text
stringlengths 1
3.78M
| meta
dict |
|---|---|
Monadic and Queue-Based Tree Search
import Control.Monad
import qualified Data.Sequence as Seq
import Test.SmallCheck
Can we define instances of MonadPlus whose search strategy can not be easily reproduced with a queue-based strategy? Are there queue-based strategies that cannot be implemented as instances of MonadPlus ?
Such instances can be used to search a tree
data Tree a = Return a | Plus (Tree a) (Tree a)
deriving ( Eq , Show )
by replacing the tree constructors with monadic operations:
searchM :: MonadPlus m => Tree a -> m a
searchM (Return x) = return x
searchM (Plus s t) = searchM s `mplus` searchM t
We want to use SmallCheck to compare search strategies so we define a Serial instance for trees.
instance Serial a => Serial (Tree a)
where
series = cons1 Return \/ cons2 Plus
coseries = coseries
If we have an implementation of a queue, i.e., an instance of the type class Queue
class Queue q
where
enqueue :: a -> q a -> q a
dequeue :: q a -> Maybe (a, q a)
then we can also search a tree by queuing its nodes:
searchQ :: Queue q => q (Tree a) -> Tree a -> [a]
searchQ q t = search (enqueue t q)
where
search q = maybe [] continue (dequeue q)
continue (Return x, q) = x : search q
continue (Plus s t, q) = search (enqueue s (enqueue t q))
Depth First Search
Depth first search can easily be implemented with the [] -instance of MonadPlus or a [] -instance of Queue , viz., a stack:
instance Queue []
where
enqueue = (:)
dequeue [] = Nothing
dequeue (x:xs) = Just (x,xs)
Indeed, searching a tree with searchM for lists and searchQ for a stack yields the same results:
prop_dfs :: Tree Bool -> Bool
prop_dfs t = searchM t == searchQ [] t
check_dfs :: IO ()
check_dfs = smallCheck 4 prop_dfs
Breadth First Search
Breadth first search can be implemented with a FIFO queue:
instance Queue Seq.Seq
where
enqueue = flip (Seq.|>)
dequeue q | Seq.EmptyL <- Seq.viewl q = Nothing
| x Seq.:< xs <- Seq.viewl q = Just (x,xs)
We can implement breadth first search as an instance of MonadPlus using matrices:
newtype Matrix a = Matrix { unMatrix :: [[a]] }
flat :: Matrix a -> [a]
flat (Matrix rows) = concat rows
instance Monad Matrix
where
return x = Matrix [[x]]
Matrix m >>= f = undefined
instance MonadPlus Matrix
where
mzero = Matrix []
Matrix xs `mplus` Matrix ys = Matrix ([] : merge xs ys)
merge :: [[a]] -> [[a]] -> [[a]]
merge [] yss = yss
merge xss [] = xss
merge (xs:xss) (ys:yss) = (xs++ys) : merge xss yss
Let's check that we have indeed implemented the same strategy with the Seq instance of Queue and the Matrix instance of MonadPlus :
prop_bfs :: Tree Bool -> Bool
prop_bfs t = flat (searchM t) == searchQ Seq.empty (mirror t)
check_bfs :: IO ()
check_bfs = smallCheck 4 prop_bfs
The queuing approach to breadth-first search visits the nodes of each level of a tree in reverse order, so we need to mirror the tree in order to get the same results.
mirror :: Tree a -> Tree a
mirror (Return a) = Return a
mirror (Plus s t) = Plus (mirror t) (mirror s)
Interleaving
We can slightly modify the [] -instance of MonadPlus to interleave results from different subtrees.
newtype Inter a = Inter { unInter :: [a] }
instance Monad Inter
where
return x = Inter ( return x)
Inter xs >>= f = Inter (xs >>= unInter . f)
instance MonadPlus Inter
where
mzero = Inter mzero
Inter xs `mplus` Inter ys = Inter (xs `inter` ys)
inter :: [a] -> [a] -> [a]
inter [] ys = ys
inter (x:xs) ys = x : inter ys xs
The only difference compared to the list monad is the implementation of mplus .
Challenge
Define an instance InterQ of Queue such that the property
prop_inter :: Tree Bool -> Bool
prop_inter t = unInter (searchM t) == searchQ emptyInterQ t
holds for all values of type Tree Bool .
Fair Interleaving
Oleg Kiselyov defines an instance of MonadPlus that can be used to fairly enumerate values of an infinite tree with better memory requirements than breadth first search.
data Stream a = Nil | Choice a (Stream a) | Incomplete (Stream a)
The data type for streams is similar to lists but has an additional constructor to postpone the computation of incomplete (not yet computed) streams.
instance Monad Stream
where
return x = Choice x Nil
Nil >>= f = Nil
Choice a r >>= f = f a `mplus` (Incomplete (r >>= f))
Incomplete i >>= f = Incomplete (i >>= f)
instance MonadPlus Stream
where
mzero = Nil
mplus Nil r' = Incomplete r'
mplus (Choice a r) r' = Choice a (mplus r' r)
mplus r@(Incomplete i) r' =
case r' of
Nil -> r
Choice b r' -> Choice b (mplus i r')
Incomplete j -> Incomplete (mplus i j)
The twist of this instance is the implementation of bind that is responsible for the good memory requirements. When starting with a Tree , bind is never called (that is why we didn't need to define it for breadth first search). Hence, good performance is only achieved when using the monadic operations directly in the computation rather than constructing a search tree first that has no occurrences of bind.
I speculate that it is difficult to define a queue-based search algorithm (that searches Tree s) with the same performance characteristics as search that is expressed directly in the Stream monad.
Mastering the Challenge
Trying to master the challenge lead to the following attemts:
First Try: Alternating Queue
What if we add left children to the front and right children to the back of the queue, always dequeing at the front ? We can achieve this effect by enqueing alternately at the front and the back of the queue.
data AlterQ a = AlterQ Bool ( Seq.Seq a)
emptyAlterQ :: AlterQ a
emptyAlterQ = AlterQ False Seq.empty
instance Queue AlterQ
where
enqueue x (AlterQ b q) = AlterQ ( not b) (ins x q)
where ins = if b then flip (Seq.|>) else (Seq.<|)
dequeue (AlterQ b q)
| Seq.EmptyL <- Seq.viewl q = Nothing
| x Seq.:< xs <- Seq.viewl q = Just (x,AlterQ b xs)
Does it pass the tests?
prop_alter :: Tree Bool -> Bool
prop_alter t = unInter (searchM t) == searchQ emptyAlterQ t
check_alter :: IO ()
check_alter = smallCheck 4 prop_alter
It doesn't. SmallCheck produces the following counter example:
Plus (Plus (Return True ) (Plus (Return True ) (Return True )))
(Plus (Plus (Return True ) (Return False )) (Return True ))
Let's examine it. We can see that all labels but one are True , so the single occurrence of False must be placed at different prositions in the compared enumerations. If we replace all labels with distinct numbers, the tree looks as follows:
((1 (2 3)) ((4 5) 6))
With the interleaving monad, the children of the root are enumerated as [1,2,3] and [4,6,5] , which are then interleaved to produce the list [1,4,2,6,3,5] .
The alternating queue evolves as follows:
(1 (2 3)) ((4 5) 6) 1 ((4 5) 6) (2 3) --> 1 (4 5) (2 3) 6 4 (2 3) 6 5 --> 4 2 6 5 3
Unlike the interleaving monad, it produces the list [1,4,2,6,5,3] .
Second Try: Toms Queue
Tom Schrijvers send me another solution that seems to work introcuding it as follows:
The code below is a bit messy still. The main idea is that the queue sort of tracks the shape of the model tree. It crucially depends on the fact that two dequeues in a row mean that a solution has been produced.
data TreeFocus a = Init0
| Init1 a
| Root
| Branch0 [NNode a]
| Branch a [NNode a]
| Branch1 [NNode a]
data NNode a = VValue a
| BBranch (NNode a) (NNode a)
data TomsQ a = TomsQ (TreeFocus a)
emptyTomsQ = TomsQ Init0
instance Queue TomsQ
where
enqueue x (TomsQ tf) = TomsQ (enq x tf)
where enq x Init0 = Init1 x
enq x Root = Branch0 [VValue x]
enq x (Branch0 p) = Branch x p
enq x (Branch1 p) = Branch0 (VValue x : p)
dequeue (TomsQ tf) = do (x,tf') <- deq tf
return (x,TomsQ tf')
where deq Root = mzero
deq (Init1 x) = return (x,Root)
deq (Branch x p) = return (x,Branch1 p)
deq (Branch1 p) = deq (ascend p)
ascend [] = Root
ascend (x:xs) = ascend' xs x
ascend' [] x = descend x
ascend' (y:ys) x = ascend' ys (BBranch y x)
descend (VValue x) = Init1 x
descend (BBranch l r) = descend' l [r]
descend' (VValue x) p = Branch x p
descend' (BBranch l r) p = descend' l (r:p)
|
{
"pile_set_name": "OpenWebText2"
}
|
That's Not Me (film)
That's Not Me is an Australian independent comedy film directed by Gregory Erdstein. It was filmed between 2015 and 2016 in Melbourne, Australia, and Los Angeles, US. The screenplay was written by Gregory Erdstein and lead actress Alice Foulcher. That's Not Me had its World Premiere in February 2017 at the Santa Barbara International Film Festival and its Australian Premiere in June 2017 at the Sydney Film Festival. It was released theatrically at selected cinemas across Australia in September 2017.
Synopsis
Cast
Alice Foulcher as Polly / Amy Cuthbert
Isabel Lucas as Zoe Cooper
Richard Davies as Jack Campbell
Belinda Misevski as Ariel
Rowan Davie as Oliver Brook
Andrew S. Gilbert at Stephen Cuthbert
Catherine Hill as Diane Cuthbert
Steve Mouzakis as Anthony
Janine Watson as Patricia Clarke
Lloyd Allison-Young as Simon
Andrew O'Keefe as John Davidson
Christopher Kirby as Cameron
Benjamin Rigby as Evan (casting director)
Ming-Zhu Hii as Corrie (director)
Arthur Angel as Nick (producer)
Paul Ashcroft as Mars
Reception
Critical response
That's Not Me has been met with positive reviews, and holds a Rotten Tomatoes approval rating of 87%.
Luke Buckmaster of The Guardian gave the film four stars, writing "An outstanding performance from emerging actor Alice Foulcher takes this lean and plucky film about stymied ambition to another level. A young and spunky cast and crew have installed in this smart and sassy dramedy a highly disciplined, tonally cohesive style. It is refreshing to see that kind of storytelling discipline particularly from a first-time film-maker."
Junkee Media called the film an "An emotionally resonant and comedic quarter life crisis… It’s a simple set-up delivered endlessly in comedy, but managed so well in That's Not Me that you remember how rare it is that balance is achieved in Australian films." The Sydney Arts Guide praised the film and performances, writing: "There’s not a dud note in That's Not Me thanks to a solid foundation in a script by Alice Foulcher and Gregory Erdstein, and anchored by a winning lead performance by Foulcher and helmed with an assured hand by Erdstein. The support casting is impeccable…Isabel Lucas is ferociously good". Jake Watt of Switch called the film "a marvel of indie ingenuity, with dollops of charm and confident direction." Karl Quinn writing for The Age said the film is "bursting with comedy, humanity and interesting ideas", the Huffington Post called it "a stunning exploration of identity, the industry and the thirst for fame…the perfect blend of comedy and tragedy”, whilst Concrete Playground praised it as "earnest, astute, insightful and thoroughly amusing. This is a movie that is both universal and unmistakably Australian – and that’s just one of many delicate balancing acts that That’s Not Me achieves".
Louise of Urban Cinefile writes that "Foulcher is a knockout. She is unselfconscious and instantly likeable. Sibling rivalry, celebrity and chasing dreams have never been so much fun in this energetic, uplifting character-driven comedy that soars as surely as the trajectory of its irresistible star”. Time Out gave the film four stars, with critic Nick Dent writing "Alice Foulcher deserves to be a lock for Best Actress [for the 2017 AACTA awards]. [She] conveys low self-esteem with the comedic flair of a Kristin Wiig." Andy Howell of Ain't It Cool writes “[Alice Foulcher] shoulders all the drama and gives one of the best twin performances I’ve ever seen... Having nuanced drama embedded in a comedy is a tightrope walk, but she’s got the skills to land it.” Leigh Paatsch of the Herald Sun gave the film a positive review, noting "a wonderful performance by Foulcher in a deceptively demanding role". Film Alert 101 suggests that Foulcher "may well be the comic talent of her age", and radio station 2ser 107.3 describes her as "absolutely superb throughout".
The film was also flagged by the Santa Barbara Independent as a Must-See Pick of the Santa Barbara International Film Festival, and sold out a number of sessions at the festival.
Accolades
At the 2017 Sydney Film Festival That's Not Me came fourth at the Foxtel Movies Audience Awards and ninth in the Top 10 Audience Awards at the 2017 Melbourne International Film Festival. Alice Foulcher received a Best Actress nomination at the 2018 Australian Film Critics Assosciation awards< for her performance in the film. That's Not Me won the award for Best Film Under $200k at the inaugural 2018 Ozflix Independent Film Awards. The film was ranked #5 of The Guardian's Top 10 Australian Films of 2017.
References
External links
Category:2017 films
Category:Australian comedy films
Category:Australian films
Category:English-language films
|
{
"pile_set_name": "Wikipedia (en)"
}
|
Autographed well-wishes from Liverpool FC dedicated to die-hard supporter Firdaus Osman, who suffered a cardiac arrest and remains in intensive care. (Photo courtesy of Faiz Osman)
*UPDATE (25 April 2016): The Changi General Hospital has said that its medical team had not advocated to the family to “pull the plug” and that its doctor’s recommendation to the family was to remove Firdaus’ breathing tube as the patient was assessed to be able to breathe on his own. The hospital said that this is a standard of care for any patient on the ventilator and that this information was also conveyed to the family. This contradicts what a member of the family said. Faiz, the younger brother of Firdaus, told Yahoo Singapore, “The doctors at CGH said he had no hope and advice (sic) my family to pull the plug”.*
A classy gesture from Liverpool FC has brought tears of joy from a Singaporean fan after he had a near-death experience.
The English football giants sent a get-well-soon card to Firdaus Osman, who is currently warded at Singapore General Hospital (SGH).
Addressed directly to him, the Reds thanked the 28-year-old for his support and the card was signed by all the first-team members, as well as head coach Jürgen Klopp.
Firdaus was admitted in critical condition earlier this month on 5 April, after suffering a sudden cardiac arrest while getting food with his colleagues after working a night shift.
His younger brother, Faiz, related to Yahoo Singapore how Firdaus was brought to Changi General Hospital (CGH) after he collapsed. His heart was determined to have stopped for around 40 minutes, but was successfully resuscitated.
“He was on life support for quite some time,” said Faiz. “It took him at least five days to open his eyes, but he still remained motionless.”
View photos
Firdaus Osman. His heart stopped for 40 minutes before he was resuscitated. (Photo courtesy of Faiz Osman)
Faiz decided to play You Will Never Walk Alone, the club’s anthem, when that happened - and was astonished when his brother responded.
“I know he is a die-hard supporter of Liverpool,” he explained. “The happiest thing to see was that he actually smiled for the first time during his coma and that brought tears of joy to us as a family. It gave us hope and belief.”
After being advised to pull the plug, the family sought a second opinion at SGH and eventually decided to transfer Firdaus there.
It was after the transfer that the idea of getting in contact with Liverpool FC occurred to Faiz. Writing in his email that he hoped they could “help him and make him happy”, he simply wanted to share his brother’s plight and did not know what kind of response to expect.
Just two days after he wrote, Liverpool responded through Chanelle Weightman, a member of their Customer Experience Team.
“I was surprised they actually sent me a personalised certificate with the autographs of all the players and the head coach,” Faiz said. “I was really happy and delighted, and I went to print and laminate it straight away.”
View photos
Story continues
|
{
"pile_set_name": "OpenWebText2"
}
|
There is nothing in the world more helpless and irresponsible and depraved than a man in the depths of an ether binge, and I knew we'd get into that rotten stuff pretty soon. – Raoul Duke
The Idiot’s Guide to a Happy Marriage: For Men
If you haven’t figured out these tricks by now, there might still be time to save your relationship. Might. So here we go. Those few days out of the month:
1. Keep a spare pair of boxing gloves on hand for defensive blocks. Think of it as a workout. Build muscle and coordination. How nice, you don’t even have to go to the gym. Hey, give it ten years and you’ll be looking sharp and buff. You should thank her.
2. Accept the fact that you are stupid and anyone who goes near her is stupid. She has a soft spot for the kids but keep kickable pets away.
3. Try extra hard to pretend you’re listening. You just might get away with it if you look up when those lips start moving faster than you can handle.
Rate this:
Share this:
Like this:
LikeLoading...
Related
Published by Edward Kowalski
Pretending to be an up and coming author. During this phase, I might have some off-the-wall comments about politics, society, and life in general. Which is not anywhere near the first two topics.
View all posts by Edward Kowalski
|
{
"pile_set_name": "Pile-CC"
}
|
Although the threat of Santa knowing if you've been bad or good might come in handy to keep kids in line during the holiday season, it turns out to be an empty one. A new study finds that Santa (read: Mom and Dad) will give children presents whether they've been naughty or nice.
Walmart conducted a national survey of parents and kids, asking various questions about holiday gift giving and getting. Eighty percent of parents said their kids will get the same number of gifts, regardless of their behavior. But Santa's hold still works over kids: 62 percent surveyed said they believed they'd get more presents if they were nice over naughty.
Mom Amber Plante told USA Today that she'd rather her two sons have fond memories of Christmas morning, rather than using it to teach a lesson: "I'd rather my boys have fuzzy memories of happy times ripping open their presents, not of being harshly taught a lesson that, frankly, could be taught any other day of the year."
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
How to calculate logarithms by using a necklace?
I have read that before the french revolution on various salons it was a popular trick to calculate logarithms just by using a necklace.
