated UPLC-MS/MS method \[[@CR18], [@CR19]\]. We used a ThermoScientific UltiMate 3000 UPLC system for liquid chromatography and a Maxis Q-TOF (Quadrupole-Time-of-Flight) mass spectrometer (Bruker Daltonics), controlled by the Otof Control and Hystar software packages (Bruker Daltonics) and equipped with ESI source. UPLC conditions of analysis are 1.7 μm C18 (50 × 2.1 mm) UHPLC Column (Phenomenex), column temperature 40 °C, flow rate 0.5 ml/min, mobile phase A 98% water/2% acetonitrile/0.1% formic acid (*v*/*v*), mobile phase B 98% acetonitrile/2% water/0.1% formic acid (*v*/*v*). A linear gradient was used for the chromatographic separation: 0--2 min 0--20% B, 2--8 min 20--99% B, 8--9 min 99--99% B, 9--10 min 0% B. Full-scan MS spectra (*m/z* 80--2000) were acquired in a data-dependant positive ion mode. Instrument parameters were set as follows: nebulizer gas (nitrogen) pressure 2 Bar, capillary voltage 4500 V, ion source temperature 180 °C, dry gas flow 9 l/min, and spectra rate acquisition 10 spectra/s. MS/MS fragmentation of 10 most intense selected ions per spectrum was performed using ramped collision induced dissociation energy, ranged from 10 to 50 eV to get diverse fragmentation patterns. MS/MS active exclusion was set after 4 spectra and released after 30 s.
Mass spectrometry data collected from the skin of 12 individuals can be found here MSV000081582.
LC-MS data processing {#Sec12}
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LC-MS raw data files were converted to mzXML format using Compass Data analysis software (Bruker Daltonics). MS1 features were selected for all LC-MS datasets collected from the skin of 12 individuals and blank samples (total 2275) using the open-source software MZmine \[[@CR66]\]---see Additional file [4](#MOESM4){ref-type="media"}: Table S3 for parameters. Subsequent blank filtering, total ion current, and internal standard normalization were performed (Additional file [5](#MOESM5){ref-type="media"}: Table S4) for representation of relative abundance of molecular features (Fig. [2](#Fig2){ref-type="fig"}, Additional file [1](#MOESM1){ref-type="media"}: Figure S1), principal coordinate analysis (PCoA) (Fig. [4](#Fig4){ref-type="fig"}). For steroid compounds in Fig. [5](#Fig5){ref-type="fig"}a--d, bile acids (Additional file [1](#MOESM1){ref-type="media"}: Figure S5A-D), and acylcarnitines (Additional file [1](#MOESM1){ref-type="media"}: Figure S5E, F) compounds, crop filtering feature available in MZmine \[[@CR66]\] was used to identify each feature separately in all LC-MS data collected from the skin of 12 individuals (see Additional file [4](#MOESM4){ref-type="media"}: Table S3 for crop filtering parameters and feature finding in Additional file [6](#MOESM6){ref-type="media"}: Table S5).
Heatmap in Fig. [2](#Fig2){ref-type="fig"} was constructed from the bucket table generated from LC-MS1 features (Additional file [7](#MOESM7){ref-type="media"}: Table S6) and associated metadata (Additional file [8](#MOESM8){ref-type="media"}: Table S7) using the Calour command line available here: <https://github.com/biocore/calour>. Calour parameters were as follows: normalized read per sample 5000 and cluster feature minimum reads 50. Procrustes and Pearson correlation analyses in Additional file [1](#MOESM1){ref-type="media"}: Figures S10 and S11 were performed using the feature table in Additional file [9](#MOESM9){ref-type="media"}: Table S8, normalized using the probabilistic quotient normalization method \[[@CR67]\].
16S rRNA amplicon sequencing {#Sec13}
----------------------------
16S rRNA sequencing was performed following the Earth Microbiome Project protocols \[[@CR68], [@CR69]\], as described before \[[@CR18]\]. Briefly, DNA was extracted using MoBio PowerMag Soil DNA Isolation Kit and the V4 region of the 16S rRNA gene was amplified using barcoded primers \[[@CR70]\]. PCR was performed in triplicate for each sample, and V4 paired-end sequencing \[[@CR70]\] was performed using Illumina HiSeq (La Jolla, CA). Raw sequence reads were demultiplexed and quality controlled using the defaults, as provided by QIIME 1.9.1 \[[@CR71]\]. The primary OTU table was generated using Qiita (<https://qiita.ucsd.edu/>), using UCLUST (<https://academic.oup.com/bioinformatics/article/26/19/2460/230188>) closed-reference OTU picking method against GreenGenes 13.5 database \[[@CR72]\]. Sequences can be found in EBI under accession number EBI: ERP104625 or in Qiita ([qiita.ucsd.edu](http://qiita.ucsd.edu)) under Study ID 10370. Resulting OTU tables were then rarefied to 10,000 sequences/sample for downstream analyses (Additional file [10](#MOESM10){ref-type="media"} Table S9). See Additional file [11](#MOESM11){ref-type="media"}: Table S10 for read count per sample and Additional file [1](#MOESM1){ref-type="media"}: Figure S13 representing the samples that fall out with rarefaction at 10,000 threshold. The dataset includes 35 blank swab controls and 699 empty controls. The blank samples can be accessed through Qiita ([qiita.ucsd.edu](http://qiita.ucsd.edu)) as study ID 10370 and in EBI with accession number EBI: ERP104625. Blank samples can be found under the metadata category "sample_type" with the name "empty control" and "Swabblank." These samples fell below the rarefaction threshold at 10,000 (Additional file [11](#MOESM11){ref-type="media"}: Table S10).
To rule out the possibility that personal care products themselves contained the microbes that induced the changes in the armpit and foot microbiomes that were observed in this study (Fig. [7](#Fig7){ref-type="fig"}), we subjected the common personal care products that were used in this study during T4--T6 also to 16S rRNA sequencing. The data revealed that within the limit of detectability of the current experiment, few 16S signatures were detected. One notable exception was the most dominant plant-originated bacteria chloroplast detected in the sunscreen lotion applied on the face (Additional file [1](#MOESM1){ref-type="media"}: Figure S9D), that was also detected on the face of individuals and at a lower level on their arms, sites where stable microbial communities were observed over time (Additional file [1](#MOESM1){ref-type="media"}: Figure S9E, F). This finding is in agreement with our previous data from the 3D cartographical skin maps that revealed the presence of co-localized chloroplast and lotion molecules \[[@CR18]\]. Other low-abundant microbial signatures found in the sunscreen lotion include additional plant-associated bacteria: mitochondria \[[@CR73]\], *Bacillaceae* \[[@CR74], [@CR75]\], *Planococcaceae* \[[@CR76]\], and *Ruminococcaceae* family \[[@CR77]\], but all these bacteria are not responsible for microbial changes associated to beauty product use, as they were poorly detected in the armpits and feet (Fig. [7](#Fig7){ref-type="fig"}).
To assess the origin of Cyanobacteria detected in skin samples, each Greengenes \[[@CR72]\] 13_8 97% OTU table (per lane; obtained from Qiita \[[@CR78]\] study 10,370) was filtered to only features with a p\_\_Cyanobacteria phylum. The OTU maps for these tables---which relate each raw sequence to an OTU ID---were then filtered to only those observed p\_\_Cyanobacteria OTU IDs. The filtered OTU map was used to extract the raw sequences into a single file. Separately, the unaligned Greengenes 13_8 99% representative sequences were filtered into two sets, first the set of representatives associated with c\_\_Chloroplast (our interest database), and second the set of sequences associated with p\_\_Cyanobacteria without the c\_\_Chloroplast sequences (our background database). Platypus Conquistador \[[@CR79]\] was then used to determine what reads were observed exclusively in the interest database and not in the background database. Of the 4,926,465 raw sequences associated with a p\_\_Cyanobacteria classification (out of 318,686,615 total sequences), at the 95% sequence identity level with 100% alignment, 4,860,258 sequences exclusively recruit to full-length chloroplast 16S by BLAST \[[@CR80]\] with the bulk recruiting to streptophytes (with Chlorophyta and Stramenopiles to a lesser extent). These sequences do not recruit non-chloroplast Cyanobacteria full length 16S.
Half-life calculation for metabolomics data {#Sec14}
-------------------------------------------
In order to estimate the biological half-life of molecules detected in the skin, the first four timepoints of the study (T0, T1, T2, T3) were considered for the calculation to allow the monitoring of personal beauty products used at T0. The IUPAC's definition of biological half-life as the time required to a substance in a biological system to be reduced to half of its value, assuming an approximately exponential removal \[[@CR81]\] was used. The exponential removal can be described as *C*~(*t*)~ = *C*~0~*e*^−*tλ*^ where *t* represents the time in weeks, *C*~0~ represents the initial concentration of the molecule, *C*~(*t*)~ represents the concentration of the molecule at time *t*, and *λ* is the rate of removal \[<http://onlinelibrary.wiley.com/doi/10.1002/9780470140451.ch2/summary>\]. The parameter *λ* was estimated by a mixed linear effects model in order to account for the paired sample structure. The regression model tests the null hypothesis that *λ* is equal to zero and only the significant (*p* value \< 0.05) parameters were considered.
Principal coordinate analysis {#Sec15}
-----------------------------
We performed principal coordinate analysis (PCoA) on both metabolomics and microbiome data. For metabolomics, we used MS1 features (Additional file [5](#MOESM5){ref-type="media"}: Table S4) and calculated Bray--Curtis dissimilarity metric using ClusterApp (<https://github.com/mwang87/q2_metabolomics>).
For microbiome data, we used rarefied OTU table (Additional file [10](#MOESM10){ref-type="media"}: Table S9) and used unweighted UniFrac metric \[[@CR36]\] to calculate beta diversity distance matrix using QIIME2 (https://qiime2.org). Results from both data sources were visualized using Emperor (<https://biocore.github.io/emperor/>) \[[@CR28]\].
Molecular networking {#Sec16}
--------------------
Molecular networking was generated from LC-MS/MS data collected from skin samples of 11 individuals MSV000081582, using the Global Natural Products Social Molecular Networking platform (GNPS) \[[@CR29]\]. Molecular network parameters for MS/MS data collected from all body parts of 11 individuals during T0--T9 MSV000081582 are accessible here <http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=284fc383e4c44c4db48912f01905f9c5>. Molecular network parameters for MS/MS data collected from armpits T0--T3 MSV000081582 and deodorant used by individual 1 and 3 MSV000081580 can be found here [http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=f5325c3b278a46b29e8860ec57915ad](http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=f5325c3b278a46b29e8860ec5791d5ad) and here <http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=aaa1af68099d4c1a87e9a09f398fe253>, respectively. Molecular networks were exported and visualized in Cytoscape 3.4.0. \[[@CR82]\]. Molecular networking parameters were set as follows: parent mass tolerance 1 Da, MS/MS fragment ion tolerance 0.5 Da, and cosine threshold 0.65 or greater, and only MS/MS spectral pairs with at least 4 matched fragment ions were included. Each MS/MS spectrum was only allowed to connect to its top 10 scoring matches, resulting in a maximum of 10 connections per node. The maximum size of connected components allowed in the network was 600, and the minimum number of spectra required in a cluster was 3. Venn diagrams were generated from Cytoscape data <http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=284fc383e4c44c4db48912f01905f9c5> using Cytoscape \[[@CR82]\] Venn diagram app available here <http://apps.cytoscape.org/apps/all>.
Shannon molecular and bacterial diversity {#Sec17}
-----------------------------------------
The diversity analysis was performed separately for 16S rRNA data and LC-MS data. For each sample in each feature table (LC-MS data and microbiome data), we calculated the value of the Shannon diversity index. For LC-MS data, we used the full MZmine feature table (Additional file [5](#MOESM5){ref-type="media"}: Table S4). For microbiome data, we used the closed-reference BIOM table rarefied to 10,000 sequences/sample. For diversity changes between timepoints, we aggregated Shannon diversity values across groups of individuals (all, females, males) and calculated mean values and standard errors. All successfully processed samples (detected features in LC-MS or successful sequencing with 10,000 or more sequences/sample) were considered.
Beauty products and chemical standards {#Sec18}
--------------------------------------
Samples (10 mg) from personal care products used during T0 and T7--T9 MSV000081580 (Additional file [2](#MOESM2){ref-type="media"}: Table S1) and common beauty products used during T4--T6 MSV000081581 (Additional file [3](#MOESM3){ref-type="media"}: Table S2) were extracted in 1 ml 50:50 ethanol/water. Sample extractions were subjected to the same UPLC-Q-TOF MS method used to analyze skin samples and described above in the section "[Metabolite extraction and UPLC-Q-TOF mass spectrometry analysis](#Sec11){ref-type="sec"}." Authentic chemical standards MSV000081583 including 1-dehydroandrostenedion (5 μM), chenodeoxyglycocholic acid (5 μM), dehydroisoandrosterone sulfate (100 μM), glycocholic acid (5 μM), and taurocholic acid (5 μM) were analyzed using the same mass spectrometry workflow used to run skin and beauty product samples.
Monitoring beauty product ingredients in skin samples {#Sec19}
-----------------------------------------------------
In order to monitor beauty product ingredients used during T4--T6, we selected only molecular features present in each beauty product sample (antiperspirant, facial lotion, body moisturizer, soothing powder) and then filtered the aligned MZmine feature table (Additional file [5](#MOESM5){ref-type="media"}: Table S4) for the specific feature in specific body part samples. After feature filtering, we selected all features that had a higher average intensity on beauty product phase (T4--T6) compared to non-beauty product phase (T1--T3). The selected features were annotated using GNPS dereplication output <http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=69319caf219642a5a6748a3aba8914df>, plotted using R package ggplot2 (<https://cran.r-project.org/web/packages/ggplot2/index.html>) and visually inspected for meaningful patterns.
Random forest analysis {#Sec20}
----------------------
Random forest analysis was performed in MetaboAnalyst 3.0 online platform <http://www.metaboanalyst.ca/faces/home.xhtml>. Using LC-MS1 features found in armpit samples collected on T3 and T6. Random forest parameters were set as follows: top 1000 most abundant features, number of predictors to try for each node 7, estimate of error rate (0.0%).
BugBase analysis {#Sec21}
----------------
To determine the functional potential of microbial communities within our samples, we used BugBase \[[@CR83]\]. Because we do not have direct access to all of the gene information due to the use of 16S rRNA marker gene sequencing, we can only rely on phylogenetic information inferred from OTUs. BugBase takes advantage of this information to predict microbial phenotypes by associating OTUs with gene content using PICRUSt \[[@CR84]\]. Thus, using BugBase, we can predict such phenotypes as Gram staining, or oxidative stress tolerance at each timepoint or each phase. All statistical analyses in BugBase are performed using non-parametric differentiation tests (Mann--Whitney *U*).
Taxonomic plots {#Sec22}
---------------
Rarefied OTU counts were collapsed according to the OTU's assigned family and genus name per sample, with a single exception for the class of chloroplasts. Relative abundances of each family-genus group are obtained by dividing by overall reads per sample, i.e., 10,000. Samples are grouped by volunteer, body site, and time/phase. Abundances are aggregated by taking the mean overall samples, and resulting abundances are again normalized to add up to 1. Low-abundant taxa are not listed in the legend and plotted in grayscale. Open-source code is available at <https://github.com/sjanssen2/ggmap/blob/master/ggmap/snippets.py>
Dissimilarity-based analysis {#Sec23}
----------------------------
Pairwise dissimilarity matrices were generated for metabolomics and 16S metagenomics quantification tables, described above, using Bray--Curtis dissimilarity through QIIME 1.9.1 \[[@CR71]\]. Those distance matrices were used to perform Procrustes analysis (QIIME 1.9.1), and Mantel test (scikit-bio version 0.5.1) to measure the correlation between the metabolome and microbiome over time. The metabolomics dissimilarities were used to perform the PERMANOVA test to assess the significance of body part grouping. The PCoA and Procrustes plots were visualized in EMPeror. The dissimilarity matrices were also used to perform distance tests, comparing the distances within and between individuals and distances from time 0 to times 1, 2, and 3 using Wilcoxon rank-sum tests (SciPy version 0.19.1) \[[@CR19]\].
Statistical analysis for molecular and microbial data {#Sec24}
-----------------------------------------------------
Statistical analyses were performed in R and Python (R Core Team 2018). Monotonic relationships between two variables were tested using non-parametric Spearman correlation tests. The *p* values for correlation significance were subsequently corrected using Benjamini and Hochberg false discovery rate control method. The relationship between two groups was tested using non-parametric Wilcoxon rank-sum tests. The relationship between multiple groups was tested using non-parametric Kruskal--Wallis test. The significance level was set to 5%, unless otherwise mentioned, and all tests were performed as two-sided tests.
Additional files
================
{#Sec25}
Additional file 1:**Figure S1.** Beauty products ingredients persist on skin of participants. **Figure S2.** Beauty product application impacts the molecular and bacterial diversity on skin of 11 individuals while the chemical diversity from personal beauty products used by males and females on T0 is similar. **Figure S3.** Longitudinal impact of ceasing and resuming the use of beauty products on the molecular composition of the skin over time. **Figure S4.** Molecular networking to highlight MS/MS spectra found in each body part. **Figure S5.** Longitudinal abundance of bile acids and acylcarnitines in skin samples. **Figure S6.** Characterization of steroids in armpits samples. **Figure S7.** Characterization of bile acids in armpit samples. **Figure S8.** Characterization of Acylcarnitine family members in skin samples. **Figure S9.** Beauty products applied at one body part might affect other areas of the body, while specific products determine stability versus variability of microflora at each body site. **Figure S10.** Representation of Gram-positive bacteria over time and the molecular features from the shampoo detected on feet. **Figure S11.** Procrustes analysis to correlate the skin microbiome and metabolome over time. **Figure S12.** Correlation between specific molecules and bacteria that change over time in armpits of individual 11. **Figure S13.** Representation of the number of samples that were removed (gray) and those retained (blue) after rarefaction at 10,000 threshold. (DOCX 1140 kb) Additional file 2:**Table S1.** List of personal (T0 and T7--9) beauty products and their frequency of use. (XLSX 30 kb) Additional file 3:**Table S2.** List of ingredients of common beauty products used during T4--T6. (PDF 207 kb) Additional file 4:**Table S3.** Mzmine feature finding and crop filtering parameters. (XLSX 4 kb) Additional file 5:**Table S4.** Feature table for statistical analysis with blank filtering and total ion current normalization. (CSV 150242 kb) Additional file 6:**Table S5.** Feature table for individual feature abundance in armpits. (XLSX 379 kb) Additional file 7:**Table S6.** Feature table for Calour analysis. (CSV 91651 kb) Additional file 8:**Table S7.** Metadata for Calour analysis. (TXT 129 kb) Additional file 9:**Table S8.** feature table with Probabilistic quotient normalization for molecular--microbial analysis. (ZIP 29557 kb) Additional file 10:**Table S9.** OTU table rarefied to 10,000 sequences per sample. (BIOM 9493 kb) Additional file 11:**Table S10.** 16S rRNA sequencing read counts per sample. (TSV 2949 kb)
We thank all volunteers who were recruited in this study for their participation and Carla Porto for discussions regarding beauty products selected in this study. We further acknowledge Bruker for the support of the shared instrumentation infrastructure that enabled this work.
Funding {#FPar1}
=======
This work was partially supported by US National Institutes of Health (NIH) Grant. P.C.D. acknowledges funding from the European Union's Horizon 2020 Programme (Grant 634402). A.B was supported by the National Institute of Justice Award 2015-DN-BX-K047. C.C. was supported by a fellowship of the Belgian American Educational Foundation and the Research Foundation Flanders. L.Z., J.K, and K.Z. acknowledge funding from the US National Institutes of Health under Grant No. AR071731. TLK was supported by Vaadia-BARD Postdoctoral Fellowship Award No. FI-494-13.
Availability of data and materials {#FPar2}
==================================
The mass spectrometry data have been deposited in the MassIVE database (MSV000081582, MSV000081580 and MSV000081581). Molecular network parameters for MS/MS data collected from all body parts of 11 individuals during T0-T9 MSV000081582 are accessible here <http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=284fc383e4c44c4db48912f01905f9c5>. Molecular network parameters for MS/MS data collected from armpits T0--T3 MSV000081582 and deodorant used by individual 1 and 3 MSV000081580 can be found here <http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=f5325c3b278a46b29e8860ec5791d5ad> and here <http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=aaa1af68099d4c1a87e9a09f398fe253>, respectively. OTU tables can be found in Qiita ([qiita.ucsd.edu](http://qiita.ucsd.edu)) as study ID 10370, and sequences can be found in EBI under accession number EBI: ERP104625.
AB and PCD contributed to the study and experimental design. AB, KD, and TLK contributed to the metabolite and microbial sample collection. AB contributed to the mass spectrometry data collection. AB, RS, and AVM contributed to the mass spectrometry data analysis. RS contributed to the metabolomics statistical analysis and microbial--molecular correlations. GH, TS, KS, and CB contributed to the 16S rRNA sequencing. AB and GA contributed to the metadata organization. TK, SJ, CC, AA, and DMD contributed to the microbial data analysis and statistics. LZ, JK, and KZ contributed to the additional data analysis. AB, PCD, and RK wrote the manuscript. All authors read and approved the final manuscript.
All participants signed a written informed consent in accordance with the sampling procedure approved by the UCSD Institutional Review Board (Approval Number 161730).
Dorrestein is on the advisory board for SIRENAS, a company that aims to find therapeutics from ocean environments. There is no overlap between this research and the company. The other authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
|
Julian Garcia-Selleck of Miami, Florida has been arrested for allegedly defrauding South Florida’s largest insurer out of almost $100,000 in water damage claims. Officials said Garcia-Selleck’s alleged fraud scheme will cause tax rate hikes “for many years to come.”
According to Florida’s Department of Financial Services, Garcia-Selleck reportedly acted as an unlicensed adjuster for four years. He is accused of meeting homeowners who wanted help with handling their insurance claims against Citizens Property Insurance.
Garcia-Selleck allegedly promised to assist homeowners with the claims process by filing claims on their behalf. He then purportedly hired an artist to paint fake water stains on walls, floors, and ceilings of homes in order to increase the water damage claims or to create fake water damage claims.
Garcia-Selleck also reportedly hired public notaries to notarize fraudulent damage claims and forge homeowner signatures. He then purportedly sent these claims to insurance companies without the homeowners’ consent or knowledge. In total, the Department of Financial Services claims that Garcia-Selleck cashed almost $100,000 worth of claims checks from insurance companies.
Citizens Property Insurance has approved hefty premium hikes in the past two years to counter the effects of fraud schemes by unlicensed third parties. The company’s CEO, Barry Gilway, told news sources that premiums will continue to increase “for years to come” if the state legislature doesn’t pass laws restricting unlicensed third parties from pursuing claims on behalf of homeowners. |
Free ammonia pretreatment improves anaerobic methane generation from algae.
Anaerobic methane generation from algae is hindered by the slow and poor algae biodegradability. A novel free ammonia (NH3 i.e. FA) pretreatment technology was proposed in this work to enhance anaerobic methane generation from algae cultivated using a real secondary effluent. The algae solubilisation was 0.05-0.06 g SCOD/g TCOD (SCOD: soluble chemical oxygen demand; TCOD: total chemical oxygen demand) following FA pretreatment of 240-530 mg NH3-N/L for 24 h, whereas the solubilisation was only 0.01 g SCOD/g TCOD for the untreated algae. This indicates that FA pretreatment at 240-530 mg NH3-N/L could substantially enhance algae solubilisation. Biochemical methane potential tests revealed that FA pretreatment on algae at 240-530 mg NH3-N/L is able to significantly enhance anaerobic methane generation. The hydrolysis rate (k) and biochemical methane potential (P0) of algae increased from 0.21 d-1 and 132 L CH4/kg TCOD to 0.33-0.50 d-1 and 140-154 L CH4/kg TCOD, respectively, after the algae was pretreated by FA at 240-530 mg NH3-N/L. Further analysis indicated that FA pretreatment improved k of both quickly and slowly biodegradable substrates, and also increased P0 of the slowly biodegradable substrate although it negatively affected P0 of the quickly biodegradable substrate. This FA technology is a closed-loop technology. |
A new uncrackable security system created by researchers at the University of St Andrews, King Abdullah University of Science and Technology (KAUST) and the Center for Unconventional Processes of Sciences (CUP Sciences) is set to revolutionise communications privacy.
The international team of scientists have created optical chips that enable information to be sent from user to user using a one-time unhackable communication that achieves ‘perfect secrecy’, allowing confidential data to be protected more securely than ever before on public classical communication channels.
The proposed system uses silicon chips that contain complex structures that are irreversibly changed to send information in a one-time key that can never be recreated nor intercepted by an attacker.
The technology overcomes the major threat of quantum computers, which are soon predicted to be able to crack existing communication methods, uses existing communication networks and takes up less space on networks.
The results, published in the scientific journal Nature Communications, open a new pathway towards implementing ‘perfect secrecy’ cryptography at the global scale with contained costs.
First author, Professor Andrea di Falco of the School of Physics and Astronomy at the University of St Andrews, said: “This new technique is absolutely unbreakable, as we rigorously demonstrated in our article.
“It can be used to protect the confidentiality of communications exchanged by users separated by any distance, at an ultrafast speed close to the light limit and in inexpensive and electronic compatible optical chips.”
Current standard cryptographic techniques allow information to be sent quickly but can be broken by future computers and quantum algorithms. The research team says their new method for encrypting data is unbreakable and uses existing communication networks, taking up less space on the networks than traditional encrypted communications.
Leader of the study, Dr Andrea Fratalocchi, Associate Professor of Electrical Engineering at KAUST, said: “With the advent of more powerful and quantum computers, all current encryptions will be broken in very short time, exposing the privacy of our present and, more importantly, past communications.
“For instance, an attacker can store an encrypted message that is sent today and wait for the right technology to become available to decipher the communication.
“Implementing massive and affordable resources of global security is a worldwide problem that this research has the potential to solve for everyone, and everywhere. If this scheme could be implemented globally, crypto-hackers will have to look for another job.”
The new technique achieves ‘perfect secrecy’ meaning a hacker will never be able to access the information contained in the communication.
Keys generated by the chip, which unlock each message, are never stored and are not communicated with the message, nor can they ever be recreated, even by the users themselves, adding extra security.
Dr Aluizio M Cruz, co-founder and CEO of the Center for Unconventional Processes of Sciences (CUP Sciences) in California and study author, said: “This system is the practical solution the cyber security sector has been waiting for since the perfect secrecy theoretical proof in 1917 by Gilbert Vernam.
“It’ll be a key candidate to solving global cyber security threats, from private to national security, all the way to smart energy grids.”
The researchers are currently working on developing commercial applications of this patented technology, have a fully functional demo and are building user-friendly software for this system.
The paper ‘Perfect secrecy cryptography via mixing of chaotic waves in irreversible time-varying silicon chips’ is published in Nature Communications and available online.
DOI: 10.1038/s41467-019-13740-y
University of St Andrews
Founded in the 15th century, St Andrews is Scotland’s first university and the third oldest in the English-speaking world. Teaching began in the community of St Andrews on the east coast of Scotland in 1410 and the University was formally constituted by the issue of Papal Bull in 1413.
The University of St Andrews is one of Europe’s most research-intensive seats of learning; over a quarter of its turnover comes from research grants and contracts. It is one of the top-rated universities in Europe for research, teaching quality and student satisfaction and is consistently ranked among the UK’s top five in leading independent league tables.
The University is the UK University of the Year in The Times and Sunday Times University Guide 2020. The 2020 Guardian University Guide ranked the University as top in Scotland and the second in the UK behind Cambridge.
About KAUST
Established in 2009, King Abdullah University of Science and Technology (KAUST) is a graduate research university devoted to finding solutions for some of the world’s most pressing scientific and technological challenges in the areas of food, water, energy and the environment. With 19 research areas related to these themes and state-of-the art labs, KAUST has created a collaborative and interdisciplinary problem-solving environment, which has resulted in more than 11,000 published papers to date.
With over 100 different nationalities living, working and studying on campus, KAUST has brought together the best minds and ideas from around the world with the goal of advancing science and technology through distinctive and collaborative research.
KAUST is a catalyst for innovation, economic development and social prosperity in Saudi Arabia and the world.
Issued by the University of St Andrews Communications Office.
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Q:
Python: How do I repeatedly get user input that can time out each time
NOTES: Running Python 2.7, working on a macbook (OSX)
I want to query my user for an input, but if no input occurs after a time interval, run something else and try again. Here's what I have written:
import sys, select
def test():
waittime = 4
i, o, e = select.select( [sys.stdin], [], [], waittime)
if i:
print 'got i'
else:
print 'did not get i'
test()
What this DOES: If user does not press [return], waits 3 seconds, prints 'did not get i', reruns the function. If user presses [return], if (i) statement runs indefinitely.
What I WANT it do do: If the user presses [return], print 'got i', rerun the function, WAIT FOR USER TO PRESS RETURN. If user does not press return, wait three seconds, print 'did not get i', try again.
Thanks in advance for any help!
-Erik
A:
First I solved that with multithreading, but I guess it was overboard.
import sys,time,select
anidle = 0.0
while True:
time.sleep(0.01)
incoming = select.select([sys.stdin],[],[],0.0)[0]
if len(incoming) > 0:
anidle = 0.0
aline = sys.stdin.readline()
# process the input here
print 'Input:', aline
break
anidle += 0.01
if anidle > 4:
# process no input for 4 seconds here
print 'No input.'
break
|
Cholecystokinin octapeptides influence tolerance to ethanol in mice.
The effects of graded doses of cholecystokinin octapeptide sulphate (CCK-8-S) and non-sulphated CCK-8 (CCK-8-NS) on the development of tolerance to the hypothermic effect of ethanol were investigated in mice. The animals were pretreated with daily doses of CCK-8-S, CCK-8-NS (0.003-30 nmol/animal s.c.) or vehicle, followed two hours later by the i.p. administration of ethanol (4 g/kg). The same treatments were repeated on three consecutive days. The hypothermic response to ethanol administration gradually diminished, this phenomenon being accepted as indicating the development of tolerance to ethanol. Both CCK-8-S and CCK-8-NS inhibited the development of tolerance. While CCK-8-S resulted in a linear dose-response effect (0.3-30 nmol/animal), CCK-8-NS gave rise to a bell-shaped curve with effective blocking doses of 0.3-3 nmol/animal. There was no difference in colonic temperature between peptide and vehicle-treated, ethanol-naive animals, indicating that the peptide did not change the initial sensitivity to ethanol. |
Q:
Fail in JSON using Twig
Inside a JSON template I find an entry using id, the result title can't be seen using entry.title but I can see it with entry[0].title. There is another step or encoding I have to use?
A:
If you are using something like this to get your entry:
{% set entry = craft.entries.section('blog').limit(1).id('21') %}
then Craft is actually returning an ElementCriteriaModel object, even if it is only one entry.
To ensure that the entry variable only contains a single entry, you need to call the first() method like this:
{% set entry = craft.entries.section('blog').limit(1).id('21').first() %}
More details in the docs here: https://craftcms.com/docs/templating/elementcriteriamodel
|
Table of Contents
Van Buren, Alhanati, Introduction.
Grotstein, "Orphans of O" The Negative Therapeutic
Reaction and the Longing for the Childhood that Never Was.
Ferro, Experiencing Emotions, Avoiding Emotions: Between
Hercules and Puss-in-Boots. Williams, Incorporation of an
Invasive Object. Fix Korbivcher, The Theory of
Transformations and Autistic States. Autistic Transformations: A
Proposal. Robinson, A Binocular View of Adhesion: From
Prenatal Contiguity to Postnatal Appetite. Wilheim, The
Trauma of Conception - Cellular Memory. Van
Buren, Thoughts Without a Thinker. Gonzalez, Nothing
Comes From Nothing: Failed Births, Dead Babies. Chuster,
The Origins of the Unconscious: Framework of The Future Mind.
Reiner, Pre-verbal Language in the Treatment of a Mother
and Infant: A Clinical Exploration. Norman,
Transformations of Early Infantile Experience: A 6-month Old in
Psychoanalysis. Salomonsson "Talk to Me Baby, Tell Me
What's The Matter Now." Semiotic and Developmental Perspectives on
Communication in Psychoanalytic Infant Treatment.
About the Author
Jane Van Buren is a Psychoanalyst in full time private practice in
Los Angeles, California and training and supervising analyst at the
Psychoanalytic Centre of California. She has written widely on the
themes of women and children, culture and psychoanalysis. Shelley
Alhanati is a psychoanalyst in northern California, and is a
Supervising Analyst and faculty member of the Psychoanalytic
Institute of Northern California. She has lectured and written
widely on various topics in psychoanalytic theory as well as on
fetal, infant, and child developmental research.
Reviews
'This is an exceptional book!the scholarship is outstanding and the
integrity of the authors and their work is evident throughout'
Thomas H. Ogden, Director, Centre for the Advanced Study of the
Psychoses; Personal and Supervising Analyst, Psychoanalytic
Institute of Northern California, USA
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/*
* Copyright 2017-present Open Networking Foundation
*
* Licensed under the Apache License, Version 2.0 (the "License");
* you may not use this file except in compliance with the License.
* You may obtain a copy of the License at
*
* http://www.apache.org/licenses/LICENSE-2.0
*
* Unless required by applicable law or agreed to in writing, software
* distributed under the License is distributed on an "AS IS" BASIS,
* WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
* See the License for the specific language governing permissions and
* limitations under the License.
*/
package org.onosproject.drivers.ovsdb;
import org.onlab.packet.IpAddress;
import org.onosproject.net.DeviceId;
import org.onosproject.net.PortNumber;
import org.onosproject.net.behaviour.PortConfigBehaviour;
import org.onosproject.net.behaviour.QosDescription;
import org.onosproject.net.device.PortDescription;
import org.onosproject.net.driver.AbstractHandlerBehaviour;
import org.onosproject.net.driver.DriverHandler;
import org.onosproject.ovsdb.controller.OvsdbClientService;
import org.onosproject.ovsdb.controller.OvsdbController;
import org.onosproject.ovsdb.controller.OvsdbNodeId;
import org.slf4j.Logger;
import static org.slf4j.LoggerFactory.getLogger;
/**
* OVSDB-based implementation of port config behaviour.
*/
public class OvsdbPortConfig extends AbstractHandlerBehaviour implements PortConfigBehaviour {
private final Logger log = getLogger(getClass());
@Override
public void applyQoS(PortDescription portDesc, QosDescription qosDesc) {
OvsdbClientService ovsdbClient = getOvsdbClient(handler());
if (ovsdbClient == null) {
return;
}
ovsdbClient.applyQos(portDesc.portNumber(), qosDesc.qosId().name());
}
@Override
public void removeQoS(PortNumber portNumber) {
OvsdbClientService ovsdbClient = getOvsdbClient(handler());
if (ovsdbClient == null) {
return;
}
ovsdbClient.removeQos(portNumber);
}
// OvsdbNodeId(IP) is used in the adaptor while DeviceId(ovsdb:IP)
// is used in the core. So DeviceId need be changed to OvsdbNodeId.
private OvsdbNodeId changeDeviceIdToNodeId(DeviceId deviceId) {
String[] splits = deviceId.toString().split(":");
if (splits.length < 1) {
return null;
}
IpAddress ipAddress = IpAddress.valueOf(splits[1]);
return new OvsdbNodeId(ipAddress, 0);
}
private OvsdbClientService getOvsdbClient(DriverHandler handler) {
OvsdbController ovsController = handler.get(OvsdbController.class);
OvsdbNodeId nodeId = changeDeviceIdToNodeId(handler.data().deviceId());
return ovsController.getOvsdbClient(nodeId);
}
}
|
Maldevelopment of neural crest cells in patients with typical uveal coloboma.