Could someone from your community explain this trick?
A:
(a) Suspend a necklace from two horizontally aligned nails. Draw the horizontal
through the endpoints, and the vertical axis through the lowest point.
(b) Put a third nail through the lowest point and extend one half of the necklace
horizontally.
(c) Connect the endpoint to the midpoint of the drawn horizontal, and bisect the
line segment. Drop the perpendicular through this point, draw the horizontal
axis through the point where the perpendicular intersects the vertical axis, and
take the distance from the origin of the coordinate system to the lowest point of
the necklace to be the unit length. We will show below that the resulting graph now has
the equation $y = \frac{(e^x + e^{-x})}{2}$ in this coordinate system.
(d) To find $\text{log}(y)$, find $(y + 1/y )/2$ on the y-axis and measure the corresponding x-value (on the necklace returned to its original form). This assumes that $y > 1$. To find logarithms of negative values, use the fact that $log(1/y ) = − log(y)$. If you seek the logarithm of a very large value, then you may end up too high on
the y-axis; in such cases you can either try hanging the endpoints closer together
or using logarithm laws to express the desired logarithm in terms of those of
lower values.
SOURCE: https://www.maa.org/sites/default/files/pdf/awards/college.math.j.47.2.95.pdf
|
{
"pile_set_name": "StackExchange"
}
|
Navigation-guided endoscopic biopsy for intraparenchymal brain tumor.
To evaluate the efficacy of intraparenchymal brain tumor biopsy using endoscopy and a navigation system (navigation-guided endoscopic biopsy) as a diagnostic tool, a case series of intraparenchymal tumor biopsies was reviewed. Navigation-guided endoscopic biopsy was applied in 9 cases, stereotactic needle biopsy in 16 cases, and open biopsy with or without navigation system in 34 cases. In all biopsy cases, 84.7% of biopsy points were sampled accurately, and 93.2% of diagnoses by biopsy were correct. Comparison of each type of biopsy showed that the resected volumes in navigation-guided endoscopic biopsy and open biopsy tended to be larger than those in stereotactic biopsy, and the mean operation time for the open biopsy procedure was the longest. To define the most applicable device or examination method to increase sampling accuracy, various factors were analyzed in 59 procedures. Navigation-guided endoscopic biopsy was the most accurate of the three types of biopsy, although the statistical difference was not significant. Older patients, histological diagnosis of high-grade glioma or malignant lymphoma, positive photodynamic diagnosis, and positive intraoperative pathology were significant factors in improving the sampling accuracy. Navigation-guided endoscopic biopsy could provide a larger sample volume within a relatively short operation time. The biopsy can be easily combined with both photodynamic diagnosis and intraoperative pathology, significantly improving the histological diagnostic yield.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
General topics of cancer vaccination
====================================
The conference started with an introductory lecture by Chris Schmidt, addressing key aspects why cancer vaccines do not work as expected. Initially, cancer vaccines were tested in the systemic disease setting and after obtaining positive results in this patient population, moved to the minimal residual disease (MRD) setting because of the hypothesis that if a vaccine worked in a macroscopic disease setting, it should work better in the MRD setting (less immunosuppression). However, in the MRD setting adjuvant vaccines have often failed, which may be due to too short follow-up periods. On the other hand, it could also be postulated that the systemic disease setting just indicates the availability of large amounts of antigen, where the vaccine can trigger an anti-vaccine T cell response that attack the tumor and in this way activate a second wave of anti-tumor CTL. This relates to the vaccine targets: a meta-analysis of all immunotherapy trials indicated that the rate of objective clinical responses is higher when undefined antigens are used as compared to defined antigens \[[@B1],[@B2]\]. This argues that many targets need to be attacked but that till now: (1) we do not know which are the relevant targets; or (2) other molecules are present in tumor extracts that influence the regulatory environment in a way that defined antigens cannot; or (3) effective immune responses only act at sites of macroscopic tumor. Another reason why cancer treatments in general and vaccines in specific fail to cure patients could be related to the issue of timing of therapy. This was addressed by Brendon Coventry, who presented data indicating that the endogenous anti-tumor immune response follows a cyclical pattern (measured by CRP) which is dependent on antigen persistence and that this cycle could likely potentially correlate with numbers of effector T cells and regulatory T cells (Treg) over time. Preliminary evidence suggests that efficacy of chemo-, radio- or immunotherapy could be boosted by appropriate timing to putative \'therapeutic windows\' in the individual patient\'s CRP cycle \[[@B3]\]. Furthermore, cancer vaccines do not encounter a naïve environment, but instead need to counter tumor-induced tolerogenic mechanisms. Treg are major players in immunosuppression, but in humans there are controversies as to the exact phenotype of these cells. Increased percentages of Treg have been described in various malignancies, but it is also important to take into account that absolute lymphocyte counts and percentage of CD4^+^T cells are also abnormal in cancer patients. Therefore, it is necessary to measure absolute numbers of Treg in blood instead of percentages. To date however, no regimen is available to reproducibly deplete Treg before proceeding to cancer vaccination. This could be due to the fact that we are looking at total Treg, which may not all be functional? This urges us to focus on identifying functional Treg. To this regard, Michael Quinn presented results about TNFRII^+^Treg, which express higher levels of FoxP3 than conventional Treg, express CCR4 (migration to tumor) and CCR7 (migration to lymph nodes -interferes with priming of anti-tumor responses). Furthermore, preliminary results indicated that although total Treg levels increase during chemotherapy, TNFRII^+^Treg are selectively depleted by chemotherapy and the remaining TNFRII^+^Treg express lower levels of FoxP3, that have a reduced suppressive capacity.
Feasibility and safety of DC vaccination in cancer patients
===========================================================
Most clinical trials conducted to date with DC vaccines are phase I feasibility studies. Despite many alterations in the immune system of cancer patients, all presenters reported that it was feasible to generate the desired numbers of DC to complete the planned vaccination scheme in most patients. However, Allan Dietz pointed out that we need to cautiously report the characteristics of the generated DC, because the phenotype of DC in trials is consistently different than in preclinical studies with normal donors. This deficiency in DC differentiation in tumor bearing patients is independent of tumor type and maturation method and there appear to be tumor-specific conditions for optimal maturation of DC.
In most of the presented studies, DC vaccination was safe, well tolerated, with minimal side effects. However, Dagmar Marx and Stefaan Van Gool reported the occurrence of some grade III/IV adverse events in a minority of patients, but this could possibly be related to disease localization in the brain (both studies in brain tumors) \[[@B4],[@B5]\]. Some participants reported the induction of auto-immune effects like vitiligo, but in general most participants agreed that some degree of auto-immunity is probably beneficial for DC vaccine efficacy.
Patient selection
=================
As outlined above, it was originally hypothesized that DC vaccines should perform better in the MRD setting as compared to patients with widespread disease. However, this does not always appear to be the case, which is possibly due to the altered immune system in cancer patients and the high degree of immunosuppression. Therefore, it would be ideal if we could select patients that are likely to benefit from DC vaccination. To this regard, Angus Dalgleish reported on a study where pre-vaccine sera from responders and non-responders were compared. This led to the identification of molecules that can distinguish responder patients from the non-responder group with 67% sensitivity and 100% specificity. All identified molecules are pro-inflammatory and are increased in the non-responder population; however, no details were given about the exact nature of these molecules. Bart Neyns reported that baseline CRP, LDH, and WHO performance status can also identify melanoma patients likely to benefit from DC vaccinations. Chris Schmidt showed that low S-100B predicts response to treatment in melanoma. Allan Dietz presented data showing that suppressive monocytes are increased in several malignancies and these cells mediate a global immune paralysis. Suppressive monocytes were found to be prognostic for cancer survival independent of therapy \[[@B6],[@B7]\]. Selection of patients on the basis of the CRP inflammatory cycle was also raised by Brendon Coventry as a possibility for patient selection with respect to timing of administration and targeting of therapy, in order to induce the desired immune response.
Clinical effects of DC vaccines
===============================
Clinical responses are of course largely affected by the setting in which vaccination occurs (measurable disease versus MRD), the type of cancer and the life expectancy of the patients. Furthermore, the evaluation of clinical efficacy can be impeded by the application of concurrent or subsequent therapeutic regimens. Moreover, most trials conducted to date are phase I clinical trials in which clinical efficacy is very difficult to assess. Nevertheless some promising results have been obtained. In general, long-term objective responses (CR or PR) are observed in a minority of patients, while a greater proportion of patients presents with disease stabilization. In particular, Bart Neyns pointed out that stabilization is often followed by disease regression and that clinical responses could be delayed even up to several months after initiation of treatment, indicating an immune-related response pattern (as described for anti-CTLA4 therapy). Therefore, immune-related response criteria (irRC) may be more relevant than RECIST/WHO criteria for the assessment of anti-tumor activity \[[@B8],[@B9]\]. Furthermore, most participants agree that long-term disease stabilization resulting in prolonged survival is also a relevant clinical outcome, which is of benefit for patients. The typical slow response pattern observed also indicates that DC vaccination is no option for patients with rapidly progressing disease and that patient selection is critical.
Immune response monitoring after immunotherapy
==============================================
The rationale behind DC-based immunotherapy is that injected DC will induce a tumor-specific immune response resulting in tumor shrinkage/clearance. So, ideally we should be able to identify patients that respond to therapy by analyzing the anti-tumor immune response generated by the DC vaccine. However, to date, limited studies show a correlation between immune responders and clinical responders, indicating that either we are not analyzing the right portion of the immune response or that the mode of action (MOA) of DC vaccines is not as expected. Chris Schmidt emphasized that we should monitor responses to the tumor and not only to the vaccine and they also observed that DC from complete responders surprisingly had lower IL-12p70/IL-10 ratios, which is not conform the stereotype of immunogenic DC. Viggo Van Tendeloo and Massimo Di Nicola reported that higher levels of activated NK cells correlated with clinical response, indicating that DC vaccines not only act on the T cell response but also on innate immunity \[[@B10],[@B11]\]. Massimo Di Nicola used killed autologous tumor cells to load DC and observed that killed tumor cell preparations from responding patients showed higher calreticulin and heat shock protein 90 expression compared to non-responders, indicating immunogenic tumor cell death is needed to obtain responses with tumor lysate pulsed DC \[[@B12]\]. The group of Jolanda de Vries developed a skin test where the skin-infiltrating lymphocytes (SKILS) in DTH sites are tested for antigen specificity. The presence of tumor-specific SKILS correlated with survival and can thus be used as a predictor of clinical response \[[@B13],[@B14]\]. Despite the fact that in most studies a correlation between immune response and clinical efficacy could not be established, Antoni Ribas suggested that, in future trials, immune monitoring studies need to be expanded and associated with the observed clinical responses to assess the underlying immune mechanisms and the MOA of DC vaccines.
Maximizing DC biology potential
===============================
Initial studies on DC vaccination predominantly used immature or cytokine matured DC. However, since then several improvements have been developed to enhance the DC\'s capacity to stimulate T cells and even circumvent immunosuppression. Bart Neyns presented data from so-called TriMix DC, i.e. DC transfected with mRNA encoding constitutively active TLR4 (caTLR4), CD40L and CD70. These TriMix DC are highly mature and secrete high levels of IL-12p70. When co-transfected with TAA encoding mRNA, TriMix DC induce potent TAA-specific CTL in advanced melanoma patients \[[@B15]\]. CD4^+^T cells are essential for the induction of potent CTL response, but data concerning Th cell induction by DC vaccines are scarce. Martin Cannon highlighted that we should try to redirect DC-activated Treg responses to anti-tumor Th17 responses since it was shown in ovarian cancer that these 2 cell types are inversely correlated and that tumor-associated polyfunctional Th17 cells are associated with improved clinical outcome \[[@B16]\]. Therefore, they treated DC with IL-15 and a p38 MAPK inhibitor and these cells are capable of inducing TNFα^+^FoxP3^-^IL-17 secreting CD4^+^T cells that show reduced PD-1 expression and tumor-specific CTL. DC treated with IL-15 and p38 MAPK inhibitor show decreased expression of B7-H1 and reduced IDO activity. Scott Pruitt presented data of local delivery of immune modulators by DC. Therefore, DC were transfected with RNA encoding the GITRL fusion protein and/or anti-CTLA4 mAb. These mediators are then produced locally by DC, thereby preventing side effects that occur with systemic administration as observed with anti-CTLA4 mAb \[[@B17]\]. Previous studies have shown that injected DC poorly traffic to lymph nodes where they should interact with T cells. Jeffrey Weber therefore designed a system to attract T cells to the injection site and induce in this way and \"artificial lymph nodal aggregate\" for T cell priming. To achieve this, DC are adenovirally transduced with CCL21/SLC and pulsed with peptides. The trial is still ongoing, but immunohistochemical analysis of the injection site shows substantial T cell infiltration. Another intriguing approach consists of redirecting the immune response from an anti-tumor response to an anti-viral response. Dagmar Marx and Volker Schirrmacher reported studies combining DC with the oncolytic Newcastle Disease Virus (NDV). NDV mediates lysis of tumor cells, either *in vitro*to pulse DC with viral oncolysates or *in vivo*to provide a supply of tumor antigens in the body of the patients. The tumor cells then present viral antigens to which a more potent immune response can be generated since there is less tolerance and the virus itself also drives DC polarization towards Th1 inducers \[[@B18]-[@B21]\].
Combination strategies
======================
Increasing evidence suggests that DC vaccines on their own are not capable to induce tumor regression in a substantial amount of patients, but should instead be used in combinatorial approaches. Many potential rationales exist for combination of DC with chemotherapy. Chemotherapy could have effects on MDSC and/or Treg, could increase the susceptibility of tumor cell apoptosis or lead to increased tumor cell immunogenicity, as shown by Angus Dalgleish. He also postulates that combination with immune response modifiers like low dose IL-2, Imiquimod or IMiDs would also be promising. Antoni Ribas showed data from a trial combining DC vaccines with the anti-CTLA4 mAb Tremelimumab, in which 4/16 patients experienced long term responses \[[@B22]\]. Jolanda de Vries presented data about the combination of DC vaccines with Daclizumab pre-treatment to deplete Treg, but although TAA-specific T cells could be generated, these T cells had impaired effector functions and the combination did not result in a significant effect on survival \[[@B23]\]. An attractive idea is to combine DC vaccines with adoptive T cell transfer, where DC vaccines could first prime tumor-specific T cells *in vivo*, which could subsequently be expanded *ex vivo*and then be given back to the patients. This type of combination was presented by Isabel Poschke and Gunnar Kvalheim, but studies are still ongoing. This type of combination is also complicated by the high costs. Another rationale is to incorporate DC vaccination in the standard of care (SOC) treatment if available. Surasak Phuphanich and Stefaan Van Gool presented results from this approach, with positive effects on patient survival \[[@B4],[@B5],[@B24]-[@B26]\].
Approved immunotherapeutic vaccines
===================================
Provenge^®^or Sipuleucel-T from Dendreon received the first approval for a cell-based immunotherapy and hence is an important step in the development of similar strategies. This therapeutic vaccine was briefly discussed during the meeting. Historically, this vaccine is categorized as a DC vaccine, although it does not consist of \"pure\" DC; hence the term antigen pulsed activated peripheral blood mononuclear cells is probably more correct. The latest phase III trial demonstrated that the effect is merely noted on overall survival (4 month survival benefit), with less evidence of an antitumor effect (1/341 PR, 3% of patients with 50% PSA decrease). Two thirds of patients receiving sipuleucel-T developed antibody responses, and nearly three fourths had T cell proliferative responses. Survival was improved for patients who had an antibody response but not for those with a T cell response. Although these data are encouraging, they also highlight again that still very little is known about the real MOA of such immunotherapeutics. Furthermore, the high cost of such treatments may impact its use and further development \[[@B27],[@B28]\]. It would also be very interesting to investigate whether the effect of Provenge^®^can be enhanced by combination with approaches aiming at modulating the immunosuppressive environment.
Discussion
==========
The general discussion of the meeting focused on a few key questions to rapidly move DC vaccination forward.
The first part of the discussion concentrated on the discrepancy between proof of principle and proof of efficacy. Most participants agree that the desired endpoint is clinical activity (OS, PFS, overall response rate) and that immune monitoring is less important. The main problem with this point of view is that efficacy data are difficult to obtain in phase I clinical trials, so a controlled trial would need to be performed. Other variables that can affect the selection of the desired endpoint is whether the patient population is homogeneous or heterogeneous, whether there is bulk tumor or minimal residual disease\... It is probably best to carefully select patients and assess safety and MOA in a phase I trial and then rapidly move to randomized controlled trials. Alternatively, vaccination could be added to the SOC and comparative effectiveness research could be performed. When focusing on the response rate, responses (CR, PR or even SD) should always be prolonged in time. Besides assessing clinical efficacy, immune monitoring studies are critical to understand the MOA of DC vaccines and also reporting of vaccine characteristics remains crucial in this regard.
Another discussion point focused on the question why clinical data are disappointing. Probably this relates to our ignorance about the MOA of DC vaccines. Till now, there are no convincing data about the timing of vaccination, how frequently we need to vaccinate and for which period of time. Nevertheless, the approval by the FDA of Provenge^®^, the first cellular immunotherapeutic, has paved the way for further development of DC vaccines and will certainly boost the field further.
Furthermore, we urgently need to get more knowledge about how to efficiently skew immune responses towards the desired phenotype for tumor eradication. Studies to resolve these issues are thus warranted. Furthermore, the concept that DC vaccines should be regarded as bystander therapeutics urges us to go ahead with the rational design of combinatorial approaches with chemotherapeutic regimens, other immunotherapeutic regimens aiming at breaking tolerance, immune response modifiers or targeted therapies (anti-angiogenic molecules, STAT3 inhibitors,\...).
Next, the discussion moved to the issue of patient selection for inclusion in DC trials. The rationale argues for inclusion of less advanced patients in which we should then be able to follow a tumor marker to assess efficacy. However, is a patient that can mount an immune response really an end stage patient? Furthermore, it is not ethical to treat patients with DC vaccines if they can still benefit from a SOC treatment. Therefore, it was proposed to try to integrate DC vaccination in the SOC treatment if available or try to combine DC vaccination with available treatment approaches. On the other hand, patients should be carefully selected before inclusion in DC trials to obtain maximal benefit as possible, based on baseline characteristics that are known to correlate with improved outcome and on the aggressiveness of the disease progression.
Finally, how can we improve the potential of DC therapy? Ideally, we should move from *ex vivo*generated DC to purified myeloid or plasmacytoid DC or even *in vivo*DC targeting, but before this can be pursued we need to better understand the immunoregulatory network. The use of multiple defined antigens or the whole tumor antigenic spectrum is encouraged to avoid escape and to induce a broad response, even if this implies the risk to induce some auto-immune effects, which seems to be beneficial for DC vaccine efficacy. Furthermore, studies should focus on the induction of broad polyfunctional immune responses encompassing both innate and adaptive immunity.
In conclusion, this meeting brought together experts in different aspects of DC vaccine development and provided a platform for exchange of ideas, interesting new findings, encountered barriers and potential innovative new approaches. Hopefully this cross-fertilization between scientists will result in the translation to successful clinical trials that can move forward the DC vaccination approach.
List of abbreviations
=====================
CR: complete response; CRP: C-Reactive Protein; CTL: cytotoxic T lymphocyte; DC: dendritic cell; DTH: delayed type hypersensitivity; IMiD: immunomodulatory drug; irRC: immune-related response criteria; LDH: lactate dehydrogenase; MDSC: myeloid-derived suppressor cells; MOA: mode of action; MRD: minimal residual disease; NDV: Newcastle disease virus; NK: natural killer cell; OS: overall survival; PFS: progression-free survival; PR: partial response; RECIST: response evaluation criteria in solid tumors; SD: stable disease; SKILs: skin-infiltrating lymphocytes; SOC: standard of care; TAA: tumor-associated antigen; Th cell: T helper cell; TLR: toll-like receptor; Treg: regulatory T cell; WHO: World Health Organization.
Competing interests
===================
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Appendix: Meeting participants
==============================
Zwi Berneman, University Hospital, Antwerp, Belgium
Martin Cannon, University of Arkansas for Medical Sciences, Little Rock, USA
Raja Choudhury, Karolinska Institute, Stockholm, Sweden
Brendon Coventry, University of Adelaide, Adelaide, Australia
Angus Dalgleish, St George\'s University of London, London, UK
Jolanda de Vries, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
Allan Dietz, Mayo Clinic, Rochester, USA
Massimo Di Nicola, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
Steve Emery, German Cancer Research Center, Tumor Immunology Program, Heidelberg, Germany
Rolf Kiessling, Karolinska Institute, Stockholm, Sweden
Gunnar Kvalheim, Oslo University Hospital, Oslo, Norway
Dirk Lorenzen, Institute for Tumor Immunology, Duderstadt, Germany
Dagmar Marx, Institute for Tumor Immunology, Duderstadt, Germany
Bart Neyns, Brussels University Hospital, Brussels, Belgium
Surasak Phuphanich, Cedars-Sinai Medical Center, Los Angeles, USA
Isabel Poschke, Karolinska Institute, Stockholm, Sweden
Scott K. Pruitt, Duke University Medical Center, Durham, USA
Michael A. Quinn, University of Melbourne, Melbourne, Australia
Antoni Ribas, University of California at Los Angeles, Los Angeles, USA
Volker Schirrmacher, German Cancer Research Center, Tumor Immunology Program, Heidelberg, Germany
Chris Schmidt, Queensland Institute of Medical Research, Brisbane, Australia
Inge Marie Svane, Department of Oncology, Copenhagen University Hospital, Denmark
Kris Thielemans, Brussels University Hospital, Brussels, Belgium
Stefaan Van Gool, Pediatric Neuro-oncology, University Hospital Leuven, Catholic University of Leuven, Belgium
Viggo Van Tendeloo, University Hospital, Antwerp, Belgium
Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, USA
Acknowledgements
================
The author would like to express her sincere gratitude to the speakers at the Dendritic Cell Therapy for Oncology Roundtable Conference for their open-minded participation to the conference and valuable feedback during the preparation of the report.
|
{
"pile_set_name": "PubMed Central"
}
|
Q:
How to send cookie containing an unicode character in https GET request using poor windows sockets
I'm creating win32 application and I work with one particular site. From previous requests I extracted some cookies and I want to implement them. But the problem is, one of these cookies contains unicode letter (latyn small letter e with dot above; 279 in ASCII table). It is the only cookie which is url-encoded. When decoding, I get char \u0117 and visual studio compiler gives me warning that it is unicode char and treats it as ? mark.
This is url-encoded cookie:
Set-Cookie: logged_user=%7B%22id%22%3A%22625936%22%2C%22email%22%3A%22vytautas.leveris%40gmail.com%22%2C%22display_name%22%3A%22Vytautas+L%5Cu0117veris%22%2C%22full_name%22%3A%22Vytautas+L%5Cu0117veris%22%2C%22photo%22%3A%22https%3A%5C%2F%5C%2Fwww.15min.lt%5C%2Fassets%5C%2Fimages%5C%2Fuser-default-icon.png%22%2C%22photo_small%22%3A%22https%3A%5C%2F%5C%2Fwww.15min.lt%5C%2Fassets%5C%2Fimages%5C%2Fuser-default-icon.png%22%2C%22photo_normal%22%3A%22https%3A%5C%2F%5C%2Fwww.15min.lt%5C%2Fassets%5C%2Fimages%5C%2Fuser-default-icon.png%22%2C%22staff%22%3Afalse%2C%22bookmarks%22%3A2%2C%22nb%22%3A1%7D; path=/
This is url-decoded cookie:
Set-Cookie: logged_user={\"id\":\"625936\",\"email\":\"vytautas.leveris@gmail.com\",\"display_name\":\"Vytautas L\u0117veris\",\"full_name\":\"Vytautas L\u0117veris\",\"photo\":\"https:\/\/www.15min.lt\/assets\/images\/user-default-icon.png\",\"photo_small\":\"https:\/\/www.15min.lt\/assets\/images\/user-default-icon.png\",\"photo_normal\":\"https:\/\/www.15min.lt\/assets\/images\/user-default-icon.png\",\"staff\":false,\"bookmarks\":2,\"nb\":1}; path=/
And finally, all http GET request:
strcpy(request,"GET / HTTP/1.1\r\nHost: www.15min.lt\r\nCookie: PHPSESSID=652e6dd2ac78de5db5392e53b9a0355a; logged_user={\"id\":\"625936\",\"email\":\"vytautas.leveris@gmail.com\",\"display_name\":\"Vytautas L\u0117veris\",\"full_name\":\"Vytautas L\u0117veris\",\"photo\":\"https:\/\/www.15min.lt\/assets\/images\/user-default-icon.png\",\"photo_small\":\"https:\/\/www.15min.lt\/assets\/images\/user-default-icon.png\",\"photo_normal\":\"https:\/\/www.15min.lt\/assets\/images\/user-default-icon.png\",\"staff\":false,\"bookmarks\":2,\"nb\":1}; remember_me=625936; device_token_625936=84c45e719fedc5949ced93ca0df54152\r\nUser-Agent: WindowsSockets2\r\n\r\n");
As I send message through winsock, I use char type.
Do I need to convert everything to wchar_t*? But then what about sending wchar_t* to server? Or perhaps I could change this character representation \u0117 into UTF8 char sequence? Any help and comments would be welcom.
A:
I'd recommend to treat the data as opaque sequence of bytes, i.e., convert you custom data to UTF-8 bytes, run base 64 and use it as cookie value. See also: https://stackoverflow.com/a/49205256/696632. Then reverse the operation on the receiver side. You will probably require unsigned char*for the opaque byte data.
|
{
"pile_set_name": "StackExchange"
}
|
Factors affecting the moisture permeability of lipid-based edible films: a review.
Moisture transfers inside food products could be controlled or limited by the use of edible films. These are usually based on hydrophobic substances such as lipids to improve barrier efficiency. Water permeability of films is affected by many factors, depending on both the nature of barrier components, the film structure (homogeneous, emulsion, multilayer, etc.), crystal type, shape, size and distribution of lipids, and thermodynamics such as temperature, vapor pressure, or the physical state of water in contact to the films. After a brief presentation of lipids and hydrophobic substances used as moisture barrier, cited in the scientific literature, this article reviews all of the parameters affecting barrier performances of edible films and coatings.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Background
==========
Anterior cruciate ligament (ACL) injury leads to knee joint instability \[[@B1]\] and failure to return to sports activities at the same level \[[@B2]\]. After ACL injury, rehabilitation can last for six months or longer before an athlete can return to sports activity \[[@B3]\]. Osteoarthritic changes can be found even when ACL reconstruction is performed \[[@B4]\]. Therefore in recent years, prevention of ACL injuries has become a key issue. Most ACL injury prevention training programs are composed of plyometrics, balance training, agility training, and instructions to avoid the characteristic stance that is slight knee flexion and forceful valgus rotation associated with ACL injury \[[@B5]-[@B10]\]. Although the subjects and details of the training programs are different, the results show a decrease in the incidence of ACL injury \[[@B5]-[@B9]\].
Some research studies have investigated the effects of training programs on knee kinematics during landing tasks; however the results were different among the studies \[[@B11]-[@B14]\]. An increase in knee flexion has been reported as a result of conducting plyometric training \[[@B11]\], plyometric or balance training \[[@B12]\], and videotape feedback \[[@B13]\]. Only Myer et al. \[[@B12]\] reported changes in the kinematics of the knee in the frontal plane, i.e., both plyometric and balance training decreased the knee abduction angle during a medial drop landing. In other studies \[[@B11],[@B14]\], no differences in knee valgus were found after plyometric or agility training. Among all these studies, knee kinematics have only been analyzed in the sagittal and frontal plane. Even though tibial rotation is usually observed at the time of ACL injury, the effects of training programs for knee kinematics in the horizontal plane has not yet been analyzed.
Other research studies investigated the effects of training programs on electromyography during athletic tasks; however activation of mainly the hip-musculature has been reported \[[@B11],[@B15],[@B16]\]. DeMorat et al. \[[@B17]\] ascertained that aggressive quadriceps loading with the knee in slight flexion produces significant anterior tibial translation and internal tibial rotation and leads to ACL injury. Chappell et al. \[[@B18]\] reported that females tend to have greater quadriceps activation before landing than males. Pre-activation is thought to be important for the dynamic stability of the knee. Thus, it is necessary to evaluate the effects of ACL injury prevention training programs on the electromyography of the quadriceps and hamstrings of female athletes including pre-activation.
Thus, the purpose of this study was to determine the effects of a jump and balance training program on knee kinematics including tibial rotation as well as on electromyography of the quadriceps and hamstrings in female athletes. Since the training program aims at reducing ACL injury, subjects were instructed to avoid landing with their body in the characteristic position of ACL injury, which includes slight knee flexion and valgus rotation with either internal or external tibial rotation \[[@B19]-[@B21]\]. Furthermore, for the training program to be successful, hamstrings activation should increase to counteract against aggressive quadriceps loading. Therefore, our hypothesis was that training will increase knee flexion angle, decrease knee valgus, decrease internal tibial rotation, and increase hamstrings activation before ground contact during a single limb landing.
Methods
=======
Population
----------
Eight female basketball athletes belonging to Waseda University basketball team participated in this study. Exclusion criteria included any lower extremity reconstructive surgery in the past two years or unresolved musculoskeletal disorders that prohibited subjects from participating in sports. The average age of the subjects was 19.4 (0.7) yrs (Mean (SD)), the average height was 1.70 (0.05) m, the average weight was 64.1 (7.8) kg and the average BMI was 22.2 (1.6). Prior to participation, each subject signed a Human Subjects Informed Consent Document approved by Waseda University ethics committee.
Experimental Task
-----------------
All subjects performed a single limb drop landing from a 30 cm platform as described in a previous study \[[@B22]\]. The subjects were instructed to put their hands on their lower torso, stand on their right foot, and jump 30 cm away from the platform. The subjects were to land on their right foot in a neutral position. Upon landing, each subject was instructed to place their center of mass as far forward as possible in an attempt to limit horizontal motion and land without jumping up. Throughout the experiment, the subjects were barefooted to exclude the influence of differences in their shoes. Subjects were allowed several preparation trials until they could conduct the experimental task precisely. Measurement was continued until three successful trials were accomplished consecutively. We defined a failed trial when the subjects (1) could not maintain a single limb landing position, (2) landed farther than or within 30 cm of the platform, or (3) jumped up from the platform. Subjects took a sufficient rest period between the trials to avoid the effects of fatigue. The experimental task was performed three times: the initial test (Pre-training 1), five weeks later (Pre-training 2), and one week after completing training (Post-training). The training program began two weeks after the second experimental task and lasted for five weeks.
Data Collection
---------------
All experiments took place at the National Rehabilitation Center for Persons with Disabilities in Saitama, Japan. A seven camera VICON 370 motion analysis system (Oxford Metrics Ink., Oxford, UK) was used to record the 3-D movements of the lower limb. The laboratory was equipped with 2 force plates (9287A; Kistler Japan Co., Ltd., Tokyo, Japan). The motion and force data were recorded at 200 Hz and 1000 Hz, respectively.
For each subject, 24 markers of 9 mm diameter were secured to the lower limb using double-sided adhesive tape as described in a previous study \[[@B22]\]. The markers were used to implement the Point Cluster Technique (PCT) \[[@B23]\]. The PCT provides a minimally invasive estimation of the *in vivo*motion of the knee. By using a cluster system of skin markers on a limb segment, the PCT assumes to cancel out the noise resulted from skin deformation. We developed our algorithm of the PCT following the procedure described by Andriacchi et al. \[[@B23]\]. The knee kinematics, including knee flexion/extension, valgus/varus, and internal/external tibial rotation as well as the anterior/posterior tibial translation, were calculated using the joint coordinate system proposed by Grood and Suntay \[[@B24]\].
Simultaneous electromyographic activity of the rectus femoris (RF), biceps femoris (BF) and semimembranosus (SM) were measured. Pre-amplified surface Ag/AgCl electrodes sensors (DelSys, Inc., Boston, USA) were used to detect muscular activity. A single-ended amplifier (gain = 1000) was used, while the common mode rejection rate was -92 dB. Double-sided adhesive strips were used to adhere the electrodes to the subject\'s skin. Additionally surgical tape (NICHIBAN Co., Ltd. Tokyo, Japan) was placed over the electrodes as well as around the thigh and shank to retard movement of the electrodes on the skin that would cause movement artifacts. The surface electromyography (EMG) electrodes were placed at the midpoint between the top of the patella and the anterior superior iliac spine over the muscle belly of the RF as well as at a point located distally at one-third of the distance between the knee-joint space and the ischial tuberosity over the muscle bellies of the BF and the SM. A reference electrode was placed on the head of the fibula. The EMG data was recorded at 1000 Hz.
EMG data were recorded 1) while the subjects performed a maximum voluntary knee flexion and extension at 60 degrees of knee flexion against a resistance for three seconds, 2) during a static trial, i.e., while the subjects remained in a standing position for 1 second, and 3) while the subjects performed the single limb drop landing as previously described.
Training Program
----------------
Training lasted approximately 20 minutes a day, 3 days a week for 5 weeks. The program was developed based on a thorough review of the literature \[[@B6],[@B25]-[@B27]\] (Table [1](#T1){ref-type="table"}). Because the exisiting programs last for considerably long durations, this program was newly designed in order to decrease the training time to 20 minutes. During training, subjects practiced their fundamental basketball skills and additionally carried out jump and balance training to increase their landing skills. During the first three weeks of training, the technique phase (Phase1) which focused on improving the subject\'s landing technique was implemented. Three basic techniques were stressed: 1) a soft landing with a great bend to the hip, knee and ankle joint; 2) landing on the ball of the foot with the trunk leaning forward; 3) keeping the subject\'s knee neutral without medial motion. The last two weeks of training, the performance phase (Phase2), focused on increasing the intensity of training and on the use of proper techniques throughout several movements. A trainer or therapist attended the training every time and instructed the athletes to learn these landing techniques throughout each training session.
######
Description of the exercises performed during the jump and balance training
Exercise Time or Repetitions Exercise Time or Repetitions
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- --------------------- ------------------------------------ ---------------------
***Phase1: Technique*** ***Phase2: Performance***
1\. Squat jumps 20 sec 1\. Squat jumps 20 sec
2\. 180°jumps 20 sec 2\. Scissors jumps 20 sec
3\. Single leg balance 20 sec 3\. Single leg balance and pass 20 sec
4\. Hop jump (both leg) 20 sec 4\. Hop jump (single leg) 20 sec
5\. Broad jump and hold 28 m 5\. Single-leg hop and hold 14 m/leg
6\. Crossover hop, hop, hop, stick 28 m 6\. Crossover hop, hop, hop, stick 28 m
**Squat jumps**: Drop into deep knee, hip, and ankle flexion and then take off into a maximal vertical jump. On landing, immediately return to the starting position and repeat the initial jump.
**180°jumps**: Initiates a 2-footed jump with a direct vertical motion combined with a 180°rotation in midair, keeping arms away from the body to help maintain balance. When landing, immediately reverses this jump to the opposite direction.
**Single-leg balance (and pass)**: This drill is performed on a balance device that provides an unstable surface. Begin by standing on one foot on the device. After the subject has improved, the training drills can incorporate ball catches and passes.
**Hop jumps**: Start by standing next to a small square balance board. Hop onto the board and then hop off on the opposite side. Repeat hopping on and off the board.
**Broad jump and hold**: Begin by swinging arms forward and jumping horizontally and vertically at approximately a 45°angle to achieve a maximum horizontal distance. The athlete lands with her knees flexed to approximately 90°.
**Crossover hop, hop, hop, stick**: Start on a single limb and jump at a diagonal across the body landing on the opposite limb with the foot pointing straight ahead and immediately redirect the jump in the opposite diagonal direction.