To clarify the pathogenesis of ocular and systemic anomalies associated with typical uveal coloboma. The records of 72 patients with typical uveal coloboma (35 males and 37 females) treated at Nagoya City University Hospital during a 16-year period were reviewed. Typical uveal coloboma was bilateral in 33 patients and unilateral in 35 patients; 4 patients were unclassified because of severe contralateral microphthalmos. Uveal coloboma was an isolated defect in 23 (37%) patients. Other ocular anomalies were present in 19 (31%) patients, systemic anomalies were found in 7 (11%) patients, and both other ocular and systemic anomalies were noted in 13 patients (21%). The associated ocular anomalies included microphthalmos in 28 eyes of 23 patients, persistent pupillary membrane in 28 eyes of 18 patients, and posterior embryotoxon in 20 eyes of 15 patients. The accompanying systemic anomalies included ear anomalies, retarded growth, and retarded development in 18 patients; heart anomalies in 13 patients; genital hypoplasia in 12 patients; and congenital facial palsy in 10 patients. The collection of malformations known as the CHARGE association was diagnosed in 14 (19%) patients. Abnormal development of neural crest cells appeared to be responsible for the majority of associated ocular and systemic anomalies in patients in the present series, suggesting that typical uveal coloboma may be related to maldevelopment of the neural crest cells. The present findings indicated that ophthalmologists should be aware of the possible association of typical uveal coloboma with systemic anomalies. |
Dysregulated translaion initiation causes malignant transformation or other chronic diseases by different mechanisms. Therefore, studies on the mechanism of translation initiation help to enhance human health and well being. The long-term goal of this proposal is to understand the complex pathway leading to the accurate initiation of translation. In translation initiation, eukaryotic initiation factor 1 (elF1), elF5, and all three subunits of elF2 are implicated in the stringent AUG selection for yeast mRNAs. The C-terminal domain (CTD) of elF5 binds elF1 and bridges interaction between elF2 and a five-subunit factor elF3, mediating fomration of the multifactor complex (MFC) which also contains the methionyl initiator tRNA. When bound to the ribosome, the MFC interactions rearrange, allowing elF5-CTD to interact with the elF4G subunit of elF4F complex bound to S'-capped mRNA and promoting formation of ribosomal preinitiation complex. Under the previous aims in this GM67841 proposal, evidence was provided that the accuracy of translation initiation depends on the function of the MFC, but how this complex assembles and functions is still unclear. In particular, it is very important to correlate the functions of the MFC and preinitiation complexes to the structure of individual elFs, which has started to unveil. In collaboration with Dr. Gerhard Wagner at Harvard Medical School, the Asano group has solved the structure of yeast elF1 and identified its interfaces to the NTDs of elF2[unreadable] and elFSc and the CTDs of elF4G and elF5. Genetic and biochemical studies showed how these interactions may rearrange during preinitiation complex assembly and function. In this renewal proposal, the first aim is to solve the structure of elF5-CTD in collaboration with the Wagner group, and use this information to direct its well-designed mutagenesis studies. The second aim is to reconstitute full MFC from purified constituents, and use it to understand the mechanism of its assembly activation and hypothetical control by elF5 phosphorylation. Finally, the third aim is to study the critical partners of the MFC in the preinitiation complex, elF4G-CTD and the ribosomal RNA. The data obtained from the previous aims will be used to predict elF5-CTD-binding face of elF4G-CTD and perform site-directed mutagenesis studies on the latter. >30 Ts- mutations mapping in rRNA obtained under an aim in the previous proposal will be used together with new mutations to be introduced at the predicted 40S subunit interface to mRNA. |
Our Princess Lucy Tiara features peaks and swirls accented with rhinestones. Each Princess Comb Lucy Tiara measures 3" high x 5 1/2" wide and is made of copper. The Princess Lucy Tiara has a front comb to help keep it in place.
WARNING: NOT INTENDED for use By Children 12 and under.
Product Code: TIAPLU
Please allow ample time for delivery. The delivery date for this product is noted above for US shipping only. Please refer to checkout for delivery dates outside of the Contiguous 48 States.
Shipping charges are based on the value of the merchandise and not the number of shipments. For additional shipping information, please contact our Customer Service Department at 800-314-8736.
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This stunning Harper Tiara presents beautiful, white plastic
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Complete your little girl's royal look with a
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Read about the unique virtualization technology that allows you to create multiple virtual systems on a single physical system, and assign fine-grained CPU and memory resources to an Oracle RAC workload. |
Adult neurogenesis in non-mammalian vertebrates.
Adult neurogenesis is an exciting and rapidly advancing field of research. It addresses basic biological questions, such as the how and why of de novo neuronal production during adulthood, as well as medically relevant issues, including the potential link between adult neural stem cells and psychiatric disorders, or how stem cell manipulation might be used as a strategy for neuronal replacement. Current research mainly focuses on rodents, but we review here recent examination of non-mammalian vertebrates, which demonstrates that bona fide adult neural stem cells exist in these species. Importantly, especially in teleost fish, these cells can be abundant and located in various brain areas. Hence, non-mammalian vertebrate species provide invaluable comparative material for extracting core mechanisms of adult neural stem cell maintenance and fate. |
(function() {
'use strict';
var L = require('leaflet');
var Formatter = require('./formatter');
var ItineraryBuilder = require('./itinerary-builder');
module.exports = L.Control.extend({
includes: ((typeof L.Evented !== 'undefined' && L.Evented.prototype) || L.Mixin.Events),
options: {
pointMarkerStyle: {
radius: 5,
color: '#03f',
fillColor: 'white',
opacity: 1,
fillOpacity: 0.7
},
summaryTemplate: '<h2>{name}</h2><h3>{distance}, {time}</h3>',
timeTemplate: '{time}',
containerClassName: '',
alternativeClassName: '',
minimizedClassName: '',
itineraryClassName: '',
totalDistanceRoundingSensitivity: -1,
show: true,
collapsible: undefined,
collapseBtn: function(itinerary) {
var collapseBtn = L.DomUtil.create('span', itinerary.options.collapseBtnClass);
L.DomEvent.on(collapseBtn, 'click', itinerary._toggle, itinerary);
itinerary._container.insertBefore(collapseBtn, itinerary._container.firstChild);
},
collapseBtnClass: 'leaflet-routing-collapse-btn'
},
initialize: function(options) {
L.setOptions(this, options);
this._formatter = this.options.formatter || new Formatter(this.options);
this._itineraryBuilder = this.options.itineraryBuilder || new ItineraryBuilder({
containerClassName: this.options.itineraryClassName
});
},
onAdd: function(map) {
var collapsible = this.options.collapsible;
collapsible = collapsible || (collapsible === undefined && map.getSize().x <= 640);
this._container = L.DomUtil.create('div', 'leaflet-routing-container leaflet-bar ' +
(!this.options.show ? 'leaflet-routing-container-hide ' : '') +
(collapsible ? 'leaflet-routing-collapsible ' : '') +
this.options.containerClassName);
this._altContainer = this.createAlternativesContainer();
this._container.appendChild(this._altContainer);
L.DomEvent.disableClickPropagation(this._container);
L.DomEvent.addListener(this._container, 'mousewheel', function(e) {
L.DomEvent.stopPropagation(e);
});
if (collapsible) {
this.options.collapseBtn(this);
}
return this._container;
},
onRemove: function() {
},
createAlternativesContainer: function() {
return L.DomUtil.create('div', 'leaflet-routing-alternatives-container');
},
setAlternatives: function(routes) {
var i,
alt,
altDiv;
this._clearAlts();
this._routes = routes;
for (i = 0; i < this._routes.length; i++) {
alt = this._routes[i];
altDiv = this._createAlternative(alt, i);
this._altContainer.appendChild(altDiv);
this._altElements.push(altDiv);
}
this._selectRoute({route: this._routes[0], alternatives: this._routes.slice(1)});
return this;
},
show: function() {
L.DomUtil.removeClass(this._container, 'leaflet-routing-container-hide');
},
hide: function() {
L.DomUtil.addClass(this._container, 'leaflet-routing-container-hide');
},
_toggle: function() {
var collapsed = L.DomUtil.hasClass(this._container, 'leaflet-routing-container-hide');
this[collapsed ? 'show' : 'hide']();
},
_createAlternative: function(alt, i) {
var altDiv = L.DomUtil.create('div', 'leaflet-routing-alt ' +
this.options.alternativeClassName +
(i > 0 ? ' leaflet-routing-alt-minimized ' + this.options.minimizedClassName : '')),
template = this.options.summaryTemplate,
data = L.extend({
name: alt.name,
distance: this._formatter.formatDistance(alt.summary.totalDistance, this.options.totalDistanceRoundingSensitivity),
time: this._formatter.formatTime(alt.summary.totalTime)
}, alt);
altDiv.innerHTML = typeof(template) === 'function' ? template(data) : L.Util.template(template, data);
L.DomEvent.addListener(altDiv, 'click', this._onAltClicked, this);
this.on('routeselected', this._selectAlt, this);
altDiv.appendChild(this._createItineraryContainer(alt));
return altDiv;
},
_clearAlts: function() {
var el = this._altContainer;
while (el && el.firstChild) {
el.removeChild(el.firstChild);
}
this._altElements = [];
},
_createItineraryContainer: function(r) {
var container = this._itineraryBuilder.createContainer(),
steps = this._itineraryBuilder.createStepsContainer(),
i,
instr,
step,
distance,
text,
icon;
container.appendChild(steps);
for (i = 0; i < r.instructions.length; i++) {
instr = r.instructions[i];
text = this._formatter.formatInstruction(instr, i);
distance = this._formatter.formatDistance(instr.distance);
icon = this._formatter.getIconName(instr, i);
step = this._itineraryBuilder.createStep(text, distance, icon, steps);
if(instr.index) {
this._addRowListeners(step, r.coordinates[instr.index]);
}
}
return container;
},
_addRowListeners: function(row, coordinate) {
L.DomEvent.addListener(row, 'mouseover', function() {
this._marker = L.circleMarker(coordinate,
this.options.pointMarkerStyle).addTo(this._map);
}, this);
L.DomEvent.addListener(row, 'mouseout', function() {
if (this._marker) {
this._map.removeLayer(this._marker);
delete this._marker;
}
}, this);
L.DomEvent.addListener(row, 'click', function(e) {
this._map.panTo(coordinate);
L.DomEvent.stopPropagation(e);
}, this);
},
_onAltClicked: function(e) {
var altElem = e.target || window.event.srcElement;
while (!L.DomUtil.hasClass(altElem, 'leaflet-routing-alt')) {
altElem = altElem.parentElement;
}
var j = this._altElements.indexOf(altElem);
var alts = this._routes.slice();
var route = alts.splice(j, 1)[0];
this.fire('routeselected', {
route: route,
alternatives: alts
});
},
_selectAlt: function(e) {
var altElem,
j,
n,
classFn;
altElem = this._altElements[e.route.routesIndex];
if (L.DomUtil.hasClass(altElem, 'leaflet-routing-alt-minimized')) {
for (j = 0; j < this._altElements.length; j++) {
n = this._altElements[j];
classFn = j === e.route.routesIndex ? 'removeClass' : 'addClass';
L.DomUtil[classFn](n, 'leaflet-routing-alt-minimized');
if (this.options.minimizedClassName) {
L.DomUtil[classFn](n, this.options.minimizedClassName);
}
if (j !== e.route.routesIndex) n.scrollTop = 0;
}
}
L.DomEvent.stop(e);
},
_selectRoute: function(routes) {
if (this._marker) {
this._map.removeLayer(this._marker);
delete this._marker;
}
this.fire('routeselected', routes);
}
});
})();
|
x
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Photo White Forest Cake CODE: 2590
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Photo White Forest CakeAlong with the rich whipped cream mixed with sweet White Chocolate, that encircles this Cake, add a personal Photo on the top of it to further its beauty. All the lovers of the White Chocolate will love this Cake.Send your photo at amitv@archiesonline.com.Product Contains:- 1 Kg White Forest Photo Printed Cake₹20452045 |
Dermal penetration of fentanyl: inter- and intraindividual variations.
Fentanyl is a potent synthetic opioid that is increasingly being used in transdermal drug delivery systems. The target organ concentration of a drug administered dermally will depend on the rate of dermal absorption and the systemic elimination. We have studied the intra- and interindividual variation in dermal penetration of fentanyl in an in vitro model (static diffusion cells) with human skin, and compared the absorption of fentanyl from an aqueous solution with absorption from a commercial patch. The intraindividual variation in dermal penetration of fentanyl in aqueous solution was limited (18%) and no differences in penetration characteristics were observed between breast and abdominal skin. The interindividual variation in dermal penetration of fentanyl was extensive, with maximal fluxes ranging from 21-105 ng/cm2/hr following application of an infinite dose of fentanyl to the donor chamber. Use of transdermal drug delivery systems (patches) reduced the inter-individual variation. The permeability coefficients after application of fentanyl in aqueous solution and through patches were identical (0.0011 cm/hr). One person had a higher than average penetration rate following patch application, which may indicate that the human skin and not the patch barrier was the rate-determining factor for the other individuals included in this study. |
992 F.2d 1220
NOTICE: Ninth Circuit Rule 36-3 provides that dispositions other than opinions or orders designated for publication are not precedential and should not be cited except when relevant under the doctrines of law of the case, res judicata, or collateral estoppel.UNITED STATES of America, Plaintiff-Appellee,v.Angelo T. COMMITO, Defendant-Appellant.
Nos. 92-10331 thru 92-10335.
United States Court of Appeals, Ninth Circuit.
Submitted April 16, 1993.*Decided May 3, 1993.
Before SCHROEDER, PREGERSON and D.W. NELSON, Circuit Judges.
1
MEMORANDUM**
2
Angelo Commito, a healthcare program broker, was involved in an extensive healthcare program kickback scheme. In December 1985, the FBI began a sting operation against Commito believing that he was involved in organizing kickbacks in exchange for the placement of health plans with various employer buyers. This investigation ended in 1988 and charges were brought against Commito in the Northern District of Georgia (CR-89-0051-MHP, and CR-89-0060-MHP), the District of Maryland (CR-89-0014-MHP), the Southern District of California (CR-88-0597-MHP) and the Northern District of California (CR-88-0597-MHP). On July 18, 1989 these cases were consolidated in the Northern District court of California.
3
On February 26, 1991, Commito was convicted in an unrelated case in the District of Maryland of conspiracy to defraud the United States and bribery of a public official. He was sentenced to ten months imprisonment but was released on bond pending appeal of his conviction. On November 4, 1991, Commito made arrangements to enter guilty pleas in the consolidated cases before the Northern district court. Commito pled guilty to one count of wire fraud in two cases (CR-89-0060-MHP and CR-88-0811-MHP) and two counts of wire fraud, one count of mail fraud, and one count of theft in another case (CR-88-0597-MHP). The remaining charges were dismissed. Commito's mail fraud count was the only guideline offense; Commito's other five convictions were pre-guideline offenses.
4
At sentencing, the district court placed Commito on five years probation for each pre-guideline count to be served concurrently. Turning its attention to the guideline count of mail fraud, the court found that the base offense level was six. Aggregating the losses that resulted from each pre-guideline offense and the one guideline offense, the court found that the total loss from Commito's crimes was $443,896.00. Pursuant to U.S.S.G. § 2F1.1(b), Commito's base offense level was increased by seven points. Pursuant to § 2F1.1(b)(2), the court increased the base level by another two levels because the kickback scheme involved more than minimal planning. Finally, the court increased Commito's offense level by another four points for his leadership role in the plot under § 3B1.1(a). Granting Commito a two point reduction for acceptance of responsibility, the court found that Commito's base offense level was 17 and imposed a 30 month sentence. The district court ordered the pre-guideline sentences to run concurrently to the guideline sentence, and that the outstanding sentence handed down by the Maryland court was to run consecutively to the sentences in the consolidated cases.
5
Commito appeals his sentence on two grounds. First, he contends that the district court erred in adjusting his sentence under § 3B1.1(a). Second, Commito argues that the district court erred by ordering the pre-guideline sentences to run consecutively to his guideline sentence.
I. The Upward Adjustment
6
When adjusting a sentence upward, a district court must find by a preponderance of the evidence that the facts support an upward adjustment. United States v. Restrepo, 946 F.2d 654, 661 (9th Cir.1991) (en banc). The district court's factual determinations are reviewed for clear error, but its legal interpretations of the Guidelines are reviewed de novo. United States v. Wilson, 900 F.2d 1350, 1355 (9th Cir.1990).
7
Section 3B1.1(a) instructs the court to increase a defendant's offense level by four points if "the defendant was an organizer or leader of a criminal activity that involved five or more participants or was otherwise extensive...." U.S.S.G. § 3B1.1(a). The introductory commentary to Chapter 3, Part B of the Sentencing Guidelines was amended, effective November 1, 1990, to read:
8
The determination of a defendant's role in the offense is to be made on the basis of all conduct within the scope of § 1B1.3 (Relevant Conduct), i.e. all conduct included under § 1B1.3(a)(1)-(4), and not solely on the basis of elements and acts cited in the count of conviction.
9
Pursuant to this amendment, the definition of the word "offense" is not restricted to the offense of conviction. Thus for purposes of § 3B1.1(a), a court may consider relevant conduct.
10
The district court held that it may consider the conduct underlying Commito's pre-guideline offenses when deciding whether he warranted an upward adjustment under § 3B1.1(a) notwithstanding that the guideline offense conduct took place prior to the effective date of the amendment to the introduction to § 3B.1. Because the guideline offense was committed prior to the effective date of the amendment, Commito argues that the application of the amendment violates the ex post facto clause.
11
Commito's argument is without merit. We already have determined that this amendment only clarified § 3B1.1(a). United States v. Lillard, 929 F.2d 500, 503 (9th Cir.1991). Amendments that "clarify rather than substantively change the guidelines do not present ex post facto issues when they are applied retrospectively" to conduct that occurred before the clarification. United States v. Scarano, 975 F.2d 580, 587 (9th Cir.1992). Therefore, the district court could properly consider Commito's pre-guideline offenses as relevant conduct when deciding whether he warranted an adjustment under § 3B1.1(a).
12
Next, Commito contends that the district court erred when it found that he was a leader or organizer of the kickback scheme. The district court did not speak to this issue at great length. Rather, the court incorporated the pre-sentence report into its statement of reasons and then concluded that the report supported a finding by a preponderance of the evidence that Commito was the "mastermind" behind the kickback scheme. The district court also stated that it would even reach this finding by focusing only on the guideline offense, and ignoring the relevant pre-guideline offense conduct.
13
In order to adjust Commito's sentence under § 3B1.1(a), the district court must make two distinct findings: 1) that, at a minimum, five participants, were involved in Commito's criminal activity; and 2) that Commito was a leader of the criminal scheme. A district court may meet its requirement of evaluating the evidence on the record by incorporating the pre-sentence report into the record. United States v. Avila, 905 F.2d 295, 298 (9th Cir.1990).
14
This circuit has interpreted Note 3 to require that "some degree of control or organizational authority over others" be found before a defendant may be considered a leader. United States v. Mares-Molino, 913 F.2d 770, 773 (9th Cir.1990) (emphasis supplied). It is not necessary, however, for the court to find that a defendant supervised each of the minimum five participants. "The section simply states that an adjustment occurs if a defendant was an 'organizer or leader of a criminal activity that involved five or more participants....' " United States v. Smith, 924 F.2d 889, 896 (9th Cir.1991) (emphasis in original).
15
The pre-sentence report does not support an upward adjustment under § 3B.1(a) based on the guideline offense alone. In its statement of reasons, the district court focused on Commito's leadership role in the kickback scheme. The pre-sentence report, however, does not support a finding that Commito had organizational authority over the mail fraud. Rather, the pre-sentence report indicates that it was Carl Mattison who initiated, organized, and directed others in the plan to place an Employees Assistance program with National Semi-Conductor, Inc. The district court may have considered other evidence that establishes that Commito was the organizer of the mail fraud plan, but that evidence was not discussed. Thus we must rely, as did the district court, on the statement of facts contained in the pre-sentence report.
16
In addition, the court did not consider whether five participants were involved in the mail fraud scheme. The pre-sentence report reveals that only two criminally responsible individuals were involved in this offense: Commito and Carl Mattison. Therefore, the district court erred when it found that Commito was subject to a § 3B.1(a) adjustment based on the mail fraud offense alone.
17
Once the pre-guideline offenses are taken into account, however, we cannot say that an upward adjustment under § 3B1.1(a) was clearly erroneous. Although the district court made no finding as to the number of participants involved, the pre-sentence report reveals that far more than five individuals joined with Commito in the criminal activity. In addition, the pre-sentence report overwhelming supports the district court's finding that Commito organized the kickback scheme: Commito put the FBI agents in touch with other individuals willing to engage in a kickback scheme, organized the method of payment, and arranged for the concealment of those payments from the various companies being defrauded. Therefore, we affirm Commito's guideline sentence.
II. The Consecutive Sentence
18
Commito contends that the district court punished him twice for his pre-guideline offenses because the court considered the losses that resulted from the pre-guideline conduct when it adjusted Commito's sentence upward pursuant to § 2F1.1, and then ordered that the pre-guideline sentence run concurrent to the adjusted guideline sentence. Commito is correct that his pre-guideline sentence runs consecutive to his guideline sentence and that this violates the Double Jeopardy Clause. Commito, however, misunderstands the source of the problem. The problem is not with the district court's judgment, but with the commitment order.
19
The district court did not order that Commito's pre-guideline sentence run consecutive to his guideline sentence. Rather the judgment explicitly states that the pre-guideline sentences are to run concurrently with the guideline sentence in order to avoid imposing double punishment for the conduct underlying the pre-guideline offenses. See Scarano, 975 F.2d at 580; United States v. Niven, 952 F.2d 289, 293 (9th Cir.1991). The judgment goes on to say that the unserved sentence outstanding from the district of Maryland case was to run consecutive to all the consolidated sentences.
20
The clerk who entered the judgment appears to have misread the court's judgment. Instead of ordering that the sentence handed down by the Maryland court run consecutive to the consolidated counts, the clerk entered an order that the pre-guideline count III sentence of five years probation in CR-88-0597 was to run consecutive to the guideline count XIX in the same case. The commitment order does not mention the outstanding sentence imposed by the Maryland court.1 We assume this was the result of an error on the part of the clerk entering the sentencing order.
21
In short, the district court agreed with Commito that if it took the losses in the pre-guideline counts into consideration in increasing his base offense level in the guideline count pursuant to § 2F1.1, it must then order the pre-guideline sentences to run concurrently to the guideline sentence in order to avoid double punishment for the conduct underlying the pre-guideline counts.
22
Therefore, we affirm Commito's sentence, but we remand this case and instruct the district court to amend its commitment order to conform to its order of judgment pursuant to Fed.R.Crim.Proc. 36.
23
AFFIRMED IN PART AND REMANDED IN PART.
*
The panel unanimously finds this case suitable for decision without oral argument. Fed.R.App.P. 34(a); 9th Cir.R. 34-4
**
This disposition is not appropriate for publication and may not be cited to or by the courts of this circuit except as provided by 9th Cir.R. 36-3
1
The clerk correctly entered Judge Patel's order that the other four pre-guideline sentences were to run concurrent to count III
|
Evaluating medication effects outside of clinical trials: new-user designs.
Recent clinical trials demonstrating that hormone replacement therapy (HRT) does not prevent coronary heart disease in women have again raised doubts concerning observational studies. Although much of the explanation probably lies in what might be called the "healthy HRT user" effect, another contributing factor may be that most observational studies included many prevalent users: women taking HRT for some time before study follow-up began. This practice can cause two types of bias, both of which plausibly may have contributed to the discrepancy between observational and randomized studies. First, prevalent users are "survivors" of the early period of pharmacotherapy, which can introduce substantial bias if risk varies with time, just as in studies of operative procedures that enroll patients after they have survived surgery. This article provides several examples of medications for which the hazard function varies with time and thus would be subject to prevalent user bias. Second, covariates for drug users at study entry often are plausibly affected by the drug itself. Investigators often do not adjust for these factors on the causal pathway, which may introduce confounding. A new-user design eliminates these biases by restricting the analysis to persons under observation at the start of the current course of treatment. This article thus argues that such designs should be used more frequently in pharmacoepidemiology. |
Problem Solving with MiniZinc - newtang
http://blog.jpalardy.com/posts/problem-solving-with-minizinc/
======
antman
Very nice presentation. Another extensive list of examples:
[http://www.hakank.org/minizinc/](http://www.hakank.org/minizinc/)
|
The backbone of our “curriculum” for this study is made up of books from the library (yay for free!). Our library has several different series of children’s geography books, and we’ve been systematically checking them out as we work our way through the states.
I read these state books out loudto all 4 of the kids. Joshua obviously is soaking in more of this information than Zoe is, but I still think it’s valuable for her to be there. In fact, I’m usually pleasantly surprised to hear how much the littler ones are picking up and remembering.
As we read,I ask my kids questions to get them to talk about what they’re hearing (like, “Why do you think that Illinois has so much farmland and Colorado doesn’t?). If I’ve been to a particular state, I tell them what it was like. If we know someone who lives in a state, I point that out. We talk about the topography and the population, and compare these things to states we’ve studied previously.
We also usually get our well-loved state puzzle out so that the kids can get a good idea of how our current state compares to other states and so that they can see the states that border it.
After we’ve finished reading a state book, we get out pencils, crayons, markers, and paper, and all 4 kids work on making a “state paper”.
We write the state name at the top of the paper and trace the state puzzle piece. After that, we draw various things we learned about that state….the state flower and tree, the state flag, what the state produces, some of its landmarks, and so on.
This is Sonia’s Illinois paper…do notice the upside-down John Deer tractor. I think she accidentally turned her paper around when she was drawing that.
The building on the left there is the Sears Tower (oh, sorry…the Willis Tower), and you can see she remembered that Illinois has lots of farms, that it produces wheat and corn (that’s a pot full of corn there with corn sticking out of the bottom. Hmm.), that the BlackHawks play in Chicago, and that the state tree is the white oak and the state flower is a violet.
The point of this is not to produce perfect drawings, but to help my children remember what they’re learning. Reading, discussing, and drawing all help new information stick in their minds.
To keep our state papers organized, we put the state papers in a 3-ring binder (each kid has their own).
One of the best things about this method is that it doesn’t even really feel like school. I often read state books to the kids while they eat their lunch, and our discussions feel as natural as any lunch conversation does. And when we get out drawing materials, it doesn’t feel like painful work…they usually have fun drawing the things they remember and they’re usually excited to show their drawings to Mr. FG when he gets home from work.
And of course, you can’t beat the fact that this course of study costs almost nothing. The books from the library are free, we already have an overabundance of pencils, markers, and crayons, and the cost of 4 pieces of paper is negligible.
Oh, I forgot to mention FOOD! You remind me of myself when I taught my small groups of children. I even had the same USA puzzle! I remember clearly when my students made gumbo in class as part of a unit on Louisiana. Teachers all along the hallway stopped in for a taste!
WOW! I like the drawing of IL! I’m living there now! Pretty neat! That does look like fun! My kids are in public school but when we go to our Library, I would pick up books on different countries and scan thru those with the kids. My kids also receive a Kids of Courage magazine by-monthly. It is written by The Voice of the Martyrs. We recently cooked from the little magazine featuring children and families persecuted in different parts of the world. It was yummy, banana fritters from Malaysia! It is a GREAT way of learning! Go Frugal-Girl!
When you get to the point of history through regular books, I have a suggestion for Michigan. The Loon Feather, by Iola Fuller. The blurb says: “‘The Loon Feather’ is the story of an Indian girl, Oneta, daughter of Tecumseh, destined to grow up with the incompatible traditions of her own people and of the white traders on Mackinac Island. She learns French from a ‘black coat’ in a mission school, gradually becomes bound to the world of her French stepfather, Pierre Debans, and is educated in a convent in Quebec. Only when Debans, unable to reconcile tribal ways with his European background, nearly sparks an Indian uprising does Oneta make a choice between her two heritages.
This was one of my favorites growing up in the 50s and spending some time in Michigan. There’s a good dose of history, plus it’s a well written story. Includes things like the fur trade. They don’t carry it in my library, sadly, but I looked it up on Abebooks.com and they have it for $1.
A good set of books is Childhoods of Famous Americans. I was addicted to these as a 9-10-11 year old. They move quickly. I think they give a good background for history and a close look at people’s daily lives. I read them for fun, of course, but with guidance and supplement they would be even better. They are by various authors including, Bradford Smith (“Dan Webster, Union Boy”), Augusta Stevenson (“Paul Revere, Boy of Old Boston”), Helen Monsell (“Dolly Madison, Quaker Girl”). I actually saw a paperback reprint of the Paul Revere book at the Smithsonian about 10 years ago. (Remembered this one because it was dedicated to my grandfather, who was a bookseller).
What a great way to teach your kid’s! Here in Idaho we are proud of our potatoes (they are world famous), but we are also know for other forms of agriculture, our beautiful opals, rugged mountains, beautiful outdoor scenery, and wildlife. Have fun with your fun geography lessons!
What a great idea. We have gone through Story of the World and I want to get into the 50 states. How do you decide which order to go in? Regional, alpha, etc. Do you make them memorize capitals too? Thanks for the info.
I have to say that I do love “schooling” the most when it becomes unschooly. Children do seem to retain more in a natural setting. Applause on the comparative questioning. It scores higher with Bloom’s Taxonomy. Keep up the great work. I always enjoy your posts about homeschooling.
thanks so much for the great idea! i do the same with reading, but i love the idea of them coloring a page about the info.I need to get them more involved! i just started homeschooling & i love to hear
( & use) your great ideas!
I agree. My friend from a neighborhood I grew up in was home schooled. He is now the editor of a major newspaper. Most people his age cannot spell from regular school let alone understand more complex words ect..
Excellent! While I do not plan to home school my kids, I do plan to supplement the education that they get and this is exactly the kind of “curriculum” I’m interested in. We have a lift the flap book about the states, with just their capitals, shapes, and flags, but I bought a 50 States game for my son for Christmas. He’s not even five yet (and my 2nd isn’t arriving until March), so I’m starting slow.
So nice to see the mention of Charlotte Mason as I used this approach when I taught my daughter. WOuld you have any interest in 8 back issues of The Parents Review published by Karen Andreola. . My daughter is now in college and I just found these issues while cleaning out the attic. Let me know
I love teaching my boys like this. We are in the UK and do a similar idea for the countries of the world. We look at the location, shape, language, culture, food, flag and animals of each country. Then the boys make a page up with their most important facts. We then have some dishes from that country for our dinner. My boys are not home schooled (I wish they were) but I am always complemented by their teachers on their outstanding knowledge of the world.
I am almost 47 years old and my children are pretty well grown, but Kristen, when I read your posts about homeschooling, I so want to have more kids and homeschool them. It just seems like the best thing ever. |
About us
Short Term Programs is a platform where universities and other institutions of higher education can display their short programs for international students. Through our search engine and filtering options we make it easy for students to find a program of their interest.
Program types and names
Many universities and other institutions of higher education offer programs that are open to external students and professionals. These programs are usually made for one of three groups: prospective students, current students and professionals (or in general, people who have finished their studies). Universities do not all use the same names for these programs. Names you can see for these programs are:
Short (term) programs or short (term) courses
Summer/winter school, Summer/winter programs/courses
International summer/winter session
Open programs/courses
Lifelong learning
Pre university college/courses
University preparation programs/courses
Goal
Our goal is to list as many of these academic programs from all over the world as possible, giving students and professionals a tool to easily find and compare them. Studying at a foreign university can be a great experience and is something you will remember for the rest of your life.
History
Short Term Programs was founded in 2018 by Dirk Faber. While he was a student he studied abroad in two different countries, the USA and Italy. After his studies he worked for Utrecht University where he coordinated the short programs, receiving more than 4000 students per year, of which most from a foreign country. |
Wonder Drug for Aging (Made from One of the Deadliest Toxins on Earth) (2017) - Tomte
https://www.bloomberg.com/news/features/2017-10-26/inside-fort-botox-where-a-deadly-toxin-yields-2-8-billion-drug
======
lingzb
It'll help you live forever! (If it doesn't kill you first.)
|
[Splenic extramedullary hematopoiesis in myelofibrosis. Pathogenetic considerations apropos of a personally studied case].
A case of myelofibrosis developing in a peripheral leukaemia-type situation after splenectomy is presented. An examination of the hypotheses on the pathogenesis of myeloid metaplasia during myelofibrosis lead to the proposition that it may be caused by the "seeding" of medullary precursors in the spleen. |
Q:
Service allocate lots of memory?
I've been using Android open source service example. I just need to use it to send notification to user, but strange, it allocates lots of memory. I checked in Running Services, and it is almost 20MB (if i set ACTION_BACKGROUND) or 30MB (if i set ACTION_FOREGROUND)...
What should i do to reduce this memory usage?
I've already read this discussion I have no bitmap or webview.
Here's my service:
/**
* This is an example of implementing an application service that can
* run in the "foreground". It shows how to code this to work well by using
* the improved Android 2.0 APIs when available and otherwise falling back
* to the original APIs. Yes: you can take this exact code, compile it
* against the Android 2.0 SDK, and it will against everything down to
* Android 1.0.
*/
public class NotificationService extends Service {
static final String ACTION_FOREGROUND = "com.example.android.apis.FOREGROUND";
static final String ACTION_BACKGROUND = "com.example.android.apis.BACKGROUND";
private static final Class<?>[] mSetForegroundSignature = new Class[] {
boolean.class};
private static final Class<?>[] mStartForegroundSignature = new Class[] {
int.class, Notification.class};
private static final Class<?>[] mStopForegroundSignature = new Class[] {
boolean.class};
// protected NotificationManager mNM;
private Method mSetForeground;
private Method mStartForeground;
private Method mStopForeground;
private Object[] mSetForegroundArgs = new Object[1];
private Object[] mStartForegroundArgs = new Object[2];
private Object[] mStopForegroundArgs = new Object[1];
void invokeMethod(Method method, Object[] args) {
try {
method.invoke(this, args);
} catch (InvocationTargetException e) {
// Should not happen.
Log.w("ApiDemos", "Unable to invoke method", e);
} catch (IllegalAccessException e) {
// Should not happen.
Log.w("ApiDemos", "Unable to invoke method", e);
}
}
/**
* This is a wrapper around the new startForeground method, using the older
* APIs if it is not available.
*/
void startForegroundCompat(int id, Notification notification) {
// If we have the new startForeground API, then use it.
if (mStartForeground != null) {
mStartForegroundArgs[0] = Integer.valueOf(id);
mStartForegroundArgs[1] = notification;
invokeMethod(mStartForeground, mStartForegroundArgs);
return;
}
// Fall back on the old API.
mSetForegroundArgs[0] = Boolean.TRUE;
invokeMethod(mSetForeground, mSetForegroundArgs);
// mNM.notify(id, notification);
}
/**
* This is a wrapper around the new stopForeground method, using the older
* APIs if it is not available.
*/
void stopForegroundCompat(int id) {
// If we have the new stopForeground API, then use it.
if (mStopForeground != null) {
mStopForegroundArgs[0] = Boolean.TRUE;
invokeMethod(mStopForeground, mStopForegroundArgs);
return;
}
// Fall back on the old API. Note to cancel BEFORE changing the
// foreground state, since we could be killed at that point.
// mNM.cancel(id);
mSetForegroundArgs[0] = Boolean.FALSE;
invokeMethod(mSetForeground, mSetForegroundArgs);
}
@Override
public void onCreate() {
// mNM = (NotificationManager)getSystemService(NOTIFICATION_SERVICE);
try {
mStartForeground = getClass().getMethod("startForeground",
mStartForegroundSignature);
mStopForeground = getClass().getMethod("stopForeground",
mStopForegroundSignature);
return;
} catch (NoSuchMethodException e) {
// Running on an older platform.
mStartForeground = mStopForeground = null;
}
try {
mSetForeground = getClass().getMethod("setForeground",
mSetForegroundSignature);
} catch (NoSuchMethodException e) {
throw new IllegalStateException(
"OS doesn't have Service.startForeground OR Service.setForeground!");
}
}
@Override
public void onDestroy() {
// Make sure our notification is gone.
stopForegroundCompat(1);
}
// This is the old onStart method that will be called on the pre-2.0
// platform. On 2.0 or later we override onStartCommand() so this
// method will not be called.
@Override
public void onStart(Intent intent, int startId) {
handleCommand(intent);
}
@Override
public int onStartCommand(Intent intent, int flags, int startId) {
handleCommand(intent);
// We want this service to continue running until it is explicitly
// stopped, so return sticky.
return START_STICKY;
}
@Override
public void onRebind(Intent intent) {
super.onRebind(intent);
handleCommand(intent);
}
void handleCommand(Intent intent) {
if (intent == null)
return;
if (ACTION_FOREGROUND.equals(intent.getAction())) {
DBHelper db = new DBHelper(this);
String lastTime = db.getLastVisitTime();
if(!lastTime.equals("-1")) {
new Notifications(this).InviteUser();
}
String target = db.getTargetValue();
if(target.equals("")) {
new Notifications(this).TargetlessNotification();
}
db.close();
/*
// In this sample, we'll use the same text for the ticker and the expanded notification
CharSequence text = getString(R.string.app_name);
CharSequence description = getString(R.string.recall_user);
// Set the icon, scrolling text and timestamp
Notification notification = new Notification(R.drawable.icon, text, System.currentTimeMillis());
// The PendingIntent to launch our activity if the user selects this notification PendingIntent
contentIntent = PendingIntent.getActivity(this, 1, new Intent(this, YKEYarinaSaklaActivity.class), 0);
// Set the info for the views that show in the notification panel.
notification.setLatestEventInfo(this, text, description, contentIntent);
// Set properties of notification
notification.flags = Notification.FLAG_INSISTENT | Notification.FLAG_AUTO_CANCEL;
notification.defaults |= Notification.DEFAULT_ALL;
startForegroundCompat(1, notification);
*/
} else if (ACTION_BACKGROUND.equals(intent.getAction())) {
stopForegroundCompat(1);
}
}
@Override
public IBinder onBind(Intent intent) {
return null;
}
}
P.S.: I don't know if it's relevant or not but i'm starting this service onDestroy of my app, so it'll send notification to user on a specific time with AlarmManager. (So it should not be killed to avoid AlarmManager deleting my notification.)
A:
I've tried to simplfy my service as possible as i can, but the situation is still the same... Then i realize that somehow, usage of memory decrease by itself... So, if i have no option, i could except that.
public class NotificationService2 extends Service{
private String target, lastTime, notifCheck, notifCheck2;
@Override
public void onStart(Intent intent, int startId) {
Bundle extras = intent.getExtras();
if(extras != null) {
this.lastTime = extras.getString("lastTime");
this.target = extras.getString("target");
this.notifCheck = extras.getString("notifCheck");
this.notifCheck2 = extras.getString("notifCheck2");
}
handleCommand(intent);
super.onStart(intent, startId);
}
@Override
public int onStartCommand(Intent intent, int flags, int startId) {
Bundle extras = intent.getExtras();
if(extras != null) {
this.lastTime = extras.getString("lastTime");
this.target = extras.getString("target");
this.notifCheck = extras.getString("notifCheck");
this.notifCheck2 = extras.getString("notifCheck2");
}
handleCommand(intent);
// We want this service to continue running until it is explicitly
// stopped, so return sticky.
return START_STICKY;
}
@Override
public IBinder onBind(Intent intent) {
handleCommand(intent);
return null;
}
@Override
public void onRebind(Intent intent) {
super.onRebind(intent);
handleCommand(intent);
}
void handleCommand(Intent intent) {
if (intent == null)
return;
String lastTime = this.lastTime;
String notifCheck = this.notifCheck;
String target = this.target;
String notifCheck2 = this.notifCheck2;
if(lastTime != null && notifCheck != null) {
if(!lastTime.equals("-1") && !notifCheck.equals("1"))
new Notifications(this).InviteUser();
} else this.stopSelf();
if(target != null && notifCheck2 != null) {
if(target.equals("") && !notifCheck2.equals("1"))
new Notifications(this).TargetlessNotification();
} else this.stopSelf();
}
}
|
Q:
Finding modular inverse of every number mod 26?
I am looking at cryptography, and need to find the inverse of every possible number mod 26. Is there a fast way of this, or am i headed to the algorithm every time?
A:
Credit to @lulu's comment above.
List down the coprimes of $26$ smaller than itself: $1,3,5,7,9,11,15,17,19,21,23,25$.
Then calculate the inverse of each one.
Here is a piece of C code that you might find useful:
int Inverse(int n,int a)
{
int x1 = 1;
int x2 = 0;
int y1 = 0;
int y2 = 1;
int r1 = n;
int r2 = a;
while (r2 != 0)
{
int r3 = r1%r2;
int q3 = r1/r2;
int x3 = x1-q3*x2;
int y3 = y1-q3*y2;
x1 = x2;
x2 = x3;
y1 = y2;
y2 = y3;
r1 = r2;
r2 = r3;
}
return y1>0? y1:y1+n;
}
void Run()
{
int arr[] = {1,3,5,7,9,11,15,17,19,21,23,25};
for (int i=0; i<sizeof(arr)/sizeof(*arr); i++)
printf("%d - %d\n",arr[i],Inverse(26,arr[i]));
}
The corresponding output is: $1,9,21,15,3,19,7,23,11,5,17,25$.
You can then use these values as a lookup table whenever you want to get the inverse:
int GetInverseOf26(int n)
{
static int lut[] = {0,1,0,9,0,21,0,15,0,3,0,19,0,0,0,7,0,23,0,11,0,5,0,17,0,25};
return lut[n%26];
}
|
Happy Birthday, KotOR! Thanks For Having Such Great Star Wars
Today is the 10th anniversary of BioWare's classic Star Wars role-playing game Knights of the Old Republic. Happy birthday, KotOR! Thanks for having such great Star Wars.
Let me back up and explain what I mean by that. Last winter I was in New York talking with my boss Stephen about the animated Star Wars TV show The Clone Wars. He was telling me to check it out, and that while it has flaws that cause a lot of people write it off, it still "has some good Star Wars".
I really liked that term, because I instantly, instinctually knew what he meant. It has good Star Wars.
As it turns out, "Good Star Wars" is much easier to say than it is to define.
I brought the idea back up a little while ago in Kotaku group-chat, which led to all manner of discussion and disagreement about which games had "The Best Star Wars." We didn't reach a consensus, but we saw a lot of the usual suspects tossed around: Dark Forces, Jedi Knight II, X-Wing, and of course Knights of the Old Republic.
Owen put in a vote for Jedi Outcast, and Evan and Owen both offered the opinion that while the game itself had problems, The Force Unleashed had some great Star Wars, particularly in the back half. Luke maintains that Dark Forces had the best Star Wars of any Star Wars game. (I totally see what he's saying there.)
We're in murky territory here, given that we're talking about a phrase that I haven't defined all that well. It's not really the same thing as being a good game, right? But I know in my gut what it means to have good Star Wars, and my gut tells me that KotOR had the best Star Wars possible.
I replayed about 10 hours of KotOR a couple of months ago for the first time since I initially played the game five or so years ago. It's remarkable just how well-written and interesting this game is, particularly given how much hysterical Star Wars garbage had been thrown at us starting right around the time the game came out. It's a sign of how far we've fallen that, as I replayed, it felt like a miracle simply to see characters on screen showing believable emotions, learning to overcome their traumatic pasts and trust one another.
Sure, the main narrative was based around a typical Lights Side vs. Dark Side Jedi battle, with the fate of our heroes and the rest of the galaxy hanging in the balance. But it also let us go deep into the nooks and crannies of previously unexplored areas of George Lucas' beloved universe, from the underbelly of a Sith-controlled city to the jungles of the Wookiee homeworld. If that's not good Star Wars, I can't say what is.
But there are still so many points of contention. Can KotOR have good Star Wars if it takes place so far in the past that it's almost irrelevant to the original trilogy? Does Republic Commando have good Star Wars despite the fact that the Force doesn't show up? Mike says that "Republic Commando is more Band of Brothers than Star Wars." OK, but what about Dark Forces, then? Battlefront is a pretty straightforward game, but you get to take down an AT-AT on Hoth. That's gotta be good Star Wars, right?
And what games don't qualify? I'd say kids' games, as well as most stuff based on the prequels, most of the newer junk that treats the Force less as a moral test and more as a competition to see which side has the better magic. That pod-racing game… that didn't really have good Star Wars. Is it possible for a game to have both good and bad Star Wars?
When it comes down to it, the best definition I could come up with was this: It's not so much about whether or not the game is good (though that helps). It's about whether the game makes you feel like, as a fan of Star Wars, you're getting to do and learn some cool Star Wars shit.
So thanks, KotOR, for having some of the best Star Wars I've ever seen in a video game. I just bought the sequel on the Steam sale, and I'm curious how it stacks up. I hear it has pretty good Star Wars, too. (And don't worry, I'll download all the requisite patches and mods.)
In the meantime, I'm just going to take this primed thermal detonator of a topic and set it here for you guys to defuse in the comments. Which games had the best Star Wars? What does that phrase mean to you? And what's the one thing you hope the new Star Wars keepers at Disney can learn from the successes and failures of the past?
Actually, EA milking SWTOR does give me hope for a KOTOR3, as it would them give them masses of new potential content to include in SWTOR, making it a 2-way win for their financial side with a single game.
As much as I enjoyed KOTOR, it's not what I'd consider as having the best "Star Wars". I'd have to go for Rouge Squadron II. When I think of Star Wars, I think of the awesome space battles and this game covers the original trilogy nicely. Just my opinion though.
KOTOR had better Star Wars than the movies, all of them. The movies are enjoyable, but shallow. KOTOR took the cool aspects of the franchise and 'matured' them so to speak, all without the pressure from executives to include things that can be turned into toy lines or spin offs.
I agree. This is why I'm glad that the expanded universe exists; in it developers and writers can delve into certain themes and topics that would have little mainstream appeal. Not everyone wants a deep story; some prefer just enough intellectual and emotional stimulation to keep them entertained for 90 or so minutes. |
CHEAP. Lowdown. Debauched. In the rapidfire about-turn of events, Mohan Deep and his unauthorised biography are being bequeathed with the accusations attributed to the subject of his research—Madhubala.
CHEAP. Lowdown. Debauched. In the rapidfire about-turn of events, Mohan Deep and his unauthorised biography are being bequeathed with the accusations attributed to the subject of his research—Madhubala.
Shammi Kapoor hasn't read the book and has no intention of doing so. But that doesn't stop the man who starred in three movies with Madhubala from lashing out: "Mohan Deep is a swine. You can't cash in on the dead—it is in bad taste. It is a pity that while in America you could be sued for misrepresentation, in India sleaze only gives a shot to sales. That's the reason I believe one should let lying dogs lie. Madhubala, a wonderful person and a dedicated artiste, doesn't deserve this." Incidentally, Kapoor also hasn't been spared and has been shown first as the star's skirt-chaser and then as one spurned for her one great love, Dilip Kumar.
Shammi's views are shared by yesteryear actor, Jairaj, who worked with her in three movies—Rajputani in which Madhubala was a child artiste, Sringaar and Teerandaz. Jairaj remembers her as "one who could be sociable and reserved at the same time. She, who had the finest complexion one had ever seen, had no inhibitions because she was a good looker. Her keenness to learn made it a pleasure working with her. I assure you, she had no complexes and was a very clean girl."
Rejecting all comments pertaining to Madhubala as a maneater, veteran director Shakti Samanta remembers her as one who was "affectionate, extremely punctual and one who loved her family especially her father." However, stepson, singer Amit Kumar prefers to remain tightlipped: "I'm not interested in talking about this.I'm sorry."
Names Madhubala has been called in the past, but never any associated with narcissism and veiled suggestions of nymphomania. "She was certainly not a nymphomaniac; if she was, she wouldn't have been the sort of person she was," contends M.S.M. Desai, one of the privileged film journalists allowed by Atau-llah Khan to visit the sets of his star daughter. "Her father was very strict and since nobody, not even journalists, were allowed into her makeup room, Madhubala had few chances of flirting. Also, Mohan Deep was not around at the time of Madhubala, so how is he capable of writing about her without resorting to hearsay?"
Seconding him is film critic Iqbal Masud: "She was exploited and, unlike Nargis and Meena Kumari, couldn't strike back in a male-dominated film industry. Affairs were inevitable in the comparatively volatile filmworld but the truth is that there is a difference between being a man-puller and a man-chaser."
"Yes, she was aware of her beauty," reminisces B.K. Karanjia, former Film-fare editor and a close friend of both Madhubala and her father. "And because there were so many in love with her, she used to play one against the other. But it was out of innocence rather than shrewd calculation. Madhubala was a child at heart. Her father, Khansaheb, was a dictator but by no means a gambler. He didn't even touch liquor." Film historian Rafique Baghdadi believes that Madhubala's smile bears uncanny resemblance to that of Marilyn Monroe. But, the similarity in all probability ends there. The book meanwhile claims otherwise. And if one doesn't take into consideration what the controversy has cost the various characters, the Magna publication is affordably priced at Rs 150. And the memory of Madhubala continues to pay the steep price of fame.
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# Locally calculated
sha256 c5e2a8e188040fc34eb9362084778a2e25f8d1f888e47a2be09efa7cecd9c70d LICENSE.txt
sha256 d3c8e80bdd1cee0c2f0e60cb7a8a9482b82f651ea069e3a4453ae9a44072a632 checksec-2.2.2.tar.gz
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New Business Brings Jobs to the River Valley
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Affinity Chemical recently broke ground on their new location at Chaffee Crossing in Fort Smith, making it the fourth facility in the U.S.
The manufacturing company specializes in producing liquid aluminum sulfate, which is used in the treatment of drinking and waste water. The chemical is also used in the pulp and paper industries.
Affinity Chemical ships its raw materials by train, making Arkansas a great location to build due to its location in relation to railways.
The company claims to use green technology; causing no enviromental impact.
“At the end of the day we don’t put out any air pollution, we don’t have any water pollution”, said Managing Member Lance Johnson, “We’re not actually hooked up into the sewer so it’s a zero discharge facility that we have.”
7 comments
Steve
duh…your title “New Business Brings Jobs to River Valley” implies more jobs. Your reporter fails to mention how many jobs, job descriptions, average payroll of the new business, etc. Maybe a refresher course on “Who, What, When, and Where” in journalism might be applicable for your reporter.
Horrid
My guess – no more than 10 making about $12/hr. More jobs catering to those who didn’t go to college while those of us who did take the time to go to college and get advanced degrees ship off to other locations.
Mark Smith
Welcome to Arkansas where nepotism reigns supreme along with a gutteral dislike for the educated. Ar is 48+ in the nation in Education and seems bellbent on staying that way. It baffles me that for such a large ppopulation of faithful folks there is a LOT of unscrupulous goings on. It’s -almost like a sport to people here! Ah, forgot; we celebrate HS sports more than education as well. I gotta get with the peogram! :)
Horrid
I played sports and I’m not going to knock the benefits of playing organized team sports in building leadership…
But you’re 100% on the nepotism. It’s like this, keep people who have not been trained on thinking outside the box and they will never rise up and vote you out. Keep them thinking they can’t do any better and they have to trust that you do. That’s why they make sure to cater to the uneducated and unmotivated.
happy happy happy
A volunteer
college degrees don’t make anyone better than the unfortunate that could not afford going to college to work in factories or fast food joints. The only way a degree will help you around here is to get into management or business positions. Thus, having to makes sacrifices and move to apply the degrees for a career. JS
Horrid
With Grants, scholarships, government handouts, and loans nobody is ‘unfortunate’ if they didn’t go to college. It’s an excuse.
And, you’re right, college degrees do not make anyone better than those who didn’t go to college – However, the amount of work and time I’ve spent earning my degrees does make me ‘better’ than the one’s who dicked off while in high school (if they finished), chose not to make the decisions necessary to prepare for college, or a trade school, and then expect fast food joints and Wal-Mart to pay them $18.00/hr as ‘standard pay’.
Just like those who work in factories, I expect jobs to be available to me and expect the city ‘leaders’ to promote an environment suitable for the type of work I do. That’s the issue we’re discussing here. It’s not that we don’t want (or need) factories but we also need to diversify our economy and promote growth in non-manufacturing work for those of us who did go to college for business management, I.T, etc. |
N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials.
This systematic review and meta-analysis of randomized controlled trials (RCTs) examined the efficacy and safety of adjunctive N-acetylcysteine (NAC), an antioxidant drug, in treating major depressive disorder (MDD), bipolar disorder, and schizophrenia. The PubMed, Cochrane Library, PsycINFO, CNKI, CBM, and WanFang databases were independently searched and screened by two researchers. Standardized mean differences (SMDs), risk ratios, and their 95% confidence intervals (CIs) were computed. Six RCTs (n = 701) of NAC for schizophrenia (three RCTs, n = 307), bipolar disorder (two RCTs, n = 125), and MDD (one RCT, n = 269) were identified and analyzed as separate groups. Adjunctive NAC significantly improved total psychopathology (SMD = -0.74, 95% CI: -1.43, -0.06; I2 = 84%, P = 0.03) in schizophrenia, but it had no significant effect on depressive and manic symptoms as assessed by the Young Mania Rating Scale in bipolar disorder and only a small effect on major depressive symptoms. Adverse drug reactions to NAC and discontinuation rates between the NAC and control groups were similar across the three disorders. Adjunctive NAC appears to be a safe treatment that has efficacy for schizophrenia, but not for bipolar disorder or MDD. Further higher quality RCTs are warranted to determine the role of adjunctive NAC in the treatment of major psychiatric disorders. |
Q:
Validating a password input that contains arabic characters using Javascript
I currently validate my english based password field using the following method which contains a regex pattern.
/**
* Validates password based on following rules:
* Must contain a lowercase letter
* Must contain a Uppercase letter
* Must contain a number
* Must be longer than 8 chars
* Can contain special chars
*/
exports.isValidPassword = function (password) {
var pattern = /^(?=.*?[A-Z])(?=.*?[a-z])(?=.*?[0-9]).{8,}$/;
var result = pattern.test(password);
return result;
};
I have a new requirement in which I need to support Arabic languages, how could I accomplish this while still keeping my current rules? I have seen in the past where people put {arabic} in the regex pattern, but I'm not sure if that's the right approach for my case.
A:
[\u0621-\u064A] should match any letter in the Arabic alphabet.
Adding this to the range of allowed characters in your regex should do.
Note that Arabic does not have upper and lower case letters the way the Latin alphabet does, so you will have to think about how to define your password requirements with that in mind.
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Quality of Life after Young Ischemic Stroke of Mild Severity Is Mainly Influenced by Psychological Factors.
Long-term prognosis in terms of quality of life (QoL) in young stroke patients is of importance because they usually have a long life expectancy and extensive daily life demands. We aimed at determining which medical and psychological factors influence the QoL in young stroke patients (<50 years), after long-term follow-up. Young ischemic stroke patients admitted to the St. Elisabeth Hospital and the TweeSteden Hospital, Tilburg, the Netherlands, between 2000 and 2010 were included. One hundred seventy patients and 61 controls filled out the following questionnaires: (1) the Hospital Anxiety and Depression Scale, (2) the Fatigue Assessment Scale, and (3) the shortened World Health Organization Quality of Life scale. Using linear multiple regression analysis, we assessed the factors influencing QoL. QoL did not differ significantly between patients (median modified Rankin Scale score at follow-up, 0) and controls after a mean follow-up of 4.5 (standard deviation, 2.8) years. The presence of excessive fatigue was associated with lower scores on all domains of the QoL (P ≤ .003), but not for general health domain (P = .010). Similarly, depression was associated with worse QoL on the physical (P = .004) and psychological (P = .001) domains and anxiety with lower scores on the psychological (P < .001) QoL domain. No relationship was found between stroke-specific factors and QoL. Fatigue and to a lesser extent depression and anxiety affect the QoL in young adults after ischemic stroke of mild severity. Therefore, young stroke patients should be informed about, screened, and, if possible, treated for fatigue, depression, and anxiety. |
Brief Synopsis – True story of how the newly elected President of South Africa tried to unite his country through the use of the Rugby World Cup.
My Take on it – I have never been a fan of the sport of RUgby and really have no idea how the game is played.
I loved the way tho that this film was able to show how the use of sport can help affect people with differing views and opinions and try and unite them.
We all know in general how much of a grand figure Nelson Mandela was but to watch how this story unfolds shows how his vision of a unified South Africa which went against the mainstream thinking at the time was able to be spring boarded by the National Pride of sport.
Morgan Freeman and Matt Damon are both great here as the tow most influential people of the story and they both show their character’s convictions quite well.
The accents used by them (mostly Damon) seem a bit too much and started getting annoying part of the way through.
I’m aware of the fact that this is a film about sport, yet they show the game of Rugby a bit too much without finding a way to give those unfamiliar with sport a bit of a tutorial along the way.
Clint Eastwood once again shows with this movie that he will foreve be remembered as a great Director before actor.
He was able to put all the pieces together here in such a way that it looks and feels so great to wtach.
The story, cienamtograpy, character’s and of course music all work so well together that these elements make the film even more enjoyable to watch.
I especially love the two main theme songs used for this film: Colorblind and 9,000 Days.
Listen to them here:
Bottom Line – This story shows how sport can be used in more ways than just to have fun. The ideas shown here by Mandela are quite amazing to watch because we can see how much opposition he received while on his quest to unifying his country. Freeman and Damon are both great here, but the accents were a bit off kilting to listen to. They showed a bit too much of the games played which was a bit disconcerting since I don’t quite understand the rules of the game of Rugby. Another Eastwood directorial masterpiece that puts all the pieces together quite well. Great story, cinematography, characters and most of all music make this even more enjoyable to watch. Recommended!
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7 thoughts on “Play To the Whistle Blogathon – Invictus (2009)”
You should have experienced the atmosphere here in South Africa during that final match. It was quite something amazing. During the match, it was amazingly quiet as pretty much every single person was watching this match. |
Q:
How to fix 'undefined method' enum in rspec test with FactoryBot?
I'm trying to test an model I had created for my application, it has association with two other models, also using Factory Bot to build the test, however it does not recognize it, the error return is: Failure/Error: status :pending //// NoMethodError: undefined method 'status' in 'pending' factory.
I'm running the application with Ruby 2.6.1, Rails 5.2.3, FactoryBot 5.0.2, Rspec 3.8. I've tried the different ways to define an enum. I don't know what to do more.
Model:
class CollegeWhitelist < ApplicationRecord
enum status: {pending: 0, approved: 1, rejected: 2}
has_many :users
has_many :colleges
end
Factory:
FactoryBot.define do
factory :college_whitelist do
association :user
association :college
trait :pending do
status :pending
end
trait :approved do
status :approved
end
trait :rejected do
status :rejected
end
end
end
Rspec:
require 'rails_helper'
RSpec.describe CollegeWhitelist, type: :model do
describe "#consistency " do
it 'cannot insert the same user for the same college in permissions' do
@permission = build(:college_whitelist)
p @permission
end
end
end
I was expecting it to pass the test just printing the object at first.
A:
It's a matter of naming clashing.
You must wrap the value of the status column within curly brackets otherwise it'll call itself:
FactoryBot.define do
factory :college_whitelist do
...
trait :pending do
status { :pending }
end
trait :approved do
status { :approved }
end
trait :rejected do
status { :rejected }
end
end
end
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Diagnostic capabilities of exercise testing soon after myocardial revascularization surgery.
The purpose of this investigation was to compare data on early exercise testing for variables known to be of diagnostic/prognostic value following myocardial infarction in post-myocardial revascularization surgery patients. 70 patients were evaluated soon after surgery, by cardiac catheterization, moderate-intensity treadmill exercise testing, and rest and exercise radionuclide angiography. The results indicated no significant differences among groups with satisfactory and unsatisfactory results by catheterization compared for METs, peak heart rate, double product, ST-segment change, angina pectoris, and dysrhythmias. Significant differences were found among groups when rest and exercise ejection fraction and exercise-induced regional wall motion abnormality were taken into account. It was concluded that the moderate-intensity treadmill exercise test was ineffective in differentiating current cardiac function and arterial/graft status among postmyocardial revascularization surgery patients. Exercise radionuclide angiographic studies were able to identify groups of patients with adequate or inadequate postoperative cardiac catheterization results. |
Q:
WM_COPYDATA, PostThreadMessage, and Error 1159
I am trying to send data from one app to another using WM_COPYDATA. Both apps are console and have no window. I can send user messages just fine. When I try to send WM_COPYDATA, and setup the data structure or not, I get error 1159, which basically says I have to send using a synchronous message call... yet there is no SendThreadMessage.
It seems this is a oversight in the api or docs? There seems to be no way to use WM_COPYDATA using only threads without windows?
A:
WM_COPYDATA can only be sent and cannot be posted. Because the payload is marshaled between processes, temporary data structures are created to support that marshaling. They need to be destroyed when the message processing is complete. That implies that the message must be delivered synchronously.
All of this means that you cannot use PostThreadMessage. Instead you will need to create a window to act as the recipient of such messages. Note that this window can be a message-only window and does not need to be visible.
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Islanders players make a commitment to helping those less fortunate
Giving back to the community is a part of the Islanders commitment to Long Island.
Several players have created charity programs that they will participate in during this season, with each contributing to various causes. Josh Bailey, Matt Martin, Matt Moulson, John Tavares, Kyle Okposo and Michael Grabner have either decided to team up with a local or national charity or create their own program which will benefit the Islanders Children’s Foundation.
“Obviously, we are pretty fortunate in life, and I know I’ve been blessed so I just want to give back somehow,” said Islanders forward Martin, who teamed up with Defending the Blue Line this season. “I just think it’s very important for us to give back to people – especially to those people who have done so much for us – and show them that we appreciate them.”
Matt Martin works with Defending the Blue Line to bring a military veteran and his/her child to Islanders games.
Defending the Blue Line gives opportunities to the children of service men and women who normally wouldn’t get the chance to experience certain activities, especially when a parent is overseas fighting in the war. Each home game this season, Martin will host a veteran and their child to enjoy the game, and after the game, each will have the opportunity to meet Matt and get autographs.
“I felt like giving back to some of the people who went over and fought in the war would be a pretty good idea,” Martin said. “I haven’t really met too many people in the war, so it will be interesting for me as well. We’re very lucky to live in a free country, and they’ve been through some really tough times, so I just want them to get to a hockey game with their families and I just want them to enjoy life a little bit.”
Isles forward Josh Bailey is continuing his Bailey’s Buddy program which was created last season. This program invites children who are sick, underprivileged or in need of mentoring for the opportunity to enjoy a game.
“It went really well last year, so I figured, why not do it again,” Bailey said. “I get tickets for every home game for the child to come and they can bring a parent or mentor. They’ll get a gift package for coming to the game, and after the game, they’ll come down to the locker room to meet me for a little bit and get a tour of the locker room.”
He added, “They get to see a lot of the guys, get some autographs and kind of get the whole postgame experience. I think they really enjoy it. There are some children who are already huge Islanders fans and know more about the team than I do, and there are kids that have never seen or played hockey before. There’s always a good mix of children.”
Josh Bailey continues his Bailey's Buddies program, hosting children that are sick, underprivileged or in need of mentoring at Islanders games.
Another player inviting guests to all Islanders home games this season is John Tavares. Like, Bailey’s Buddy Program, Tavares will invite children who are ill, underprivileged or of special needs to come out to the Coliseum for a game. Working with the Special Olympics of Long Island and other local charitable organizations, Tavares will host the children and a family member and give them the opportunity to come down to the locker room postgame.
Moulson, like Martin, has decided to team up with another military charity program. After attending a Wounded Warrior event with his wife, Alicia, they decided they wanted to help the organization any way that they could.
“My wife and I were fortunate enough to attend one of the events this past summer and it was extremely touching,” Moulson said. “We heard some really heartfelt speeches by some of the guys in the program and really learned how the program has helped them.”
After getting a positive response from the Wounded Warrior program, Moulson knew it was the right thing for him to do.
“We really wanted to help the organization because it’s something very important, especially with the people who serve the country and serve all of us,” he said. “Unfortunately, they had to suffer injuries and different mental illnesses, so we really want to pay tribute to them. It will be good to meet them and really get to know a little bit about them.”
Moulson teamed up with a familiar face for his second charity program this season. He and his brother-in-law, Jonathan Quick – goaltender for the Los Angeles Kings – created the 326 Foundation. Last season, Moulson donated to the Islanders Children’s Foundation based upon each goal that he scored, but after talking with Quick and their wives, they decided to build upon last season’s objective.
We decided to team up to raise some more money for the Islanders Children’s Foundation, but also the Kings Care Foundation. We decided on wins for him – hopefully, he gets a lot of them – and goals for me. Hopefully, I get a lot of those, too.- Matt Moulson
“We decided to team up to raise some more money for the Islanders Children’s Foundation, but also the Kings Care Foundation,” Moulson said. “We decided on wins for him – hopefully, he gets a lot of them – and goals for me. Hopefully, I get a lot of those, too.”
For each goal Moulson scores, he will donate $500 to the fund, while Quick will make his own donation for each win he achieves. At the end of the season, the money will be dispersed to both organizations’ children’s foundations. Though Moulson would like to disperse the donations to as many people as possible, he said this fund is just the beginning.
“We would obviously love to help everyone, but it’s hard to get to everyone,” he said. “Right now, we’re concentrating on the kids, but we’ll take it from there and see how it develops over the next few seasons.”
Both Okposo and Grabner will also contribute to the ICF based upon their goal totals. Each will donate $300 for each goal they score. Grabner will be sure to match or go over his team-leading 34 goals last season to help contribute more to the foundation.
No matter the charity or program, Islanders players are always committed to helping the community. If you know of a child or military veteran who would benefit from any of the above programs, please submit their story to Ann.Rina@newyorkislanders.com |
Discovery and development of gliflozins
Gliflozins are a class of drugs in the treatment of type 2 diabetes (T2D). They act by inhibiting sodium/glucose cotransporter 2 (SGLT-2), and are therefore also called SGLT-2 inhibitors. The efficacy of the drug is dependent on renal excretion and prevents glucose from going into blood circulation by promoting glucosuria. The mechanism of action is insulin independent.
Three drugs have been accepted by the Food and Drug Administration (FDA) in the United States; dapagliflozin, canagliflozin and empagliflozin. Canagliflozin was the first SGLT-2 inhibitor that was approved by the FDA, being accepted in March 2013. Dapagliflozin and empagliflozin were accepted in 2014.
Introduction
Role of kidneys in glucose homeostasis
There are at least four members of SLC-5 gene family, which are secondary active glucose transporters. The sodium glucose transporters proteins SGLT-1 and SGLT-2 are the two premier members of the family. These two members are found in the kidneys, among other transporters, and are the main co-transporters there related to the blood sugar. They play a role in renal glucose reabsorption and in intestinal glucose absorption.
Blood glucose is freely filtered by the glomeruli and SGLT-1 and SGLT-2 reabsorb glucose in the kidneys and put it back into the circulation cells. SGLT-2 is responsible for 90% of the reabsorption and SGLT-1 for the other 10%.
SGLT-2 protein
Sodium/glucose co-transporter (SGLT) proteins are bound to the cell membrane and have the role of transporting glucose through the membrane into the cells, against the concentration gradient of glucose. This is done by using the sodium gradient, produced by sodium/potassium ATPase pumps, so at the same time glucose is transported into the cells, the sodium is too. Since it is against the gradient, it requires energy to work. SGLT proteins cause the glucose reabsorption from the glomerular filtrate, independent of insulin.
SGLT-2 is a member of the glucose transporter family and is a low-affinity, high-capacity glucose transporter. SGLT-2 is mainly expressed in the S-1 and S-2 segments of the proximal renal tubules where the majority of filtered glucose is absorbed. SGLT-2 has a role in regulation of glucose and is responsible for most glucose reabsorption in the kidneys.
In diabetes, extracellular glucose concentration increases and this high glucose level leads to upregulation of SGLT-2, leading in turn to more absorption of glucose in the kidneys. These effects cause maintenance of hyperglycemia. Because sodium is absorbed at the same time as glucose via SGLT-2, the upregulation of SGLT-2 probably leads to development or maintenance of hypertension. In study where rats were given either ramipril or losartan, levels of SGLT-2 protein and mRNA were significantly reduced. In patients with diabetes, hypertension is a common problem so this may have relevance in this disease.
Drugs that inhibit sodium/glucose cotransporter 2 inhibit renal glucose reabsorption which leads to enhanced urinary glucose excretion and lower glucose in blood. They work independently of insulin and can reduce glucose levels without causing hypoglycemia or weight gain.
Discovery
It was originally thought that diabetes mellitus was a renal disorder because of the glucose found in the urine. Once insulin was discovered the focus of diabetes management was on the pancreas. Traditional focuses of therapeutic strategies for diabetes have been to enhance endogenous insulin secretion and to improve insulin sensitivity. In the previous decade the role of the kidney in the development and maintenance of high glucose levels has been examined. The role of the kidney led to the development of drugs that inhibit the sodium/glucose transporter 2 protein. Every day approximately 180 grams of glucose are filtered through the glomeruli and lost into the primary urine in healthy adults, but more than 90% of the glucose that is initially filtered is reabsorbed by a high capacity system controlled by SGLT-2 in the early convoluted segment of the proximal tubules. Almost all remaining filtered glucose is reabsorbed by sodium/glucose transporter 1 so under normal circumstances almost all filtered glucose will be reabsorbed and less than 100 mg of glucose finds its way into the urine of non-diabetic individuals.
Phlorizin
Phlorizin is a compound that has been known for over a century. It is a naturally occurring botanical glucoside that produces renal glucosuria and blocks intestinal glucose absorption through inhibition of the sodium/glucose symporters located in the proximal renal tubule and mucosa of the small intestine. Phlorizin was first isolated in 1835 and was subsequently found to be a potent but rather non-selective inhibitor of both SGLT-1 and SGLT-2 proteins.
Phlorizin seemed to have very interesting properties and the results in animal studies were encouraging, it improved insulin sensitivity and in diabetic rat models it seemed to increase glucose levels in urine and also normal glucose concentration in plasma occurred without hypoglycemia. Unfortunately, in spite of these properties, phlorizin was not suitable enough for clinical development for several reasons. Phlorizin has very poor oral bioavailability as it is broken down in the gastrointestinal tract, so it has to be given parenterally. Phloretin, the active metabolite of phlorizin, is a potent inhibitor of facilitative glucose transporters and phlorizin seems to lead to serious adverse events in the gastrointestinal tract like diarrhea and dehydration. Because of these reasons, phlorizin was never pursued in humans.
Although phlorizin was not suitable for further clinical trials, it served an important role in the development of SGLT-2 inhibitors. It served a basis for the recognition of SGLT inhibitors with improved safety and tolerability profiles. For an example, the SGLT inhibitors are not associated with gastrointestinal adverse events and the bioavailability is much greater.
Inhibition of SGLT-2 results as better control of glucose level, lower insulin, lower blood pressure and uric acid levels and augments calorie wasting. Some data supports the hypothesis that SGLT-2 inhibition may have direct renoprotective effects. This includes actions to attenuate tubular hypertrophy and hyperfiltration associated with diabetes and to reduce the tubular toxicity of glucose. Inhibition of SGLT-2 following treatment with dapagliflozin reduces the capacity for tubular glucose reabsorption by approximately 30–50%.
Drug development
Phlorizin consists of glucose moiety and two aromatic rings (aglycone moiety) joined by an alkyl spacer. Initially, phlorizin was isolated for treatment of fever and infectious diseases, particularly malaria. According to Michael Nauck and his partners, studies were made in the 1950s on phlorizin that showed that it could block sugar transport in the kidney, small intestine, and a few other tissues. In the early 1990s, sodium/glucose cotransporter 2 was fully characterized, so the mechanism of phlorizin became of real interest. In later studies it was said that sugar-blocking effects of phlorizin was due to inhibition of the sodium/glucose cotransporter proteins.
Most of the reported SGLT-2 inhibitors are glucoside analogs that can be tracked to the o-aryl glucoside found in the nature. The problem with using o-glucosides as SGLT-2 inhibitors is instability that can be tracked to degradation by β-glucosidase in the small intestine. Because of that, o-glucosides given orally have to be prodrug esters. These prodrugs go through changes in the body leading to carbon–carbon bond between the glucose and the aglycone moiety so c-glucoside are formed from the o-glucosides. C-glucosides have a different pharmacokinetic profile than o-glucosides (e.g. half life and duration of action) and are not degraded by the β-glucosidase. The first discovered c-glucoside was the drug dapagliflozin. Dapagliflozin was the first highly selective SGLT-2-inhibitor approved by the European Medicines Agency. All SGLT-2 inhibitors in clinical development are prodrugs that have to be converted to its active ‘A’ form for activity.