**Scissors jumps**: Start in a stride position with one foot well in front of other. Jump up, alternating foot positions in midair.
**Single-leg hop and hold**: Initiate the jump by swinging the arms forward while simultaneously extending at the hips and knees. The jump should carry the athlete up at an angle of approximately 45°and attain maximal distance for a single-leg landing. The subject is instructed to land on the jumping leg in deep knee flexion.
Data Analysis
-------------
The coordinate data obtained from the markers were not smoothed because of the expected noise-canceling property of the PCT. In each trial, we calculated the angular displacements of flexion/extension, valgus/varus, and internal/external tibial rotation using the PCT. The reference position for these measurements was obtained during the static trial. Cerulli et al. \[[@B28]\] reported that ACL strain begins to increase prior to landing and reaches a peak that corresponds to the peak ground reaction force. Therefore, we extracted each variable at the time of foot contact, as well as displacement from the event of foot contact to the event of peak vertical ground reaction force (i.e. during the landing). Moreover, we normalized the event of foot contact to the event of peak vertical ground reaction force as 100%.
The root mean square (RMS) of the EMG data was calculated for each trial. The EMG activities of the two hamstrings muscles were averaged together to represent the whole activity of the hamstrings (Ham). For the maximum voluntary contraction, the EMG data were recorded when the subject performed a maximum voluntary knee flexion and extension at 60 degrees of knee flexion against a manual resistance for three seconds. If the strength of their knee extension was greater than the manual resistance, some research assistants cooperated to provide additional resistance to their motion. The RMS of the EMG data was calculated and the mean RMS of the middle one second was used to normalize the dynamic contraction recorded during the landing (%MVC). The hamstrings/quadriceps (quadriceps refers to the rectus femoris in this experiment) ratio (HQR) was calculated to define the flexor muscle activation relative to the extensor muscle activation. The HQR was calculated according to procedures outline by Bencke et al. \[[@B15]\]. Average %MVC (RF and Ham) and HQR data output was computed during each of the following time frames: 1) 50 ms before foot contact and 2) 50 ms immediately after foot contact. The time period 50 ms before foot contact indicates pre-activity of these muscles. Considering an electromechanical delay of about 50 ms \[[@B29]\], the pre-activation force corresponds to the time before foot contact. The time period 50 ms after foot contact was chosen since a previous study found that the activity of the knee extensors peaked 46 ms after toe contact while the knee flexors showed minimum EMG activity \[[@B15]\]. It is thought that these activities include spinal reflexive neuromuscular activities \[[@B30]\].
The mean kinematics and electromyographic data of each subject were calculated from 3 successful trials. A repeated ANOVA with post-hoc Bonferroni tests was employed for statistical analysis of the kinematics data. Because the %MVC and HQR data did not distribute normally, a Friedman test with Wilcoxon matched-pairs signed rank test was employed for statistical analysis of these data. Each analysis was used to calculate differences with respect to the three time periods. Differences between preliminary trials 1 and 2 were considered as the changes due to the control session; these changes indicate the effects of learning from the landing task and day-to-day individual variation. Differences between preliminary trial 2 and the post-trial were considered as effects of the training session, which indicates how the training program influenced the subjects\' landing patterns. All statistical comparisons were performed with the level of significance set at p \< 0.05. Intra-class correlation coefficients (ICC (1, 3)), based on multiple same-day trials for kinematics and electromyographic data, and standard error of measurement (SEM) were calculated and are described in Table [2](#T2){ref-type="table"}. These data indicate substantial or almost perfect reliability \[[@B31]\].
######
ICC (1, 3) and SEM for kinematics and electromyographic data
Position at foot contact (deg)
----------- ----------------------------------- ------------------ ------- --------
Flexion Ext. tibial rot. Varus
ICC 0.93 0.94 0.95
SEM (deg) 1.80 1.42 0.61
Displacement during landing (deg)
Flexion Int. tibial rot. Varus Valgus
ICC 0.96 0.87 0.64 0.86
SEM (deg) 1.41 2.18 1.22 0.39
Electromyographic data (%MVC)
Rectus femoris Hamstrings
ICC 0.79 0.62
SEM (%) 10.84 9.49
ICC: Intraclass correlation coefficients
SEM: Standard error of measurement
Results
=======
Kinematics Data
---------------
Mean joint kinematics during the single limb drop landing is illustrated in Figure [1](#F1){ref-type="fig"}. Regarding the position of the knee at foot contact, the knee flexion angle for the Post-training trial was significantly larger than that for the Pre-training 2 trial (p \< 0.01) (Table [3](#T3){ref-type="table"}). Regarding rotational displacements that occurred during landing, the absolute change in knee flexion for the Post-training trial was significantly larger than that for the Pre-training 2 trial (p \< 0.001) (Table [4](#T4){ref-type="table"}). No other significant differences between kinematic data could be detected. The observed statistical power of ANOVA for knee flexion, internal tibial rotation, and knee valgus of the tibia at foot contact was 0.96, 0.13, and 0.12, respectively. While, the observed statistical power of ANOVA for the absolute change in knee flexion, internal tibial rotation, and knee valgus during the landing were 1.00, 0.21, and 0.56, respectively.
{#F1}
######
Mean (SE) values of position at foot contact Pre-training 1, Pre-training 2, and Post-training (deg)
Flexion External tibial rot. Varus
---------------- -------------- ---------------------- -----------
Pre-training 1 19.5 (2.4) 1.9 (2.2) 1.3 (0.9)
Pre-training 2 19.3 (2.5)\* 0.3 (2.5) 0.1 (1.2)
Post-training 24.4 (2.1)\* 1.1 (2.0) 0.6 (1.1)
\*: p \< 0.01 between Pre-training 2 and Post-training
######
Mean (SE) values of rotational displacement during the landing Pre-training 1, Pre-training 2, and Post-training (deg)
Flexion Internal tibial rot. Varus Valgus
---------------- ---------------- ---------------------- ----------- -----------
Pre-training 1 31.6 (2.5) 12.3 (1.4) 1.4 (0.3) 2.8 (0.6)
Pre-training 2 34.3 (2.5)\*\* 13.8 (1.8) 1.3 (0.3) 3.7 (0.7)
Post-training 40.2 (1.9)\*\* 13.3 (2.0) 1.3 (0.4) 4.1 (0.6)
\*\*: p \< 0.001 between Pre-training 2 and Post-training
Electromyographic Data
----------------------
For the 50 ms before foot contact, the %MVC of the Ham in the Post-training trial was significantly greater than that in the Pre-training 2 trial (p \< 0.05), while no significant differences could be determined for the RF (Figure [2a](#F2){ref-type="fig"}). On the other hand, for the 50 ms immediately after foot contact, the %MVC of the Ham and the RF were not significantly different between all trials (Figure [2b](#F2){ref-type="fig"}). The HQR were not significantly different between all trials for neither the 50 ms before foot contact nor for the 50 ms immediately after foot contact (Figure [3](#F3){ref-type="fig"}).
{#F2}
{#F3}
Discussion
==========
This paper examined the effects of a jump and balance training program designed to prevent ACL injury on both knee kinematics and muscle activity during a single limb drop landing. Our training program consisted of plyometrics, jump and balance training, fundamental skills used in basketball and instructions on proper landing techniques. Each training session lasted for only approximately 20 minutes a day, therefore a trainer, coach or therapist could realistically perform this training program easily during practice or warm-up. This jump and balance training program resulted in increased knee flexion and increased hamstrings activity. While we discuss later about each factors; further, multi-component training, including jump and balance training could result in changes in knee kinematics and femoral muscle activity.
The training program was considered to influence knee flexion during landing. However, in tibial rotation and knee varus/valgus, the difference between the training sessions was smaller than the SE and learning effects (difference from the control session). Therefore, the changes in tibial rotation and knee varus/valgus were not considered to be effects of the training program. While the results regarding knee flexion partially proved our hypothesis, our hypotheses that training would decrease knee valgus and internal tibial rotation were not supported. For frontal plane knee motion previous studies \[[@B11],[@B14]\] reported no differences in knee valgus during single limb landing after plyometric or agility training. However, Myer et al. \[[@B12]\] reported that both plyometric and balance training decreased the knee abduction angle during a medial drop landing. There is a possibility that single limb drop landing is not suitable to detect the change in frontal plane knee motion. It is also thought that the number of subjects in this study was low and the statistical power for the valgus. This low statistical power makes it difficult to demonstrate the small changes in knee valgus. For tibial rotation, although we could not compare with previous studies, it is possible that these same reasons impede detecting the change in motion in knee frontal motion (i.e. selection of task and statistical problem). Otherwise, it may be difficult to control tibial rotation, like joint laxity.
According to other studies that used video analysis, the position of the knee at the moment of injury is in slight knee flexion and valgus rotation with either internal or external tibial rotation \[[@B19]-[@B21]\]. Teitz \[[@B19]\] reported that the angle of knee flexion at the time of injury was less than 30 degrees. In this study, slight knee flexion, valgus and internal tibial rotation also occurred during the single limb drop landing. It is thought that decreasing tibial rotation and valgus rotation or increasing the angle of knee flexion is effective in preventing this knee position at the moment of ACL injury. Some previous studies \[[@B11],[@B12]\] indicated that training increases the knee flexion angle during both limb landings. The results of this study agree with those previous studies. Onate et al.\[[@B13]\] reported that videotape feedback and instruction increased peak knee flexion during landing. In this study, subjects increased not only peak knee flexion, but also initial knee flexion at foot contact. Because subjects were instructed to go through more knee flexion during training, increased peak knee flexion was not a novel finding. However, continuing the jump and balance training over a period of time also increased initial knee flexion. Thus it can be said that these increases in knee flexion are a direct effect of the jump and balance training.
Increased knee flexion angles may lead to changes in the function of the quadriceps and the hamstrings. In slight knee flexion, i.e., less than 30 degrees, contraction of the quadriceps strains the ACL \[[@B32]-[@B34]\]. Hamstrings contraction cannot reduce ACL strain with the knee slightly flexed because these muscles meet the tibia at a small angle \[[@B33],[@B35]\]. On the other hand, at angles of knee flexion greater than 60 degrees, quadriceps contraction does not increase ACL strain \[[@B34]\] and the anterior tibial translation and internal tibial rotation as a result of quadriceps contraction is decreased \[[@B36]\]. Moreover, hamstrings contraction reduces anterior tibial translation and internal tibial rotation at these angles \[[@B37]\]. Therefore, increasing the knee flexion angle during landing may have a beneficial effect to reduce the strain in the ACL. From the results of this study, the jump and balance training program which increased the knee flexion angle during landing also had the effect of decreasing the risk of ACL injury.
Hamstrings activity was also increased after training. In the training sessions, subjects were instructed to bend their knees and keep their knees neutral. Subjects were directed to keep a deep knee flexion angle during landing and to stabilize the position of their knee joint on the balance board. It is reported that peak activity of the hamstrings occur between 50-70 degrees of knee flexion \[[@B38]\]. Hamstrings contraction and coactivation of the hamstrings and the quadriceps have an important role to stabilize the knee joint \[[@B37],[@B39]-[@B41]\]. Therefore, the subjects learned the correct posture and landing technique which would increase hamstrings activity.
The activity of the hamstrings before foot contact was significantly increased. Recently several researchers have focused on pre-activated muscle patterns in response to anticipated movements and joint loads \[[@B15],[@B42]\]. Pre-activation is important for the dynamic stability of the knee because it provides fast compensation for encountered external loads. Wojtys and Huston \[[@B30]\] described the possibility that pre-activation can provide adequate muscular protection to restrain the knee. Although there are several reflexes that occur after a perturbation \[[@B40]\], the muscle activity is too slow to provide any ligament protection \[[@B43],[@B44]\]. Between preparatory and reactive muscle activation, there is a period of latency that results from electromechanical delay (EMD) \[[@B29]\]. EMD is the delay between neural stimulation of a muscle and the development of muscle tension. Pre-activation is thought to be beneficial for stabilizing the knee after a landing. For this study, although internal tibial rotation and tibial translation were not changed after training, it can be said that the increase in the pre-activity of the hamstrings helped to stabilize the knee joint during landing.
There are some limitations in this study. First, we analyzed only the kinematics of the knee joint, even though hip and ankle joint kinematics also play an important role during landing. We examined only the short term effects of the ACL injury prevention training. The incidence of ACL injury during the season was not investigated. We examined the effects of multi-component training. The effects of each training should be examined in the future. We did not consider the effects of menstrual cycle. Our study included control and training sessions, although setting up a control group and an intervention group is ideal to examine the effects of training. However, there were no changes in basketball training during these sessions, which were conducted during the preseason, and training and matches occurred at the same frequency during both sessions. Therefore, the changes in kinematics during the landing could be attributable to the intervened training. Finally, the statistical power for several of the data was relatively low. Using ANOVA at a low statistical power might cause type 2 errors. Although considerable differences in results might be significant, other findings may be overlooked. Future research should be performed to examine the long term effects of the ACL injury prevention program in a large sample size.
Conclusions
===========
The results of this study indicate that the jump and balance training increased knee flexion and hamstrings activity in female basketball athletes during a single limb drop landing. This program, which includes plyometrics, jump and balance training, fundamental basketball skills, and proper landing instructions, might have partial effects that avoid the characteristic knee position of ACL injury, thereby preventing injury. However, the expected changes in frontal and transverse kinematics of the knee were not observed.
Competing interests
===================
Grant-in-Aid for Scientific Research (C) (16500394)
Authors\' contributions
=======================
YN participated in the design of the study and drafted the manuscript. HI developed an algorithm of the PCT. MA and TF conceived of the study, and participated in its design and coordination and helped to draft the manuscript. Each author has read and concurs with the final manuscript\'s contents.
Acknowledgements
================
This work was funded by Grant-in-Aid for Scientific Research (C) (16500394) in 2004 and 2005.
|
{
"pile_set_name": "PubMed Central"
}
|
Portman says a recent analysis by the bi-partisan Congressional Budget Office says the raise to $10.10 and hour, over the next three years, would lead to a loss of about 25,000 jobs in Ohio. He says, "About 50-percent of those on minimum wage are between 16 and 24 years old, and for a lot of them, its a part-time job, and a very important job...I'm just worried it's going to result in job loss."
Portman, however, is in favor of a minimum wage which is tied to inflation, which is the standard in Ohio. "We're about 10-percent higher in Ohio, we're at $7.95 an hour...I think that's better policy."
Senate Democrats say raising the minimum wage will lift millions of Americans out of poverty, and benefit hard-working people. Senate Majority Leader Harry Reid says voters will remember the vote when they head to the polls this November for the midterm elections.
|
{
"pile_set_name": "Pile-CC"
}
|
Tuberculosis and survival in past populations: A paleo-epidemiological appraisal.
Historical assessments of the last two centuries consistently placed tuberculosis as the leading cause of mortality. However, for earlier periods, we can only calculate the frequencies of archaeological bone lesions, which tell us little about the real impact of the disease on mortality. These lesions are usually observed in individuals who have developed immune resistance, which is visible as healed osteo-articular lesions. This study aimed to test the differential impacts of tuberculosis, cribra orbitalia and cribra femoris on adult survival and sex-based survival. We analyzed 28 French adult samples from the Antiquity and the Early Middle Ages. The age-at-death of 1480 individuals was estimated using cementochronology. Survival curves and median age-at-death were calculated to test new hypotheses that challenge the parasitic and deficiency theories of bone stress markers. Comparisons between carriers and non-carriers provided new information concerning the plausible causes of bone stress markers related to infections and TB. The most likely hypothesis is skeletal demineralization and osteoclastic resorption, which are usually observed close to tubercular granuloma or distant from active lesions. The bone marrow niche of Mycobacterium tuberculosis within CD271(+) BM-MSCs stem cells is the proposed explanation for the localized cortical resorption that is observed in bone stress markers.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Related Links
DOVER, DEL. — Officials say the body of a two-star general killed in an Afghan "insider attack" will be flown to the military mortuary at Dover Air Force Base.
NATO officials issued a statement saying Maj. Gen. Harold Greene's body was being prepared to be flown to the U.S. via Dover Air Force Base. Officials at Dover AFB said Wednesday that Greene's body was scheduled to arrive about 7:30 a.m. Thursday.
Greene is the highest-ranked U.S. officer to be slain in combat since 1970 during the Vietnam War. Greene, a 34-year U.S. Army veteran, also is the highest-ranked American officer killed in combat in the wars in Afghanistan and Iraq.
Investigators are trying to determine why and how a man dressed in an Afghan army uniform opened fire Tuesday at a military compound.
|
{
"pile_set_name": "Pile-CC"
}
|
---
abstract: |
The addition of the two Forward TPCs to the STAR detector allows one to measure anisotropic flow at forward pseudorapidities. This made possible the first measurement of directed flow at collision energies of $\sqrtsNN =
200$GeV. PHOBOS’ results on elliptic flow at forward rapidities were confirmed, and the sign of $v_2$ was determined to be positive for the first time at RHIC energies. The higher harmonic, $v_4$, is consistent with the recently suggested $v_2^2$ scaling behavior.
This write-up contains results presented as a poster [@poster] at the Quark Matter conference in Oakland, California in January 2004.
author:
- 'Markus D. Oldenburg'
date: 'March 17, 2004'
title: 'Anisotropic flow in the forward directions at $\sqrt{s_\mathrm{NN}} = 200$GeV'
---
\[intro\]Introduction
=====================
In non-central heavy-ion collisions the initial spatial anisotropy of the collision region translates into a final state anisotropy in momentum space. In a hydrodynamical picture this is believed to be due to pressure gradients in the dense medium which lead to collective motion — so called transverse flow — of the generated particles.
The simplest way of characterizing these final state anisotropies is to perform a Fourier decomposition on the particle’s emission angles $\phi$ with respect to the reaction plane $\Psi_{RP}$ [@vol]. The reaction plane is given by the incident beam direction and the impact parameter and it is experimentally not known *a priori*. It has to be estimated for every event by looking at the anisotropy of particle emission itself [@fourier]. This leads to a finite resolution of the measured event plane which one has to correct for.
Spurious contributions to the measured transverse flow signal are particle correlations due to non-flow effects (e.g. resonance decays). To cope with these, several new methods of the anisotopic flow analysis, based either on cumulants [@BDO1; @BDO2] or on Lee-Yang zeros [@LeeYangZeros], have been proposed.
\[expsetup\]Experimental setup
==============================
The two Forward TPCs (FTPCs [@Ftpc]) of the STAR experiment [@STAR] extend the pseudorapidity coverage of STAR into the region $2.5<|\eta|<4.0$. The pseudorapidity resolution of these radial drift chambers is better than 5% for their full acceptance. During RHIC run 2 about 70 thousand Au+Au collisions at a center of mass energy of $\sqrtsNN = 200$GeV were taken with both FTPCs and the STAR TPC [@Tpc].
Measurements
============
Directed Flow $v_1$
-------------------
The first measurement of directed flow at RHIC energies was recently published [@v1v4Paper] (see Fig. \[v1\]). It showed that while $v_1(\eta)$ is close to zero at mid-rapidities, the signal rises to a couple of percent near pseudorapidity $|\eta| \approx 4$.
It was noted that our measurement greatly differs from the NA49 results [@NA49Paper] at lower beam energies of $158A$GeV. But if the NA49 data are shifted and both measurements are seen in the projectile frame, they look similar.
Elliptic flow $v_2$
-------------------
The comparison of our new measurement on elliptic flow $v_2(\eta)$ at forward pseudorapidities confirms the published result [@Phobosv2] obtained by the PHOBOS collaboration (see Fig. \[v2phobos\]) at high $\eta$. We observe a similar fall-off by a factor of 1.8 comparing $v_2(\eta = 0)$ with $v_2(\eta
=3)$. Both measurements were done using the event plane method.
If we compare our results for $v_2$ obtained with the method of two-particle cumulants, $v_2\{2\}$, to the four-particle cumulants, $v_2\{4\}$, we observe almost no difference in the FTPC region, while the two-particle cumulant measurement gives a 15% higher signal in the TPC. Since four-particle cumulants are much less prone to non-flow contributions we conclude that non-flow effects are less strong in the forward regions.
A new method to measure directed flow
-------------------------------------
From the above measurements it became clear that the STAR TPC sitting at mid-rapidity has very good capabilities to measure elliptic flow, while the Forward TPCs allow to measure directed flow (which appears to be close to zero at mid-rapidities).
### $v_1\left\{\mathrm{EP}1,\mathrm{EP}2\right\}$
In order to utilize the method of Fourier decomposition but to reduce non-flow contributions at the same time, we measured $v_1$ with respect to the first and second order reaction plane $\Psi_1$ and $\Psi_2$, where $\Psi_1$ was determined in the FTPCs while $\Psi_2$ was measured in the TPC. Within the recently proposed notation (see [@v1v4Paper]) we denote this measurement as $v_1\left\{\mathrm{EP}1,\mathrm{EP}2\right\}$. $$\begin{aligned}
v_1\{\mathrm{EP}1,\mathrm{EP}2\} =\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\;\\
\frac{\left\langle\cos\left(\phi+\Psi_1^{\mathrm{FTPC}}-2\Psi_2^{\mathrm{TPC}}\right)\right\rangle}{\sqrt{\left\langle\cos\left(\Psi_1^{\mathrm{FTPC}_1}+\Psi_1^{\mathrm{FTPC}_2}-2\Psi_2^{\mathrm{TPC}}\right)\right\rangle\cdot \mathrm{Res}(\Psi_2^{\mathrm{TPC}})}}\nonumber\;.\end{aligned}$$
As shown in Fig. \[v1Ep1Ep2\], the results are in reasonable agreement with the published measurement obtained by the three-particle cumulant method $v_1\{3\}$.
### The sign of $v_2$
This new method provides an elegant tool to measure the sign of $v_2$, which was assumed to be positive but had not yet been determined at RHIC energies. One of the quantities involved in the measurement of $v_1\{\mathrm{EP}1,\mathrm{EP}2\}$ is approximately equal to the product of integrated values of $v_1^2$ and $v_2$: $$\begin{aligned}
v_1^2\cdot v_2 \approx
\frac{\left\langle\cos\left(\Psi_1^{\mathrm{FTPC}_1}+\Psi_1^{\mathrm{FTPC}_2}-2\Psi_2^{\mathrm{TPC}}\right)\right\rangle}{\sqrt{M_{\mathrm{FTPC}_1}\cdot
M_{\mathrm{FTPC}_2}\cdot M_{\mathrm{TPC}}}}\;,\end{aligned}$$ where $M_{\mathrm{FTPC}_1}$, $M_{\mathrm{FTPC}_2}$, and $M_{\mathrm{TPC}}$ denote the multiplicities for a given centrality bin in the two FTPCs and the TPC, respectively. Since $v_1^2$ is always positive, the sign of $v_1^2\cdot
v_2$ determines the sign of $v_2$.
Averaged over centralities 20–60% we measure $v_1^2\cdot v_2$ in Fig. \[v1v1v2\] to be $(1.08\pm0.46) \cdot10^{-5}$. In this region the expected non-flow contributions are much smaller than for the most central and peripheral centrality bins. Therefore the sign of $v_2$ is determined to be positive: [*In-plane*]{} elliptic flow is confirmed. (This stated value for $v_1^2\cdot v_2$ and its uncertainty is based on an approximation that does not affect the statistical significance of the conclusion that $v_2$ is [*in-plane*]{}.)
The fourth harmonic $v_4$
-------------------------
Since elliptic flow $v_2$ is strong, the second order reaction plane $\Psi_2$ can be estimated with high precision at RHIC energies. This makes the study of higher order flow feasible [@v1v4Paper].
The fourth harmonic $v_4$ shows an average value of $(0.4\pm0.1)\%$ in pseudorapidity coverage of the TPC ($|\eta| < 1.2$), see Fig. \[v2v4\]. In contrast, its value of $(0.06\pm0.07)\%$ in the forward regions is consistent with zero and we place a $2\sigma$ upper limit of 0.2%. Therefore the fall-off of $v_4$ from mid-rapidities to forward rapidities appears to be stronger than for $v_2$. This behavior is consistent with scaling like $v_4\sim v_2^2$.
Future developments
===================
First attempts to make use of the newly proposed method [@LeeYangZeros] utilizing Lee-Yang zeros are encouraging. This method eliminates higher order non-flow contributions by construction. It is mathematically equivalent to the *all*-particle cumulant method $v\{\infty\}$ which takes into account all higher order non-flow effects. The great advantage of the new method is its simplicity and speed compared to the evaluation of the cumulants.
The upcoming RHIC run 4 will greatly enhance our data sample. With it we will reduce our statistical uncertainties in the forward pseudorapiditiy region significantly.
[99]{}
see http://www.star.bnl.gov/STAR/central/\
presentations/2004/qm2004/Oldenburg\_Markus.pdf
S.A. Voloshin and Y. Zhang, Z. Phys. C [**70**]{}, 665 (1996).
A.M. Poskanzer and S.A. Voloshin, , 1671 (1998).
N. Borghini, P.M. Dinh, and J.-Y. Ollitrault, , 054901 (2001).
N. Borghini, P.M. Dinh, and J.-Y. Ollitrault, , 014905 (2002).
R.S. Bhalerao, N. Borghini, J.-Y. Ollitrault, Nucl. Phys. A [**727**]{}, 373 (2003).
K.H. Ackermann , Nucl. Instrum. Meth. A [**499**]{}, 713 (2003).
K.H. Ackermann , Nucl. Instrum. Meth. A [**499**]{}, 624 (2003).
M. Anderson , Nucl. Instrum. Meth. A [**499**]{}, 659 (2003).
J. Adams , , 062301 (2004).
NA49 Collaboration, C. Alt , , 034903 (2003).
S. Manly for the PHOBOS Collaboration, Nucl. Phys. A [**715**]{}, 611c (2003).
|
{
"pile_set_name": "ArXiv"
}
|
/*
Copyright 2012 Jun Wako <wakojun@gmail.com>
This program is free software: you can redistribute it and/or modify
it under the terms of the GNU General Public License as published by
the Free Software Foundation, either version 2 of the License, or
(at your option) any later version.
This program is distributed in the hope that it will be useful,
but WITHOUT ANY WARRANTY; without even the implied warranty of
MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the
GNU General Public License for more details.
You should have received a copy of the GNU General Public License
along with this program. If not, see <http://www.gnu.org/licenses/>.
*/
/*
* scan matrix
*/
#include <stdint.h>
#include <stdbool.h>
#include <string.h>
#include <avr/io.h>
#include <avr/wdt.h>
#include <avr/interrupt.h>
#include <util/delay.h>
#include "print.h"
#include "debug.h"
#include "util.h"
#include "matrix.h"
#include "split_util.h"
#include "quantum.h"
#ifdef USE_MATRIX_I2C
# include "i2c.h"
#else // USE_SERIAL
# include "split_scomm.h"
#endif
#ifndef DEBOUNCE
# define DEBOUNCE 5
#endif
#define ERROR_DISCONNECT_COUNT 5
static uint8_t debouncing = DEBOUNCE;
static const int ROWS_PER_HAND = MATRIX_ROWS/2;
static uint8_t error_count = 0;
uint8_t is_master = 0 ;
static const uint8_t row_pins[MATRIX_ROWS] = MATRIX_ROW_PINS;
static const uint8_t col_pins[MATRIX_COLS] = MATRIX_COL_PINS;
/* matrix state(1:on, 0:off) */
static matrix_row_t matrix[MATRIX_ROWS];
static matrix_row_t matrix_debouncing[MATRIX_ROWS];
static matrix_row_t read_cols(void);
static void init_cols(void);
static void unselect_rows(void);
static void select_row(uint8_t row);
static uint8_t matrix_master_scan(void);
__attribute__ ((weak))
void matrix_init_kb(void) {
matrix_init_user();
}
__attribute__ ((weak))
void matrix_scan_kb(void) {
matrix_scan_user();
}
__attribute__ ((weak))
void matrix_init_user(void) {
}
__attribute__ ((weak))
void matrix_scan_user(void) {
}
inline
uint8_t matrix_rows(void)
{
return MATRIX_ROWS;
}
inline
uint8_t matrix_cols(void)
{
return MATRIX_COLS;
}
void tx_rx_leds_init(void)
{
#ifndef NO_DEBUG_LEDS
setPinOutput(B0);
setPinOutput(D5);
writePinHigh(B0);
writePinHigh(D5);
#endif
}
void tx_led_on(void)
{
#ifndef NO_DEBUG_LEDS
writePinLow(D5);
#endif
}
void tx_led_off(void)
{
#ifndef NO_DEBUG_LEDS
writePinHigh(D5);
#endif
}
void rx_led_on(void)
{
#ifndef NO_DEBUG_LEDS
writePinLow(B0);
#endif
}
void rx_led_off(void)
{
#ifndef NO_DEBUG_LEDS
writePinHigh(B0);
#endif
}
void matrix_init(void)
{
split_keyboard_setup();
// initialize row and col
unselect_rows();
init_cols();
tx_rx_leds_init();
// initialize matrix state: all keys off
for (uint8_t i=0; i < MATRIX_ROWS; i++) {
matrix[i] = 0;
matrix_debouncing[i] = 0;
}
is_master = has_usb();
matrix_init_quantum();
}
uint8_t _matrix_scan(void)
{
// Right hand is stored after the left in the matirx so, we need to offset it
int offset = isLeftHand ? 0 : (ROWS_PER_HAND);
for (uint8_t i = 0; i < ROWS_PER_HAND; i++) {
select_row(i);
_delay_us(30); // without this wait read unstable value.
matrix_row_t cols = read_cols();
if (matrix_debouncing[i+offset] != cols) {
matrix_debouncing[i+offset] = cols;
debouncing = DEBOUNCE;
}
unselect_rows();
}
if (debouncing) {
if (--debouncing) {
_delay_ms(1);
} else {
for (uint8_t i = 0; i < ROWS_PER_HAND; i++) {
matrix[i+offset] = matrix_debouncing[i+offset];
}
}
}
return 1;
}
#ifdef USE_MATRIX_I2C
// Get rows from other half over i2c
int i2c_transaction(void) {
int slaveOffset = (isLeftHand) ? (ROWS_PER_HAND) : 0;
int err = i2c_master_start(SLAVE_I2C_ADDRESS + I2C_WRITE);
if (err) goto i2c_error;
// start of matrix stored at 0x00
err = i2c_master_write(0x00);
if (err) goto i2c_error;
// Start read
err = i2c_master_start(SLAVE_I2C_ADDRESS + I2C_READ);
if (err) goto i2c_error;
if (!err) {
int i;
for (i = 0; i < ROWS_PER_HAND-1; ++i) {
matrix[slaveOffset+i] = i2c_master_read(I2C_ACK);
}
matrix[slaveOffset+i] = i2c_master_read(I2C_NACK);
i2c_master_stop();
} else {
i2c_error: // the cable is disconnceted, or something else went wrong
i2c_reset_state();
return err;
}
return 0;
}
#else // USE_SERIAL
int serial_transaction(int master_changed) {
int slaveOffset = (isLeftHand) ? (ROWS_PER_HAND) : 0;
#ifdef SERIAL_USE_MULTI_TRANSACTION
int ret=serial_update_buffers(master_changed);
#else
int ret=serial_update_buffers();
#endif
if (ret ) {
if(ret==2) rx_led_on();
return 1;
}
rx_led_off();
memcpy(&matrix[slaveOffset],
(void *)serial_slave_buffer, SERIAL_SLAVE_BUFFER_LENGTH);
return 0;
}
#endif
uint8_t matrix_scan(void)
{
if (is_master) {
matrix_master_scan();
}else{
matrix_slave_scan();
int offset = (isLeftHand) ? ROWS_PER_HAND : 0;
memcpy(&matrix[offset],
(void *)serial_master_buffer, SERIAL_MASTER_BUFFER_LENGTH);
matrix_scan_quantum();
}
return 1;
}
uint8_t matrix_master_scan(void) {
int ret = _matrix_scan();
int mchanged = 1;
int offset = (isLeftHand) ? 0 : ROWS_PER_HAND;
#ifdef USE_MATRIX_I2C
// for (int i = 0; i < ROWS_PER_HAND; ++i) {
/* i2c_slave_buffer[i] = matrix[offset+i]; */
// i2c_slave_buffer[i] = matrix[offset+i];
// }
#else // USE_SERIAL
#ifdef SERIAL_USE_MULTI_TRANSACTION
mchanged = memcmp((void *)serial_master_buffer,
&matrix[offset], SERIAL_MASTER_BUFFER_LENGTH);
#endif
memcpy((void *)serial_master_buffer,
&matrix[offset], SERIAL_MASTER_BUFFER_LENGTH);
#endif
#ifdef USE_MATRIX_I2C
if( i2c_transaction() ) {
#else // USE_SERIAL
if( serial_transaction(mchanged) ) {
#endif
// turn on the indicator led when halves are disconnected
tx_led_on();
error_count++;
if (error_count > ERROR_DISCONNECT_COUNT) {
// reset other half if disconnected
int slaveOffset = (isLeftHand) ? (ROWS_PER_HAND) : 0;
for (int i = 0; i < ROWS_PER_HAND; ++i) {
matrix[slaveOffset+i] = 0;
}
}
} else {
// turn off the indicator led on no error
tx_led_off();
error_count = 0;
}
matrix_scan_quantum();
return ret;
}
void matrix_slave_scan(void) {
_matrix_scan();
int offset = (isLeftHand) ? 0 : ROWS_PER_HAND;
#ifdef USE_MATRIX_I2C
for (int i = 0; i < ROWS_PER_HAND; ++i) {
/* i2c_slave_buffer[i] = matrix[offset+i]; */
i2c_slave_buffer[i] = matrix[offset+i];
}
#else // USE_SERIAL
#ifdef SERIAL_USE_MULTI_TRANSACTION
int change = 0;
#endif
for (int i = 0; i < ROWS_PER_HAND; ++i) {
#ifdef SERIAL_USE_MULTI_TRANSACTION
if( serial_slave_buffer[i] != matrix[offset+i] )
change = 1;
#endif
serial_slave_buffer[i] = matrix[offset+i];
}
#ifdef SERIAL_USE_MULTI_TRANSACTION
slave_buffer_change_count += change;
#endif
#endif
}
bool matrix_is_modified(void)
{
if (debouncing) return false;
return true;
}
inline
bool matrix_is_on(uint8_t row, uint8_t col)
{
return (matrix[row] & ((matrix_row_t)1<<col));
}
inline
matrix_row_t matrix_get_row(uint8_t row)
{
return matrix[row];
}
void matrix_print(void)
{
print("\nr/c 0123456789ABCDEF\n");
for (uint8_t row = 0; row < MATRIX_ROWS; row++) {
phex(row); print(": ");
pbin_reverse16(matrix_get_row(row));
print("\n");
}
}
uint8_t matrix_key_count(void)
{
uint8_t count = 0;
for (uint8_t i = 0; i < MATRIX_ROWS; i++) {
count += bitpop16(matrix[i]);
}
return count;
}
static void init_cols(void)
{
for(int x = 0; x < MATRIX_COLS; x++) {
_SFR_IO8((col_pins[x] >> 4) + 1) &= ~_BV(col_pins[x] & 0xF);
_SFR_IO8((col_pins[x] >> 4) + 2) |= _BV(col_pins[x] & 0xF);
}
}
static matrix_row_t read_cols(void)
{
matrix_row_t result = 0;
for(int x = 0; x < MATRIX_COLS; x++) {
result |= (_SFR_IO8(col_pins[x] >> 4) & _BV(col_pins[x] & 0xF)) ? 0 : (1 << x);
}
return result;
}
static void unselect_rows(void)
{
for(int x = 0; x < ROWS_PER_HAND; x++) {
_SFR_IO8((row_pins[x] >> 4) + 1) &= ~_BV(row_pins[x] & 0xF);
_SFR_IO8((row_pins[x] >> 4) + 2) |= _BV(row_pins[x] & 0xF);
}
}
static void select_row(uint8_t row)
{
_SFR_IO8((row_pins[row] >> 4) + 1) |= _BV(row_pins[row] & 0xF);
_SFR_IO8((row_pins[row] >> 4) + 2) &= ~_BV(row_pins[row] & 0xF);
}
|
{
"pile_set_name": "Github"
}
|
Ever wondered just what the ModelState was that keeps popping up in your ASP.NET MVC controllers? So did I. Let's break down what the ModelState is and why we use it.