T-1095
Because Phlorizin is a nonselective inhibitor with poor oral bioavailability, a phlorizin derivative was synthesised and called T-1095. T-1095 is a methyl carbonate prodrug that is absorbed into the circulation when given orally, and is rapidly converted in the liver to the active metabolite T-1095A. By inhibiting SGLT-1 and SGLT-2, urinary glucose excretion increased in diabetic animals. T-1095 did not proceed in clinical development, probably because of the inhibition of SGLT-1 but non-selective SGLT inhibitors may also block glucose transporter 1 (GLUT-1). Because 90% of filtered glucose is reabsorbed through SGLT-2, research has focused specifically on SGLT-2. Inhibition of SGLT-1 may also lead to the genetic disease glucose-galactose malabsorption, which is characterized by severe diarrhea.
ISIS 388626
According to preliminary findings of a novel method of SGLT-2 inhibition, the antisense oligonucleotide ISIS 388626 improved plasma glucose in rodents and dogs by reducing mRNA expression in the proximal renal tubules by up to 80% when given once a week. It did not affect SGLT-1. A study results on long-term use of ISIS 388626 in non-human primates observed more than 1000 fold increase in glucosuria without any associated hypoglycemia. This increase in glucosuria can be attributed to a dose-dependent reduction in the expression of SGLT-2, where the highest dose led to more than 75% reduction. In 2011, Ionis Pharmaceuticals initiated a clinical phase 1 study with ISIS-SGLT-2RX, a 12-nucleotide antisense oligonucleotide. Results from this study were published in 2017 and the treatment was "was associated with unexpected renal effects". The authors concluded that "Before the concept of antisense-mediated blocking of SGLT2 with ISIS 388626 can be explored further, more preclinical data are needed to justify further investigations."
Activity of SGLT-2 inhibitors in glycemic control
Michael Nauck recounts that meta-analyses of studies about the activity of SGLT-2 inhibitors in glycemic control in type 2 diabetes mellitus patients shows improvement in the control of glucose, when compared with placebos, metformin, sulfonylurea, thiazolidinediones, insulin and more. The HbA1c was examined after SGLT-2 inhibitors were given alone (as monotherapy) and as an add-on therapy to the other diabetes medicines. The SGLT-2 inhibitors that were used were dapagliflozin and canagliflozin and others in the same drug class. The meta-analysis was taken together from studies ranging from period of few weeks up to more than 100 weeks.
The results, summed up, were that 10 mg of dapagliflozin showed more effect than placebo in the control of glucose, when given for 24 weeks. However, no inferior efficacy of 10 mg dapagliflozin was shown when used as an add-on therapy to metformin, compared with glipizide after use for 52 weeks. 10 mg of dapagliflozin showed neither inferior efficacy compared with metformin when both of the medicines were given as monotherapy for 24 weeks.
The results from meta-analysis when canagliflozin was examined, showed that compared to a placebo, canagliflozin affects HbA1c. Meta-analysis studies also showed that 10 mg and 25 mg of empagliflozin, improved HbA1c compared with a placebo.
Structure-activity relationship (SAR)
The aglycones of both phlorizin and dapagliflozin have weak inhibition effects on SGLT-1 and SGLT-2. Two synergistic forces are involved in binding of inhibitors to SGLTs. Different sugars on the aglycone will affect and change the orientation of it in the access vestibule because one of the forces involved in the binding is the binding of sugar to the glucose site. The other force is the binding of the aglycone, which affects the binding affinity of the entire inhibitor.
The discovery of T-1095 led to an investigation of how to enhance potency, selectivity and oral bioavailability by adding various substituents to the glycoside core. As an example we can take the change of o-glycosides to c-glycosides by creating a carbon–carbon bond between the glucose and the aglycone moiety. C-glucosides are more stable than o-glucosides which leads to modified half life and duration of action. These modifications have also led to more specificity to SGLT-2. C-glucosides that have heterocyclic ring at the distal ring or proximal ring are better when it comes to anti-diabetic effect and physicochemical features all together. C-glucoside bearing thiazole at the distal ring on dapagliflozin has shown good physicochemical properties that can lead to a clinical development, but still has the same anti-diabetic activity as dapagliflozin, as shown in tables 1 and 2.
Song and his partners did preparate thiazole compound by starting with carboxyl acid. Working with that, it took them three steps to get a compound like dapagliflozin with a thiazole ring. Inhibitory effects on SGLT-2 of the compounds were tested by Song and his partners. In tables 1, 2, and 3, the IC50 value changes depending on what compound is in the ring position, in the C-4 region of the proximal phenyl ring, and how the thiazole ring relates.
Many compounds gave different IC50 value in the ring position in an in vitro activity. For an example there was a big difference if there was an n-pentyl group (IC50 = 13,3 nM), n-butyl (IC50 = 119 nM), phenyl with 2-furyl (IC50 = 0,720) or 3-thiophenyl (IC50 = 0,772). As seen in table 1, the in vitro activity increases depending on what compound is bonded to the distal ring (given that in the C-4 region of the proximal phenyl ring is a Cl atom).
Table 1: Differences in in vitro activity depending on which compound is bonded to the distal ring.
*comparator to ethyl group (IC50 = 16,7)
In table 2, the in vitro activity changes depending on the compound in the C-4 region of the proximal phenyl ring (X). Small methyl groups or other halogen atoms in the C-4 position gave IC50 ranging from 0.72–36.7 (given that the phenyl with 2-furyl is in the ring position).
Table 2: Differences in in vitro activity depending on what compound is in the C-4 region of the proximal phenyl ring.
Table 3: Difference in the IC50 value depending on how the thiazole ring relates (nothing else is changed in the structure (X = Cl, R = phenyl with 2-furyl).
See also
Sodium-glucose transport proteins
SLC5A2
SGLT1
SGLT2
Dapagliflozin
Empagliflozin
Canagliflozin
Ipragliflozin
References
Gliflozins |
package org.ovirt.engine.core.bll.storage.disk;
import java.util.ArrayList;
import java.util.Collections;
import java.util.List;
import javax.inject.Inject;
import org.ovirt.engine.core.bll.QueriesCommandBase;
import org.ovirt.engine.core.bll.context.EngineContext;
import org.ovirt.engine.core.common.businessentities.VmDeviceId;
import org.ovirt.engine.core.common.businessentities.storage.BaseDisk;
import org.ovirt.engine.core.common.businessentities.storage.Disk;
import org.ovirt.engine.core.common.businessentities.storage.DiskImage;
import org.ovirt.engine.core.common.businessentities.storage.DiskStorageType;
import org.ovirt.engine.core.common.businessentities.storage.DiskVmElement;
import org.ovirt.engine.core.common.queries.IdQueryParameters;
import org.ovirt.engine.core.dao.DiskDao;
import org.ovirt.engine.core.dao.DiskImageDao;
import org.ovirt.engine.core.dao.DiskVmElementDao;
public class GetAllDisksByVmIdQuery<P extends IdQueryParameters> extends QueriesCommandBase<P> {
@Inject
private DiskDao diskDao;
@Inject
private DiskVmElementDao diskVmElementDao;
@Inject
DiskImageDao diskImageDao;
public GetAllDisksByVmIdQuery(P parameters, EngineContext context) {
super(parameters, context);
}
@Override
protected void executeQueryCommand() {
List<Disk> allDisks = diskDao.getAllForVm(getParameters().getId(), getUserID(), getParameters().isFiltered());
List<Disk> disks = new ArrayList<>();
for (Disk disk : allDisks) {
if (disk.getDiskStorageType() == DiskStorageType.IMAGE
|| disk.getDiskStorageType() == DiskStorageType.CINDER
|| disk.getDiskStorageType() == DiskStorageType.MANAGED_BLOCK_STORAGE) {
DiskImage diskImage = (DiskImage) disk;
diskImage.getSnapshots().addAll(diskImageDao.getAllSnapshotsForLeaf(diskImage.getImageId()));
}
DiskVmElement dve = getDiskVmElement(disk);
if (dve != null) {
disk.setDiskVmElements(Collections.singletonList(dve));
disks.add(disk);
}
}
getQueryReturnValue().setReturnValue(disks);
}
private DiskVmElement getDiskVmElement(BaseDisk disk) {
return diskVmElementDao.get(new VmDeviceId(disk.getId(), getParameters().getId()));
}
}
|
Q:
How do I get the RSA* object from a char array that contains the public key in OpenSSL?
Im trying to encrypt and decrypt messages while storing the private and public keys on char vectors. I have tried d2i_PublicKey(...) and using EVP_PKEY objects in EVP_set1_RSA(...). I also do not know what are all the parameters in EVP_set1_RSA(...). Please help. Here is my code:
#include <stdio.h>
//RSA
#include <openssl/rsa.h>
#include <openssl/pem.h>
#include <openssl/err.h>
#include <arpa/inet.h>
#include <openssl/evp.h>
#include <openssl/bio.h>
#include <openssl/x509.h>
#define RSA_KEY_LENGTH 2048
#define PUB_EXP 3
#define PRINT_KEYS
//RSA
int main()
{
printf("\ngenerating keys...\n");
RSA *keypair = RSA_generate_key(RSA_KEY_LENGTH, PUB_EXP, NULL, NULL);
// ---------
printf("Converting Keys to char array..\n");
char *pri_key = NULL; // Private key
char *pub_key = NULL; // Public key
size_t pri_len; // Length of private key
size_t pub_len; // Length of public key
BIO *pri = BIO_new(BIO_s_mem());
BIO *pub = BIO_new(BIO_s_mem());
PEM_write_bio_RSAPrivateKey(pri, keypair, NULL, NULL, 0, NULL, NULL);
PEM_write_bio_RSAPublicKey(pub, keypair);
pri_len = BIO_pending(pri);
pub_len = BIO_pending(pub);
pri_key = (char*)malloc(pri_len + 1);
pub_key = (char*)malloc(pub_len + 1);
BIO_read(pri, pri_key, pri_len);
BIO_read(pub, pub_key, pub_len);
pri_key[pri_len] = '\0';
pub_key[pub_len] = '\0';
// ---------
char msg[RSA_KEY_LENGTH/8] = "HOLA, ESPERO QUE ME ENCRIPTES";
char *encrypt = NULL; // Encrypted message
char *decrypt = NULL; // Decrypted message
printf("encrypting: %s\n", msg);
/*
* Here I want to obtain an RSA *PublicKey to use it for the encryption
*/
int encrypt_len;
err = (char*)malloc(130);
printf("++++\n");
if((encrypt_len = RSA_public_encrypt(strlen(msg), (unsigned char*)msg, (unsigned char*)encrypt, PublicKey, RSA_PKCS1_OAEP_PADDING)) == -1) {
printf("err++++\n");
ERR_load_crypto_strings();
ERR_error_string(ERR_get_error(), err);
fprintf(stderr, "Error encrypting message: %s\n", err);
}
return 0;
}
A:
I've found a solution to this issue among other Stack-Overflow posts and namely here :Reading Public/Private Key from Memory with OpenSSL
The answer you waere looking for is answered by @SquareRootOfTwentyThree is his last line of code,
After extracting the Public key into a BIO variable called pub:
PEM_write_bio_RSAPublicKey(pub, keypair);
create a RSA variable and put pub inside it:
RSA *keypair2 = NULL;
PEM_read_bio_RSAPublicKey( pub, &keypair2, NULL, NULL);
After you've done this you can successfully encrypt the message as usual, using keypair2:
Encryption:
encrypt = (char*)malloc(RSA_size(keypair));
int encrypt_len;
err = (char*)malloc(130);
if((encrypt_len = RSA_public_encrypt(strlen(msg)+1, (unsigned char*)msg, (unsigned char*)encrypt, keypair2 ,RSA_PKCS1_OAEP_PADDING)) == -1) {
ERR_load_crypto_strings();
ERR_error_string(ERR_get_error(), err);
fprintf(stderr, "Error encrypting message: %s\n", err);
}
you can then decrypt it as usual, using the original keypair, without having to use it at your first encryption
Decryption:
decrypt = (char*)malloc(encrypt_len);
if(RSA_private_decrypt(encrypt_len, (unsigned char*)encrypt, (unsigned char*)decrypt, keypair, RSA_PKCS1_OAEP_PADDING) == -1) {
ERR_load_crypto_strings();
ERR_error_string(ERR_get_error(), err);
fprintf(stderr, "Error decrypting message: %s\n", err);
}
This might help if you want to transfer the "pub" variable over a network, use it to encrypt a message, then send the encrypted data back to the original machine to get it decrypted.
If you really want to use char variables, as you said in your question, you can of course copy the memory as raw to a char variable (from the BIO one) using memcpy, but don't forget to add the "\0" at the end, here, this post should help: Separating public and private keys from RSA keypair variable
|
Process the flour, sugar, and butter in a food processor until the mixture resembles fine breadcrumbs. While the motor is running, add just enough iced water to the mixture so that it forms a smooth dough and process until just combined. Wrap the dough in plastic wrap and refrigerate for at least 30 minutes.Roll the pastry out on a lightly floured surface until it is 2-3 mm thick (or desired thickness for your recipe) and line the tart tin (this recipe makes enough pastry to sufficiently line a 26cm tart tin).Preheat the oven to 180°C. Place a piece of baking paper over the pastry and fill with baking weights or uncooked rice or beans. Bake for 10 minutes then remove the weights. Bake uncovered for another 10 minutes or until the pastry is golden.Spoon in your desired filling and bake as your recipe indicates.
Some notes…The first time I made this pastry I found it shrunk away from the edges of the pie dish and didn’t crisp up as much as I would have liked. I think this happened because I added too much water. There are other factors that can cause your pastry to shrink, so here are just a few pointers to keep in mind when making your pastry:- You need to keep the pastry cold – use ice water and make sure your pastry rests in the fridge for at least 30 minutes before rolling out. Placing the tin coated with the pastry back into the fridge before baking for a bit is a good idea too :)- You could leave an extra 1–2 cm of pastry above the top of the tin and cut this off once you have baked it.- Only use as much water that is needed to combine your mixture together. |
Q:
Troubleshooting GFCI Outlet Tripping
Recently, the GFCI outlet that "powers" our back patio has started tripping. Initially, I thought the outlet was old since this only started recently (and we use our patio regularly), so I replaced it with a new one, but it still trips -- sometimes within seconds, sometimes after 10 minutes or so.
Downstream from the GFCI are two outdoor ceiling fans and three standard outlets. I've unplugged everything from the outlets and switched the fans and lights on the ceiling fans off. However, the GFCI still trips.
All three outlets + GFCI outlet have bubble covers on them.
Wiring runs like this:
Breaker --> light switch (inside) --> GFCI outlet (outside) --> 3 outlets / 2 fans
(All outdoor wires are run through PVC or metal conduit.)
At this point, my guess is that I have a short somewhere. Question is: is there a best way to troubleshoot this? I'd rather not have to take down the fans to determine if they're the cause, but if that's what I have to do, so be it. Also, is there an obvious reason why the trip sometimes happens immediately but sometimes after a few minutes?
My plan is to disconnect the load lines from the GFCI and see if it still trips. My assumption, however, is that it won't and I'll have to work down the line to see where the fault is.
A:
First, a GFCI is designed to warn not of short circuits, but of leakage (a "small", but potentially fatal, current flowing from the hot wire to the metal shell of an appliance). By tripping, it is warning you that an appliance, either directly wired into the downstream circuit or plugged into that outlet or an outlet downstream, has a ground fault, i.e. leakage.
It may take longer for a small ground fault to trip the GFCI. Another reason for the delay may be that a motor is turned on or off, since that can cause an inductive surge, erroneously tripping the GFCI.
The easiest way to find where that leakage occurs is to disconnect one item at a time, starting at the distal end, i.e. the fans. First switch them off, reset the GFCI, and wait to see if that fixes the issue. If that does not stop the tripping then shut the mains circuit breaker, open the fan junction boxes and disconnect them (put a wire nut on the dangling hot wire), close the mains breaker and retest the GFCI.
If removing everything after the GFCI does not prevent tripping, then water may be getting into the outdoor outlet or junction box, causing the issue.
Once you find the item tripping the GFCI, check if water is getting into it, rather than assuming the appliance is defective.
|
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is the first derivative of i(l) wrt l?
164*l**3
Let l(x) be the first derivative of 7 + 0 + 9 - 3*x - 4*x**2 - 6. Differentiate l(o) with respect to o.
-8
Suppose 3*x = -4*h - 3, 0 = -4*h + 2*h - 2*x - 4. Find the third derivative of -23*u**2 - 6*u**4 - 5712*u**3 - 28*u**2 + 5707*u**h wrt u.
-144*u - 30
Let m(d) = -118*d**2 - 207*d + 18. Let x(c) = 60*c**2 + 103*c - 10. Let b(j) = -4*m(j) - 7*x(j). What is the second derivative of b(u) wrt u?
104
Suppose 0 = 2*x + a + 66, x - 6*x - 3*a = 164. Let g = 42 + x. Find the second derivative of g*w + 0*w**3 + 2*w**3 - 2*w**3 - 3*w**5 wrt w.
-60*w**3
Let b(u) be the first derivative of 4/3*u**6 + 3*u**2 - 12 + 0*u**4 + 0*u + 0*u**5 + 0*u**3. What is the second derivative of b(w) wrt w?
160*w**3
Suppose 0 = -4*t - 5 - 11. Let n(v) = 35*v**2 + 7*v + 23. Let f(r) = -18*r**2 - 4*r - 11. Let w(c) = t*n(c) - 7*f(c). Differentiate w(d) with respect to d.
-28*d
Let b(m) = -8*m + 20. Let d be b(-4). Find the third derivative of 8768 - 8768 + 13*h**2 - d*h**5 wrt h.
-3120*h**2
Let o(y) = -2*y - 8. Let n be o(-5). Suppose -n*h - h + 18 = 0. Find the third derivative of -p**3 + 6*p**3 + h*p**3 - 2*p**3 + 5*p**2 wrt p.
54
Let c(z) be the third derivative of -z**9/3024 + z**5/10 - 3*z**4/8 + 9*z**2. Let h(o) be the second derivative of c(o). Differentiate h(d) wrt d.
-20*d**3
Differentiate -46*u**2 - 123*u**2 + 154 - 14*u**2 with respect to u.
-366*u
Let v(l) be the first derivative of 14 + 7*l**2 + 1/4*l**4 + 0*l**3 + 0*l. Find the second derivative of v(u) wrt u.
6*u
Let c(b) = -b**3 - b**2 - b - 1. Let j(m) = -259*m**3 - 6*m**2 - 6*m - 284. Let n(w) = -6*c(w) + j(w). What is the first derivative of n(g) wrt g?
-759*g**2
Let o(g) be the second derivative of g**6/10 + 27*g**5/20 - 11*g**4/12 + 23*g. Find the third derivative of o(q) wrt q.
72*q + 162
Let o(h) be the third derivative of -h**8/336 + 41*h**7/210 - h**4/24 - 110*h**3/3 - 244*h**2. What is the second derivative of o(y) wrt y?
-20*y**3 + 492*y**2
Let i(g) be the first derivative of 4*g**3/3 - 3*g**2 - 133*g + 204. What is the first derivative of i(j) wrt j?
8*j - 6
Let o(j) be the third derivative of -2*j + 0 - 13/60*j**5 + 0*j**3 - 5/24*j**6 + 9*j**2 + 0*j**4. Find the third derivative of o(p) wrt p.
-150
Let m(f) = f**2 + 7*f + 6. Let w be m(-5). Let x be (-16 - -12)*2/w. What is the second derivative of 2*i - x*i**4 + 4*i**4 + 5*i - 3*i**4 wrt i?
-12*i**2
What is the derivative of 3 + 25 + 73*q + 4 + 9 wrt q?
73
Find the third derivative of -894*s**2 - 60*s**3 + 1136*s**2 - 75*s**3 wrt s.
-810
Let o(j) be the first derivative of -48/5*j**5 - j**2 + 0*j**4 - 48 - 2*j + 0*j**3. What is the second derivative of o(r) wrt r?
-576*r**2
Let t(b) be the first derivative of b**4/4 - b**3/3 - 22*b**2 - 49. Find the second derivative of t(o) wrt o.
6*o - 2
Let l(g) be the first derivative of -g**7/6 + 5*g**4/12 - 18*g + 28. Let w(u) be the first derivative of l(u). Find the third derivative of w(x) wrt x.
-420*x**2
Let d(p) = p**3 + 7*p**2 + p + 1. Let s be d(-7). Let m be (-3)/s - 5/(-2). Find the third derivative of -2*j**m + 3*j**3 + j**2 + j**2 wrt j.
6
Suppose -24 = -8*b - 0*b. Find the second derivative of -9*x + 8*x + 2*x**b + 12*x**3 + x**3 wrt x.
90*x
Let p(j) = -10*j**3 - 80*j**2 - 237. Let h(n) = -8*n**3 - 73*n**2 - 238. Let k(v) = 6*h(v) - 5*p(v). Find the first derivative of k(m) wrt m.
6*m**2 - 76*m
Let d(y) = -77*y**2 + 70*y - 7. Let v(s) = 76*s**2 - 69*s + 6. Let q(i) = -6*d(i) - 7*v(i). What is the second derivative of q(b) wrt b?
-140
Let i(p) be the first derivative of 3*p**4/4 + 2*p**3 + 55*p**2/2 - 19. Find the second derivative of i(g) wrt g.
18*g + 12
Differentiate 17 - 33*c**2 - 8*c**2 + c**3 - 27*c**2 + 15 + 15*c**2 with respect to c.
3*c**2 - 106*c
Differentiate 86 + 27 + 66 + 35 - 84*d - 16 wrt d.
-84
What is the third derivative of v**4 + 26*v**2 - 40*v**2 - 71 + 67 + 2*v**3 wrt v?
24*v + 12
What is the first derivative of 241 - 13*c + 270*c - 42*c + 204*c wrt c?
419
Let x(p) be the second derivative of 0*p**2 + 0 - 31/20*p**5 + 28*p + 9/2*p**3 + 0*p**4. What is the second derivative of x(l) wrt l?
-186*l
Let t be 0 + -1 - (-13 - -10). Suppose x + 0*x = t. What is the first derivative of -5 + 0 - x*i + 2 wrt i?
-2
Let x(y) = 466*y**4 - 16*y**3 + 16*y**2 - 366. Let j(w) = 155*w**4 - 5*w**3 + 5*w**2 - 122. Let o(l) = 16*j(l) - 5*x(l). Differentiate o(h) wrt h.
600*h**3
Let t be 34*4/(-8)*-1. Suppose 1 = 2*k + s - 10, 0 = -5*k + s + t. Find the second derivative of 2*c**k + 6*c - 12*c**2 + 12*c**2 + 5*c wrt c.
24*c**2
Let l(t) be the third derivative of 0 + 0*t**6 - 17/24*t**4 + 0*t + 26*t**2 + 0*t**3 - 2/21*t**7 + 0*t**5. What is the second derivative of l(f) wrt f?
-240*f**2
Find the first derivative of 146*z**2 + 142 - 300*z**2 + 43 - 147*z**2 wrt z.
-602*z
What is the third derivative of 31*p + 36*p**5 - 15*p + 101*p**2 - 16*p wrt p?
2160*p**2
Let c(d) = 142*d**3 + 11*d**2 + 11. Let j(a) = 283*a**3 + 23*a**2 + 22. Let o(u) = 9*c(u) - 4*j(u). Find the third derivative of o(h) wrt h.
876
Let t = 5 + -1. Suppose t*b - 70 = -5*r, 5*b - 5 = 4*r - 2*r. What is the derivative of 8 + 6*p**2 - r*p**2 + 14*p**3 + 4*p**2 wrt p?
42*p**2
What is the third derivative of 58*b**5 - 5*b**5 - 5*b**3 - 103*b**2 + 3*b**3 - 37*b**2 wrt b?
3180*b**2 - 12
Let v(f) = -f**2 - 10*f - 14. Let q be v(-8). What is the third derivative of -41*b**6 - 2*b**5 + 12*b**6 + q*b**5 - 32*b**2 wrt b?
-3480*b**3
What is the third derivative of 135*z**5 - 274889*z**3 + 274889*z**3 - 203*z**2 wrt z?
8100*z**2
Let p(z) = -75*z**3 + 8*z**2 + 2694*z. Let y(s) = 18*s**3 - 2*s**2 - 673*s. Let h(x) = -2*p(x) - 9*y(x). Find the second derivative of h(o) wrt o.
-72*o + 4
Let g = -15 + 19. Suppose -g*v - 7*s + 2*s = -20, s = v - 5. Find the second derivative of -v*r + 1 + 2*r**4 - 1 - 4*r**4 wrt r.
-24*r**2
Suppose -d = -4 - 0. Let b = 2 + 11. Find the second derivative of -b*l**4 + 3*l - 11*l + 15*l**d wrt l.
24*l**2
Let o(b) be the third derivative of 4*b**7/7 - 395*b**4/24 + 298*b**2. What is the second derivative of o(w) wrt w?
1440*w**2
Suppose -4*h + 4 = -3*h. Find the second derivative of -15*x - 22*x**4 - 12*x**h + 24*x - 26*x wrt x.
-408*x**2
Let g(h) be the second derivative of 9*h**7/7 - h**6/10 + 53*h**3/6 - 2*h + 131. What is the second derivative of g(p) wrt p?
1080*p**3 - 36*p**2
Let v = -524 - -530. Let q(k) be the second derivative of 0*k**3 + 0*k**4 + 2/15*k**v + 0 - 4*k - 2*k**2 + 0*k**5. Differentiate q(h) with respect to h.
16*h**3
Let f = -723 - -728. Let c(q) be the second derivative of 0*q**f + 3/4*q**4 + 0 + 0*q**2 + 0*q**3 - 3/10*q**6 - q. What is the third derivative of c(t) wrt t?
-216*t
Find the first derivative of -185 + 15*g**4 + 344*g**2 + 2*g**4 + 347*g**2 - 692*g**2 wrt g.
68*g**3 - 2*g
Let b(o) = 3*o**2 + 6*o - 6. Let q be b(-4). What is the third derivative of -7*v**4 + 137*v**5 + 3*v**2 - 138*v**5 - 4*v**4 - q*v**2 wrt v?
-60*v**2 - 264*v
Let a(y) = 3*y**3 + 2*y + 12. Let k(m) = 11*m + 9*m**3 + 35 + 5*m**3 + 26. Let f(q) = -11*a(q) + 2*k(q). Differentiate f(p) with respect to p.
-15*p**2
Let n(u) be the first derivative of -89*u**5/5 + 77*u**2/2 + 108. What is the second derivative of n(y) wrt y?
-1068*y**2
Differentiate 122 - 9*j - j + 358 - 97*j - j**2 with respect to j.
-2*j - 107
What is the second derivative of -10*l**5 - 3*l**4 + 17*l**4 + 1201*l - 1538*l wrt l?
-200*l**3 + 168*l**2
Let q(y) = y**2 + 13*y + 14. Let a be q(-10). Let b = a - -16. Find the second derivative of z - 5*z**2 + b*z + z wrt z.
-10
Let a(z) = z**3 - 2*z + 3. Let d be a(3). Differentiate 6 + 22*p - d*p + 1 wrt p.
-2
Let k(r) be the second derivative of -2/5*r**6 + 0*r**2 + 0*r**3 - 8*r + 0*r**5 - 4/3*r**4 + 0. Find the third derivative of k(j) wrt j.
-288*j
Find the first derivative of 9*v + 1216 + 1102 - 2612 wrt v.
9
Let i(m) = 68*m**2 - 11*m + 47. Let c(y) = -34*y**2 + 6*y - 23. Let s = -43 + 49. Let z(r) = s*i(r) + 11*c(r). Differentiate z(q) with respect to q.
68*q
Let b = -10 + 13. Suppose 2*d + 3*d = s + 29, b*s = -3*d + 3. What is the second derivative of 0 - d*m**2 - 5 + 5 + m wrt m?
-10
Let a(u) be the second derivative of -541*u**5/20 - 85*u**2 - 740*u. Differentiate a(p) with respect to p.
-1623*p**2
Let y(f) be the second derivative of -5*f**6/3 + f* |
The beekeeper who saved the Pink ODI
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Johannesburg – Pierre Hefer was at home in Emmarentia, a suburb 20 minutes west of the Wanderers, quietly watching the third ODI between South Africa and Sri Lanka on TV on Saturday when a swarm of bees halted play. “When they took out the fire extinguisher, I knew I had to get down here,” Hefer said in impromptu interview at the ground. “You see, you might get rid of them for a bit, but they’ll come back, I thought they might be able to use my expertise.” Hefer got into his full bee-keeping regalia - white overalls and black gumboots - grabbed all his equipment, including a honeycomb and some home-made hives, and headed to the ground. He managed to get around the normally tight security around the Wanderers, passing cops who normally demand a parking ticket and even got into the ground without a ticket or any form of accreditation.
“I think they saw me in this outfit, noticed all the equipment and reckoned I must be what I say I am, and with play stopped, they let me in.
“It’s actually the quickest I’ve ever gotten from the top of Corlett Drive (the road which runs past the ground at the southern end) to the stadium before. It was harder to get through the crowds who were outside because there was no play,” said Hefer.
Attempts by ground staff - and also one enthusiastic member of SuperSport’s production crew – to get rid of the bees using a fire extinguisher proved useless, as did the temptation of a can of Coke in a bucket.
Hefer, using his skills and the home-made hive, attracted the bees into a large plastic tub before removing most of the swarm from the field. “When I was watching on TV, and they had surrounded that helmet (that of SA wicket-keeper Quinton de Kock), I thought it might be as much as 5 000 bees. But when I got here, it looked more like 1 000 to 2 000.”
Hefer said the bees may have been disturbed at a different location earlier in the week and then relocated to the Wanderers. “It would have been quieter on Wednesday, but then today you’ve got a game going on, all these people here and obviously they’re not welcome. They can be quite stubborn too.”
Hefer stated emphatically that bees were not attracted by the colour pink, which was prevalent at the Wanderers on Saturday as part of an initiative to raise awareness about cancer.
With most of the bees removed, play was able to resume after an interval of one hour. Hefer received a huge cheer for his efforts from a crowd numbering close to 30 000 people. “Yup, definitely the biggest audience I’ve worked in front of... that was my 15 minutes (of fame),” Hefer smiled.
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Independent Media |
/*
* Virtio PCI driver
*
* This module allows virtio devices to be used over a virtual PCI device.
* This can be used with QEMU based VMMs like KVM or Xen.
*
* Copyright IBM Corp. 2007
*
* Authors:
* Anthony Liguori <aliguori@us.ibm.com>
*
* This work is licensed under the terms of the GNU GPL, version 2 or later.
* See the COPYING file in the top-level directory.
*
*/
#include <linux/module.h>
#include <linux/list.h>
#include <linux/pci.h>
#include <linux/interrupt.h>
#include <linux/virtio.h>
#include <linux/virtio_config.h>
#include <linux/virtio_ring.h>
#include <linux/virtio_pci.h>
#include <linux/highmem.h>
#include <linux/spinlock.h>
MODULE_AUTHOR("Anthony Liguori <aliguori@us.ibm.com>");
MODULE_DESCRIPTION("virtio-pci");
MODULE_LICENSE("GPL");
MODULE_VERSION("1");
/* Our device structure */
struct virtio_pci_device
{
struct virtio_device vdev;
struct pci_dev *pci_dev;
/* the IO mapping for the PCI config space */
void __iomem *ioaddr;
/* a list of queues so we can dispatch IRQs */
spinlock_t lock;
struct list_head virtqueues;
/* MSI-X support */
int msix_enabled;
int intx_enabled;
struct msix_entry *msix_entries;
/* Name strings for interrupts. This size should be enough,
* and I'm too lazy to allocate each name separately. */
char (*msix_names)[256];
/* Number of available vectors */
unsigned msix_vectors;
/* Vectors allocated, excluding per-vq vectors if any */
unsigned msix_used_vectors;
/* Whether we have vector per vq */
bool per_vq_vectors;
};
/* Constants for MSI-X */
/* Use first vector for configuration changes, second and the rest for
* virtqueues Thus, we need at least 2 vectors for MSI. */
enum {
VP_MSIX_CONFIG_VECTOR = 0,
VP_MSIX_VQ_VECTOR = 1,
};
struct virtio_pci_vq_info
{
/* the actual virtqueue */
struct virtqueue *vq;
/* the number of entries in the queue */
int num;
/* the index of the queue */
int queue_index;
/* the virtual address of the ring queue */
void *queue;
/* the list node for the virtqueues list */
struct list_head node;
/* MSI-X vector (or none) */
unsigned msix_vector;
};
/* Qumranet donated their vendor ID for devices 0x1000 thru 0x10FF. */
static struct pci_device_id virtio_pci_id_table[] = {
{ 0x1af4, PCI_ANY_ID, PCI_ANY_ID, PCI_ANY_ID, 0, 0, 0 },
{ 0 },
};
MODULE_DEVICE_TABLE(pci, virtio_pci_id_table);
/* Convert a generic virtio device to our structure */
static struct virtio_pci_device *to_vp_device(struct virtio_device *vdev)
{
return container_of(vdev, struct virtio_pci_device, vdev);
}
/* virtio config->get_features() implementation */
static u32 vp_get_features(struct virtio_device *vdev)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
/* When someone needs more than 32 feature bits, we'll need to
* steal a bit to indicate that the rest are somewhere else. */
return ioread32(vp_dev->ioaddr + VIRTIO_PCI_HOST_FEATURES);
}
/* virtio config->finalize_features() implementation */
static void vp_finalize_features(struct virtio_device *vdev)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
/* Give virtio_ring a chance to accept features. */
vring_transport_features(vdev);
/* We only support 32 feature bits. */
BUILD_BUG_ON(ARRAY_SIZE(vdev->features) != 1);
iowrite32(vdev->features[0], vp_dev->ioaddr+VIRTIO_PCI_GUEST_FEATURES);
}
/* virtio config->get() implementation */
static void vp_get(struct virtio_device *vdev, unsigned offset,
void *buf, unsigned len)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
void __iomem *ioaddr = vp_dev->ioaddr +
VIRTIO_PCI_CONFIG(vp_dev) + offset;
u8 *ptr = buf;
int i;
for (i = 0; i < len; i++)
ptr[i] = ioread8(ioaddr + i);
}
/* the config->set() implementation. it's symmetric to the config->get()
* implementation */
static void vp_set(struct virtio_device *vdev, unsigned offset,
const void *buf, unsigned len)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
void __iomem *ioaddr = vp_dev->ioaddr +
VIRTIO_PCI_CONFIG(vp_dev) + offset;
const u8 *ptr = buf;
int i;
for (i = 0; i < len; i++)
iowrite8(ptr[i], ioaddr + i);
}
/* config->{get,set}_status() implementations */
static u8 vp_get_status(struct virtio_device *vdev)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
return ioread8(vp_dev->ioaddr + VIRTIO_PCI_STATUS);
}
static void vp_set_status(struct virtio_device *vdev, u8 status)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
/* We should never be setting status to 0. */
BUG_ON(status == 0);
iowrite8(status, vp_dev->ioaddr + VIRTIO_PCI_STATUS);
}
static void vp_reset(struct virtio_device *vdev)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
/* 0 status means a reset. */
iowrite8(0, vp_dev->ioaddr + VIRTIO_PCI_STATUS);
}
/* the notify function used when creating a virt queue */
static void vp_notify(struct virtqueue *vq)
{
struct virtio_pci_device *vp_dev = to_vp_device(vq->vdev);
struct virtio_pci_vq_info *info = vq->priv;
/* we write the queue's selector into the notification register to
* signal the other end */
iowrite16(info->queue_index, vp_dev->ioaddr + VIRTIO_PCI_QUEUE_NOTIFY);
}
/* Handle a configuration change: Tell driver if it wants to know. */
static irqreturn_t vp_config_changed(int irq, void *opaque)
{
struct virtio_pci_device *vp_dev = opaque;
struct virtio_driver *drv;
drv = container_of(vp_dev->vdev.dev.driver,
struct virtio_driver, driver);
if (drv && drv->config_changed)
drv->config_changed(&vp_dev->vdev);
return IRQ_HANDLED;
}
/* Notify all virtqueues on an interrupt. */
static irqreturn_t vp_vring_interrupt(int irq, void *opaque)
{
struct virtio_pci_device *vp_dev = opaque;
struct virtio_pci_vq_info *info;
irqreturn_t ret = IRQ_NONE;
unsigned long flags;
spin_lock_irqsave(&vp_dev->lock, flags);
list_for_each_entry(info, &vp_dev->virtqueues, node) {
if (vring_interrupt(irq, info->vq) == IRQ_HANDLED)
ret = IRQ_HANDLED;
}
spin_unlock_irqrestore(&vp_dev->lock, flags);
return ret;
}
/* A small wrapper to also acknowledge the interrupt when it's handled.