What is ModelState?
ModelState is a property of a Controller, and can be accessed from those classes that inherit from System.Web.Mvc.Controller.
The ModelState represents a collection of name and value pairs that were submitted to the server during a POST. It also contains a collection of error messages for each value submitted. Despite its name, it doesn't actually know anything about any model classes, it only has names, values, and errors.
ModelState has two purposes: to store the value submitted to the server, and to store the validation errors associated with those values.
But that's the boring explanation. Show me the code!
The Sample Project
Check out my (very simple) sample project hosted over on GitHub!
The Setup
Now, let's get started writing the code for this demo. First, we have the AddUserVM view model:
ViewModels/Home/AddUserVM.cs
public class AddUserVM { public string FirstName { get; set; } public string LastName { get; set; } public string EmailAddress { get; set; } }
Next, we have a simple view:
Views/Home/Add.cshtml
@model ModelStateDemo.ViewModels.Home.AddUserVM <h2>Add</h2> @using(Html.BeginForm()) { <div> <div> @Html.TextBoxFor(x => x.FirstName) </div> <div> @Html.TextBoxFor(x => x.LastName) </div> <div> @Html.TextBoxFor(x => x.EmailAddress) </div> <div> <input type="submit" value="Save" /> </div> </div> }
Finally, we have the controller actions:
... [HttpGet] public ActionResult Add() { AddUserVM model = new AddUserVM(); return View(model); } [HttpPost] public ActionResult Add(AddUserVM model) { if(!ModelState.IsValid) { return View(model); } return RedirectToAction("Index"); }
When we submit the form to the POST action, all of the values we entered will show up in the AddUserVM instance. But how did they get there?
The ModelStateDictionary Class
Let's look at the rendered HTML form for the Add page:
<form action="/Home/Add" method="post"> <div> <div> <label for="FirstName">First Name:</label> <input id="FirstName" name="FirstName" type="text" value=""> </div> <div> <label for="LastName">Last Name:</label> <input id="LastName" name="LastName" type="text" value=""> </div> <div> <label for="EmailAddress">Email Address:</label> <input id="EmailAddress" name="EmailAddress" type="text" value=""> </div> <div> <input type="submit" value="Save"> </div> </div> </form>
In a POST, all values in <input> tags are submitted to the server as key-value pairs. When MVC receives a POST, it takes all of the post parameters and adds them to a ModelStateDictionary instance. When debugging the controller POST action in Visual Studio, we can use the Locals window to investigate this dictionary:
The Values property of the ModelStateDictionary contains instances that are of type System.Web.Mvc.ModelState. What does a ModelState actually contain?
What's in a ModelState?
Here's what those values look like, from the same debugger session:
Each of the properties has an instance of ValueProviderResult that contains the actual values submitted to the server. MVC creates all of these instances automatically for us when we submit a POST with data, and the POST action has inputs that map to the submitted values. Essentially, MVC is wrapping the user inputs into more server-friendly classes (ModelState and ValueProviderResult) for easier use.
There's still two important properties that we haven't discussed, though: the ModelState.Errors property and the ModelStateDictionary.IsValid property. They're used for the second function of ModelState: to store the errors found in the submitted values.
Validation Errors in ModelState
Let's change our AddUserVM class:
public class AddUserVM { [Required(ErrorMessage = "Please enter the user's first name.")] [StringLength(50, ErrorMessage = "The First Name must be less than {1} characters.")] [Display(Name = "First Name:")] public string FirstName { get; set; } [Required(ErrorMessage = "Please enter the user's last name.")] [StringLength(50, ErrorMessage = "The Last Name must be less than {1} characters.")] [Display(Name = "Last Name:")] public string LastName { get; set; } [EmailAddress(ErrorMessage = "The Email Address is not valid")] [Required(ErrorMessage = "Please enter an email address.")] [Display(Name = "Email Address:")] public string EmailAddress { get; set; } }
We've added validation attributes, specifically Required, StringLength, and EmailAddress. We've also set the error messages that are to be displayed if the corresponding validation errors occur.
With the above changes in place, let's modify the Add view to display the error messages if they occur:
@model ModelStateDemo.ViewModels.Home.AddUserVM <h2>Add</h2> @using(Html.BeginForm()) { @Html.ValidationSummary() <div> <div> @Html.LabelFor(x => x.FirstName) @Html.TextBoxFor(x => x.FirstName) @Html.ValidationMessageFor(x => x.FirstName) </div> <div> @Html.LabelFor(x => x.LastName) @Html.TextBoxFor(x => x.LastName) @Html.ValidationMessageFor(x => x.LastName) </div> <div> @Html.LabelFor(x => x.EmailAddress) @Html.TextBoxFor(x => x.EmailAddress) @Html.ValidationMessageFor(x => x.EmailAddress) </div> <div> <input type="submit" value="Save" /> </div> </div> }
Notice the two helpers we are using now, ValidationSummary and ValidationMessageFor.
ValidationSummary reads all errors from the model state and displays them in a bulleted list.
ValidationMessageFor displays only errors for to the property specified.
Let's see what happens when we attempt to submit an invalid POST that is missing the email address. When we get to the POST action while debugging, we have the following values in our ModelStateDictionary:
Note that the ModelState instance for the email address now has an error in the Errors collection. When MVC creates the model state for the submitted properties, it also goes through each property in the ViewModel and validates the property using attributes associated to it. If any errors are found, they are added to the Errors collection in the property's ModelState.
Also note that IsValid is false now. That's because an error exists; IsValid is false if any of the properties submitted have any error messages attached to them.
What all of this means is that by setting up the validation in this manner, we allow MVC to just work the way it was designed. ModelState stores the submitted values, allows them to be mapped to class properties (or just as parameters to the action) and keeps a collection of error messages for each property. In simple scenarios, this is all we need, and all of it is happening behind the scenes!
Custom Validation
But what if we needed to perform more complex validation than what is provided by attributes? Say we needed to validate that the first and last names are not identical, and display a particular error message when this happens.
We can actually add errors to the model state via the AddModelError method on ModelStateDictionary:
[HttpPost] public ActionResult Add(AddUserVM model) { if(model.FirstName == model.LastName) { ModelState.AddModelError("LastName", "The last name cannot be the same as the first name."); } if(!ModelState.IsValid) { return View(model); } return RedirectToAction("Index"); }
The first parameter to the AddModelError method is the name of the property that the error applies to. In this case, we set it to LastName. You could also set it to nothing (or a fake name) if you just want it to appear in the ValidationSummary and not in a ValidationMessage.
Now the error will be displayed on the page:
Summary
The ModelState represents the submitted values and errors in said values during a POST. The validation process respects the attributes like Required and EmailAddress, and we can add custom errors to the validation if we so desire. ValidationSummary and ValidationMessageFor read directly from ModelState to display errors to the user.
I've got a very simple sample project on Github that demonstrates how the ModelState works and provides all the code and markup in this post. Take a look!
Also, if this post helped you, please consider buying me a coffee. Your support funds all of my projects and helps me keep traditional ads off this site. Thanks!
Happy Coding!
|
{
"pile_set_name": "OpenWebText2"
}
|
Saturday, May 24, 2014
The Moon Coven Series by K.B. Miller
Known as Baltimore's Paranormal Princess, KB Miller has earned the title with so many wickedly awesome books. She is now also a multi-genre author with a mix of YA Paranormal, Adult Paranormal (soon to be released) and Children's books, she has written a little something for all ages. There are books of witches, vampires, zombies, and more so just pick your flavor. I have become a loyal fan of KB since reading Haunted Moon and I am sure you will too once you get your hands on any of her books. Today I am spotlighting The Moon Coven Series as that is where it all began for her and well, for me too. There is a link for each that will send you to my review. I didn't want to clutter up the post, so if you would like to see my thoughts on each just click.
The Moon
Coven Series
Haunted
Moon
Before Lilyann stepped into her destiny to lead the coven,
there was another powerful Moon witch...her grandmother.
A teenage witch-to-be in Galway, Ireland, Leeny Moon was
prepared to take her rightful place in the circle along side of her family. That was until
she witnessed firsthand the forthcoming nightmares she would be expected to
face, vampires.
A family secret kept hidden has been exposed, and the
consequences could be deadly.
After Lilyann Moon's beloved grandmother dies shrouded by a
veil of mystery, she and her young family embers are yanked from their completely normal
lives and catapulted directly into the supernatural orld of witchcraft. A world they know
absolutely nothing about.
The town of Hampstead, Maryland has no idea of the monsters
that lurk in their midst. Or, of the dangers they will face if the Moon Coven
doesn't figure out how to embrace the magick within each of them, especially Lily.
She's suddenly up to her pointy little black hat in magickal
problems. Destiny presented her with a few more, and they're pretty major -
vampires, ghosts, and brogadhs.
The only bright spot in this nightmare was meeting Mason.
But, is she in love with the enemy? Lilyann is in a race against time to save
her town and coven. Will she survive the coming dangers, with her heart and
neck intact?
Seventeen-year-old Lochlan Moon had been groomed his entire
life to accept the torch that would eventually be handed to him, and step into
his destiny - to be the most powerful witch in almost five hundred years. He
put his heart and soul into mastering a craft passed down through the
generations of his ancestral bloodline.
Between the savage murder of a family member, and vanishing
classmates, doubts that he'd kept buried began to resurface. Someone or
something is on a monstrous killing spree in his home town of Hampstead.
Lochlan is determined to help stop whatever it is.
All the while, his future within the family's circle teeters
on a deadly precipice.
Will any of the witches survive to harness the magick
within... after the Harvest Moon?
You would think that would be Leeny Moon’s biggest trouble
this time around, but two jealous guys make the horde of hungry vampires
gunning for the powerful witch seem like a day at the park.
Leeny has embraced her birthright. She is next in line to
lead the coveted Moon coven. Out of fear of history repeating itself, Leeny
made her first kill, and for the last three years her sole mission has been to drive
the vampires out of Ireland. With the help of neighboring covens she is not
alone in her pursuit.
However, the close friendship developing between Finn
O’Donnell and Leeny is causing a problem in her budding relationship with
Seamus McNamara.
The future is up in the air as the creatures from her
nightmares invade the tiny fishing town of Galway Bay, Ireland ... again. The
revenge they seek is simple─Leeny’s blood. Who will survive the war on this
Blood Moon?
Best Selling Author, K.B. Miller is a proud native of
Baltimore, Maryland. She’s also a football nut! That's right fellas, she’s a
DIE-HARD Ravens fan! How's that for ballsy?
Currently she resides in a tiny valley nestled in the
foothills of the Blue Ridge Mountains of Pennsylvania with her husband and son
(both Steelers fans ─ eww!), two energetic puppies ─ Copper Dude and Cullen
Edward, and her mouthy blue front Amazon Parrot, Poppy.
She’s been writing for as long as she can remember, but two
years ago her loving husband─ who believed in her talent, finally gave her a
gentle push... actually, according to her, it was really more of a kick... in
the lower back-upper thigh region. She claims it hurt. After a few restless
nights she decided to allow everyone to meet all of the crazy characters in her
head, and here we are.
K.B. has as her family calls it, a ridiculous addiction to
hats, shoes, sunglasses, owls, and coffee. No problems there, right? That's
what she said.
Welcome to K.B.-land, it's a lot like Disneyland only
without all of the endless lines, overly happy people and it doesn’t cost you
an arm and a leg! LOL
|
{
"pile_set_name": "Pile-CC"
}
|
Here ericdress.com shows customers a fashion collection of current tea length green mother of the bride dresses.You can find many great items. They all have high quality and reasonable price. You can get big discount sometimes, because we always do promotions. If you need tea length green mother of the bride dresses,come here to choose. We give you good items and services.
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
Unable to set Apache httpd.config for static content on Jboss App Server
I have put alias with and without trailing slashes.Still no solution. Do we need to change Any attributes in jboss xml's also?Proxy is setting fine though.
Alias /images/ "c:/images/"
<Directory "c:/images">
Options Indexes MultiViews
AllowOverride None
Order allow,deny
Allow from all
</Directory>
<VirtualHost *>
ServerName localhost
<IfModule proxy_module>
<Proxy *>
Order allow,deny
Allow from *
</Proxy>
ProxyPass /HelloWeb http://localhost:8080/HelloWeb
ProxyPassReverse /HelloWeb http://localhost:8080/HelloWeb
<Location /HelloWeb>
Order allow,deny
Allow from all
</Location>
</IfModule>
</VirtualHost>
A:
Well i found the answer long back but forgot to answer it . (in case someone needs it)
I used proxypass instead of alias.
ProxyPass /HelloWeb/css http://localhost/Hello/css
ProxyPassReverse /HelloWeb/js http://localhost/Hello/css
<Location /HelloWeb/css>
Order allow,deny
Allow from all
</Location>
|
{
"pile_set_name": "StackExchange"
}
|
Introduction {#s1}
============
The prevalence of diabetes among adults aged ≥65 years is projected to increase dramatically by 2050 ([@B1]). Dementia affects up to 16% of diabetic patients aged ≥65 years and 24% aged ≥75 years ([@B2],[@B3]), and evidence shows that the two conditions share a pathophysiological link ([@B4]--[@B6]). As described in the federally mandated National Plan to Address Alzheimer's Disease ([@B7]), U.S. health care is poorly situated to address the needs of older adults with dementia and common comorbidities such as diabetes. This is evident in the two- to threefold increased odds of severe hypoglycemia and preventable hospitalizations in diabetic patients with comorbid dementia ([@B2],[@B8]). Improving ambulatory care, particularly reducing known risk factors for hypoglycemia, in older patients with coexisting diabetes and dementia is critical, but to date, few such efforts have been made.
There is growing consensus that because of their increased risk for hypoglycemia and reduced potential to benefit from tight glycemic control, older diabetic patients with dementia should avoid tight glycemic control (HbA~1c~ \<7% \[53 mmol/mol\]) and instead pursue moderate HbA~1c~ levels of 7% to \<9% (53 to \<75 mmol/mol). Older individuals with dementia often have other risk factors for hypoglycemia, including weight loss, changes in appetite and eating habits, and difficulty following prescribed regimens ([@B9]--[@B11]), and a reduced ability to recognize and respond appropriately to symptoms ([@B9],[@B12],[@B13]). Furthermore, older patients with dementia have an average life expectancy of 2--8 years ([@B14]--[@B16]) and are unlikely to experience benefits of tight glycemic control, which take years to accrue and are less likely in patients with long-standing diabetes ([@B11]). As such, since 2003, guidelines from the U.S. Departments of Veterans Affairs and Defense (VA/DoD) have presented a risk-stratified approach to glycemic control, recommending tight control (HbA~1c~ \<7% \[53 mmol/mol\]) only for patients with a life expectancy of 10--15 years or more and absent/mild microvascular complications ([@B17],[@B18]). The American Diabetes Association and American Geriatrics Society (AGS) subsequently adopted similar recommendations ([@B19],[@B20]), with the AGS in 2013 including the avoidance of tight glycemic control in older adults with comorbidities in its Choosing Wisely campaign ([@B21]). Although others have documented the elevated risk of hypoglycemia in older diabetic patients with dementia ([@B2]), no studies to our knowledge have focused on understanding risk factors for tight glycemic control in patients with comorbid dementia.
Choice of antidiabetic medication also may exacerbate risks to type 2 diabetic patients with dementia, especially when HbA~1c~ is tightly controlled ([@B22]). Sulfonylureas and insulin are associated with a high risk of hypoglycemia ([@B19]), and the 2013 AGS guidelines explicitly recommend against the use of glyburide and chlorpropamide in all patients aged ≥65 years ([@B20]). However, sulfonylureas and insulin are recommended as first- and second-line diabetes therapies in the general patient population due to strong evidence of efficacy in lowering HbA~1c~, low cost, market longevity, and low risk of adverse events apart from hypoglycemia ([@B17],[@B19]). As patients develop dementia, the risk of hypoglycemia increases and the risk-to-benefit balance of using these agents changes, especially if HbA~1c~ is tightly controlled. To our knowledge, no prior studies have examined the prevalence of or risk factors for the use of medications with a high risk of hypoglycemia in patients with dementia.
In this study, we addressed these gaps in the literature by identifying risk factors for tight glycemic control in older veterans with dementia receiving antidiabetic medication therapy. We also identified the prevalence and characteristics of patients at highest potential risk for hypoglycemia through their use of sulfonylurea and/or insulin after exhibiting tight glycemic control. Such data can help to inform future interventions to improve adherence to the VA diabetes treatment guidelines and AGS Choosing Wisely guidelines recommending against tight glycemic control in this population and enhance safer prescribing for veterans with dementia previously shown to be at especially high risk for severe hypoglycemic events ([@B2]).
Research Design and Methods {#s2}
===========================
Design and Data Sources {#s3}
-----------------------
We conducted a longitudinal, retrospective cohort study using administrative data from the VA health care system and Centers for Medicare & Medicaid Services. Data sources included were VA Medical SAS Datasets, records of dispensed outpatient prescriptions, and laboratory values linked to Medicare Part A, Part B, and enrollment data obtained for a larger study ([@B23],[@B24]). All baseline variables and HbA~1c~ levels were based on fiscal year (FY) 2008 data; the first 120 days of FY2009 served as the follow-up period for determining antidiabetic medication use. The VA Pittsburgh Healthcare System Institutional Review Board approved this study.