* I really need an EIO hook for the vring so I can ack the interrupt once we
* know that we'll be handling the IRQ but before we invoke the callback since
* the callback may notify the host which results in the host attempting to
* raise an interrupt that we would then mask once we acknowledged the
* interrupt. */
static irqreturn_t vp_interrupt(int irq, void *opaque)
{
struct virtio_pci_device *vp_dev = opaque;
u8 isr;
/* reading the ISR has the effect of also clearing it so it's very
* important to save off the value. */
isr = ioread8(vp_dev->ioaddr + VIRTIO_PCI_ISR);
/* It's definitely not us if the ISR was not high */
if (!isr)
return IRQ_NONE;
/* Configuration change? Tell driver if it wants to know. */
if (isr & VIRTIO_PCI_ISR_CONFIG)
vp_config_changed(irq, opaque);
return vp_vring_interrupt(irq, opaque);
}
static void vp_free_vectors(struct virtio_device *vdev)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
int i;
if (vp_dev->intx_enabled) {
free_irq(vp_dev->pci_dev->irq, vp_dev);
vp_dev->intx_enabled = 0;
}
for (i = 0; i < vp_dev->msix_used_vectors; ++i)
free_irq(vp_dev->msix_entries[i].vector, vp_dev);
if (vp_dev->msix_enabled) {
/* Disable the vector used for configuration */
iowrite16(VIRTIO_MSI_NO_VECTOR,
vp_dev->ioaddr + VIRTIO_MSI_CONFIG_VECTOR);
/* Flush the write out to device */
ioread16(vp_dev->ioaddr + VIRTIO_MSI_CONFIG_VECTOR);
pci_disable_msix(vp_dev->pci_dev);
vp_dev->msix_enabled = 0;
vp_dev->msix_vectors = 0;
}
vp_dev->msix_used_vectors = 0;
kfree(vp_dev->msix_names);
vp_dev->msix_names = NULL;
kfree(vp_dev->msix_entries);
vp_dev->msix_entries = NULL;
}
static int vp_request_msix_vectors(struct virtio_device *vdev, int nvectors,
bool per_vq_vectors)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
const char *name = dev_name(&vp_dev->vdev.dev);
unsigned i, v;
int err = -ENOMEM;
vp_dev->msix_entries = kmalloc(nvectors * sizeof *vp_dev->msix_entries,
GFP_KERNEL);
if (!vp_dev->msix_entries)
goto error;
vp_dev->msix_names = kmalloc(nvectors * sizeof *vp_dev->msix_names,
GFP_KERNEL);
if (!vp_dev->msix_names)
goto error;
for (i = 0; i < nvectors; ++i)
vp_dev->msix_entries[i].entry = i;
/* pci_enable_msix returns positive if we can't get this many. */
err = pci_enable_msix(vp_dev->pci_dev, vp_dev->msix_entries, nvectors);
if (err > 0)
err = -ENOSPC;
if (err)
goto error;
vp_dev->msix_vectors = nvectors;
vp_dev->msix_enabled = 1;
/* Set the vector used for configuration */
v = vp_dev->msix_used_vectors;
snprintf(vp_dev->msix_names[v], sizeof *vp_dev->msix_names,
"%s-config", name);
err = request_irq(vp_dev->msix_entries[v].vector,
vp_config_changed, 0, vp_dev->msix_names[v],
vp_dev);
if (err)
goto error;
++vp_dev->msix_used_vectors;
iowrite16(v, vp_dev->ioaddr + VIRTIO_MSI_CONFIG_VECTOR);
/* Verify we had enough resources to assign the vector */
v = ioread16(vp_dev->ioaddr + VIRTIO_MSI_CONFIG_VECTOR);
if (v == VIRTIO_MSI_NO_VECTOR) {
err = -EBUSY;
goto error;
}
if (!per_vq_vectors) {
/* Shared vector for all VQs */
v = vp_dev->msix_used_vectors;
snprintf(vp_dev->msix_names[v], sizeof *vp_dev->msix_names,
"%s-virtqueues", name);
err = request_irq(vp_dev->msix_entries[v].vector,
vp_vring_interrupt, 0, vp_dev->msix_names[v],
vp_dev);
if (err)
goto error;
++vp_dev->msix_used_vectors;
}
return 0;
error:
vp_free_vectors(vdev);
return err;
}
static int vp_request_intx(struct virtio_device *vdev)
{
int err;
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
err = request_irq(vp_dev->pci_dev->irq, vp_interrupt,
IRQF_SHARED, dev_name(&vdev->dev), vp_dev);
if (!err)
vp_dev->intx_enabled = 1;
return err;
}
static struct virtqueue *setup_vq(struct virtio_device *vdev, unsigned index,
void (*callback)(struct virtqueue *vq),
const char *name,
u16 msix_vec)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
struct virtio_pci_vq_info *info;
struct virtqueue *vq;
unsigned long flags, size;
u16 num;
int err;
/* Select the queue we're interested in */
iowrite16(index, vp_dev->ioaddr + VIRTIO_PCI_QUEUE_SEL);
/* Check if queue is either not available or already active. */
num = ioread16(vp_dev->ioaddr + VIRTIO_PCI_QUEUE_NUM);
if (!num || ioread32(vp_dev->ioaddr + VIRTIO_PCI_QUEUE_PFN))
return ERR_PTR(-ENOENT);
/* allocate and fill out our structure the represents an active
* queue */
info = kmalloc(sizeof(struct virtio_pci_vq_info), GFP_KERNEL);
if (!info)
return ERR_PTR(-ENOMEM);
info->queue_index = index;
info->num = num;
info->msix_vector = msix_vec;
size = PAGE_ALIGN(vring_size(num, VIRTIO_PCI_VRING_ALIGN));
info->queue = alloc_pages_exact(size, GFP_KERNEL|__GFP_ZERO);
if (info->queue == NULL) {
err = -ENOMEM;
goto out_info;
}
/* activate the queue */
iowrite32(virt_to_phys(info->queue) >> VIRTIO_PCI_QUEUE_ADDR_SHIFT,
vp_dev->ioaddr + VIRTIO_PCI_QUEUE_PFN);
/* create the vring */
vq = vring_new_virtqueue(info->num, VIRTIO_PCI_VRING_ALIGN,
vdev, info->queue, vp_notify, callback, name);
if (!vq) {
err = -ENOMEM;
goto out_activate_queue;
}
vq->priv = info;
info->vq = vq;
if (msix_vec != VIRTIO_MSI_NO_VECTOR) {
iowrite16(msix_vec, vp_dev->ioaddr + VIRTIO_MSI_QUEUE_VECTOR);
msix_vec = ioread16(vp_dev->ioaddr + VIRTIO_MSI_QUEUE_VECTOR);
if (msix_vec == VIRTIO_MSI_NO_VECTOR) {
err = -EBUSY;
goto out_assign;
}
}
spin_lock_irqsave(&vp_dev->lock, flags);
list_add(&info->node, &vp_dev->virtqueues);
spin_unlock_irqrestore(&vp_dev->lock, flags);
return vq;
out_assign:
vring_del_virtqueue(vq);
out_activate_queue:
iowrite32(0, vp_dev->ioaddr + VIRTIO_PCI_QUEUE_PFN);
free_pages_exact(info->queue, size);
out_info:
kfree(info);
return ERR_PTR(err);
}
static void vp_del_vq(struct virtqueue *vq)
{
struct virtio_pci_device *vp_dev = to_vp_device(vq->vdev);
struct virtio_pci_vq_info *info = vq->priv;
unsigned long flags, size;
spin_lock_irqsave(&vp_dev->lock, flags);
list_del(&info->node);
spin_unlock_irqrestore(&vp_dev->lock, flags);
iowrite16(info->queue_index, vp_dev->ioaddr + VIRTIO_PCI_QUEUE_SEL);
if (vp_dev->msix_enabled) {
iowrite16(VIRTIO_MSI_NO_VECTOR,
vp_dev->ioaddr + VIRTIO_MSI_QUEUE_VECTOR);
/* Flush the write out to device */
ioread8(vp_dev->ioaddr + VIRTIO_PCI_ISR);
}
vring_del_virtqueue(vq);
/* Select and deactivate the queue */
iowrite32(0, vp_dev->ioaddr + VIRTIO_PCI_QUEUE_PFN);
size = PAGE_ALIGN(vring_size(info->num, VIRTIO_PCI_VRING_ALIGN));
free_pages_exact(info->queue, size);
kfree(info);
}
/* the config->del_vqs() implementation */
static void vp_del_vqs(struct virtio_device *vdev)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
struct virtqueue *vq, *n;
struct virtio_pci_vq_info *info;
list_for_each_entry_safe(vq, n, &vdev->vqs, list) {
info = vq->priv;
if (vp_dev->per_vq_vectors &&
info->msix_vector != VIRTIO_MSI_NO_VECTOR)
free_irq(vp_dev->msix_entries[info->msix_vector].vector,
vq);
vp_del_vq(vq);
}
vp_dev->per_vq_vectors = false;
vp_free_vectors(vdev);
}
static int vp_try_to_find_vqs(struct virtio_device *vdev, unsigned nvqs,
struct virtqueue *vqs[],
vq_callback_t *callbacks[],
const char *names[],
bool use_msix,
bool per_vq_vectors)
{
struct virtio_pci_device *vp_dev = to_vp_device(vdev);
u16 msix_vec;
int i, err, nvectors, allocated_vectors;
if (!use_msix) {
/* Old style: one normal interrupt for change and all vqs. */
err = vp_request_intx(vdev);
if (err)
goto error_request;
} else {
if (per_vq_vectors) {
/* Best option: one for change interrupt, one per vq. */
nvectors = 1;
for (i = 0; i < nvqs; ++i)
if (callbacks[i])
++nvectors;
} else {
/* Second best: one for change, shared for all vqs. */
nvectors = 2;
}
err = vp_request_msix_vectors(vdev, nvectors, per_vq_vectors);
if (err)
goto error_request;
}
vp_dev->per_vq_vectors = per_vq_vectors;
allocated_vectors = vp_dev->msix_used_vectors;
for (i = 0; i < nvqs; ++i) {
if (!callbacks[i] || !vp_dev->msix_enabled)
msix_vec = VIRTIO_MSI_NO_VECTOR;
else if (vp_dev->per_vq_vectors)
msix_vec = allocated_vectors++;
else
msix_vec = VP_MSIX_VQ_VECTOR;
vqs[i] = setup_vq(vdev, i, callbacks[i], names[i], msix_vec);
if (IS_ERR(vqs[i])) {
err = PTR_ERR(vqs[i]);
goto error_find;
}
if (!vp_dev->per_vq_vectors || msix_vec == VIRTIO_MSI_NO_VECTOR)
continue;
/* allocate per-vq irq if available and necessary */
snprintf(vp_dev->msix_names[msix_vec],
sizeof *vp_dev->msix_names,
"%s-%s",
dev_name(&vp_dev->vdev.dev), names[i]);
err = request_irq(vp_dev->msix_entries[msix_vec].vector,
vring_interrupt, 0,
vp_dev->msix_names[msix_vec],
vqs[i]);
if (err) {
vp_del_vq(vqs[i]);
goto error_find;
}
}
return 0;
error_find:
vp_del_vqs(vdev);
error_request:
return err;
}
/* the config->find_vqs() implementation */
static int vp_find_vqs(struct virtio_device *vdev, unsigned nvqs,
struct virtqueue *vqs[],
vq_callback_t *callbacks[],
const char *names[])
{
int err;
/* Try MSI-X with one vector per queue. */
err = vp_try_to_find_vqs(vdev, nvqs, vqs, callbacks, names, true, true);
if (!err)
return 0;
/* Fallback: MSI-X with one vector for config, one shared for queues. */
err = vp_try_to_find_vqs(vdev, nvqs, vqs, callbacks, names,
true, false);
if (!err)
return 0;
/* Finally fall back to regular interrupts. */
return vp_try_to_find_vqs(vdev, nvqs, vqs, callbacks, names,
false, false);
}
static struct virtio_config_ops virtio_pci_config_ops = {
.get = vp_get,
.set = vp_set,
.get_status = vp_get_status,
.set_status = vp_set_status,
.reset = vp_reset,
.find_vqs = vp_find_vqs,
.del_vqs = vp_del_vqs,
.get_features = vp_get_features,
.finalize_features = vp_finalize_features,
};
static void virtio_pci_release_dev(struct device *_d)
{
struct virtio_device *dev = container_of(_d, struct virtio_device, dev);
struct virtio_pci_device *vp_dev = to_vp_device(dev);
struct pci_dev *pci_dev = vp_dev->pci_dev;
vp_del_vqs(dev);
pci_set_drvdata(pci_dev, NULL);
pci_iounmap(pci_dev, vp_dev->ioaddr);
pci_release_regions(pci_dev);
pci_disable_device(pci_dev);
kfree(vp_dev);
}
/* the PCI probing function */
static int __devinit virtio_pci_probe(struct pci_dev *pci_dev,
const struct pci_device_id *id)
{
struct virtio_pci_device *vp_dev;
int err;
/* We only own devices >= 0x1000 and <= 0x103f: leave the rest. */
if (pci_dev->device < 0x1000 || pci_dev->device > 0x103f)
return -ENODEV;
if (pci_dev->revision != VIRTIO_PCI_ABI_VERSION) {
printk(KERN_ERR "virtio_pci: expected ABI version %d, got %d\n",
VIRTIO_PCI_ABI_VERSION, pci_dev->revision);
return -ENODEV;
}
/* allocate our structure and fill it out */
vp_dev = kzalloc(sizeof(struct virtio_pci_device), GFP_KERNEL);
if (vp_dev == NULL)
return -ENOMEM;
vp_dev->vdev.dev.parent = &pci_dev->dev;
vp_dev->vdev.dev.release = virtio_pci_release_dev;
vp_dev->vdev.config = &virtio_pci_config_ops;
vp_dev->pci_dev = pci_dev;
INIT_LIST_HEAD(&vp_dev->virtqueues);
spin_lock_init(&vp_dev->lock);
/* Disable MSI/MSIX to bring device to a known good state. */
pci_msi_off(pci_dev);
/* enable the device */
err = pci_enable_device(pci_dev);
if (err)
goto out;
err = pci_request_regions(pci_dev, "virtio-pci");
if (err)
goto out_enable_device;
vp_dev->ioaddr = pci_iomap(pci_dev, 0, 0);
if (vp_dev->ioaddr == NULL)
goto out_req_regions;
pci_set_drvdata(pci_dev, vp_dev);
/* we use the subsystem vendor/device id as the virtio vendor/device
* id. this allows us to use the same PCI vendor/device id for all
* virtio devices and to identify the particular virtio driver by
* the subsytem ids */
vp_dev->vdev.id.vendor = pci_dev->subsystem_vendor;
vp_dev->vdev.id.device = pci_dev->subsystem_device;
/* finally register the virtio device */
err = register_virtio_device(&vp_dev->vdev);
if (err)
goto out_set_drvdata;
return 0;
out_set_drvdata:
pci_set_drvdata(pci_dev, NULL);
pci_iounmap(pci_dev, vp_dev->ioaddr);
out_req_regions:
pci_release_regions(pci_dev);
out_enable_device:
pci_disable_device(pci_dev);
out:
kfree(vp_dev);
return err;
}
static void __devexit virtio_pci_remove(struct pci_dev *pci_dev)
{
struct virtio_pci_device *vp_dev = pci_get_drvdata(pci_dev);
unregister_virtio_device(&vp_dev->vdev);
}
#ifdef CONFIG_PM
static int virtio_pci_suspend(struct pci_dev *pci_dev, pm_message_t state)
{
pci_save_state(pci_dev);
pci_set_power_state(pci_dev, PCI_D3hot);
return 0;
}
static int virtio_pci_resume(struct pci_dev *pci_dev)
{
pci_restore_state(pci_dev);
pci_set_power_state(pci_dev, PCI_D0);
return 0;
}
#endif
static struct pci_driver virtio_pci_driver = {
.name = "virtio-pci",
.id_table = virtio_pci_id_table,
.probe = virtio_pci_probe,
.remove = virtio_pci_remove,
#ifdef CONFIG_PM
.suspend = virtio_pci_suspend,
.resume = virtio_pci_resume,
#endif
};
static int __init virtio_pci_init(void)
{
return pci_register_driver(&virtio_pci_driver);
}
module_init(virtio_pci_init);
static void __exit virtio_pci_exit(void)
{
pci_unregister_driver(&virtio_pci_driver);
}
module_exit(virtio_pci_exit);
|
Tony Bowden's deleted the wiki. He told me I was to feel free to spider it
but his content needed removing. I made the mistake of replying:
>On Thu, Jul 28, 2005 at 06:09:58PM +0100, Matt S Trout wrote:
>> Provide me with a redacted copy of the data, or a list of content to be
>> removed then.
>>Go make demands some place else.
>>All you've done here is ensure that I remove the wiki now, rather than
>several hours for now.
>>Tony
So the wiki is now gone.
Fortunately, I was able to get a backup of most (I hope all) of it. I've
placed this backup at http://cdbi-wiki.shadowcatsystems.co.uk/ for anybody
who wants to make use of it.
I'll try and get it imported back into a kwiki, but if anybody else wants to
do so and either host it themselves or send me the data for Shadowcat to
host I'd be most grateful.
--
Matt S Trout Website: http://www.shadowcatsystems.co.uk
Technical Director E-mail: mst (at) shadowcatsystems.co.uk
Shadowcat Systems Ltd. |
274 Md. 110 (1975)
332 A.2d 646
MONTGOMERY COUNTY COUNCIL
v.
SUMMERS ET UX.
[No. 131, September Term, 1974.]
Court of Appeals of Maryland.
Decided March 4, 1975.
The cause was argued before MURPHY, C.J., and SINGLEY, SMITH, DIGGES, LEVINE and O'DONNELL, JJ.
Nathan J. Greenbaum and H. Christopher Malone, Assistant County Attorneys, with whom were Richard S. McKernon, County Attorney, and Alfred H. Carter, Deputy County Attorney, on the brief, for appellant.
No brief filed on behalf of appellees.
SMITH, J., delivered the opinion of the Court.
We shall here reinstate an assessment made by appellant, *111 Montgomery County Council (the Council), for road improvements in that county. The litigation apparently was produced by a basic misunderstanding of the formulae mandated by the code of that county for computation of such assessments.
The Council adopted an ordinance on November 10, 1970, assessing a portion of the cost of construction and reconstruction of Tilden Lane against land owned by appellees, A. Burks Summers et ux. (the Summers). The assessment was made pursuant to the authority of Montgomery County Code (1965), § 24-36 providing that upon completion of a project "the council shall by ordinance assess the costs thereof (including the actual cost of publication of notices, the conduct of hearings, advertising for bids, engineering, and all costs of financing incurred prior to the adoption of the ordinance) against the adjacent properties as provided in the road construction code in force at the time," with the "assessments [to] be computed on the basis of the linear frontage of such properties...." Pursuant to the right granted by that section, the Summers appealed the assessment to the Circuit Court for Montgomery County.
The assessment comprised the following items:
new construction
(497.4 linear feet x $26.3795429
per foot) $13,121.18
reconstruction
(45 linear feet x $5.20011388 per
foot) 234.01
*112sidewalks
(542.4 linear feet x $1.66914077
per foot) 905.34
sod
(542.4 linear feet x $.XXXXXXXXX
per foot) 470.57[1]
driveway entrance
(SLB special lot benefit; actual
cost) 364.04
_________
Subtotal $15,095.14
engineering
(10% of subtotal) 1,509.51
advertising
(1 cent per foot 542.4 feet) 5.42
_________
Total $16,610.07
Tilden Lane was improved to a width of 36 feet and was designated as a primary residential road. The land of the Summers had a total frontage on that road of 542.4 feet. New construction took place on 497.4 feet of that frontage with reconstruction on the remainder of 45 feet. Montgomery County Code (1965), § 103-15 (b) (1) provides that in the case of the reconstruction of "an arterial road within the suburban district, or where it passes through or abuts a subdivision, a primary or secondary residential road, an alley or a service drive the cost of curbs and gutters, sidewalks, returns of curbs, sidewalk and driveway entrances, and two-thirds of the cost of the paving" are to be "chargeable and assessed to the benefited abutting *113 properties" with the proviso "that where [, as was the case here,] a road is of greater width than twenty-six feet, two-thirds of the cost of paving a twenty-six foot road shall be the paving cost chargeable to the abutting owners." Section 103-15 (b) (2) provides that "[i]n the case of any road which has not previously been accepted for maintenance or is not being maintained by the county, the cost shall include," where the road is "a primary residential road the cost of grading, drainage structures, curbs and gutters, sidewalks, returns of curbs, sidewalk and driveway entrances and paving."
As the trial judge put it, he "upheld the validity of the action of the Montgomery County Council in charging a special assessment against the property of the A. Burks Summers et ux.... for new construction and reconstruction of Tilden Lane abutting their property. The court further upheld the special assessment against the [Summers'] property for reconstruction of forty-five feet of the said public street in the amount of $8.51 per [front] foot. The court then took the question of the cost per foot of new construction under advisement...." The problem that arose was that the trial judge was unable to reconcile the $8.51 per foot total assessment for reconstruction, of which $5.20 was the cost of paving two-thirds of a twenty-six foot road, with the $31.81 assessment for new construction for which he said no breakdown was included in the record.[2] We find such a breakdown. Accordingly, he proceeded to reverse so much of the special assessment as exceeded $8.60 per foot for new construction, affirming "[t]he remaining assessment for reconstruction and sidewalks, sod, the driveway entrance, applicable engineering and advertising costs." Because engineering costs were based upon 10% of the total construction costs this required a recalculation of the sum assessed for engineering costs.
The worksheets submitted to the trial judge and before us *114 show how the County Council arrived at the assessment which it called a "composite cost." It must be borne in mind that in the case of new construction the entire cost of grading, drainage structures, curbs and gutters, sidewalks, returns of curbs, sidewalk and driveway entrances, and paving for the full width were to be taken into consideration while for reconstruction the items to be considered were only curbs and gutters, sidewalks, returns of curbs, sidewalk and driveway entrances, and two-thirds of the cost of paving a twenty-six foot road. This was one project. Both new construction and reconstruction were included in it. Under new construction the County Council listed each of the expenses which could be assessed for new construction. This came to a total cost of $203,845.28. Under reconstruction but three items appeared, $19,738.16 for the cost of curbs and gutters, identical with a like sum appearing under new construction, and $12,581.66 and $7,863.54 for bituminous concrete, being portions of the items of $30,779.24 and $17,380.93 for such paving, respectively, appearing under new construction. This was the adjustment for two-thirds of the cost of paving a twenty-six foot road. The figure thus produced for reconstruction was $40,183.36. In each instance the total project charges which could be assessed to property owners were divided by 7,727.4, the number of assessable linear feet in the entire project, thus producing $26.3795429 per foot as the composite cost of new construction and $5.2011388 as the composite cost of reconstruction. The number of feet of new construction owned by the Summers, 497.4 feet, times this new construction cost equals $13,121.18, the new construction cost assessed by the County Council against the land of the Summers. There was no contest relative to the other items in the assessment. It should be noted that the entire cost of the project was $301,507.42 of which but $92,277.58 was assessed against abutting property owners. The county taxpayers bore the cost of the remainder.
We have painstakingly verified the mathematical computations of the engineers for Montgomery County and find no error in those computations, in the reasoning upon *115 which they were based, or in the applicability of those computations under the Montgomery County Code to the land of the Summers. We reiterate what Judge Prescott said for the Court in Leonardo v. County Comm., 214 Md. 287, 134 A.2d 284 (1957), cert. denied, 355 U.S. 906 (1957), reh. denied, 355 U.S. 967 (1958), quoted by us in Milestone v. Wash. Sub. San. Comm'n, 256 Md. 245, 254-55, 260 A.2d 43 (1969):
"The mode of assessment is a legislative question, subject to constitutional limitations. The mode may be committed to municipal authorities and the general rule is that the exercise of their discretion therein, if made according to a definite and just plan, will not be reviewed by the courts where neither fraud nor mistake appears. [14] McQuillin, [Municipal Corporations], § 38.111 [(3rd Ed.)]." Id. at 307.
Cf. Somerset County Sanit. v. Chamberlin, 254 Md. 630, 255 A.2d 290 (1969). Accordingly, the trial judge erred and the assessment must be reinstated.
Order vacated and case remanded for entry of an order affirming the original assessment by the Montgomery County Council; costs to be paid by the appellees.
NOTES
[1] By our calculation this should be $470.58. The county assessed at $470.57. Nobody has disputed this figure.
[2] The total of $8.51 for reconstruction and $31.81 for new construction each included the 10% engineering fee which actually was computed, as we have already shown, with reference to each property owner's individual assessment.
|
I love the fact that you can buy fresh pizza dough in the grocery store these days, but really don’t have much patience (or planning ability?) to wait for it to come to room temperature so it can be rolled out. Reading a tip about “proofing dough in a slow...
Ingredients one bunch, or bag of kale olive oil parmesan cheese sea salt, or other seasons as you like Instructions Preheat an oven to 350 degrees. Line baking sheet with parchment paper or foil With a knife your hands (ripping, goes quicker) remove the leaves from...
One more note on my new found resolution approach. I realized that simple things can be resolutions as well. I’ve chosen a few for myself, to be tackled in the kitchen. These are my secondary resolutions – the measurable and “check it off my...
New Years Resolutions – notorious setups for failure. I am not a fan. But my issue is not the actual idea of resolutions – it is simply the manner that people choose to resolve. The all to common “lose weight” or “start a diet” are...
A little blurb on Amazon Wishlists. This is a feature of Amazon.com that I poo-poo’d for quite a while, until I started shopping more seriously on Amazon. Some credit to Matt Solar, too, who really helped promote them to me. The most obvious use for them is near... |
Judith Foss
Judith C. Foss was an American politician from Maine. Foss, a Republican from Yarmouth, Maine, served in the Maine House of Representatives from 1985 to 1994.
Foss sought the Republican Party's nomination for governor in 1994. She finished in fourth place out of eight candidates.
References
Category:Year of birth missing (living people)
Category:Living people
Category:People from Yarmouth, Maine
Category:Maine Republicans
Category:Members of the Maine House of Representatives
Category:Women state legislators in Maine |
Daiya, Gardein in the Running for peta2’s Libby Awards
More than ever, young people are turning away from meat, eggs, and dairy products and a growing number of food companies are answering their calls for vegan products. peta2, PETA‘s youth division, has nominated several grocery-store brands and products for the eighth annual Libby Awards. “Libby” is for “liberation”—as in animal liberation—and this year’s meat-, egg-, and dairy-free choices are more delicious than ever, PETA officials say.
Nominees for Best Vegan Cheese—a new category this year—include Daiya‘s Swiss Style Slices, a meltable choice for grilled cheese, veggie burgers and more. Quickly rising plant-based meat company Gardein‘s in the running for Best Vegan Meat, thanks to its Sizzling Szechuan Beefless Strips, an addition to stir-frys, pastas, and skewers. And competing for Best Vegan Snack is GoPicnic‘s Hummus & Crackers box, an on-the-go kit that includes a square of dairy-free chocolate.
“Animal rights is one of the fastest-growing social movements in America and worldwide, and young people are leading the charge by insisting on cruelty-free eating,” says PETA director of iouth outreach and campaigns Marta Holmberg. “All our animal-friendly nominees are winners because they’re offering some of the best and most delicious food products on the market.”
Other food-related categories include Best Vegan-Friendly Restaurant Chain and Best Accidentally Vegan Snack. Voting ends on December 13. Winners will be chosen by peta2 based on several factors, including vote count, and will be announced on December 17. |
What's Up with Socially Responsible Investing?
Socially responsible investing (SRI) lets you target individual companies or socially conscious mutual funds. For example, you might look to avoid tobacco, alcohol or gambling firms, and instead support companies with a good track record in social justice, environmental sustainability and alternative energy/clean technology efforts.
SRI is growing into a widely followed practice with dozens of new funds and pooled investment vehicles available to retail investors. Mutual funds and ETFs can provide an added advantage of gaining exposure to companies across many sectors with a single investment.
The goals of socially responsible investment are twofold: social impact and financial gain. Community investing that goes directly to organizations with a track record of social responsibility has the added sweetness of helping communities that may not have had access to funding through banks or other financial institutions. You may want to funnel your money so it goes to affordable housing and loans. You may want to improve communities to reduce dependency on government assistance, for example.
You may be more keyed in to global warming and climate change and want to positively impact the environment through the companies you invest in. You can look for firms working on reducing emissions or sustaining clean energy sources. At the same time, you may exclusively avoid coal mining and fracking in order to vanquish from your portfolio any investments that have a negative impact on the environment.
Of course, "socially responsible" means different things to different people. There are investment options for the devout, for example. Consider the Ave Maria funds, which are guided by Catholic teachings in making investing decisions. A variety of funds make it a point to avoid so-called sin stocks, such as alcohol and gambling. The Muslim religion has strict rules about loans, so many Muslims want to avoid stocks in financial institutions.
Another Tack
On the other hand, there is at least one fund that goes in the other direction: The Vice Fund, which focuses on sin stocks, invests primarily in stocks generating the majority of their revenue from alcohol, tobacco, gaming and defense industries. You can target casino operators, gaming equipment manufacturers, defense equipment makers, or alcohol and tobacco producers. Some investors believe that the goal of investing is simply to make money, and the good we do comes from the charitable donations we make with our profits.
Whatever your thoughts are, socially responsible investing is here to stay. According to one study, more than one of every five dollars under professional management in the U.S.—$8.72 trillion as of year-end 2015—was invested in SRI strategies. You want to provide important societal benefits and aim for strong financial performance. Socially responsible investing, you believe, has an impact on companies as it gains traction with business and the investing public.
Of course, investing decisions are complicated and important. Before making any decisions, think over the risks and implications and consult with financial professionals.
Our firm provides the information in this e-newsletter for general guidance only,
and does not constitute the provision of legal advice, tax advice, accounting services,
investment advice, or professional consulting of any kind. The information provided herein should not be
used as a substitute for consultation with professional tax, accounting, legal, or other competent
advisers. Before making any decision or taking any action, you should consult a professional adviser who
has been provided with all pertinent facts relevant to your particular situation. Tax articles in this
e-newsletter are not intended to be used, and cannot be used by any taxpayer, for the purpose of
avoiding accuracy-related penalties that may be imposed on the taxpayer. The information is provided
"as is," with no assurance or guarantee of completeness, accuracy, or timeliness of the information,
and without warranty of any kind, express or implied, including but not limited to warranties of
performance, merchantability, and fitness for a particular purpose. |
Cryopreservation of avian lymphoid cells.
Conditions were standardized for optimum cryopreservation of avian lymphoid cells. Several factors that influenced cryopreservation were examined. The optimum procedure was as follows: a maximum of 50 x 10(6) cells/ml were suspended in the freezing medium, which contained 5-10% dimethyl sulfoxide (DMSO), and the cell suspension was frozen slowly at a rate of -1 C degree/min. The frozen cells were kept at -196 C. Cryopreserved cels were thawed rapidly in a 37 C water bath until the last ice crystal had thawed. The method of diluting out DMSO from thawed cells was critical, and results were best if dilutions were made at room temperature (20-25C) with diluent prewarmed to room temperature. Dilution was begun by adding 0.1 ml diluent to 1.0 ml freshly thawed cell suspension. Thereafter, diluent was added by doubling the volume after each 1-min interval until 12.7 ml of diluent had been added over 6 min. The recovery of viable cells from cryopreserved cells varied from 51.2% to 98.3% (mean 86.0%) for lymphoblastoid line cells and from 24.8% to 87.2% (mean 50.6%) for spleen cells obtained from normal chickens. Viable cryopreserved cells were reactive in a 4-hr Cr-release cytotoxicity assay and responded vigorously to phytohemagglutinin. The standardized method of freezing and thawing avian lymphoid cells may facilitate preservation of large stocks of standard reference cells with predetermined functions for laboratory studies, particularly those involving in vitro assays of cellular immunity. |
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[Immunoblastic highly malignant lymphoma of the uterine cervix].
Report on a case of a highly malignant solitary lymphoma of the cervix uteri in a 51-year-old patient. The only noticeable finding leading to the diagnosis was the pathological result of the routine cervical smear. Solitary malignant lymphomas of the cervix must be seen as systemic diseases. They should therefore be treated by local surgical intervention and consecutive systemical chemotherapy in an interdisciplinary conception. |
(Slip Opinion) OCTOBER TERM, 2013 1
Syllabus
NOTE: Where it is feasible, a syllabus (headnote) will be released, as is
being done in connection with this case, at the time the opinion is issued.
The syllabus constitutes no part of the opinion of the Court but has been
prepared by the Reporter of Decisions for the convenience of the reader.
See United States v. Detroit Timber & Lumber Co., 200 U. S. 321, 337.
SUPREME COURT OF THE UNITED STATES
Syllabus
LAW v. SIEGEL, CHAPTER 7 TRUSTEE
CERTIORARI TO THE UNITED STATES COURT OF APPEALS FOR
THE NINTH CIRCUIT
No. 12–5196. Argued January 13, 2014—Decided March 4, 2014
Petitioner Law filed for Chapter 7 bankruptcy. He valued his Califor-
nia home at $363,348, claiming that $75,000 of that value was cov-
ered by California’s homestead exemption and thus was exempt from
the bankruptcy estate. See 11 U. S. C. §522(b)(3)(A). He also
claimed that the sum of two voluntary liens—one of which was in fa-
vor of “Lin’s Mortgage & Associates”—exceeded the home’s nonex-
empt value, leaving no equity recoverable for his other creditors. Re-
spondent Siegel, the bankruptcy estate trustee, challenged the “Lin”
lien in an adversary proceeding, but protracted and expensive litiga-
tion ensued when a supposed “Lili Lin” in China claimed to be the
beneficiary of Law’s deed of trust. Ultimately, the Bankruptcy Court
concluded that the loan was a fiction created by Law to preserve his
equity in the house. It thus granted Siegel’s motion to “surcharge”
Law’s $75,000 homestead exemption, making those funds available to
defray attorney’s fees incurred by Siegel in overcoming Law’s fraudu-
lent misrepresentations. The Ninth Circuit Bankruptcy Appellate
Panel and the Ninth Circuit affirmed.
Held: The Bankruptcy Court exceeded the limits of its authority when
it ordered that the $75,000 protected by Law’s homestead exemption
be made available to pay Siegel’s attorney’s fees. Pp. 5–12.
(a) A bankruptcy court may not exercise its authority to “carry out”
the provisions of the Code, 11 U. S. C. §105(a), or its “inherent power
. . . to sanction ‘abusive litigation practices,’ ” Marrama v. Citizens
Bank of Mass., 549 U. S. 365, 375–376, by taking action prohibited
elsewhere in the Code. Here, the Bankruptcy Court’s “surcharge”
contravened §522, which (by reference to California law) entitled Law
to exempt $75,000 of equity in his home from the bankruptcy estate,
§522(b)(3)(A), and which made that $75,000 “not liable for payment of
2 LAW v. SIEGEL
Syllabus
any administrative expense,” §522(k), including attorney’s fees, see
§503(b)(2). The surcharge thus exceeded the limits of both the court’s
authority under §105(a) and its inherent powers. Pp. 5–7.
(b) Siegel argues that an equitable power to deny an exemption by
“surcharging” exempt property in response to a debtor’s misconduct
can coexist with §522. But insofar as that argument equates the sur-
charge with an outright denial of Law’s homestead exemption, it
founders on this case’s procedural history. The Bankruptcy Appellate
Panel recognized that because no one timely objected to the home-
stead exemption, it became final before the surcharge was imposed.