Sample {#s4}
------
To construct the sample, we first used VA data to identify all veterans who *1*) were age ≥65 years as of the start of FY2008 (1 October 2007) and *2*) were given two or more inpatient or outpatient diagnoses for type 2 diabetes (ICD-9 250.x, 250.x2) in FY2008--2009 (with first diagnosis in FY2008) or received an oral diabetes medication through the VA in FY2008 ([@B25]). We then linked to Medicare claims and enrollment data to further refine the sample ([Fig. 1](#F1){ref-type="fig"}). We applied the Medicare Chronic Conditions Warehouse ICD-9 diagnosis code list for Alzheimer's Disease and Related Disorders (ADRD) to both VA records and Medicare claims to identify patients with dementia ([@B26],[@B27]). The ICD-9 codes in this algorithm include Alzheimer disease, vascular dementia, and a range of other specific related disorders (see [Supplementary Table 1](http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc14-0599/-/DC1) for full list of diagnoses). This definition contains only minor differences from an algorithm shown to have good sensitivity and specificity compared with a gold standard clinical dementia assessment ([@B27]). Patients without an ADRD ICD-9 code who filled a VA prescription for an antidementia medication (galantamine, rivastigmine, donepezil, memantine, or tacrine) in FY2008 were also included. Next, because veterans aged ≥65 years are eligible to enroll in Medicare and use non-VA health care in addition to VA care (yet we did not have access to non-VA prescription drug records), we took two steps to restrict the sample to patients with diabetes managed primarily within the VA: *1*) eliminating all patients whose Medicare records indicated enrollment in a non-VA source of drug coverage during follow-up (i.e., Medicare Part D stand-alone plan, Medicare Advantage plan, employer-sponsored plan eligible for a Centers for Medicare & Medicaid Services retiree drug subsidy) and *2*) excluding all remaining patients with HbA~1c~ levels solely monitored outside the VA, indicated by no HbA~1c~ values in VA records and at least one procedure code for an HbA~1c~ test in Medicare claims. Next, to ensure accurate capture of outpatient medications used in the 120-day follow-up period, we excluded patients who died or resided in a VA or Medicare-covered hospital or nursing home for ≥30 days during the follow-up period and, as a result, may not have needed to refill an outpatient VA prescription during the follow-up period. Finally, we excluded all remaining patients who did not fill at least one VA prescription for antidiabetic medication during follow-up.
{#F1}
Measures {#s5}
--------
### Outcomes {#s6}
We extracted the last available HbA~1c~ value in FY2008 from VA laboratory data to quantify patients' glycemic control as tightly controlled (\<7% \[53 mmol/mol\]), moderately controlled (7% to \<9% \[53 to \<75 mmol/mol\]), poorly controlled (≥9% \[≥75 mmol/mol\]), and not monitored (no HbA~1c~ tests recorded in either VA or Medicare data). We also captured whether the HbA~1c~ value was obtained in an outpatient versus inpatient setting for use in sensitivity analyses.
We used outpatient VA drug-dispensing records for the first 120 days of FY2009 to identify patient use of antidiabetic medication associated with a high risk of hypoglycemia, defined as having at least one fill for a sulfonylurea and/or insulin. We used a 120-day window to determine the period prevalence of use of these drugs in close relation to the last HbA~1c~ measurement. A 120-day window was chosen because even individuals obtaining 90-day antidiabetic prescriptions would be expected to fill at least one prescription during this period, allowing for some potential nonadherence. For descriptive purposes, we also captured other specific antidiabetic medication classes (biguanides \[metformin\], thiazolidinediones \[TZDs\], α-glucosidase inhibitors, meglitinides, dipeptidyl peptidase-4 \[DPP-4\] inhibitors, amylin analogs, and GLP-1 receptor agonists) that patients used in this time period and created a summary variable for their overall antidiabetic regimen (noninsulin monotherapy, noninsulin multitherapy, insulin alone, or insulin plus other noninsulin agent).
### Covariate Risk Factors {#s7}
We assessed sociodemographic, clinical, and health care utilization factors in relation to tight glycemic control and use of high-risk medications. Patient sex, age (65--74, 75--84, or ≥85 years), and race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, or other) were determined from VA utilization files. Missing VA race/ethnicity values were supplemented with the Research Triangle Institute race code in the Medicare enrollment file ([@B28]). Whether patients had a copay for VA medications in the follow-up period was also extracted. We used the Elixhauser comorbidity measure ([@B29],[@B30]) applied to diagnoses in VA and Medicare files to identify comorbidities present in ≥5% of the present sample as well as recent weight loss (3% of patients) because of an a priori hypothesis that weight loss is an important contributor to tight glycemic control. Detailed information on the specific ICD-9-CM diagnosis codes used to define each comorbid condition can be found at [www.hcup-us.ahrq.gov/toolssoftware/comorbidity/comorbidity.jsp](http://www.hcup-us.ahrq.gov/toolssoftware/comorbidity/comorbidity.jsp). We used VA and Medicare records to determine whether patients had at least one inpatient hospital or nursing home stay in FY2008. Finally, we determined whether dementia was documented within the VA, as indicated by either a VA ADRD diagnosis code or a VA prescription fill for an antidementia medication versus documented only in Medicare claims.
Analytic Approach {#s8}
-----------------
We examined descriptive statistics for all study variables in the full sample and each glycemic control group. To determine the association of sociodemographic, clinical, and health care utilization factors with HbA~1c~ control, we used multinomial logistic regression with robust SEs. Moderate control, which reflects guideline-concordant care, was the reference category. Finally, for patients whose last HbA~1c~ value in FY2008 indicated tight control (*n* = 8,276), we estimated a logistic regression model for use of medication with high hypoglycemic risk. We also conducted a sensitivity analysis using multinomial logistic regression to model use of sulfonylurea but no insulin, use of insulin but no sulfonylurea, and use of both sulfonylurea and insulin as separate outcomes, relative to use of neither agent, and report the results in [Supplementary Table 2](http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc14-0599/-/DC1).
Results {#s9}
=======
Sample Characteristics {#s10}
----------------------
[Table 1](#T1){ref-type="table"} shows characteristics of 15,880 community-dwelling veterans aged ≥65 years with type 2 diabetes and dementia. Almost all patients were male (99%), and 80% were non-Hispanic white. Comorbidities were common, including hypertension (81%), deficiency anemia (21%), chronic lung disease (19%), and peripheral vascular disease (17%).
######
Characteristics of community-dwelling older veterans with diabetes and comorbid dementia by level of glycemic control
Patient characteristics All patients
(*n* = 15,880) Tightly controlled
(*n* = 8,276) Moderately controlled
(*n* = 5,669) Poorly controlled
(*n* = 1,131) Not monitored (*n* = 804)
------------------------------------------------------------------------------ ----------------------------- ---------------------------------- ------------------------------------- --------------------------------- ---------------------------
Male sex 15,643 (99) 8,157 (99) 5,581 (98) 1,115 (99) 790 (98)
Race/ethnicity
Hispanic 1,242 (8) 566 (7) 475 (8) 137 (12) 64 (8)
White, non-Hispanic 12,629 (80) 6,742 (81) 4,489 (79) 776 (69) 622 (77)
Black, non-Hispanic 1,618 (10) 781 (9) 573 (10) 177 (16) 87 (11)
Other 391 (2) 187 (2) 132 (2) 41 (4) 31 (4)
Age
65--74 years 3,857 (24) 1,882 (23) 1,442 (25) 367 (32) 166 (21)
75--84 years 8,745 (55) 4,657 (56) 3,058 (54) 586 (52) 444 (55)
≥85 years 3,278 (21) 1,737 (21) 1,169 (21) 178 (16) 194 (24)
Has medication copay 9,515 (60) 4,990 (60) 3,431 (61) 638 (56) 456 (57)
Comorbidities
Congestive heart failure 2,860 (18) 1,416 (17) 1,080 (19) 226 (20) 138 (17)
Heart valve disease 1,168 (7) 648 (8) 394 (7) 69 (6) 57 (7)
Peripheral vascular disease 2,624 (17) 1,412 (17) 943 (17) 166 (15) 103 (13)
Hypertension 12,815 (81) 6,727 (81) 4,646 (82) 945 (84) 497 (62)
Chronic lung disease 2,979 (19) 1,600 (19) 1,032 (18) 212 (19) 135 (17)
Hypothyroidism 1,628 (10) 884 (11) 588 (10) 109 (10) 47 (6)
Renal failure 2,511 (16) 1,266 (15) 941 (17) 211 (19) 93 (12)
Solid tumor without metastasis 2,073 (13) 1,110 (13) 755 (13) 137 (12) 71 (9)
Obesity 1,080 (7) 517 (6) 432 (8) 102 (9) 29 (4)
Weight loss 436 (3) 260 (3) 129 (2) 20 (2) 27 (3)
Fluid and electrolyte disorder 2,016 (13) 1,043 (13) 722 (13) 166 (15) 85 (11)
Deficiency anemia 3,308 (21) 1,821 (22) 1,168 (21) 203 (18) 116 (14)
Psychoses 2,065 (13) 1,105 (13) 709 (13) 166 (15) 85 (11)
Depression 2,463 (16) 1,317 (16) 858 (15) 189 (17) 99 (12)
Inpatient stay in FY2008 2,416 (15) 1,246 (15) 837 (15) 243 (21) 90 (11)
VA documentation of dementia 11,213 (71) 5,869 (71) 3,958 (70) 818 (72) 578 (72)
Last HbA~1c~ value in baseline year (FY2008)[§](#t1n1){ref-type="table-fn"}
HbA~1c~ (%) 6.8 (6.3--7.6) 6.3 (6.0--6.6) 7.5 (7.2--8.0) 9.8 (9.3--10.7) N/A
HbA~1c~ (mmol/mol) 51 (45--60) 45 (42--49) 58 (55--64) 84 (78--93) N/A
Medication use in follow-up period (first 120 days of FY2009)
Medication regimen
Noninsulin monotherapy 7,298 (46) 4,942 (60) 1,756 (31) 156 (14) 444 (55)
Noninsulin multitherapy 3,081 (19) 1,438 (17) 1,337 (24) 180 (16) 126 (16)
Insulin alone 3,308 (21) 1,237 (15) 1,502 (27) 421 (37) 148 (18)
Insulin plus other agent 2,193 (14) 659 (8) 1,074 (19) 374 (33) 86 (11)
Medication class[\#](#t1n2){ref-type="table-fn"}
Insulin 5,501 (35) 1,896 (23) 2,576 (45) 795 (70) 234 (29)
Sulfonylurea 8,927 (56) 4,690 (57) 3,204 (57) 548 (49) 485 (60)
Metformin 6,487 (41) 3,593 (43) 2,238 (39) 382 (34) 274 (34)
TZDs 826 (5.2) 339 (4) 375 (7) 74 (7) 38 (5)
α-Glucosidase inhibitors 233 (1) 81 (1) 116 (2) 28 (3) 8 (1)
Use of medications with high hypoglycemic risk
No insulin/no sulfonylurea 2,842 (18) 2,063 (25) 598 (11) 42 (4) 139 (17)
No insulin/yes sulfonylurea 7,537 (47) 4,317 (52) 2,495 (44) 294 (26) 431 (54)
Yes insulin/no sulfonylurea 4,111 (26) 1,523 (18) 1,867 (33) 541 (48) 180 (22)
Yes insulin/yes sulfonylurea 1,390 (9) 373 (5) 709 (13) 254 (22) 54 (7)
Data are *n* (%) or median (interquartile range). Tightly controlled, HbA~1c~ \<7% (53 mmol/mol); moderately controlled, HbA~1c~ 7 to \<9% (53 to \<75 mmol/mol); poorly controlled, HbA~1c~ ≥9% (≥75 mmol/mol); not monitored, no evidence of having received any FY2008 HbA~1c~ tests in VA or Medicare records. N/A, not applicable.
§Presented for the 15,076 patients with HbA~1c~ values in FY2008.
\#Data not shown for use of meglitinides, DPP-4 inhibitors, amylin analogs, and GLP-1 agonists; \<1% of the total sample used these agents.
The majority (52%; *n* = 8,276) of patients had tight glycemic control, 36% had moderate control, 7% had poor control, and 5% did not have HbA~1c~ monitored in FY2008. Within the tight control group, the mean and median HbA~1c~ value was 6.3% (45 mmol/mol; minimum 3.8% \[18 mmol/mol\], maximum 6.9% \[52 mmol/mol\], interquartile range 6.0--6.6% \[42--49 mmol/mol\]). More than 97% of HbA~1c~ values were obtained in an outpatient setting, and exclusion of inpatient HbA~1c~ values did not substantively affect the distribution of HbA~1c~ values seen in the overall sample or within glycemic control categories.
[Table 1](#T1){ref-type="table"} also provides information on the medication regimens and specific medication classes used by the sample. Overall, noninsulin monotherapy was most common (46%) followed by insulin alone (21%), noninsulin multitherapy (19%), and insulin plus another noninsulin agent (14%). Sulfonylureas, metformin, and insulin were the most common classes used, followed by TZDs and α-glucosidase inhibitors. Meglitinides, DPP-4 inhibitors, amylin analogs, and GLP-1 receptor agonists were each used very rarely (\<1% of the sample).
Overall, 82% (*n* = 13,038) of the sample used a regimen associated with an increased risk of hypoglycemia, including 47% (*n* = 7,537) using sulfonylurea without insulin, 26% (*n* = 4,111) using insulin without sulfonylurea, and 9% (*n* = 1,390) using both agents ([Table 1](#T1){ref-type="table"}). Among tightly controlled patients, 75% (*n* = 6,213) used such a regimen, including 52% (*n* = 4,317) using sulfonylurea, 18% (*n* = 1,523) using insulin, and 5% (*n* = 373) using both agents. Of the 6,213 tightly controlled patients using either sulfonylureas or insulin, 29% (*n* = 1,811) also took at least one other agent not associated with a high hypoglycemic risk (data not shown).
Predictors of Glycemic Control Levels {#s11}
-------------------------------------
The multinomial regression model revealed patient age, specific comorbidities, and race/ethnicity to be independently associated with having tight versus moderate glycemic control ([Table 2](#T2){ref-type="table"}). Compared with patients aged 65--74 years, those who were 75--84 or ≥85 years old had higher odds of HbA~1c~ \<7% (53 mmol/mol). Heart valve disease, chronic lung disease, weight loss, and deficiency anemia were associated with increased odds of HbA~1c~ \<7% (53 mmol/mol), whereas congestive heart failure, renal failure, and obesity were associated with lower odds of HbA~1c~ \<7% (53 mmol/mol). Compared with non-Hispanic white patients, Hispanic patients also had lower odds of HbA~1c~ \<7% (53 mmol/mol). Racial/ethnic minority status and having an FY2008 inpatient stay were associated with higher odds of poor glycemic control, whereas older age and deficiency anemia were associated with lower odds.
######
Factors independently associated with level of HbA~1c~ control in community-dwelling older veterans with diabetes and comorbid dementia
Tightly controlled
(HbA~1c~ \<7% \[53 mmol/mol\]) Poorly controlled
(HbA~1c~ ≥9% \[75 mmol/mol\]) HbA~1c~ not monitored
---------------------------------------- --------------------------------------------------- ------------------------------------------------- ----------------------- ------ ------------ --------- ------ ------------ ---------
Male sex 1.10 0.83--1.46 0.49 1.02 0.59--1.75 0.94 0.81 0.45--1.46 0.48
Race/ethnicity
White non-Hispanic (reference) --- --- --- --- --- --- --- --- ---
Black non-Hispanic 0.91 0.81--1.02 0.11 1.68 1.39--2.04 \<0.001 1.16 0.91--1.49 0.24
Hispanic 0.77 0.67--0.87 \<0.001 1.58 1.28--1.96 \<0.001 0.96 0.72--1.28 0.79
Other 0.94 0.75--1.19 0.62 1.73 1.21--2.49 0.003 1.62 1.07--2.44 0.022
Age
65--74 years (reference) --- --- --- --- --- --- --- --- ---
75--84 years 1.16 1.07--1.26 0.001 0.81 0.70--0.94 0.005 1.29 1.06--1.56 0.011
≥85 years 1.13 1.02--1.25 0.021 0.66 0.54--0.81 \<0.001 1.43 1.13--1.80 0.002
Has medication copay 0.97 0.90--1.04 0.34 0.99 0.86--1.13 0.83 0.84 0.72--0.99 0.036
Congestive heart failure 0.84 0.76--0.92 \<0.001 1.07 0.90--1.28 0.43 1.09 0.88--1.35 0.42
Heart valve disease 1.16 1.01--1.32 0.033 0.91 0.70--1.20 0.51 1.22 0.91--1.64 0.19
Peripheral vascular disease 1.03 0.94--1.13 0.56 0.86 0.72--1.03 0.11 0.84 0.67--1.05 0.13
Hypertension 0.96 0.88--1.05 0.38 1.08 0.91--1.29 0.37 0.39 0.33--0.45 \<0.001
Chronic lung disease 1.10 1.01--1.21 0.038 1.00 0.84--1.18 0.99 1.08 0.88--1.32 0.48
Hypothyroidism 1.03 0.92--1.15 0.62 0.96 0.77--1.19 0.68 0.60 0.44--0.82 0.001
Renal failure 0.90 0.82--1.00 0.045 1.13 0.94--1.35 0.21 0.78 0.61--0.99 0.045
Solid tumor without metastasis 0.99 0.90--1.09 0.85 0.90 0.74--1.10 0.31 0.67 0.52--0.87 0.003
Obesity 0.83 0.72--0.95 0.007 1.07 0.85--1.35 0.56 0.57 0.38--0.84 0.004
Weight loss 1.36 1.09--1.69 0.006 0.93 0.45--1.19 0.21 1.77 1.14--2.74 0.010
Fluid and electrolyte disorder 0.97 0.87--1.08 0.57 1.11 0.91--1.36 0.29 1.09 0.83--1.41 0.55
Deficiency anemia 1.12 1.02--1.22 0.016 0.76 0.64--0.92 0.003 0.78 0.63--0.98 0.030
Psychoses 1.08 0.97--1.20 0.14 1.04 0.86--1.26 0.68 0.87 0.68--1.11 0.26
Depression 1.05 0.95--1.15 0.35 1.05 0.88--1.25 0.60 0.91 0.72--1.15 0.45
Inpatient stay in FY2008 1.04 0.93--1.15 0.50 1.45 1.21--1.73 \<0.001 0.90 0.70--1.17 0.44
VA documentation of dementia diagnosis 1.05 0.98--1.14 0.18 0.99 0.86--1.16 0.94 0.97 0.82--1.15 0.71
Multinomial logistic regression was used, with moderate control (HbA~1c~ ≥7% \[53 mmol/mol\] and \<9% \[75 mmol/mol\]) as the reference category. OR, odds ratio.