And a trustee who fails to make a timely objection cannot challenge
an exemption. Taylor v. Freeland & Kronz, 503 U. S. 638, 643–644.
Assuming the Bankruptcy Court could have revisited Law’s entitle-
ment to the exemption, §522 specifies the criteria that render proper-
ty exempt, and a court may not refuse to honor a debtor’s invocation
of an exemption without a valid statutory basis. Federal courts may
apply state law to disallow state-created exemptions, but federal law
itself provides no authority for bankruptcy courts to deny an exemp-
tion on a ground not specified in the Code. Pp. 7–10.
(c) Neither the holding of Marrama v. Citizens Bank nor its dictum
points toward a different result. There, the debtor’s bad faith kept
him from converting his bankruptcy from a Chapter 7 liquidation to a
Chapter 13 reorganization as permitted by §706(a). But that was be-
cause his conduct prevented him from qualifying under Chapter 13,
and thus he could not satisfy §706(d), which expressly conditions
conversion on the debtor’s ability to qualify under Chapter 13.
Pp. 10–11.
(d) This ruling forces Siegel to shoulder a heavy financial burden
due to Law’s egregious misconduct and may produce inequitable re-
sults for other trustees and creditors, but it is not for courts to alter
the balance that Congress struck in crafting §522. Cf. Guidry v.
Sheet Metal Workers National Pension Fund, 493 U. S. 365, 376–377.
P. 11.
(e) Ample authority remains to address debtor misconduct, includ-
ing denial of discharge, see §727(a)(2)–(6); sanctions for bad-faith liti-
gation conduct under the Bankruptcy Rules, §105(a), or a bankruptcy
court’s inherent powers; enforcement of monetary sanctions through
the normal procedures for collecting money judgments, see §727(b); or
possible prosecution under 18 U. S. C. §152. Pp. 11–12.
435 Fed. Appx. 697, reversed and remanded.
SCALIA, J., delivered the opinion for a unanimous Court.
Cite as: 571 U. S. ____ (2014) 1
Opinion of the Court
NOTICE: This opinion is subject to formal revision before publication in the
preliminary print of the United States Reports. Readers are requested to
notify the Reporter of Decisions, Supreme Court of the United States, Wash
ington, D. C. 20543, of any typographical or other formal errors, in order
that corrections may be made before the preliminary print goes to press.
SUPREME COURT OF THE UNITED STATES
_________________
No. 12–5196
_________________
STEPHEN LAW, PETITIONER v. ALFRED H. SIEGEL,
CHAPTER 7 TRUSTEE
ON WRIT OF CERTIORARI TO THE UNITED STATES COURT OF
APPEALS FOR THE NINTH CIRCUIT
[March 4, 2014]
JUSTICE SCALIA delivered the opinion of the Court.
The Bankruptcy Code provides that a debtor may ex
empt certain assets from the bankruptcy estate. It further
provides that exempt assets generally are not liable for
any expenses associated with administering the estate. In
this case, we consider whether a bankruptcy court none
theless may order that a debtor’s exempt assets be used to
pay administrative expenses incurred as a result of the
debtor’s misconduct.
I. Background
A
Chapter 7 of the Bankruptcy Code gives an insolvent
debtor the opportunity to discharge his debts by liquidat
ing his assets to pay his creditors. 11 U. S. C. §§704(a)(1),
726, 727. The filing of a bankruptcy petition under Chap
ter 7 creates a bankruptcy “estate” generally comprising
all of the debtor’s property. §541(a)(1). The estate is
placed under the control of a trustee, who is responsible
for managing liquidation of the estate’s assets and distri
bution of the proceeds. §704(a)(1). The Code authorizes
2 LAW v. SIEGEL
Opinion of the Court
the debtor to “exempt,” however, certain kinds of property
from the estate, enabling him to retain those assets post
bankruptcy. §522(b)(1). Except in particular situations
specified in the Code, exempt property “is not liable” for
the payment of “any [prepetition] debt” or “any adminis
trative expense.” §522(c), (k).
Section 522(d) of the Code provides a number of exemp
tions unless they are specifically prohibited by state law.
§522(b)(2), (d). One, commonly known as the “homestead
exemption,” protects up to $22,975 in equity in the debt
or’s residence. §522(d)(1) and note following §522; see
Owen v. Owen, 500 U. S. 305, 310 (1991). The debtor may
elect, however, to forgo the §522(d) exemptions and in
stead claim whatever exemptions are available under
applicable state or local law. §522(b)(3)(A). Some States
provide homestead exemptions that are more generous
than the federal exemption; some provide less generous
versions; but nearly every State provides some type of
homestead exemption. See López, State Homestead Ex
emptions and Bankruptcy Law: Is It Time for Congress To
Close the Loophole? 7 Rutgers Bus. L. J. 143, 149–165
(2010) (listing state exemptions).
B
Petitioner, Stephen Law, filed for Chapter 7 bankruptcy
in 2004, and respondent, Alfred H. Siegel, was appointed
to serve as trustee. The estate’s only significant asset was
Law’s house in Hacienda Heights, California. On a sched
ule filed with the Bankruptcy Court, Law valued the
house at $363,348 and claimed that $75,000 of its value
was covered by California’s homestead exemption. See
Cal. Civ. Proc. Code Ann. §704.730(a)(1) (West Supp.
2014). He also reported that the house was subject to two
voluntary liens: a note and deed of trust for $147,156.52 in
favor of Washington Mutual Bank, and a second note and
deed of trust for $156,929.04 in favor of “Lin’s Mortgage &
Cite as: 571 U. S. ____ (2014) 3
Opinion of the Court
Associates.” Law thus represented that there was no
equity in the house that could be recovered for his other
creditors, because the sum of the two liens exceeded the
house’s nonexempt value.
If Law’s representations had been accurate, he presum
ably would have been able to retain the house, since Siegel
would have had no reason to pursue its sale. Instead, a
few months after Law’s petition was filed, Siegel initiated
an adversary proceeding alleging that the lien in favor of
“Lin’s Mortgage & Associates” was fraudulent. The deed
of trust supporting that lien had been recorded by Law in
1999 and reflected a debt to someone named “Lili Lin.”
Not one but two individuals claiming to be Lili Lin ulti
mately responded to Siegel’s complaint. One, Lili Lin of
Artesia, California, was a former acquaintance of Law’s
who denied ever having loaned him money and described
his repeated efforts to involve her in various sham trans
actions relating to the disputed deed of trust. That Lili
Lin promptly entered into a stipulated judgment disclaim
ing any interest in the house. But that was not the end of
the matter, because the second “Lili Lin” claimed to be the
true beneficiary of the disputed deed of trust. Over the
next five years, this “Lili Lin” managed—despite suppos
edly living in China and speaking no English—to engage
in extensive and costly litigation, including several ap
peals, contesting the avoidance of the deed of trust and
Siegel’s subsequent sale of the house.
Finally, in 2009, the Bankruptcy Court entered an order
concluding that “no person named Lili Lin ever made a
loan to [Law] in exchange for the disputed deed of trust.”
In re Law, 401 B. R. 447, 453 (Bkrtcy. Ct. CD Cal.). The
court found that “the loan was a fiction, meant to preserve
[Law’s] equity in his residence beyond what he was enti
tled to exempt” by perpetrating “a fraud on his creditors
and the court.” Ibid. With regard to the second “Lili Lin,”
the court declared itself “unpersuaded that Lili Lin of
4 LAW v. SIEGEL
Opinion of the Court
China signed or approved any declaration or pleading
purporting to come from her.” Ibid. Rather, it said, the
“most plausible conclusion” was that Law himself had
“authored, signed, and filed some or all of these papers.”
Ibid. It also found that Law had submitted false evidence
“in an effort to persuade the court that Lili Lin of China—
rather than Lili Lin of Artesia—was the true holder of the
lien on his residence.” Id., at 452. The court determined
that Siegel had incurred more than $500,000 in attorney’s
fees overcoming Law’s fraudulent misrepresentations. It
therefore granted Siegel’s motion to “surcharge” the en
tirety of Law’s $75,000 homestead exemption, making
those funds available to defray Siegel’s attorney’s fees.
The Ninth Circuit Bankruptcy Appellate Panel affirmed.
BAP No. CC–09–1077–PaMkH, 2009 WL 7751415 (Oct.
22, 2009) ( per curiam). It held that the Bankruptcy
Court’s factual findings regarding Law’s fraud were not
clearly erroneous and that the court had not abused its
discretion by surcharging Law’s exempt assets. It ex
plained that in Latman v. Burdette, 366 F. 3d 774 (2004),
the Ninth Circuit had recognized a bankruptcy court’s
power to “equitably surcharge a debtor’s statutory ex
emptions” in exceptional circumstances, such as “when a
debtor engages in inequitable or fraudulent conduct.” 2009
WL 7751415, *5, *7. The Bankruptcy Appellate Panel
acknowledged that the Tenth Circuit had disagreed with
Latman, see In re Scrivner, 535 F. 3d 1258, 1263–1265
(2008), but the panel affirmed that Latman was correct.
2009 WL 7751415, *7, n. 10. Judge Markell filed a con
curring opinion agreeing with the panel’s application of
Latman but questioning “whether Latman remains good
policy.” 2009 WL 7751415, *10.
The Ninth Circuit affirmed. In re Law, 435 Fed. Appx.
697 (2011) ( per curiam). It held that the surcharge was
proper because it was “calculated to compensate the estate
for the actual monetary costs imposed by the debtor’s
Cite as: 571 U. S. ____ (2014) 5
Opinion of the Court
misconduct, and was warranted to protect the integrity of
the bankruptcy process.” Id., at 698. We granted certiorari.
570 U. S. ___ (2013).
II. Analysis
A
A bankruptcy court has statutory authority to “issue
any order, process, or judgment that is necessary or ap
propriate to carry out the provisions of ” the Bankruptcy
Code. 11 U. S. C. §105(a). And it may also possess “inher
ent power . . . to sanction ‘abusive litigation practices.’ ”
Marrama v. Citizens Bank of Mass., 549 U. S. 365, 375–
376 (2007). But in exercising those statutory and inherent
powers, a bankruptcy court may not contravene specific
statutory provisions.
It is hornbook law that §105(a) “does not allow the
bankruptcy court to override explicit mandates of other
sections of the Bankruptcy Code.” 2 Collier on Bankruptcy
¶105.01[2], p. 105–6 (16th ed. 2013). Section 105(a) con
fers authority to “carry out” the provisions of the Code, but
it is quite impossible to do that by taking action that the
Code prohibits. That is simply an application of the axiom
that a statute’s general permission to take actions of a
certain type must yield to a specific prohibition found
elsewhere. See Morton v. Mancari, 417 U. S. 535, 550–551
(1974); D. Ginsberg & Sons, Inc. v. Popkin, 285 U. S. 204,
206–208 (1932).1 Courts’ inherent sanctioning powers are
——————
1 The second sentence of §105(a) adds little to the analysis. It states:
“No provision of this title providing for the raising of an issue by a
party in interest shall be construed to preclude the court from,
sua sponte, taking any action or making any determination necessary
or appropriate to enforce or implement court orders or rules, or to
prevent an abuse of process.” Even if the “abuse of process” language
were deemed to confer additional authority beyond that conferred by
the first sentence (which is doubtful), that general authority would also
be limited by more specific provisions of the Code.
6 LAW v. SIEGEL
Opinion of the Court
likewise subordinate to valid statutory directives and
prohibitions. Degen v. United States, 517 U. S. 820, 823
(1996); Chambers v. NASCO, Inc., 501 U. S. 32, 47 (1991).
We have long held that “whatever equitable powers
remain in the bankruptcy courts must and can only be
exercised within the confines of ” the Bankruptcy Code.
Norwest Bank Worthington v. Ahlers, 485 U. S. 197, 206
(1988); see, e.g., Raleigh v. Illinois Dept. of Revenue, 530
U. S. 15, 24–25 (2000); United States v. Noland, 517 U. S.
535, 543 (1996); SEC v. United States Realty & Improve-
ment Co., 310 U. S. 434, 455 (1940).
Thus, the Bankruptcy Court’s “surcharge” was unau
thorized if it contravened a specific provision of the Code.
We conclude that it did. Section 522 (by reference to
California law) entitled Law to exempt $75,000 of equity
in his home from the bankruptcy estate. §522(b)(3)(A).
And it made that $75,000 “not liable for payment of any
administrative expense.” §522(k).2 The reasonable attor
ney’s fees Siegel incurred defeating the “Lili Lin” lien were
indubitably an administrative expense, as a short march
through a few statutory cross-references makes plain:
Section 503(b)(2) provides that administrative expenses
include “compensation . . . awarded under” §330(a);
§330(a)(1) authorizes “reasonable compensation for actual,
necessary services rendered” by a “professional person
employed under” §327; and §327(a) authorizes the trustee
to “employ one or more attorneys . . . to represent or assist
the trustee in carrying out the trustee’s duties under this
title.” Siegel argues that even though attorney’s fees
incurred responding to a debtor’s fraud qualify as “admin
istrative expenses” for purposes of determining the trus
——————
2 The statute’s general rule that exempt assets are not liable for
administrative expenses is subject to two narrow exceptions, both per
taining to the use of exempt assets to pay expenses associated with the
avoidance of certain voidable transfers of exempt property. §522(k)(1)–
(2). Neither of those exceptions is relevant here.
Cite as: 571 U. S. ____ (2014) 7
Opinion of the Court
tee’s right to reimbursement under §503(b), they do not so
qualify for purposes of §522(k); but he gives us no reason
to depart from the “ ‘normal rule of statutory construc
tion’ ” that words repeated in different parts of the same
statute generally have the same meaning. See Depart-
ment of Revenue of Ore. v. ACF Industries, Inc., 510 U. S.
332, 342 (1994) (quoting Sorenson v. Secretary of Treasury,
475 U. S. 851, 860 (1986)).
The Bankruptcy Court thus violated §522’s express
terms when it ordered that the $75,000 protected by Law’s
homestead exemption be made available to pay Siegel’s
attorney’s fees, an administrative expense. In doing so,
the court exceeded the limits of its authority under §105(a)
and its inherent powers.
B
Siegel does not dispute the premise that a bankruptcy
court’s §105(a) and inherent powers may not be exercised
in contravention of the Code. Instead, his main argument
is that the Bankruptcy Court’s surcharge did not contra
vene §522. That statute, Siegel contends, “establish[es]
the procedure by which a debtor may seek to claim exemp
tions” but “contains no directive requiring [courts] to allow
[an exemption] regardless of the circumstances.” Brief for
Respondent 35. Thus, he says, recognition of an equitable
power in the Bankruptcy Court to deny an exemption by
“surcharging” the exempt property in response to the
debtor’s misconduct can coexist comfortably with §522.
The United States, appearing in support of Siegel, agrees,
arguing that §522 “neither gives debtors an absolute right
to retain exempt property nor limits a court’s authority to
impose an equitable surcharge on such property.” Brief
for United States as Amicus Curiae 23.
Insofar as Siegel and the United States equate the
Bankruptcy Court’s surcharge with an outright denial of
Law’s homestead exemption, their arguments founder
8 LAW v. SIEGEL
Opinion of the Court
upon this case’s procedural history. The Bankruptcy
Appellate Panel stated that because no one “timely op
pose[d] [Law]’s homestead exemption claim,” the exemp
tion “became final” before the Bankruptcy Court imposed
the surcharge. 2009 WL 7751415, at *2. We have held
that a trustee’s failure to make a timely objection prevents
him from challenging an exemption. Taylor v. Freeland &
Kronz, 503 U. S. 638, 643–644 (1992).
But even assuming the Bankruptcy Court could have
revisited Law’s entitlement to the exemption, §522 does
not give courts discretion to grant or withhold exemptions
based on whatever considerations they deem appropriate.
Rather, the statute exhaustively specifies the criteria that
will render property exempt. See §522(b), (d). Siegel
insists that because §522(b) says that the debtor “may
exempt” certain property, rather than that he “shall be
entitled” to do so, the court retains discretion to grant or
deny exemptions even when the statutory criteria are met.
But the subject of “may exempt” in §522(b) is the debtor,
not the court, so it is the debtor in whom the statute vests
discretion. A debtor need not invoke an exemption to
which the statute entitles him; but if he does, the court
may not refuse to honor the exemption absent a valid
statutory basis for doing so.
Moreover, §522 sets forth a number of carefully cali
brated exceptions and limitations, some of which relate to
the debtor’s misconduct. For example, §522(c) makes
exempt property liable for certain kinds of prepetition
debts, including debts arising from tax fraud, fraud in
connection with student loans, and other specified types of
wrongdoing. Section 522(o) prevents a debtor from claim
ing a homestead exemption to the extent he acquired the
homestead with nonexempt property in the previous 10
years “with the intent to hinder, delay, or defraud a credi
tor.” And §522(q) caps a debtor’s homestead exemption at
approximately $150,000 (but does not eliminate it en
Cite as: 571 U. S. ____ (2014) 9
Opinion of the Court
tirely) where the debtor has been convicted of a felony that
shows “that the filing of the case was an abuse of the
provisions of ” the Code, or where the debtor owes a debt
arising from specified wrongful acts—such as securities
fraud, civil violations of the Racketeer Influenced and
Corrupt Organizations Act, or “any criminal act, inten
tional tort, or willful or reckless misconduct that caused
serious physical injury or death to another individual
in the preceding 5 years.” §522(q) and note following
§522. The Code’s meticulous—not to say mind-numbingly
detailed—enumeration of exemptions and exceptions to
those exemptions confirms that courts are not authorized
to create additional exceptions. See Hillman v. Maretta,
569 U. S. ___, ___ (2013) (slip op., at 12); TRW Inc. v.
Andrews, 534 U. S. 19, 28–29 (2001).
Siegel points out that a handful of courts have claimed
authority to disallow an exemption (or to bar a debtor from
amending his schedules to claim an exemption, which is
much the same thing) based on the debtor’s fraudulent
concealment of the asset alleged to be exempt. See, e.g.,
In re Yonikus, 996 F. 2d 866, 872–873 (CA7 1993); In re
Doan, 672 F. 2d 831, 833 (CA11 1982) ( per curiam); Stew-
art v. Ganey, 116 F. 2d 1010, 1011 (CA5 1940). He sug
gests that those decisions reflect a general, equitable
power in bankruptcy courts to deny exemptions based on a
debtor’s bad-faith conduct. For the reasons we have given,
the Bankruptcy Code admits no such power. It is of course
true that when a debtor claims a state-created exemption,
the exemption’s scope is determined by state law, which
may provide that certain types of debtor misconduct war
rant denial of the exemption. E.g., In re Sholdan, 217
F. 3d 1006, 1008 (CA8 2000); see 4 Collier on Bankruptcy
¶522.08[1]–[2], at 522–45 to 522–47. Some of the early
decisions on which Siegel relies, and which the Fifth Cir
cuit cited in Stewart, are instances in which federal courts
applied state law to disallow state-created exemptions.
10 LAW v. SIEGEL
Opinion of the Court
See In re Denson, 195 F. 857, 858 (ND Ala. 1912); Cowan
v. Burchfield, 180 F. 614, 619 (ND Ala. 1910); In re Ansley
Bros., 153 F. 983, 984 (EDNC 1907). But federal law
provides no authority for bankruptcy courts to deny an
exemption on a ground not specified in the Code.
C
Our decision in Marrama v. Citizens Bank, on which
Siegel and the United States heavily rely, does not point
toward a different result. The question there was whether
a debtor’s bad-faith conduct was a valid basis for a bank
ruptcy court to refuse to convert the debtor’s bankruptcy
from a liquidation under Chapter 7 to a reorganization
under Chapter 13. Although §706(a) of the Code gave the
debtor a right to convert the case, §706(d) “expressly
conditioned” that right on the debtor’s “ability to qualify as
a ‘debtor’ under Chapter 13.” 549 U. S., at 372. And
§1307(c) provided that a proceeding under Chapter 13
could be dismissed or converted to a Chapter 7 proceeding
“for cause,” which the Court interpreted to authorize
dismissal or conversion for bad-faith conduct. In light of
§1307(c), the Court held that the debtor’s bad faith could
stop him from qualifying as a debtor under Chapter 13,
thus preventing him from satisfying §706(d)’s express
condition on conversion. Id., at 372–373. That holding
has no relevance here, since no one suggests that Law
failed to satisfy any express statutory condition on his
claiming of the homestead exemption.
True, the Court in Marrama also opined that the Bank
ruptcy Court’s refusal to convert the case was authorized
under §105(a) and might have been authorized under the
court’s inherent powers. Id., at 375–376. But even that
dictum does not support Siegel’s position. In Marrama,
the Court reasoned that if the case had been converted to
Chapter 13, §1307(c) would have required it to be either
dismissed or reconverted to Chapter 7 in light of the debt
Cite as: 571 U. S. ____ (2014) 11
Opinion of the Court
or’s bad faith. Therefore, the Court suggested, even if the
Bankruptcy Court’s refusal to convert the case had not
been expressly authorized by §706(d), that action could
have been justified as a way of providing a “prompt, rather
than a delayed, ruling on [the debtor’s] unmeritorious at
tempt to qualify” under §1307(c). Id., at 376. At most,
Marrama’s dictum suggests that in some circumstances a
bankruptcy court may be authorized to dispense with
futile procedural niceties in order to reach more expedi
tiously an end result required by the Code. Marrama
most certainly did not endorse, even in dictum, the view
that equitable considerations permit a bankruptcy court to
contravene express provisions of the Code.
D
We acknowledge that our ruling forces Siegel to shoul
der a heavy financial burden resulting from Law’s egre
gious misconduct, and that it may produce inequitable
results for trustees and creditors in other cases. We have
recognized, however, that in crafting the provisions of
§522, “Congress balanced the difficult choices that exemp
tion limits impose on debtors with the economic harm that
exemptions visit on creditors.” Schwab v. Reilly, 560 U. S.
770, 791 (2010). The same can be said of the limits im
posed on recovery of administrative expenses by trustees.
For the reasons we have explained, it is not for courts to
alter the balance struck by the statute. Cf. Guidry v.
Sheet Metal Workers Nat. Pension Fund, 493 U. S. 365,
376–377 (1990).
* * *
Our decision today does not denude bankruptcy courts
of the essential “authority to respond to debtor misconduct
with meaningful sanctions.” Brief for United States as
Amicus Curiae 17. There is ample authority to deny the
dishonest debtor a discharge. See §727(a)(2)–(6). (That
12 LAW v. SIEGEL
Opinion of the Court
sanction lacks bite here, since by reason of a postpetition
settlement between Siegel and Law’s major creditor, Law
has no debts left to discharge; but that will not often be
the case.) In addition, Federal Rule of Bankruptcy Pro
cedure 9011—bankruptcy’s analogue to Civil Rule 11—
authorizes the court to impose sanctions for bad-faith
litigation conduct, which may include “an order directing
payment. . . of some or all of the reasonable attorneys’ fees
and other expenses incurred as a direct result of the viola
tion.” Fed. Rule Bkrtcy. Proc. 9011(c)(2). The court may
also possess further sanctioning authority under either
§105(a) or its inherent powers. Cf. Chambers, 501 U. S.,
at 45–49. And because it arises postpetition, a bankruptcy
court’s monetary sanction survives the bankruptcy case
and is thereafter enforceable through the normal proce
dures for collecting money judgments. See §727(b). Fraud
ulent conduct in a bankruptcy case may also subject a debtor
to criminal prosecution under 18 U. S. C. §152, which
carries a maximum penalty of five years’ imprisonment.
But whatever other sanctions a bankruptcy court may
impose on a dishonest debtor, it may not contravene ex
press provisions of the Bankruptcy Code by ordering that
the debtor’s exempt property be used to pay debts and
expenses for which that property is not liable under the
Code.
The judgment of the Court of Appeals is reversed, and
the case is remanded for further proceedings consistent
with this opinion.
It is so ordered.
|
= GameDev CSV Exporter =
#type: node
#context: sop
#internal: gamedev::rop_csv_exporter
#icon:
#tags: tech, model
""" Export geometry attibutes to a CSV file. """
[Image:/images/csv_rop.PNG]
CSV (comma separated values) is a common low level interchange format when no other format is available. It can be easily loaded as spreadsheet form into tools like Microsoft Excel or Google Sheets, and most scripting languages have built in support for reading CSV files.
This ROP exports @P for selected geometry by default, or can export custom attributes if required. It also gives simple control over the formatting, but if more complex export formatting is required a python sop might be more appropriate; the script code in this HDA can be used as reference to build a custom CSV exporter.
@parameters
Render:
Export a CSV file to the specified location.
Export Node:
Houdini path of the geometry to be exported.
CSV Path:
Location and name to save the CSV file.
Separate Vector Components:
Export the vector components into separate columns of a spreadsheet when enabled. If disabled, vectors will be saved in curly braces, eg {1,2,3}.
Component Suffixes:
Suffix to use for vector components, so if the suffix is x, and the vector is P, the column name will be Px.
Filtered Export:
When enabled use the following multiparm to define which attributes to export, otherwise just export @P.
Attribute:
Name of attribute to export.
|
1. Introduction {#sec1}
===============
For medical decision making, predictive biomarkers play an important role for various diseases \[[@B1]--[@B4]\]. A biomarker is called "predictive," if the difference between the effectiveness of two or more treatment options depends on the value of that biomarker \[[@B5], [@B6]\]. In the presence of a qualitative biomarker-treatment interaction \[[@B7]\], i.e., when the choice of the "optimal" treatment for a given patient depends on the patient\'s value of a certain biomarker, the biomarker can be used for treatment stratification \[[@B8]\]. Biomarkers used in clinical practice for treatment stratification are, e.g., the human epidermal growth factor receptor 2 (HER-2) status for breast cancer patients \[[@B9], [@B10]\] or presence of epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancers (NSCLC) \[[@B11]\]. Consequently, the identification of biomarkers that allow prediction of the treatment effect when different treatment options are available is essential to increase clinical decision making in the sense of a stratified or personalized medicine \[[@B12]\].
In practice, investigation of such treatment effect heterogeneity over the range of a certain biomarker in data obtained from a randomized clinical trial is often performed by subgroup analyses \[[@B13]\], where the difference in outcome between the study groups, quantified, e.g., by a hazard ratio, an odds ratio, or a mean difference, is estimated for patient subgroups with similar characteristics \[[@B14]\] and compared using a statistical test for interaction, which can be performed by including the product of the biomarker and the variable indicating treatment allocation in an appropriate regression model \[[@B15], [@B16]\]. While this procedure is intuitive and straightforward for categorical variables, e.g., gender or presence of comorbidities as diabetes, investigation of treatment effect heterogeneity with respect to continuous variables, e.g., age or continuously measured blood parameters, requires categorization of the variable, when subgroup analyses are to be performed. Such categorization of continuous variables was criticized due to loss of information leading to a loss of power for detection of true interactions, implication of biological implausible effects, and lack of comparability of results from different studies \[[@B17], [@B18]\]. Therefore, various approaches were proposed in the literature that allow to model and test for treatment effect heterogeneity over the range of a continuous variable that do not require categorization of the variable \[[@B19]--[@B21]\].
In this article, we describe a simulation study comparing different approaches for detection of an interaction between one (predefined) continuous covariate and treatment. We simulated data as they would be expected to be collected in a randomized clinical trial intended to compare efficacy of two treatment groups or of treatment versus placebo. Consequently, patients are allocated randomly into one of two treatment arms and the distribution of the variable of interest (often referred to as a biomarker \[[@B22]\]) is expected to be the same for both treatment groups. As most predictive biomarkers were identified for treatment of cancer \[[@B23]\], a time-to-event outcome is considered, as typically overall survival or progression-free survival is considered as primary endpoint in randomized phase III oncological trials \[[@B24]\]. Results obtained by methods relying on categorization of the continuous variable as well as methods that do not use such categorization were investigated. We considered a method splitting the continuous biomarker at its median to determine two subgroups for further analysis, the use of four subgroups determined by splitting data at the quartiles, and use of an "optimal" cutoff value found by maximization of the Wald statistics of the interaction term in a Cox regression model. Additionally, we applied the Subpopulation Treatment Effect Pattern Plot (STEPP) approach that incorporates overlapping subgroups \[[@B25]\], the Cox regression model \[[@B26]\] assuming a linear covariate-treatment interaction term, the Multivariable Fractional Polynomials for Interaction (MFPI) approach that incorporates nonlinear transformations for the interaction term \[[@B19]\], and the Local Partial-Likelihood Bootstrap (LPLB) that uses local estimates of the treatment effect at different values of the variable of interest \[[@B27]\]. Different scenarios with absence and presence of biomarker-treatment interactions were investigated in order to estimate and compare type I error probability and statistical power of the different approaches under the given scenarios. Sample size and censoring distribution are varying to investigate the impact of these characteristics on the outcome.
The article is organized as follows. In [Section 2](#sec2){ref-type="sec"}, the simulation study is described. The different methods used for identification of a biomarker-treatment interaction are shortly introduced in [Section 2.1](#sec2.1){ref-type="sec"}, and references to original articles and further articles including more detailed descriptions of the considered methods are given. The setting of the simulation study and the relevant aspects that were varied are described in [Section 2.2](#sec2.2){ref-type="sec"}. Results of the simulation study, namely, observed type I error probabilities for scenarios with no true biomarker-treatment interactions and estimates for statistical power for scenarios with truly present biomarker-treatment interactions, are presented in [Section 3](#sec3){ref-type="sec"}. A discussion of the results with concluding remarks and strengths and limitations of our simulation study is given in [Section 4](#sec4){ref-type="sec"}.
2. Methods {#sec2}
==========
The methods investigated in the simulation study are described in [Section 2.1](#sec2.1){ref-type="sec"}. Details on the settings used in the simulation study and the data generating process are given in [Section 2.2](#sec2.2){ref-type="sec"}. Data were generated and analysed using the statistical software R \[[@B28]\]. Cox regression was performed using the function *coxph* provided in the R library *survival* \[[@B29], [@B30]\]. For convenience, the continuous covariate of interest will be called "biomarker" and denoted as *Z* throughout the section. Treatment allocation will be represented by a binary treatment variable *T* with *T*={0,1}, where *T*=1 represents, e.g., an experimental treatment and *T*=0 a placebo control or standard treatment. As it appears to be the most relevant effect size in practice, homogeneity of the hazard ratio between the study groups in regard to the biomarker of interest was investigated. For all statistical tests, a significance level of *α*=5% was used. Exact 95% confidence intervals for rejection probabilities were calculated.
2.1. Methods Used to Test for a Biomarker-Treatment Interaction {#sec2.1}
---------------------------------------------------------------
### 2.1.1. Median Split {#sec2.1.1}
In many applications investigating treatment-effect heterogeneity in regard to a continuous biomarker, individuals are divided into two subgroups of equal size. This is achieved by splitting the data at the median of the biomarker *Z*. This procedure will be denoted as "Median split" in this article. A binary indicator variable that is assigned the value of one if the biomarker value is above or equal to the observed median and zero else is derived. To test for biomarker-treatment interaction, a Cox regression model with this indicator variable, the binary treatment indicator, and their product (the interaction term) is fitted to the data. The *p* value of the Wald test for the interaction term was used to decide whether the null hypothesis of no biomarker-treatment interaction can be rejected on the prespecified significance level of *α*=5%.
### 2.1.2. Quartile Split {#sec2.1.2}
As an alternative approach, individuals were divided into four subgroups with splits at the corresponding quartiles of the biomarker of interest ("Quartile split"). The categorical variable indicating the corresponding subgroup was used as a dummy coded nominal independent variable in a Cox regression model. Additionally, the binary treatment indicator and an interaction term between the dummy coded categorical variable indicating the biomarker quartile and treatment were included. A likelihood ratio test with three degrees of freedom provided in the R library *car* \[[@B31]\] was performed to test for presence of a biomarker-treatment interaction.
### 2.1.3. "Optimal" Split {#sec2.1.3}
For this approach, henceforth called "Optimal split", an "optimal" cutoff value for splitting the continuous variable into two subgroups was determined in a first step. Of all possible cutoff values (restricted to a minimum subgroup size of 10% of the overall sample size), the one leading to the largest value of the Wald statistic for the interaction term between the dichotomized biomarker and treatment in a Cox regression model also including the corresponding main effects as independent variables was used to define the subgroups for assessment of treatment effect heterogeneity. In a second step, these subgroups were treated as if they were predefined subgroups, and assessment of a biomarker-treatment interaction was performed as described for the Median split procedure in [Section 2.1.1](#sec2.1.1){ref-type="sec"}.
### 2.1.4. Subpopulation Treatment Effect Pattern Plot (STEPP) Method {#sec2.1.4}
The Subpopulation Treatment Effect Pattern Plot ("STEPP") method was proposed by Bonetti and Gelber \[[@B25]\]. In the STEPP procedure, heterogeneity of the treatment effect over the range of a biomarker of interest is assessed by estimating the effect in multiple overlapping subgroups. Additionally, methods for estimation of simultaneous confidence intervals and for testing the null hypothesis of no biomarker-treatment interaction were developed \[[@B25], [@B32]\]. Two different versions, a "tail-oriented" and a "sliding window" approach, were proposed initially. In our simulation study, we used the "sliding window" approach, where the number of individuals within two consecutive subgroups is held (approximately) constant by adding and eliminating the same number of observations and the number of observations overlapping between two consecutive subgroups is chosen a priori. For our analysis, the number of individuals within each subgroup was chosen to be *n*/5 and the number of overlapping individuals to be *n*/10. So, the subgroup sizes were 50, 100, and 200 for scenarios with 250, 500, and 1000 observations, and the number of overlapping observations was 25, 50, and 100, respectively. This led to a total number of nine subgroups considered irrespective of the sample size. A test on homogeneity of the hazard ratio over all subgroups was performed to test for a biomarker-treatment interaction. A permutation test as recommended in \[[@B32]\] was conducted using 500 permutations for each simulated dataset. Further details on the STEPP procedure can be found in \[[@B33], [@B34]\]. For application of STEPP, the R library *stepp* \[[@B35]\] was used.
### 2.1.5. Cox Regression Model with Linear Interaction {#sec2.1.5}
To avoid categorization of the continuous biomarker of interest *Z*, a Cox regression model \[[@B26]\] assuming a linear interaction between *Z* and treatment *T* was considered. This procedure implies that the log-hazard ratio between the study groups is linearly associated with the biomarker value. The main effects of the biomarker *Z*, the treatment group *T*, and their product *Z* × *T* were used as independent variables in a Cox regression model. The *p* value of the Wald test for the interaction term was considered to decide on rejection of the null hypothesis of no biomarker-treatment interaction. This procedure will be called "Cox model with linear interaction" or shortly "Cox (linear Int.)" throughout the article.
### 2.1.6. Multivariable Fractional Polynomials for Interaction (MFPI) {#sec2.1.6}
To allow for nonlinear interaction terms, Royston and Sauerbrei proposed the Multivariable Fractional Polynomials for Interaction ("MFPI") approach \[[@B19]\], which is based on the Multivariable Fractional Polynomials (MFP) approach presented by Royston and Altman \[[@B36]\]. A nonlinear transformation is considered for the biomarker of interest, and a model including main effects of treatment and the transformed biomarker as well as their interaction is compared to a model including only the corresponding main effects. In the original publication, a model with two polynomial transformations *p* ~1~ and *p* ~2~ (FP2) out of the set *p* ∈ {−2, −1, −0.5, 0,0.5, 1,2,3}, where *p*=0 indicates a logarithmic transformation, was described. Identification of the best transformation was proposed to be determined in the model without an interaction term by finding the combination of transformations providing the highest (log-)likelihood value (later called flex1 approach). Based on the results of a simulation study \[[@B37], [@B38]\] considering a continuous outcome, an alternative approach with only one polynomial transformation (FP1) and separate determination of the best transformation in the model with and without interaction (flex3, potentially leading to nonnested models) was recommended. We applied both approaches, the FP2-flex1 and the FP1-flex3 approach, to our simulated data. To test for presence of a biomarker-treatment interaction, likelihood ratio tests comparing the models with and without interaction terms were performed for both strategies.
### 2.1.7. Local Partial-Likelihood Bootstrap (LPLB) {#sec2.1.7}
Another method proposed in the literature for modelling nonlinear interaction effects between a continuous biomarker and treatment is the Local Partial-Likelihood Estimation proposed by Fan et al. \[[@B21]\]. Liu et al. developed a bootstrapping method, called Local Partial-Likelihood Bootstrap ("LPLB"), that allows to test for the presence of an overall treatment effect and to test whether the treatment effect is heterogeneous over the range of a continuous biomarker \[[@B27]\]. In the LPLB approach, linear approximations of the treatment effect estimate at a given biomarker value are obtained by first-order Taylor approximations using weighted data in the local neighbourhood of the biomarker value of interest. The proposed bootstrap test makes use of the residual bootstrap \[[@B39]\]. The obtained local estimates of the log-hazard ratio are compared to the estimate obtained from a standard Cox regression model assuming a constant treatment effect over the biomarker range. The maximum observed standardized difference of the local estimates to the constant log-hazard ratio is considered as test statistic. For our simulation study, we used the R library *lplb* \[[@B40]\] to apply the LPLB procedure. Local estimates were obtained for every decile of the empirical biomarker distribution. A bandwidth, indicating the amount of observations in the neighbourhood used for local estimation, of 0.2 was used and an Epanechnikov kernel was considered for weighting. Five hundred bootstrap samples were drawn for each generated dataset.
2.2. Simulation Settings {#sec2.2}
------------------------
Data were generated to mimic data observed in a randomized clinical trial primarily intended for comparison of two different treatment options. Consequently, simulated individuals were randomly allocated to one of two treatment groups (*T*={0,1}) with equal probability for each group. The covariate of interest was randomly generated from a uniform distribution with a minimum value of zero and a maximum value of one. Event times were drawn from an exponential distribution with the individual hazard rate depending on the allocated treatment group and the drawn covariate value as described in [Section 2.2.1](#sec2.2.1){ref-type="sec"}. Censoring times were drawn from exponential distributions with rates as described in [Section 2.2.3](#sec2.2.3){ref-type="sec"}. The lower value of the two time variables was allocated as observed time and an observed event was indicated, if the drawn event time was smaller than the corresponding censoring time, and a censored observation was indicated else.
### 2.2.1. Functional Form {#sec2.2.1}
In order to estimate the type I error probability and the statistical power for detection of truly present interaction effects associated with the different approaches, different scenarios were investigated. Overall, six different functional forms were considered, two without presence of an interaction effect (Scenarios 1 and 2) and four scenarios considering different shapes of interaction terms (Scenarios 3 to 6). All scenarios are visualized in [Figure 1](#fig1){ref-type="fig"}, showing the hazard rates used for simulation of the event times in dependence of the biomarker value (dashed black and solid grey line and black scale/axis) and the resulting hazard ratios (using a logarithmic scale) between the treatment groups (red line and scale/axis).
Scenario 1 .No associations between treatment and risk for an event and between the biomarker of interest and risk for an event are present; the hazard rate for each individual was set to 1, irrespective of treatment group and biomarker value ([Figure 1(a)](#fig1){ref-type="fig"}).$$\begin{matrix}
{\lambda\left( {x\, \mid \, z,T = 0} \right) = \lambda\left( {x\, \mid \, z,T = 1} \right) = 1,} \\
\end{matrix}$$where *λ*(*x*) indicates the hazard rate as a function of time. Consequently, the hazard ratio between the groups is 1 for all covariate values, indicating no biomarker-treatment interaction.$$\begin{matrix}
{\text{HR}\left( z \right) = 1.} \\
\end{matrix}$$
Scenario 2 .In the second scenario, the hazard rate depends on the value of the biomarker *Z* for both treatment groups, but the hazard ratio between the treatment groups is the same for all biomarker values, so no biomarker-treatment interaction is present ([Figure 1(b)](#fig1){ref-type="fig"}).$$\begin{matrix}
{\lambda\left( {x\, \mid \, z,T = 0} \right) = 0.5\,\exp\left( \left( {2z - 1} \right)^{2} \right),} \\
{\lambda\left( {x\, \mid \, z,T = 1} \right) = \exp\left( \left( {2z - 1} \right)^{2} \right),} \\
\end{matrix}$$leading to a hazard ratio of two for all values of Z.$$\begin{matrix}
{\text{HR}\left( z \right) = 2.} \\
\end{matrix}$$
Scenario 3 .In the third scenario, a true linear interaction (on the log-hazard scale) between the biomarker of interest and treatment is present, leading to a hazard ratio between the treatment groups of one for a biomarker value of *Z*=0 and to a hazard ratio of exp(0.75)=2.12 for a value of *Z*=1.$$\begin{matrix}
{\lambda\left( {x\, \mid \, z,T = 0} \right) = 0.7\,\exp\left( {0.5z} \right),} \\
{\lambda\left( {x\, \mid \, z,T = 1} \right) = 0.7\,\exp\left( {0.5z + 0.75z} \right) = 0.7\,\exp\left( {1.25z} \right).} \\
\end{matrix}$$The hazard ratio increases linearly on a logarithmic scale.$$\begin{matrix}
{\text{HR}\left( z \right) = \text{exp}\left( {0.75z} \right).} \\
\end{matrix}$$The scenario is displayed in [Figure 1(c)](#fig1){ref-type="fig"}).
Scenario 4 .In the fourth scenario, a true qualitative biomarker-treatment interaction, with a higher risk for an event under treatment *T*=0 as compared to treatment *T*=1 for patients with a small value of *Z* and a higher risk for an event under *T*=1 for individuals with a large value of *Z*, is considered ([Figure 1(d)](#fig1){ref-type="fig"}). The hazard ratio is monotonically, but not linearly increasing over the biomarker range.$$\begin{matrix}
{\lambda\left( {x\, \mid \, z,T = 0} \right) = 0.9,} \\
{\lambda\left( {x\, \mid \, z,T = 1} \right) = 0.35\text{ exp}\left( {1.7\sqrt{z} - 0.2z^{2} - 0.3z} \right).} \\
\end{matrix}$$The qualitative interaction is indicated by a hazard ratio being smaller than one for values of *Z* \< 0.424 and larger than one for *Z* \> 0.424.$$\begin{matrix}
{\text{HR}\left( z \right) = \frac{0.35\text{ exp}\left( {1.7\sqrt{z} - 0.2z^{2} - 0.3z} \right)}{0.9} = 0.389\text{ exp}\left( {1.7\sqrt{z} - 0.2z^{2} - 0.3z} \right).} \\
\end{matrix}$$
Scenario 5 .In Scenario 5, the risk for an event is similar under both treatments for most of the individuals, but the risk increases under treatment *T*=1 for large values of *Z* ([Figure 1(e)](#fig1){ref-type="fig"}).$$\begin{matrix}
{\lambda\left( {x\, \mid \, z,T = 0} \right) = 0.9,} \\
{\lambda\left( {x\, \mid \, z,T = 1} \right) = 0.9 + 1.75z^{8}.} \\
\end{matrix}$$Consequently, the hazard ratio is close to one for small and moderate values of *Z* but increases for large values. For *Z*=1, the hazard ratio reaches a value of 2.94.$$\begin{matrix}
{\text{HR}\left( z \right) = 1 + \frac{1.75z^{8}}{0.9}.} \\
\end{matrix}$$
Scenario 6 .In the sixth scenario, the hazard ratio for group *T*=0 depending on *Z* follows a U-shape, while the hazard ratio for *T*=1 is inversely U-shaped ([Figure 1(f)](#fig1){ref-type="fig"}).$$\begin{matrix}
{\lambda\left( {x\, \mid \, z,T = 0} \right) = 0.75\,\exp\left( {0.4\left( {2z - 1} \right)^{2}} \right),} \\
{\lambda\left( {x\, \mid \, z,T = 1} \right) = 1.25\,\exp\left( {- 0.5\left( {2z - 1} \right)^{2}} \right).} \\
\end{matrix}$$This setting leads to a qualitative biomarker-treatment interaction with lower risks for an event under *T*=1 for small and large values of *Z* and lower risks under *T*=0, else indicated by an inversely U-shaped hazard ratio over the range of *Z*.$$\begin{matrix}
{\text{HR}\left( z \right) = \frac{5}{3}\exp\left( {- 0.9\left( {2z - 1} \right)^{2}} \right).} \\
\end{matrix}$$
### 2.2.2. Sample Size {#sec2.2.2}
In order to evaluate whether properties of the methods under consideration are related to the sample size of the trial, three different settings for sample sizes were chosen. The generated datasets included 250, 500, or 1000 individuals, which appear to be typical sample sizes for randomized clinical trials.
### 2.2.3. Censoring Distribution {#sec2.2.3}
In addition to the sample size, censoring distributions were varied to produce scenarios with different numbers of observed events. Censoring times were drawn from exponential distributions with hazard rates of *λ* ~cens~=0.3 or *λ* ~cens~=2, respectively, to produce scenarios with censoring proportions of about 25% and about 67%, leading to numbers of about 188, 375, and 750 expected events for scenarios with low amount of censored observations and of 83, 167, and 333 expected events for scenarios with high amount of censored observations.
3. Results {#sec3}
==========
For each of the 36 scenarios described in [Section 2.2](#sec2.2){ref-type="sec"}, 1000 datasets were generated and the methods presented in [Section 2.1](#sec2.1){ref-type="sec"} were applied. The *p* value of the corresponding statistical test on biomarker-treatment interaction was saved and compared to the conventional significance level of *α*=5%. Resulting frequencies of type I errors, i.e., proportions of simulated datasets for which a statistically significant biomarker-treatment interaction was found, although it is not present in the corresponding scenario (Scenarios 1 and 2), are shown in [Figure 2](#fig2){ref-type="fig"} for all considered methods and are also tabulated with 95% confidence intervals in [Table 1](#tab1){ref-type="table"}. It can be seen that for the method using the "optimal" cutpoint to define two subgroups to be compared, the probability for a false-positive result was about 50% for both scenarios simulating data under the null hypothesis, irrespective of sample size and amount of censored observations. The Multivariable Fractional Polynomial for Interaction (MFPI) procedure with the FP1-flex3 strategy also provided an increased type I error probability of about 10%. This was mainly caused by those datasets for which different polynomial transformations for the biomarker were selected for models with and without consideration of a biomarker-treatment interaction, leading to a comparison of nonnested regression models. When only simulated datasets were considered, in which the same transformations were used for the models with and without interaction term and consequently two nested models were compared, the estimated type I error probabilities ranged from 3.8% to 6.6%. Contrarily, for datasets with different chosen transformations, the null hypothesis was falsely rejected in 14.1% to 23.8% of the corresponding simulation runs. For the simulations under Scenario 2 with a low sample size of 250 observations and a high amount of censored observations, leading to an expected number of about 83 events, type I error frequencies exceeding the nominal significance level were observed for all methods.
In Figures [3](#fig3){ref-type="fig"} (Scenarios 3 and 4) and [4](#fig4){ref-type="fig"} (Scenarios 5 and 6) and in Tables [2](#tab2){ref-type="table"} (Scenarios 3 and 4) and [3](#tab3){ref-type="table"} (Scenarios 5 and 6), the results of the scenarios with true biomarker-treatment interaction are presented. Consequently, the frequency of rejected null hypotheses can be interpreted as an estimate for the statistical power of the methods under the corresponding settings. As the procedure using two subgroups defined by an optimal, data-driven cutpoint (Optimal split) and the MFPI (FP1-flex3) approach provided type I error probabilities relevantly exceeding the nominal level of *α*=5%, these procedures are not considered in the comparison of statistical power and are consequently not displayed in Figures [3](#fig3){ref-type="fig"} and [4](#fig4){ref-type="fig"}. Nevertheless, the results are presented in Tables [2](#fig2){ref-type="fig"} and [3](#fig3){ref-type="fig"} in italics for completeness.
For the scenario fulfilling the assumption of the standard Cox regression model with a linear interaction term (Scenario 3), the Cox model with linear interaction outperformed all the other investigated methods by achieving the highest observed statistical power (Figures [3(a)](#fig3){ref-type="fig"} and [3(b)](#fig3){ref-type="fig"} and [Table 2](#tab2){ref-type="table"}). The MFPI (FP2-flex1) approach performed slightly better than the approach using two subgroups defined by a split at the median of the variable when the number of expected events was large, but for the scenario with 1000 observations and a low amount of censored observations, the observed power was about 10 percentage points lower for these methods as compared to the Cox regression model with an interaction term considering the biomarker as continuous variable (Cox model with linear interaction: 83.8%; MFPI (FP2-flex1): 74.7%; Median split: 70.2%). The method splitting the data into four subgroups (Quartile split), the STEPP, and the LPLB performed worse than the other approaches.
In Scenario 4, considering a situation with a slightly nonlinear interaction, the Cox regression model considering the continuous biomarker performed best again, followed (at least for scenarios with a large number of events) by the MFPI (FP2-flex1) approach. For small to moderate event numbers, the methods relying on categorization of the data (Median split and Quartile split) performed similarly to MFPI (FP2-flex1). With the chosen settings, the estimated power for LPLB and STEPP was smaller than for the other investigated methods (Figures [3(c)](#fig3){ref-type="fig"} and [3(d)](#fig3){ref-type="fig"} and [Table 2](#tab2){ref-type="table"}).
In the rather complex Scenario 5 with an almost identical risk for an event under both treatments for most patients and an increasing difference between treatments for large values of the biomarker, the MFPI (FP2-flex1) approach performed best in scenarios with a large number of observed events. In scenarios with a high amount of censored observations, the Cox model with linear interaction performed slightly better (small to moderate sample size) or very similar (large sample size) to MFPI (FP2-flex1) (Figures [4(a)](#fig4){ref-type="fig"} and [4(b)](#fig4){ref-type="fig"} and [Table 3](#tab3){ref-type="table"}). When censoring was low and sample size was large, the LPLB approach reached an observed power that was close to MFPI (FP2-flex1) and slightly better than the Cox regression model. While categorization using a Median split was much worse than the other methods for most settings under Scenario 5 (e.g., with an observed power for *n*=1000 and low amount of censored observations of 46.6%), splitting the study population in four subgroups (Quartile split) provided results that were relevantly better than Median split (estimated power for the mentioned settings of 70.9%), but worse than MFPI (FP2-flex1) (87.5%), Cox regression with linear interaction (76.2%), or LPLB (83.4%).
In Scenario 6, the only investigated scenario with nonmonotonous hazard ratio over the range of the biomarker of interest, the Cox model with linear interaction and the procedure defining subgroups at the observed median (Median split) were not able to identify the present biomarker-treatment interaction (estimated power between 4.6% and 6.2% for Cox model with linear interaction and between 3.9% and 6.4% for Median split). The highest empirical power was observed for LPLB and the method defining four subgroups at the observed quartiles (Quartile split). STEPP and MFPI were able to identify the association between biomarker and treatment effect in a relevant amount of generated datasets but performed worse than LPLB and Quartile split (Figures [4(c)](#fig4){ref-type="fig"} and [4(d)](#fig4){ref-type="fig"} and [Table 3](#tab3){ref-type="table"}).
4. Discussion {#sec4}
=============
It is well known and accepted that different patients react differently to the same treatment. Consequently, for making a treatment decision, characteristics of the patient or of the disease, e.g., of a tumour, should be considered. Predictive biomarkers, i.e., variables that are associated with the treatment effect, e.g., a hazard ratio between two treatment groups, play an important role for treatment selection. Evidence, whether a biomarker is truly predictive, can only be derived from randomized trials involving patients with different values of the biomarker of interest \[[@B8]\]. In practice, treatment effect heterogeneity over different factors of a categorical variable or over the range of a continuous variable in data collected in a randomized clinical trial is often analysed by the means of subgroup analyses, estimating the treatment effect within patients with similar characteristics and comparing treatment effects between subgroups using a test on interaction \[[@B14]\]. While this procedure is straightforward for categorical variables, it relies on categorization of continuous variables. It was shown for different research questions that categorization leads to a loss of power for detection of true associations \[[@B41], [@B42]\], and the interpretation of subgroup analyses based on categorized continuous variables was often criticized due to its lack of biological plausibility and its increased chance of spurious findings \[[@B17], [@B18], [@B43]\]. One common approach to investigate such interactions between continuous biomarkers and treatment without categorization is the inclusion of the product of the biomarker and the treatment indicator as independent variable in a regression model assuming a linear interaction term. To allow a more flexible modelling of relationships between treatment effects and biomarker values, various methods relaxing the linearity assumption for the interaction term, e.g., the Subpopulation Treatment Effect Pattern Plot (STEPP), the Multivariable Fractional Polynomials for Interaction (MFPI) \[[@B19]\], or the Local Partial-Likelihood Bootstrap (LPLB) \[[@B27]\] approach, were developed.
Comparisons between those methods rarely exist in the literature. Royston and Sauerbrei applied the MFPI and the STEPP method to different datasets \[[@B44]\]. Recently, we investigated the interaction between age and treatment in a randomized trial comparing carotid artery stenting (CAS) to carotid endarterectomy (CEA) for patients with symptomatic, severe carotid artery stenosis (SPACE trial \[[@B45], [@B46]\]). In this analysis, very similar results were obtained from different methods including Cox regression with linear interaction, STEPP, MFPI, and LPLB \[[@B47]\]. To our best knowledge, only a small number of simulation studies were performed to compare the properties of the different procedures under known scenarios. Royston and Sauerbrei performed a simulation study to compare different MFPI strategies to other regression models and approaches relying on categorization of continuous variables in settings with a continuous outcome \[[@B37], [@B38]\]. Under all the different MFPI strategies investigated there, the MFPI (FP1-flex3) approach, using one polynomial transformation and allowing for different functional forms in the models with and without considering a covariate-treatment interaction, was identified as the "best" MFPI approach. Bonetti et al. performed a simulation study to evaluate the impact of the parameter settings of the STEPP approach on type I error and statistical power and compared the results to those of a Cox regression model with linear interaction term \[[@B32]\]. Liu et al. also compared performance of their proposed LPLB approach to the Cox regression model with a linear interaction term \[[@B27]\]. Due to the lack of information on the properties of different available methods proposed in the literature for identification of a biomarker-treatment interaction, we performed a simulation study comparing estimates for type I error probability and statistical power of relevant methods under various scenarios. Our aim was to perform a study in the sense of a "neutral" simulation study as described in \[[@B48]\] as we do not favour any of the investigated methods and were not involved in the development or publication of any of them.
As to be expected, we observed that the procedure using an optimal cutoff value determined by maximizing the Wald statistic of the interaction term between the dichotomized biomarker of interest and treatment in a Cox regression model for definition of the subgroups leads to a tremendously increased type I error probability of about 50%. This was observed similarly in simulations presented by Altman et al. who investigated the naïve use of minimum *p* value categorization of a potentially prognostic variable \[[@B49]\]. Interestingly, an increased type I error probability of about 10% in both scenarios with data simulated under the null hypothesis was also observed for the MFPI (FP1-flex3) approach irrespective of sample size and censoring distribution. This was caused by datasets for which different transformations were selected for the models with and without an interaction term. In the simulation study by Royston and Sauerbrei \[[@B37]\], no relevant increase in the probability of false-positive findings was identified for the MFPI (FP1-flex3) approach for most of their investigated scenarios with observed relative frequencies of type one errors ranging from 5% to 7%. Only for scenarios with complex functional forms and a covariate of interest following a skewed distribution (called "badly behaved distribution of *x*" in \[[@B37]\]), an increased type I error probability of up to 20% was found. Maybe this problem is less pronounced in a linear regression setting with quantitative outcome than for our investigated time-to-event endpoint. The originally proposed MFPI (FP2-flex1) approach did not lead to an increased probability of false-positive results and performed generally well for all scenarios. While it was superior to all other methods in a scenario with a hazard ratio constant over a wide range of the biomarker and increasing for individuals with large values when the number of events was large, it was slightly less efficient than a Cox regression model with a linear interaction term in the presence of a truly linear or close to linear biomarker-treatment interaction. Generally, the Cox regression model with a linear interaction term performed better than the other investigated methods for many scenarios. It provided an acceptable probability of false-positive results and higher statistical power than all other methods in the scenario with a truly linear interaction. For small to moderate event numbers, the Cox regression model also outperformed the other methods in scenarios with nonlinear monotonous interaction effects. In one scenario with data generated to provide a nonmonotonous interaction effect over the range of the biomarker of interest, the Cox regression model assuming a linear interaction term was not able to detect this association. For the LPLB procedure, type I error frequencies did not exceed the nominal significance level relevantly and adequate statistical power as compared to the other methods was observed for scenarios with complex functional form of the hazard ratio over the biomarker range. The procedure splitting the data into two subgroups (Median split) led to decreased power for most scenarios, which was also described for other research questions dealing with categorization of continuous covariates \[[@B41], [@B42]\]. For complex associations, the split into a small number of subgroups might be an adequate first step for data exploration, which was also recommended in the EMA guideline on subgroup analyses \[[@B14]\], or might be used for verification of nonlinear associations found by a corresponding method as also recommended in \[[@B38]\].
Our simulation study has several limitations. Due to limited time and space, only a small number of different scenarios could be investigated. We considered two scenarios in which data were generated under the null hypothesis of no biomarker-treatment interaction and four settings with true biomarker-treatment interactions of different shapes. Additionally, we varied the sample size and used two different amounts of censored observations. We did not vary further aspects of the data generating process as the distribution of the covariate of interest or the influence of further covariates. While some of the methods as fitting a Cox regression model with linear interaction to the data or application of the MFPI approach do not rely on the specification of tuning parameters, other methods such as STEPP or LPLB allow a greater level of user involvement by letting the applicant choose, e.g., the size of the subgroups or the number of overlapping individuals in STEPP or the number of points used for local estimation and the bandwidth in LPLB. As we only used one setting for each of the methods as described in [Section 2.1](#sec2.1){ref-type="sec"}, our findings are only valid for these specific choices, but might not transfer to the methods in general. Further simulation studies are needed to investigate the role of the different tuning parameters on the performance of these methods. In practical applications, subject knowledge could allow more adequate specifications, which might improve performance of the methods compared to our fixed settings. Additionally, we only investigated one potential predictive biomarker and treated it as if investigation of interaction of that biomarker with treatment was the prespecified primary research question. In practice, these kinds of analyses will often be performed as exploratory secondary or add-on analyses, potentially involving multiple biomarkers of interest, and multiplicity issues typically evolving in these situations will have to be addressed adequately. If testing the interaction between a predefined biomarker and treatment is of major interest, this has to be considered in the planning phase of a clinical trial and consequently in the sample size calculation, as often a large sample size is necessary to detect biomarker-treatment interactions \[[@B50]\].
It has to be considered that our simulation study only aims at detection of biomarker-treatment interactions. According to Chen et al., three steps are needed to establish a predictive biomarker in clinical practice: identification of a biomarker, selection of adequate subgroups for treatment stratification, and assessment of clinical utility. Consequently, after identification of a predictive biomarker, subgroups that should be treated by different treatment options have to be identified. For continuous biomarkers, this could be achieved by either application of classification techniques \[[@B51]\] or by exploring the pattern of the treatment effect estimate over the range of the biomarker value. Intuitive visualization as provided by STEPP or by the "treatment effect plot" \[[@B52]\] of the MFPI procedure can be helpful. Additionally, further aspects such as potential risks, patient acceptance, and costs have to be taken into account. Clinical utility might be investigated by randomized clinical trials using biomarker-stratified or biomarker-strategy designs as described by Ondra et al. \[[@B53]\].
As a conclusion of our simulation study, we recommend to perform more detailed and sophisticated analyses for detection of biomarker-treatment interactions than the commonly performed subgroup analyses involving dichotomization of continuous variables. Cox regression models considering linear interaction terms will increase the probability for detection of true interactions as compared to the use of dichotomized variables in many applications. Methods developed for detection of nonlinear interactions can help to identify predictive biomarkers in the presence of complex patterns. We believe that better use of available statistical methods will help to identify and establish predictive biomarkers and increase the number, up to now limited \[[@B54]\], of biomarkers used in clinical practice for treatment stratification and consequently help to improve health care for individual patients.
This work was supported by the German Research Foundation (DFG) and the Technical University of Munich within the funding programme Open Access Publishing.
Data Availability
=================
All findings are based on simulated data. R code for data generation can be obtained from the corresponding author upon reasonable request.
Conflicts of Interest
=====================
The authors declare that there are no conflicts of interest regarding the publication of this article.
{#fig1}
{#fig2}
{#fig3}
{#fig4}
######
Estimated type I error probabilities with exact 95% confidence intervals (in brackets) for Scenarios 1 and 2 for all investigated methods.
*n* = 250 *n* = 500 *n* = 1000
------------------- --------------- --------------- --------------- --------------- --------------- ------- ------
Scenario 1 Median split 4.7% 5.3% 4.9% 4.4% 5.0% 6.4%
(3.5--6.2%) (4.0--6.9%) (3.6--6.4%) (3.2--5.9%) (3.7--6.5%) (5.0--8.1%)
Quartile split 6.3% 5.3% 4.2% 5.1% 3.5% 5.7%
(4.9--8.0%) (4.0--6.9%) (3.0--5.6%) (3.8--6.7%) (2.4--4.8%) (4.3--7.3%)
Optimal split 43.6% 39.9% 45.8% 40.9% 45.5% 46.6%
(40.5--46.7%) (36.8--43.0%) (42.7--48.9%) (37.8--44.0%) (42.4--48.6%) (43.5--49.7%)
STEPP 4.8% 5.9% 5.1% 4.2% 4.0% 6.3%
(3.6--6.3%) (4.5--7.5%) (3.8--6.7%) (3.0--5.6%) (2.9--5.4%) (4.9--8.0%)
Cox (linear int.) 4.9% 5.2% 4.8% 4.4% 4.8% 5.8%
(3.6--6.4%) (3.9--6.8%) (3.6--6.3%) (3.2--5.9%) (3.6--6.3%) (4.4--7.4%)
MFPI (FP1-flex3) 10.1% 10.6% 10.4% 12.0% 10.3% 13.5%
(8.3--12.1%) (8.8--12.7%) (8.6--12.5%) (10.1--14.2%) (8.5--12.4%) (11.4--15.8%)
MFPI (FP2-flex1) 4.9% 5.6% 4.9% 4.7% 6.0% 7.0%
(3.6--6.4%) (4.3--7.2%) (3.6--6.4%) (3.5--6.2%) (4.6--7.7%) (5.5--8.8%)
LPLB 4.6% 4.5% 4.2% 4.4% 3.9% 5.8%
(3.4--6.1%) (3.3--6.0%) (3.0--5.6%) (3.2--5.9%) (2.8--5.3%) (4.4--7.4%)
Scenario 2 Median split 4.2% 6.0% 5.7% 4.2% 5.7% 4.3%
(3.0--5.6%) (4.6--7.7%) (4.3--7.3%) (3.0--5.6%) (4.3--7.3%) (3.1--5.7%)
Quartile split 5.3% 6.7% 5.1% 4.5% 5.0% 5.4%
(4.0--6.9%) (5.2--8.4%) (3.8--6.7%) (3.3--6.0%) (3.7--6.5%) (4.1--7.0%)
Optimal split 50.8% 42.8% 53.9% 45.9% 52.0% 47.4%
(47.7--53.9%) (39.7--45.9%) (50.8--57.0%) (42.8--49.0%) (48.9--55.1%) (44.3--50.5%)
STEPP 5.4% 8.2% 6.8% 6.8% 7.8% 6.9%
(4.1--7.0%) (6.6--10.1%) (5.3--8.5%) (5.3--8.5%) (6.2--9.6%) (5.4--8.7%)
Cox (linear int.) 4.5% 8.2% 4.8% 6.4% 5.0% 5.2%
(3.3--6.0%) (6.6--10.1%) (3.6--6.3%) (5.0--8.1%) (3.7--6.5%) (3.9--6.8%)
MFPI (FP1-flex3) 8.1% 12.6% 9.1% 10.3% 8.1% 7.8%
(6.5--10.0%) (10.6--14.8%) (7.4--11.1%) (8.5--12.4%) (6.5--10.0%) (6.2--9.6%)
MFPI (FP2-flex1) 5.5% 6.5% 6.5% 5.6% 4.1% 5.9%
(4.2--7.1%) (5.1--8.2%) (5.1--8.2%) (4.3--7.2%) (3.0--5.5%) (4.5--7.5%)
LPLB 6.2% 5.8% 7.3% 4.8% 7.7% 6.1%
(4.8--7.9%) (4.4--7.4%) (5.8--9.1%) (3.6--6.3%) (6.1--9.5%) (4.7--7.8%)
######
Estimated power with exact 95% confidence intervals (in brackets) for Scenarios 3 and 4 for all investigated methods.
*n* = 250 *n* = 500 *n* = 1000
------------------- ----------------- ----------------- ----------------- ----------------- ----------------- --------- -------
Scenario 3 Median split 23.5% 14.1% 40.8% 25.1% 70.2% 40.9%
(20.9--26.3%) (12.0--16.4%) (37.7--43.9%) (22.4--27.9%) (67.3--73.0%) (37.8--44.0%)
Quartile split 19.2% 12.4% 36.4% 17.7% 66.0% 31.2%
(16.8--21.8%) (10.4--14.6%) (33.4--39.5%) (15.4--20.2%) (63.0--68.9%) (28.3--34.2%)
Optimal split *71.4%* *57.6%* *86.4%* *71.7%* *97.1%* *84.6%*
*(68.5--74.2%)* *(54.5--60.7%)* *(84.1--88.5%)* *(68.8--74.5%)* *(95.9--98.0%)* *(82.2--86.8%)*
STEPP 13.4% 10.5% 29.2% 15.5% 55.1% 26.4%
(11.3--15.7%) (8.7--12.6%) (26.4--32.1%) (13.3--17.9%) (52.0--58.2%) (23.7--29.2%)
Cox (linear int.) 29.9% 15.2% 54.2% 31.6% 83.8% 51.9%
(27.1--32.8%) (13--17.6%) (51.1--57.3%) (28.7--34.6%) (81.4--86.0%) (48.8--55.0%)
MFPI (FP1-flex3) *30.2%* *18.2%* *54.2%* *32.5%* *82.8%* *51.1%*
*(27.4--33.2%)* *(15.9--20.7%)* *(51.1--57.3%)* *(29.6--35.5%)* *(80.3--85.1%)* *(48--54.2%)*
MFPI (FP2-flex1) 20.4% 12.7% 42.9% 21.0% 74.7% 41.2%
(17.9--23.0%) (10.7--14.9%) (39.8--46.0%) (18.5--23.7%) (71.9--77.4%) (38.1--44.3%)
LPLB 15.2% 9.1% 32.7% 16.2% 61.2% 30.9%
(13.0--17.6%) (7.4--11.1%) (29.8--35.7%) (14.0--18.6%) (58.1--64.2%) (28.0--33.9%)
Scenario 4 Median split 26.8% 14.1% 52.3% 24.4% 78.7% 38.7%
(24.1--29.7%) (12.0--16.4%) (49.2--55.4%) (21.8--27.2%) (76--81.2%) (35.7--41.8%)
Quartile split 22.8% 14.2% 48.6% 24.2% 79.4% 37.6%
(20.2--25.5%) (12.1--16.5%) (45.5--51.7%) (21.6--27.0%) (76.8--81.9%) (34.6--40.7%)
Optimal split *77.6%* *57.8%* *92.3%* *72.6%* *99.1%* *88.8%*
*(74.9--80.1%)* *(54.7--60.9%)* *(90.5--93.9%)* *(69.7--75.3%)* *(98.3--99.6%)* *(86.7--90.7%)*
STEPP 14.8% 8.3% 36.8% 17.6% 68.9% 29.9%
(12.7--17.2%) (6.7--10.2%) (33.8--39.9%) (15.3--20.1%) (65.9--71.8%) (27.1--32.8%)
Cox (linear int.) 33.9% 17.7% 64.4% 32.4% 89.8% 49.2%
(31.0--36.9%) (15.4--20.2%) (61.3--67.4%) (29.5--35.4%) (87.8--91.6%) (46.1--52.3%)
MFPI (FP1-flex3) *40.4%* *25.8%* *72.0%* *38.8%* *92.4%* *56.3%*
*(37.3--43.5%)* *(23.1--28.6%)* *(69.1--74.8%)* *(35.8--41.9%)* *(90.6--94.0%)* *(53.2--59.4%)*
MFPI (FP2-flex1) 22.3% 14.5% 51.2% 25.6% 84.7% 41.3%
(19.8--25.0%) (12.4--16.8%) (48.1--54.3%) (22.9--28.4%) (82.3--86.9%) (38.2--44.4%)
LPLB 19.4% 8.4% 44.1% 20.1% 75.2% 33.8%
(17.0--22.0%) (6.8--10.3%) (41.0--47.2%) (17.7--22.7%) (72.4--77.8%) (30.9--36.8%)
Due to increased type I error probabilities, results for Optimal split and MFPI (FP1-flex3) are presented in italics.
######
Estimated power with exact 95% confidence intervals (in brackets) for Scenarios 5 and 6 for all investigated methods.
*n* = 250 *n* = 500 *n* = 1000
------------------- ----------------- ----------------- ----------------- ----------------- ----------------- --------- -------
Scenario 5 Median split 16.1% 10.4% 26.7% 17.7% 46.6% 29.3%
(13.9--18.5%) (8.6--12.5%) (24.0--29.6%) (15.4--20.2%) (43.5--49.7%) (26.5--32.2%)
Quartile split 23.0% 10.5% 41.3% 21.2% 70.9% 40.1%
(20.4--25.7%) (8.7--12.6%) (38.2--44.4%) (18.7--23.9%) (68.0--73.7%) (37.0--43.2%)
Optimal split *79.7%* *60.2%* *93.8%* *78.3%* *99.4%* *91.9%*
*(77.1--82.2%)* *(57.1--63.2%)* *(92.1--95.2%)* *(75.6--80.8%)* *(98.7--99.8%)* *(90.0--93.5%)*
STEPP 15.9% 7.4% 35.0% 14.8% 68.7% 31.0%
(13.7--18.3%) (5.9--9.2%) (32.0--38.0%) (12.7--17.2%) (65.7--71.6%) (28.1--34.0%)
Cox (linear int.) 25.6% 16.3% 47.0% 30.6% 76.2% 51.1%
(22.9--28.4%) (14.1--18.7%) (43.9--50.1%) (27.8--33.6%) (73.4--78.8%) (48.0--54.2%)
MFPI (FP1-flex3) *39.7%* *22.6%* *67.3%* *39.7%* *93.8%* *66.5%*
*(36.7--42.8%)* *(20.0--25.3%)* *(64.3--70.2%)* *(36.7--42.8%)* *(92.1--95.2%)* *(63.5--69.4%)*
MFPI (FP2-flex1) 26.8% 13.2% 50.6% 27.1% 87.5% 51.8%
(24.1--29.7%) (11.2--15.5%) (47.5--53.7%) (24.4--30.0%) (85.3--89.5%) (48.7--54.9%)
LPLB 22.5% 9.3% 46.9% 21.9% 83.4% 45.3%
(19.9--25.2%) (7.6--11.3%) (43.8--50.0%) (19.4--24.6%) (80.9--85.7%) (42.2--48.4%)
Scenario 6 Median split 5.3% 3.9% 5.1% 5.1% 6.4% 4.9%
(4.0--6.9%) (2.8--5.3%) (3.8--6.7%) (3.8--6.7%) (5.0--8.1%) (3.6--6.4%)
Quartile split 24.3% 13.0% 42.0% 16.0% 73.8% 36.5%
(21.7--27.1%) (11.0--15.2%) (38.9--45.1%) (13.8--18.4%) (71.0--76.5%) (33.5--39.6%)
Optimal split *73.8%* *56.5%* *88.1%* *67.1%* *97.6%* *86.3%*
*(71.0--76.5%)* *(53.4--59.6%)* *(85.9--90.0%)* *(64.1--70.0%)* *(96.4--98.5%)* *(84.0--88.4%)*
STEPP 14.8% 7.9% 31.4% 12.7% 61.6% 25.9%
(12.7--17.2%) (6.3--9.7%) (28.5--34.4%) (10.7--14.9%) (58.5--64.6%) (23.2--28.7%)
Cox (linear int.) 6.1% 5.9% 4.8% 5.1% 6.2% 4.6%
(4.7--7.8%) (4.5--7.5%) (3.6--6.3%) (3.8--6.7%) (4.8--7.9%) (3.4--6.1%)
MFPI (FP1-flex3) *23.0%* *16.5%* *30.6%* *18.5%* *50.9%* *27.3%*
*(20.4--25.7%)* *(14.3--18.9%)* *(27.8--33.6%)* *(16.1--21.0%)* *(47.8--54.0%)* *(24.6--30.2%)*
MFPI (FP2-flex1) 20.0% 11.2% 28.6% 12.8% 45.9% 26.9%
(17.6--22.6%) (9.3--13.3%) (25.8--31.5%) (10.8--15.0%) (42.8--49.0%) (24.2--29.8%)
LPLB 22.2% 10.4% 41.5% 17.9% 74.6% 36.7%
(19.7--24.9%) (8.6--12.5%) (38.4--44.6%) (15.6--20.4%) (71.8--77.3%) (33.7--39.8%)
Due to increased type I error probabilities, results for Optimal split and MFPI (FP1-flex3) are presented in italics.
[^1]: Guest Editor: Tomas Krilavičius
|
A cyclist suffered severe head trauma on Friday afternoon following a crash at 11th and Howard.
According to the SFPD, the incident occurred around 4pm, when the victim—a 60-year-old woman—was traveling in the wrong direction in the southbound bike lane on 11th Street. She became startled when a vehicle began making a turn and slammed on her brakes, causing her to be thrown from the bike and land on her face.
The victim was transferred to the hospital with a severe head injury, including brain bleeding. Details on her current condition were not disclosed. |
Conventional automation systems have been available in the marketplace for many years. For example, the internationally-known X10 standard was one of the first standards commercialized for automating systems within a home, office, school, or other structure. The X10 standard enables commands to be sent over the existing wiring in a structure, so that a controller can send messages to a controlled device. That is, one or more devices may communicate with one another over existing electrical wiring using the X10 standard. Existing X10 standard devices generally require a user to manually set an address on each switch and outlet of a system, wherein a switch with a given address supplies or terminates power to a corresponding outlet pre-set with the identical address.
Recent efforts to conserve energy have sparked additional interest in home automation. The existing and available solutions in the prior art, however, may require large expenditures of capital and/or expert domain knowledge to facilitate installation. Existing technologies are further limited by the fact that conventional outlets function in the same way regardless of the load (e.g., the particular electronic device) operably coupled to the outlet. In other words, a conventional outlet functions exactly the same regardless of whether a refrigerator, a clock radio, an incandescent light bulb, a vacuum cleaner, a life support device, or another electronic device is plugged into the outlet. Such inflexible and non-discriminatory outlet set-up is not cost efficient, and does not optimize energy conservation.
Automation systems may provide information on the use of energy and/or other resources, such as statistics about the relative energy consumption of different locations and devices. To facilitate capturing the statistics, the system must be aware of the physical and/or logical locations of the different components connected to the system, e.g., where the components are located with respect to one another. Existing methods of capturing location information include equipping all components with Global Positioning System (GPS) equipment or similar technology, which can add significant cost to each device. It is also possible to have a skilled technician meticulously program the location of each device into a database, which is time consuming and requires special training that likewise can increase the cost of the system.
Thus, there remains a need for improved and cost-effective methods and systems for mapping components of an automation system. |
server-side gadgets, as suggested by Trevor, and for inline scripting.
The idea of having a single scripting language that can be used by our
tools/gadgets community is certainly appealing, and the ever-growing
ecosystem around both client-side and server-side JS is as well.
Tim's reply:
I agree that server-side JS would be ideal from a user perspective,
which is why I've researched the various compiler/interpreter options
for it in some detail. I've settled on Lua as my preferred solution
despite its relative unfamiliarity among our users because:
All memory allocation, including stack space, is done via a configurable hook function. Thus memory accounting can easily be implemented (I've done it already). Infinite recursion does not lead to a segfault, and there's no chance of a user script sending a server into swap.
It's fast. The interpreter is fast, and there's a mature JIT compiler which is very easy to integrate. Code compiled with the Lua JIT compiler executes much faster than code written in PHP running under Zend. Execution speed is critical for the citation application, which has a lot of code executed very often.
It's designed to be integrated, so development time is very small. The C interface is well-documented.
It can be embedded in the same address space as PHP while still allowing memory and CPU limits. I've benchmarked PHP -> Lua and Lua -> PHP calls at around 0.5us on my laptop, which is at least an order of magnitude faster than any IPC solution.
Lua is intended to be easy to learn, and easy to use for short scripting tasks. It has a feature set very similar to JavaScript, with first-class functions and prototype-based OOP.
Of the potential JavaScript solutions, Rhino is the one I liked the
most, and spent the most time talking with Brion about. The problem
with it is that it's not feasible to embed it in the same address
space as PHP, and startup time is very slow, so you'd have to
implement it as a standalone daemon listening on a TCP or Unix socket.
That architecture would be complex to develop, would have poor
performance compared to Lua, and would probably make it impossible to
implement memory limits via control of the Java heap size.
Neither SpiderMonkey nor V8 give you the ability to control memory and
stack usage. They're both difficult to embed due to poor documentation
and the relative scarcity of embedded implementations. The developers
are very focused on the browsers that they primarily support, and less
so on a broader ecosystem of end users.
-- Tim Starling
Trevor's reply:
These are all excellent reasons, and it's clear you've done some solid research, but I can't help but feel that the user experience would be taking a back seat to ease of integration of we use Lua. I feel strongly that having a one language system shouldn't really be a nice-to-have, it should be a requirement, especially if we are talking about introducing yet another language.
...Make the syntax of [any] template language identical to JavaScript....
There's also an abandoned but mostly functional JavaScript interpreter written in PHP out there[1]. I realize that it would not be as fast as running programs in V8 or Rhino, but if we are talking about replacing complex templates with JavaScript code, we are still likely to see a dramatic improvement even with a slower interpreter because people will be able to express themselves much simpler ways. An added bonus is that that MediaWiki doesn't add any dependencies because it's all done in PHP code.
I have use Node.js a lot, and know of modules such as node-sandbox[2] which provide some of the limitation and isolation that is needed. Some JavaScript to PHP bridging will need to be added of course, and it's not 100% clear how to best do that, but I'm sure it's possible to do.
It's also very likely that JavaScript code running on Node.js is going to start being used on the server side in our infrastructure in the near future. Chat, real-time collaboration, and other websocket/long-polling communication services are natural uses of Node.js, and nearly impossible to do in PHP, even with a very small amount of users.
Hopefully we can come up with something that can take advantage of the rising popularity and familiarity of JavaScript to make our wiki easier to learn and use.
Tim:
.....
I think there's a risk that the citation templates would actually
execute more slowly in an interpreter running on top of PHP, such as
WikiScripts or this JavaScript implementation, than they do currently.
The nature of the code is such that it puts quite a lot of performance
pressure on the executor.
I'm anxious to see benchmarks of the citation templates converted to
run in WikiScripts, because I think they'll be shockingly bad and will
vindicate my approach.
There's no memory limit. It's just a few lines of wrapper JavaScript
and a wall clock timer. It's trivial to write a script that fills up
all memory and sends a server into swap. That's not a failure mode we
want, from a sysadmin perspective.
The stability of the site is the most important consideration. We have
a reach of 400 million people and a metatemplate editor community of
about 10. So I reckon approximately 99.99999% of our users care more
about whether the site is up than whether we use Lua or JavaScript.
-- Tim Starling
Michael Dale:
Some thoughts:
Has a php based interpreter for Lua been written? Would the template
language make mediaWiki incompatible for vanilla php based installs? WMF
would ( of course ) be running some native embeddable interpreter, but
the idea of a php based fall-back seems attractive.
Has a JavaScript Lua interpret been written? Would browser based rich
text editors need to include a Lua interpreter of some kind? Would the
existing wikitext backwards compatibility be obtainable as "near
hanging fruit" per the rich text editor efforts that ~has to~ run in
JavaScript? Has the JavaScript wikitext parser work been compared to its
php counterparts? Is there any possibility of crossover development
efforts there?
How do Lua based libraries for CSS DOM / HTML / XML traversal and
manipulation compare to JavaScript based libraries?
Is there really a risk that Rino, v8 or IonMonkey based JavaScript JIT
would be slower than the existing php based template system? It may be
the startup time and memory management of JS is less flexible in the
current ecosystem of tools. Will that hold true into the future? If Lua
has better embeddable performance characteristics right now, does that
mean its "better suited"?
Do we want to preserve the class of "template editor community" to small
numbers of individuals? Can we run tests of any kind to help compare
ease of addressing traditional and foreseen needs of server side wiki
scripting comparing JS to Lua?
While the accessibility and "ease of use" characteristics are harder to
evaluate and test than direct embed time and memory constraints
characteristics it seems performance characteristics should inherently
play a back seat to user accessibility, and crossover development since
performance constraints can be addressed with predictable engineering
efforts while less accessible or less 'well understood' language can
adversely effect contributions and development times in ways that are
not easy to directly address on a mass scale by "just adding hardware".
If WMF needs to allocate X times as much RAM and Y times more CPU it
seems like a more predictable cost than teaching of people Lua. Unless
the development costs of implementing JavaScript wiki script somehow
greatly outweigh all these variable accessibility and cross development
costs for a larger set of individuals, it seem like JavaScript would be
the preferred solution.
There seems to be so much momentum and network effects around JavaScript
that I would think the debate would be around "how" to implement
JavaScript as the next wiki script language not "if" it should be the
next wiki script language.
peace,
--michael
Tim:
No.
MediaWiki installations on shared hosts and the like can support Lua
by installing the standard interpreter binary (say by FTP upload) and
shelling out to it. Support for such a scheme is already implemented,
it was done by Fran Rogers in 2008.
No. However, there is an incomplete Lua to JS translator.
I don't see why that would be necessary.
There's no DOM manipulation involved in the target application, so I
don't see why that would be a concern.
No. I said there was a risk that an interpreter written in PHP and
running on top of Zend may be slower than the existing PHP template
I'm not a futurologist. I am, however, tired of waiting for the
perfect solution to magically appear.
No.
The design of the interface between the scripting language and PHP
will have to be done with input from the people who write templates
currently. The feature set of JavaScript and Lua is pretty much
identical, so it's hard to imagine how testing could identify
something that favours one language over the other.
It doesn't matter how much RAM you buy. If there's no limit on how
much RAM a script uses, then it will be able to exhaust all available
resources.
It doesn't matter how many cores you have: script execution will run
on a single core, and users will have to sit around waiting while
execution completes.
That assumes we have enough development time to spend on implementing
the features we need inside some JavaScript compiler. We don't have an
hour of development time to spend for every hour of editor time we
save, because there are more editors than developers.
-- Tim Starling
Erik:
Tim, many thanks for the detailed explanation of why you chose to go
for a Lua prototype implementation. This as well as the other comments
in this thread has been hugely valuable to me.
I've looked at the prior wikitech threads and I haven't seen these
specific arguments there, so I'm guessing this (as well as some of the
other considerations mentioned in this thread) would be valuable to
share either on-list or on-wiki. I'd also suggest that detailed
technical discussion take place there so more folks have a chance to
weigh in or write code to prove people wrong. :)
My tentative takeaways so far (which I'm happy to post to a relevant
public thread as well):
1) IMO this would be useful to keep as a possible hacking and
discussion project for New Orleans, depending on the state of the
implementations at that time.
2) There's been agreement in this thread that JS would be preferable
from a user/dev perspective, but it's also clear that Lua is the
closest thing we have so far to a working implementation that can
scale for the particular use case of inline-scripts (which, not to
forget, really is a tough one since we need to have all template code
in a page with hundreds of templates executed with minimal wait time
for the editor on save or preview).
I'd love to see proof-of-concept implementations of inline-scripting
in JS that could scale with acceptable performance/execution
characteristics.
3) Given that it's not entirely clear that Brainfuck<Template
programming or the other way around, it's pretty evident that any
inline scripting solution that meets the real world use cases would be
a huge improvement on current state. That doesn't mean we don't have
an obligation to get things right -- but I'd be thrilled to see
something deployed that gets us 80% of the way there. ;-)
One open question I have, which came up briefly in this discussion:
Are there significant implications of this decision for the
editor/parser work? My understanding is that the visual editor will
never have to execute template code -- that it will only need to be
aware of the template calls and the rendered output as delivered by
the server. Is that correct? Are there cases where the client will
have to execute these inline scripts, either in the context of the
editor, or in some other specific future applications we or others may
want to develop?
I'm fine with a solution that's imperfect for devs, but I want to make
sure we're not accidentally painting ourselves into corners. :)
Thanks,
Erik
Brion:
This is still a bit icky, and won't work at all on some hosts that disable or limit execution/shell-outs. That may be a decision we're willing to make, but it does up the dependency & installation requirements for anybody that actually wants to make use of these templates.
If based on a fully-compatible parser in the client side to do all the rendering, then yes. If communicating with a server-side parser to render out templates, then probably not.
Since we expect to start editor test deployments with client-side JS code this may or may not be something we need to worry about (since I presume it won't be a while yet before we have those JS or Lua templates running in production).
nod resource limits are a hard requirement here. It's trivial to write JS code to use up all your RAM:
On node.js this crashes the process after just 29 iterations, as V8's heap size is currently locked at a relatively small 1 or 1.9GB and it doesn't take long to reach that; if you're more patient, you could easily stay under that limit and still lock up huge amounts of memory for as long as each script runs.
We need to be able to halt the embedded script after some amount of time (wall clock or opcode ticks, whatever) or on some amount of memory usage.
I know the JS systems have a way to halt on time -- browsers will pop up a "Do you want to stop this script?" dialog if something runs too long -- but don't know offhand how easy it is to limit on memory usage, especially if an IPC or network-based server handles multiple scripts from one process context.
If they're one-off spawned processes then you can of course use ulimit as we do for shelling out to convert, latex etc -- if using a networked server then it may be necessary to do some fancy footwork setting up process-wide limits (and/or setting heap limits explicitly, if possible) and respawning processes if/when they fail.
Just as a note -- SpiderMonkey (the C++-based JS engine in Firefox) at least has support for allocating data from different script domains in separate "compartments" which can at least be monitored separately in about:memory in the latest versions. Whether it's possible to have it actually cap those compartments separately I don't know.
I'm actually not exactly sure how to limit the Lua heap size either though; the documentation doesn't seem very clear on that...
I think running untrusted JavaScript on the client side with no memory
limit would be almost as bad as running it on the server side.
The abstraction of memory allocation is the hard part. If they have
that but not memory limits, we could probably add memory limits.
Yes, and return NULL when the limit is exceeded. Here's my custom
allocator:
Lua is able to tolerate having its allocator function return NULL,
unlike most C programs which develop nasty bugs or crash when malloc()
returns NULL. It does a longjmp() (or throws an exception when
compiled under C++) to return control to lua_pcall(), which then
returns an error message to its caller.
longjmp() safety is not entirely trivial. The calling code has to be
aware of the possibility of a longjmp() so that it doesn't leak memory
or corrupt the state in other ways. It's basically the same as
exception safety in C++, except without the compiler support, and
without the bulk of the participating developers being aware of the issue.
Indeed. :) One would want to do some sandboxing there as well... JS-on-JS sandboxing could be done with an intermediary layer like caja[1] or by separating into an isolated iframe context; in any case that's not a bridge that needs immediate crossing. |
INTRODUCTION
============
The incidence of cardiovascular disease (CVD), the leading cause of death globally, continues to rise as life expectancy increases.[@B1][@B2] Cellular senescence is linked to the onset and the progression of CVD. Various stimuli, including DNA damage and oxidative stress, have been reported to trigger cellular senescence.[@B3] Moreover, clinical risk factors such as inflammation, hypertension, and obesity were reported to accelerate vascular aging, so-called early vascular aging.[@B4] Senescent cells show shortened telomere length and reduced proliferation although they maintain cellular viability.[@B5] Senescent cells are phenotypically characterized by enlarged and flattened cell morphology and accumulated senescence associated β-galactosidase (SA-β-gal).[@B6] Furthermore, SA-β-gal-positive cells express different sets of genes, such as p53 and p16,[@B7] which are negative regulators of the cell cycle and also serve as markers of cellular senescence.
Maladaptive activation of the renin-angiotensin system (RAS) has been shown to play a critical role in the development of CVD of different etiologies including hypertension[@B8] and diabetes.[@B9] Angiotensin II (Ang II) is a potent systemic vasoconstrictor and is involved in several vascular pathologies by promoting pathologic hypertrophy, fibrosis, extracellular matrix deposition and inflammation via Ang II type 1 receptor (AT1R).[@B10][@B11][@B12] There is some evidence suggesting the role of Ang II in vascular senescence[@B13][@B14] and the protective effect of RAS inhibition against it.[@B14][@B15][@B16] AT1R blockers (ARBs) are mainly used for the treatment of hypertension and have been reported to exert pleiotropic effects to protect against oxidative and inflammatory actions.[@B17][@B18] Fimasartan, developed by Boryung Pharmaceutical Co., Ltd. (Seoul, Korea), is an ARB with a selective AT1R blocking effect.[@B19] Recent studies have reported the pleiotropic effect of fimasartan beyond blood pressure lowering in myocardial infarction[@B20] and inflammation.[@B21]
CYR61 is an important downstream molecule of AT1R.[@B22] CYR61 is a cysteine-rich angiogenic protein 61 that is the first member of the CCN family (CCN1) of secreted extracellular matrix proteins in mammals.[@B23] CYR61 was originally cloned as an immediate early gene expressed in fibroblasts after growth factor stimulation.[@B24] CYR61 expression has been reported to be associated with vascular restenosis, angiogenesis, and tumor growth.[@B25] Also, we previously showed that CYR61 blocking inhibits vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia.[@B26]
Therefore, in this study, we evaluated cellular senescence following Ang II. We hypothesized that Ang II induced VSMC senescence by regulating the expression of CYR61. We also evaluated the protective role of ARB, fimasartan, against vascular senescence.
METHODS
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Reagents and antibodies
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Ang II was purchased from Sigma-Aldrich (Merck Millipore Corporation, Darmstadt, Germany). PD98059, ERK1/2 inhibitor, and SB203580, p38 MAP kinase inhibitor, were purchased from Invitrogen (Carlsbad, CA, USA). Fimasartan, ARB, was provided by Boryung Pharmaceutical Co., Ltd (Seoul, Korea). Primary antibodies against p53, p16 and β-actin antibodies were purchased from Santa Cruz Biotechnology (Dallas, TX, USA), and Phospho-ERK1/2, ERK1/2, Phospho-p38 MAPK and p38 MAPK antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA). CYR61 antibody was purchased from Abcam. Secondary antibodies were purchased from Santa Cruz Biotechnology (Dallas, TX, USA).
Cell culture and adenoviral vectors
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Human coronary artery smooth muscle cells (hCSMCs) were purchased from Lonza (CC-2583, Basel, Switzerland). Six- to eight-passage hCSMCs were cultured in SMC growth medium consisting of basal media, insulin, human recombinant epidermal growth factor, human recombinant fibroblast growth factor, gentamicin, amphotericin, and 5% fetal bovine serum at 37°C in an atmosphere of 95% air and 5% CO~2~ based on manufacturer\'s recommendations. Recombinant adenoviral vectors, expressing CYR61 cDNA (Ad-CYR61) and antisense CYR61 cDNA (Ad-AS-CYR61) fragments, were used for the overexpression or suppression of CYR61 gene in cultured hCSMCs. As a control, an adenoviral vector expressing green fluorescence proteins only (Ad-GFP) was used.
SA-β-gal staining assay
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Cellular senescence was examined by SA-β-gal activity using Senescence Detection Kit (Calbiochem, Merck Millipore Corporation, Darmstadt, Germany). Briefly, cultured hCSMCs were washed with 1× PBS and fixed with Fixative Solution at room temperature for 15 minutes, and washed with PBS again. Then fixed cells were incubated with Staining Solution Mix at 37°C overnight. Cellular images were acquired with a fluorescence microscope (DM 5500B, LEICA Microsystems, Milton Keynes, UK) using a digital imaging system (DFC360FX, LEICA). SA-β-gal positive cells were counted per 50 cells and normalized to vehicle treated cells.
Total RNA isolation and quantitative real-time polymerase chain reaction (PCR)
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Changes in CYR61 gene expression were determined by quantitative real-time PCR. Cultured hCSMCs were washed twice with PBS and cell pellets were collected for RNA isolation. And total RNA was isolated from the cell pellets by the RNeasy mini Kit (Qiagen, Hilden, Germany) and reversely transcribed using the amfiRivert cDNA Synthesis Premix (GenDEPOT, Katy, TX, USA) based on manufacturer\'s instructions. Quantitative PCR performed using SYBR Green PCR kit (Applied Biosystem, Foster City, CA, USA) and StepOnePlus Real-Time PCR System (Applied Biosystem). Real-time PCR was performed with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) primers (forward: 5′-GGA AGG TGA AGG TCG GAG TC-3′, reverse: 5′-GAA GGG GTC ATT GAT GGC AAC-3′), CYR61 primers (forward: 5′-TCT CGT TGC TGC TCA TGA AAT T-3′, reverse: 5′-TAG AGT GGG TAC ATC AAA GCT TCA G-3′), p53 primers (forward: 5′-GCC CAA CAA CAC CAG CTC CT-3′, reverse: 5′-CCT GGG CAT CCT TGA GTT CC-3′) and p16 primers (forward: 5′-CCC AAC GCA CCG AAT AGT TA-3′, reverse: 5′-ACC AGC GTG TCC AGG AAG -3′). All genes were normalized to the GAPDH mRNA level.
Western blot assay
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Cultured hCSMCs with the indicated reagents were washed twice with PBS and collected. Cell pellets were lysed in RIPA cell lysis buffer (Santa Cruz Biotechnology), and protein concentration was determined by BCA protein assay (Thermo Scientific Pierce, Rockford, IL, USA). The 30 µg of proteins were loaded and separated on 8% or 10% sodium dodecyl sulfate-polyacrylamide gels and transferred to activated polyvinylidene fluoride membranes (Immobilon-P; Merck Millipore, Darmstadt, Germany) by methanol. The transferred membranes were blocked with blocking buffer (5% skim milk in TBST) at room temperature for 60 minutes and incubated with the indicated primary antibodies in blocking buffer overnight at 4°C. The membranes were washed three times with TBST and incubated at room temperature with secondary antibodies conjugated to horseradish peroxidase at 1:2,500 for 60 minutes in TBST with 2% skim milk and washed three times again. Proteins were detected using enhanced chemiluminescence detection reagents (Promega, Madison, WI, USA) and the protein levels were acquired through densitometric scanning. Obtained values were expressed in arbitrary densitometric units and normalized to those of β-actin to correct for total protein loading.
Statistical analysis
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All data were presented as mean±standard deviation. Statistical analyses were performed with GraphPad Prism (GraphPad Software, Inc., La Jolla, CA, USA) using the student\'s t-test for comparing 2 groups or one-way analysis of variance followed by the Turkey post hoc test for comparing \>2 groups. A probability value of less than 0.05 was considered statistically significant.
RESULTS
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Ang II induces Ang II-induced cellular senescence in hCSMCs, whereas fimasartan inhibits it
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We treated hCSMCs with 1 to 100 nM of Ang II and evaluated cellular senescence by counting SA-β-gal-positive cells. Ang II treatment for 7 days significantly increased SA-β-gal-positive cells at 10 nM (2.63±0.75-fold) and at 100 nM (3.31±0.26-fold) compared with the control ([Figure 1A](#F1){ref-type="fig"}). In contrast, Ang II-induced SA-β-gal activity (5.77±1.05-fold vs. the control) was significantly inhibited by pretreatment with 1 μM of fimasartan (2.0±0.53-fold vs. the control with Ang II, [Figure 1B](#F1){ref-type="fig"}).
{#F1}
Next, we evaluated the expression levels of cell senescence regulators, p53 and p16 following Ang II treatment by western blot analysis and Real-time PCR.[@B13] Both p53 and p16 protein expressions were significantly increased (p53: 1.39±0.17, p16: 1.19±0.10-fold vs. the control, [Figure 2A](#F2){ref-type="fig"} and [Supplementary Figure 1](#S1){ref-type="supplementary-material"}) and their mRNA levels were similarly increased (p53: 3.20±0.78, p16: 7.79±1.01-fold vs. the control, [Figure 2B](#F2){ref-type="fig"}), while these Ang II-induced increases were completely inhibited in both protein (p53: 1.02±0.12, p16: 0.96±0.07-fold vs. the control, [Figure 2A](#F2){ref-type="fig"} and [Supplementary Figure 1](#S1){ref-type="supplementary-material"}) and mRNA (p53: 0.15±0.13, p16: 0.27±0.22-fold vs. the control, [Figure 2B](#F2){ref-type="fig"}) by fimasartan.
{#F2}
These observations suggest that Ang II promotes the hCSMCs senescence via accumulated stress through the AT1R-p53/p16 dependent pathway, and fimasartan blocks the AT1R to regulate hCSMCs senescence.
Ang II-induced CYR61 promotes cellular senescence via AT1R-p53-dependent pathway
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It was previously reported that the expression of CYR61 is induced by Ang II, and CYR61 was reported to induce cellular senescence in fibroblasts.[@B27] Therefore, we investigated whether CYR61 mediates Ang II-induced cellular senescence in hCSMCs. First, we performed quantitative real-time PCR to assess the CYR61 gene transcription on Ang II-treated hCSMCs. The CYR61 mRNA expression levels were increased in Ang II-treated hCSMCs over 10 nM (10 nM: 1.52±0.27, 100 nM: 1.54±0.28-fold vs. the control, [Figure 3A](#F3){ref-type="fig"}). Ang II rapidly induced CYR61 mRNA expression within 30 minutes (1.5±0.34-fold vs. the control) and peaked at 120 minutes (3.1±0.80-fold vs. the control, [Figure 3B](#F3){ref-type="fig"}). Conversely, Ang II-induced CYR61 mRNA expression (1.55±0.36-fold. vs. the control) was completely inhibited by fimasartan (0.95±0.23-fold vs. the control, [Figure 3C](#F3){ref-type="fig"}).
{#F3}
We investigated whether CYR61 directly induces hCSMCs senescence. For the overexpression or the suppression of CYR61, we used a replication adenovirus encoding CYR61-specific cDNA (Ad-CYR61) or CYR61-specific antisense cDNA (Ad-As-CYR61) fragments. In CYR61-overexpressed hCSMCs, SA-β-gal (+) cells were significantly increased (3.47±0.65-fold vs. the control transfected with Ad-GFP, [Figure 4A](#F4){ref-type="fig"}). Conversely, when CYR61 expression was blocked with Ad-AS-CYR61, Ang II-induced SA-β-gal (+) cell numbers were significantly decreased (Ang II-treated hCSMC with Ad-GFP: 3.73±0.23 and Ang II-treated hCSMC with Ad-As-CYR61: 1.77±0.60-fold vs. the vehicle-treated hCSMC with Ad-GFP, [Figure 4B](#F4){ref-type="fig"}).
{#F4}
p16 and p53 were reported to be involved in different pathways of cellular senescence.[@B7] Therefore, we examined whether CYR61-induced hCSMC senescence was related to the p16- or p53-dependent pathway. In CYR61-overexpressed hCSMCs, expression of CYR61 and p53 was increased, whereas p16 expression was not changed in protein (CYR61: 37.94±3.26-fold, p53: 1.57±0.16-fold, p16: 0.95±0.10-fold vs. the control transfected with Ad-GFP, [Figure 5A](#F5){ref-type="fig"}, and [Supplementary Figure 2A-C](#S2){ref-type="supplementary-material"}) and mRNA (CYR61: 3.23±0.60-fold, p53: 11.90±1.18-fold, p16: 1.03±0.40-fold vs. the control transfected with Ad-GFP, [Figure 5B](#F5){ref-type="fig"}). In addition, the p53 expression by CYR61 was increased in a dose-dependent manner (25 MOI: 1.36-fold, 125 MOI: 1.42-fold, 250 MOI: 1.71-fold vs. the control transfected with Ad-GFP, [Figure 5C](#F5){ref-type="fig"} and [Supplementary Figure 2D and E](#S2){ref-type="supplementary-material"}). However, in CYR61-suppressed hCSMCs using Ad-As-CYR61, induction of p53 by Ad-CYR61 or Ang II was significantly suppressed, whereas p16 expression was not changed in both condition ([Figure 5D and E](#F5){ref-type="fig"} and [Supplementary Figure 2F-K](#S2){ref-type="supplementary-material"}).
{#F5}
These results showed that Ang II induced CYR61 via AT1R and CYR61 mediated Ang II-induced hCSMCs senescence. Also, CYR61-induced cellular senescence was mediated by the p53-dependent pathway, not by the p16-dependent pathway.
Ang II induces CYR61 expression through the ERK/p38 MAPK signaling pathway
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Lastly, we investigated the mechanisms of CYR61-associated Ang II dependent hCSMCs senescence in more detail. It was previously reported that Ang II-related cellular senescence was contributed to by MAPK, such as ERK1/2 and p38 MAPK.[@B28] Based on these reports, we investigated the role of ERK/p38 MAPK pathways in CYR61-mediated hCSMCs senescence. First, we evaluated ERK1/2 and p38 MAPK activation by measuring phosphorylation in Ang II-treated hCSMCs. As expected, the phosphorylation levels were both increased by Ang II, and blocked by fimasartan pretreatment ([Figure 6A](#F6){ref-type="fig"} and [Supplementary Figure 3A and B](#S3){ref-type="supplementary-material"}). Next, we evaluated CYR61 expression in the presence of either PD98059, an ERK1/2 inhibitor, or SB203580, a p38 MAPK inhibitor, in Ang II-stimulated hCSMCs. Ang II increases CYR61 mRNA expression level (2.06±0.30-fold vs. the control, [Figure 6B](#F6){ref-type="fig"}), and both inhibitors completely inhibited CYR61 expression mRNA level (ERK inhibitor: 0.92±0.29-fold, p38 MAPK inhibitor: 0.59±0.19-fold vs. the control, [Figure 6B](#F6){ref-type="fig"}). Immunoblot analysis showed that the inhibition of ERK1/2 by PD98059 attenuated the expression of both CYR61 and p53 but not p16, whereas p38 MAPK inhibition by SB203580 attenuated CYR61 and p16 but not p53 ([Figure 6C](#F6){ref-type="fig"} and [Supplementary Figure 3C-G](#S3){ref-type="supplementary-material"}). These data showed that CYR61 was downstream of ERK1/2 and p38 MAPK, and directly controlled p53 expression, but not p16 in Ang II-induced hCSMCs senescence.
{#F6}
The proposed signaling pathways of Ang II-induced hCSMCs senescence were summarized in [Figure 7](#F7){ref-type="fig"}.
{#F7}
DISCUSSION
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In this study, we demonstrated that Ang II induced hCSMC senescence via AT1R, which was protected against by fimasartan. We showed that CYR61 plays an important role in Ang II-induced cellular senescence in hCSMCs. Ang II, through activating ERK1/2, p38 MAPK, p16 and p53, induces vascular senescence, and CYR61 is mediates between ERK1/2 and p53. Therefore, ERK1/2-CYR61-p53 signaling axis may be a crucial pathway regulating Ang II-induced cellular senescence ([Figure 7](#F7){ref-type="fig"}).
Vascular aging is characterized by changes in vascular structure and functions including intimal thickening and medial stiffness.[@B29] VSMCs are the primary cell type in the tunica media, and the status of VSMCs can influence the structure and the function of blood vessels. Previous reports suggested several mechanisms for the promotion of stress-induced vascular cell senescence by Ang II. For example, Ang II activates intracellular reactive oxygen species generation-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH, in turn, activates several MAPKs such as ERK1/2 and p38 MAPK, thus promoting vascular senescence.[@B28] Also, oxidative stress induced by Nox1-based NADPH oxidase plays important roles in Ang II-induced cellular senescence.[@B30]
Here, we showed that Ang II significantly induced hCSMC senescence via CYR61 expression and ARB, fimasartan, near completely inhibited CYR61-mediated cellular senescence. Given these findings, we proposed that Ang II induces hCSMC senescence via accumulated stress through CYR61 and ERK/p38 MAPK/p53 signaling pathway, and AT1R blocking effectively regulates VSMC senescence.
The main purpose of this study was to investigate Ang II-dependent vascular aging mechanism and anti-senescent effect of fimasartan. We clearly showed fimasartan completely blocks Ang II-induced senescence in hCSMCs. Moreover, we showed that CYR61 has important role in previously known Ang II-induced cellular senescence mechanisms. However, in order to clinically apply these results, we need to confirm the role of CYR61 and effect of fimasartan in animal experiments. Therefore, in future studies, it is necessary to confirm the role of CYR61 and the effect of fimasartan using the Ang II-induced animal aging model.
In conclusion, we showed that Ang II induced hCSMC senescence via CYR61 and ERK/p38 MAPK/p53 signaling pathway, and fimasartan suppressed Ang II-induced hCSMC senescence. These results provide the evidence that blockade of CYR61 may contribute to suppression of vascular aging and CVD.
**Funding:** This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) by the Korean government (MSIP & MOHW) (No. 2015M3A9B6029139).
**Conflict of Interest:** The authors have no financial conflicts of interest.
**Author Contributions:** **Conceptualization:** Lee HY.**Data curation:** Kim I, Park CS.**Formal analysis:** Lee HY, Kim I, Park CS.**Funding acquisition:** Lee HY.**Investigation:** Lee HY.**Methodology:** Kim I.**Project administration:** Lee HY.**Software:** Kim I, Park CS.**Supervision:** Lee HY.**Validation:** Kim I.**Visualization:** Kim I.**Writing - original draft:** Kim I.**Writing - review & editing:** Lee HY, Kim I, Park CS.
SUPPLEMENTARY MATERIALS
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###### Supplementary Figure 1
Ang II induces p53 and p16 expression, whereas Fima inhibits it, related to [Figure 2](#F2){ref-type="fig"}. hCSMCs were treated with Ang II at 100 nM for 4 hours, and/or pretreated Fima at 1 μM for 2 hours. Western blot analyses showed expression of (A) p53 and (B) p16 after Ang II treatment. Bar graphs show data from 3 independent experiments. Values are given as mean±standard deviation (n=3).
###### Supplementary Figure 2
Ang II-CYR61 dependent cellular senescence was mediated by the p53-dependent pathway, but not by the p16-dependent pathway, related to [Figure 5](#F5){ref-type="fig"}. hCSMCs were transfected with the indicated adenoviral vectors for 4 hours. Control were transfected with Ad-GFP. (A) CYR61 and (B) p53 expressions were increased in transfection with Ad-CYR61 (50 MOI). In contrast, (C) p16 expression was not changed. (D, E) CYR61-induced p53 expressions were increased in a MOI-dependent manner. (F, G) CYR61 inhibition by Ad-AS-CYR61 (50 MOI) significantly inhibited p53 expression, (H) whereas no significant change was observed in p16 expression. (I, J) CYR61 inhibition by Ad-AS-CYR61 (50 MOI) significantly inhibited Ang II-induced p53 expression, (K) whereas no significant change was observed in p16 expression. Bar graphs show data from 3 independent experiments. Values are given as mean±standard deviation (n=3).
###### Supplementary Figure 3
p53 expression of Ang II-induced senescent hCSMCs was through ERK/p38 MAPK/CYR61 signaling pathway, related to [Figure 6](#F6){ref-type="fig"}. (A, B) Western blot analysis shows that Ang II (100 nM, 240 minutes) induced the phosphorylation of ERK1/2 and p38 MAPK, which was inhibited by ARB, Fima (1 μM). (C, D) Ang II-induced activation of ERK and p38 MAPK are inhibited by PD98059 (20 μM, 20 minutes) and SB203580 (10 μM, 20 minutes), respectively, but ERK1/2 was activated by SB203580. (E) CYR61 expression is attenuated both by PD98059 and SB203580, (F) whereas p53 expression levels are suppressed only by PD98059. (G) Whereas p16 expression level was decreased only by SB203580, respectively. Bar graphs show data from 3 independent experiments. Values are given as mean±standard deviation (n=3).
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