Predictors of Use of Medications With High Risk of Hypoglycemia {#s12}
---------------------------------------------------------------
Among the 8,276 patients with tight control, several significant risk factors emerged for use of medications with high hypoglycemic risk ([Table 3](#T3){ref-type="table"}). Male sex; black race; age 75--84 or ≥85 vs. 65--74 years; presence of congestive heart failure, peripheral vascular disease, or renal failure; and having had a hospitalization or nursing home stay in FY2008 were all associated with higher odds of use of sulfonylureas and/or insulin versus neither agent. Fluid/electrolyte disorder or depression was also associated with lower odds of use of a high-risk regimen.
######
Independent predictors of use of antidiabetic medications with high risk of hypoglycemia in community-dwelling older veterans with diabetes and comorbid dementia with tight glycemic control
OR 95% CI *P* value
--------------------------------- ------ ------------ -----------
Male sex 1.77 1.19--2.63 0.004
Race/ethnicity
White non-Hispanic (reference) --- --- ---
Black non-Hispanic 1.27 1.05--1.53 0.015
Hispanic 0.92 0.75--1.13 0.42
Other 0.84 0.60--1.16 0.28
Age
65--74 years (reference) --- --- ---
75--84 years 1.28 1.13--1.45 \<0.001
≥85 years 1.60 1.37--1.88 \<0.001
Has medication copay 0.93 0.83--1.04 0.20
Congestive heart failure 1.51 1.28--1.78 \<0.001
Valvular disease 0.88 0.72--1.08 0.22
Peripheral vascular disease 1.2 1.05--1.41 0.010
Hypertension 1.10 0.97--1.26 0.14
Chronic lung disease 0.94 0.82--1.08 0.38
Hypothyroidism 0.91 0.77--1.08 0.28
Renal failure 4.60 3.67--5.78 \<0.001
Solid tumor without metastasis 0.97 0.83--1.13 0.67
Obesity 1.01 0.82--1.26 0.91
Weight loss 0.88 0.65--1.20 0.43
Fluid and electrolyte disorder 0.83 0.70--1.00 0.047
Deficiency anemia 0.96 0.84--1.10 0.59
Psychoses 0.94 0.81--1.10 0.47
Depression 0.85 0.74--0.98 0.026
Inpatient stay in FY2008 1.26 1.06--1.49 0.008
VA documentation of dementia 1.09 0.97--1.22 0.16
Tight glycemic control, HbA~1c~ \<7% (53 mmol/mol). OR, odds ratio.
Conclusions {#s13}
===========
In a national cohort of \>15,000 outpatients with medication-treated type 2 diabetes and dementia, we found that more than one-half had HbA~1c~ \<7% (53 mmol/mol), despite clear guidelines recommending higher glycemic targets. In addition, 75% of tightly controlled patients with dementia used medications that further exacerbated their potential risk for hypoglycemia. Even in the context of heightened hypoglycemia risk resulting from the combination of comorbid dementia and tight glycemic control, the results suggest that the large majority of providers do not substitute sulfonylureas and insulin with lower-risk antidiabetic agents. These findings highlight the need for interventions to encourage appropriate deintensification and alteration of medications when diabetic patients develop dementia, which has not been reflected in previous diabetes quality initiatives.
The study has several important strengths. Despite growing numbers of older diabetic patients with dementia and their heightened vulnerability to tight control, few studies have examined glycemic control levels partly because large enough data sources containing HbA~1c~ values for this population are rare outside the VA. A recent study documented high prevalence (45--50%) of tight glycemic control generally among veterans with a range of risk factors for hypoglycemia, including dementia ([@B31]). The present study extends this work by focusing specifically on dementia status and examining risk factors for tight control or sulfonylurea/insulin use and by using Medicare data to help to identify patients with dementia. The incorporation of Medicare claims in identifying dementia patients is critical given past research demonstrating its importance in accurately capturing comorbidities for older veterans ([@B32]). In addition, we believe that the present study is the first to document the very high rate of use of sulfonylureas and insulin in tightly controlled patients with dementia, an important and modifiable contributor to these patients' risk for hypoglycemia.
We identified key risk factors for tight glycemic control in patients with dementia. Age ≥75, weight loss, chronic lung disease, and deficiency anemias increase the odds of tight glycemic control, whereas obesity is protective. Providers and patients may not recognize that changes in appetite and weight associated with dementia itself, advancing age, or other comorbidities may make it easier to control blood glucose with less intense antidiabetic regimens or that medication may no longer be required. The results suggest that interventions should encourage the review and deintensification of medication regimens in patients who lose weight or reach advanced ages.
We also found that patients with concomitant congestive heart failure or renal failure exhibited lower odds of tight control compared with dementia patients without these comorbidities; these diagnoses are noted in VA/DoD guidelines as indications to avoid tight glycemic control. The explicit mention of the role of dementia in setting glycemic control targets, as in the newly revised 2013 AGS guidelines ([@B20]) and a recently proposed quality indicator for diabetes overtreatment ([@B22]), may be an essential first step in encouraging appropriate diabetes treatment deintensification in this population. Although the present findings suggest some contributing factors to the lack of appropriate deintensification of diabetes treatment in patients with dementia, future research should directly engage providers, patients, and caregivers to uncover their perceptions of how dementia should alter glycemic control targets and barriers to pursuing less intensive targets as well as what role guidelines play in these decisions.
The present findings also highlight the need for initiatives to support safer antidiabetic prescribing choices for patients with dementia. The widespread use of sulfonylureas and insulin likely reflects VA/DoD guidelines recommending both options as first-line antidiabetic therapies along with metformin and as add-on therapies to metformin or each other if glycemic goals are not achieved, with no discussion of how dementia should affect medication choice. The greatly increased odds of sulfonylureas and/or insulin use in patients with congestive heart failure and renal failure and those aged ≥75 years also likely reflect VA/DoD (and other) guidelines, which list these conditions and age ≥80 years as contraindications to the use of metformin, leaving sulfonylurea and insulin as the preferred agents over other classes of agents with lower hypoglycemic risk. Although these other antidiabetic medication classes (i.e., TZDs, DPP-4 inhibitors, GLP-1 agonists, α-glucosidase inhibitors) have lower associated risk of hypoglycemia, they have lower efficacy in reducing HbA~1c~ and lack robust evidence regarding their safety profile and associated treatment burden in older patients with dementia. Although these alternative agents were not on the VA national formulary at the time of the study (except for acarbose), they were available to all prescribers when necessary through a nonformulary request process. Because clinical trials comparing various antidiabetic medications in older patients with dementia are unlikely to occur, well-designed observational studies are needed to guide prescribing choices for this rapidly growing population. In the meantime, the present results suggest a need for provider outreach efforts to consider medication options with a lower hypoglycemic risk and encourage the use of the minimally intensive regimen required to achieve moderate glycemic control levels.
The results of this study should be interpreted in light of several limitations. First, our focus was on understanding patient characteristics associated with two established risk factors for hypoglycemia (i.e., HbA~1c~ \<7% \[53 mmol/mol\], use of sulfonylureas and/or insulin), and we did not capture data on actual hypoglycemic events. Whether deintensification of therapy in response to tight glycemic control or substitution of insulin and sulfonylurea with other antidiabetic agents results in reduced hypoglycemic events in diabetic patients with dementia is an important direction for future research. In addition, the relationship between glycemic control levels and the progression of dementia is unknown. Whether tight glycemic control hinders or hastens dementia progression should be explored in future studies. Second, although guidelines recommend higher HbA~1c~ targets for older patients with dementia, some patients with mild dementia in otherwise excellent health and good functional status may opt for tighter glycemic targets. Although we did capture extensive information on the presence of comorbid conditions, we were not able to account for patients' functional status or preferences in the analyses. Likewise, insulin therapy may be appropriate for older dementia patients with long-standing diabetes who are unable to attain HbA~1c~ targets with noninsulin agents alone. We did not examine dose of medications; thus, it is possible that some tightly controlled patients were prescribed very low doses. However, by limiting the analysis of hypoglycemic medication use to patients with HbA~1c~ \<7% (53 mmol/mol), such patients face a particularly high risk of hypoglycemia and may benefit from deintensification of insulin dose or a switch to a non--insulin-containing regimen.
Although this study is unique in capturing such a large number of patients with both diabetes and dementia as well as important clinical variables like HbA~1c~, we acknowledge that the observational study design, relying solely on administrative data, has inherent limitations. In particular, we were not able to capture the full range of covariates that may be associated with glycemic control and medication choice, such as assistance with at-home diabetes self-management from informal family caregivers or nurse-provided home care. We also did not examine interactions between covariates because of a lack of theory to guide such analyses and relatively small numbers of patients with some comorbid conditions (e.g., weight loss). Future research may consider possible multiplicative effects of specific comorbid conditions or other risk factors identified in this study. Patients may also have had HbA~1c~ tests and medications filled outside the VA that we were unable to capture, although we reduced this possibility by limiting the sample to patients who filled antidiabetic medications in the VA and did not have another major source of drug coverage. In addition, we used a single HbA~1c~ value to classify patients' glycemic control at one point in time and therefore cannot determine the extent to which their glycemic control levels were transient versus stable. We also acknowledge that the data are several years old, and care of dementia patients may have improved since, especially in light of increased attention to the possible risks of tight control and hypoglycemia in older patients with comorbidities. Finally, the results reflect a primarily male veteran population and may not generalize to women or nonveterans.
In conclusion, the results show a high rate of intense treatment of diabetes in older patients with comorbid dementia, potentially placing them at elevated risk for hypoglycemia and serious adverse events. Equally disconcerting is the high frequency of use of medications known to cause hypoglycemia. The findings present a compelling need for the development of quality initiatives to encourage review of glycemic targets and antidiabetic medications in this rapidly growing group of patients, especially those aged ≥75 years and those with weight loss.
This article contains Supplementary Data online at <http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc14-0599/-/DC1>.
**Funding.** C.T.T., S.Z., M.M., and M.J.F. are supported by VA Health Services Research & Development (CIN 13-405). W.F.G. is supported by a VA Health Services Research & Development Career Development Award (CDA 09-207).
The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.
**Duality of Interest.** No potential conflicts of interest relevant to this article were reported.
**Author Contributions.** C.T.T. contributed to the study concept and design, study supervision, data acquisition, data analysis and interpretation, statistical analysis, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. W.F.G. and X.Z. contributed to the study concept and design, data acquisition, data analysis and interpretation, and critical revision of the manuscript for important intellectual content. C.B.G. contributed to the study concept and design, data analysis and interpretation, and critical revision of the manuscript for important intellectual content. S.Z. contributed to the data acquisition, data analysis and interpretation, and critical revision of the manuscript for important intellectual content. M.M. contributed to the study supervision, data acquisition, data analysis and interpretation, and critical revision of the manuscript for important intellectual content. M.J.F. contributed to the study supervision; administrative, technical, and material support; data analysis and interpretation; and critical revision of the manuscript for important intellectual content. C.T.T. is the guarantor of this work, and as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
**Prior Presentation.** Parts of this study were presented in poster form at the 2013 Annual Scientific Meeting of the Gerontological Society of America, New Orleans, LA, 20--24 November 2013.
|
{
"pile_set_name": "PubMed Central"
}
|
Prince Alihabad, visiting the Wilson family in the Old South, takes an interest in their daughter when he learns they have oil property in Texas, making Buster, her boyfriend, jealous. When Mr. Wilson is murdered and the land deed stolen, police...
This feature presents Williams and Jones as down and out in the Great Southwest. They pose as theatrical experts and get free room and board in the Holliday home for helping Honeydew prepare to win a beauty pageant. Florida, the other daughter, is...
QuickView
Display a larger image and more item information when the pointer pauses over a thumbnail
|
{
"pile_set_name": "Pile-CC"
}
|
Københavns Vestegns Politi søger vidner i forbindelse med den voldsomme brand, der hærgede den nye politibygning i Glostrup tidligere på måneden.
I begyndelsen af februar tog det adskillige brandfolk en hel nat at slukke en omfattende brand, der hærgede Rigspolitiets nye bygning i Glostrup.
Nu oplyser politiinspektør Svend Foldager til TV 2, at branden sandsynligvis var påsat.
- Jeg kan sige det sådan, at der er en altovervejende sandsynlighed for, at det ikke var en teknisk installation, der var skyld i branden. Så er der to andre muligheder: At den var påsat, eller at det var en ulykke. Sidstnævnte vurderer vi heller ikke som særlig sandsynligt, siger Svend Foldager til TV 2.
Blot nogle få måneder før, Rigspolitiets Nationalt Kriminalteknisk Center skulle rykke ind i nye og moderne lokaler i Glostrup, brød den næsten færdige bygning i brand.
Branden raserede tre etager samt taget, og ifølge Hovedstadens Beredskab skete der omfattende skader på bygningen.
Dengang afviste politiet, at der skulle være tale om en påsat brand, men det virker ifølge politiinspektør Svend Foldager nu som en af de mere sandsynlige årsager.
Københavns Vestegns Politi er derfor meget interesseret i at høre fra vidner, der har bemærket noget usædvanligt i området torsdag 9. februar i tidsrummet mellem klokken 17 og 17.25.
Politiet søger ung mand, der blev set på stedet
Især vil politiet gerne i kontakt med en ung mand, som er blevet set løbe fra området omkring Ingo-benzintanken ved Ejby Industrivej og direkte ind i den nye politibygning fra håndværkerindgangen i bygningens sydvestlige hjørne.
- Vi vil meget gerne i kontakt med manden, da han kan have vigtige oplysninger i sagen, siger Svend Foldager, der på nuværende tidspunkt ikke kan komme ind på, om manden er mistænkt i sagen.
Manden beskrives i en pressemeddelelse som cirka 175 centimeter høj og bred af bygning. Han var iført sort strikhue, som gik helt ned til øjenbrynene samt et sort tørklæde, der dækkede den nederste del af ansigtet.
Han bar sorte, forvaskede joggingbukser og en sort, kort jakke.
En gennemgang af overvågningen viser, at personen løb fra området omkring klokken 17.18. Manden forsvandt ind i villakvarteret nordvest for Nordre Ringvej.
Den nye bygning ligger på Ejby Industrivej, hvor en række af Rigspolitiets afdelinger - blandt andet Nationalt Efterforskningscenter - også har til huse.
Nationalt Kriminalteknisk Center holder i dag til på Slotsherrensvej i Vanløse. Derfor vil branden ikke betyde noget for kriminalteknikernes arbejde.
Vidner kan henvende sig til politiet på telefon 43 86 14 48.
|
{
"pile_set_name": "OpenWebText2"
}
|
Alien Outpost
Other Formats
Product Notes
2021: An invading race of aliens known as the Heavies are narrowly defeated in the First Earth War. But thousands of them were left behind as a new war on terror rages. In the aftermath, a series of remote operating bases are created to defend the planet. Three Seven is the deadliest, positioned in the most hostile place on Earth. A documentary film crew is sent to record daily life in Outpost 37, where the men, led by hardened commander Captain Spears (Rick Ravanello, Dark Haul), are under constant enemy fire. When a member of the crew disappears during a Heavy ambush, the unit launches a raid deep into enemy territory to rescue him and make a terrifying discovery. Directed by Jabbar Raisani (Visual Effects Supervisor on Game Of Thrones, Machete, Predators), this explosive actioner is a non-stop barrage on the senses and a first-rate science-fiction masterpiece.
Technical Information
2021: An invading race of aliens known as the Heavies are narrowly defeated in the First Earth War. But thousands of them were left behind as a new war on terror rages. In the aftermath, a series of remote operating bases are created to defend the planet. Three Seven is the deadliest, positioned in the most hostile place on Earth. A documentary film crew is sent to record daily life in Outpost 37, where the men, led by hardened commander Captain Spears (Rick Ravanello, Dark Haul), are under constant enemy fire. When a member of the crew disappears during a Heavy ambush, the unit launches a raid deep into enemy territory to rescue him and make a terrifying discovery. Directed by Jabbar Raisani (Visual Effects Supervisor on Game Of Thrones, Machete, Predators), this explosive actioner is a non-stop barrage on the senses and a first-rate science-fiction masterpiece.
|
{
"pile_set_name": "Pile-CC"
}
|
In roughly 3 1⁄ 2 months, UFC heavyweight champion Stipe Miocic will take on light heavyweight champion Daniel Cormier in the UFC 226 main event. It’s a champ vs. champ showdown that will either see Cormier become a two-division titlist, or Miocic extend his own heavyweight title defense record to four.
There are admittedly not many viable title challengers for Miocic in his own division, which is part of the reason the Cormier matchup has high intrigue and was booked in the first place. One man who has risen up the ranks quickly is Curtis Blaydes, who is coming off a big win over Mark Hunt at UFC 221. In an interview with Submission Radio, Blaydes gave his take on Stipe-DC, and why he believes Miocic will get the job done on July 7th.
“It is a tough one,” Blaydes said. “This is another great match-up. Daniel Cormier, who is I think undefeated as a heavyweight, to put him against, as you said, possibly the greatest heavyweight champion we’ve had, I think it’s a great match-up. I’m going with Stipe. I think it’s going to be a banger. I think it’s going to be five rounds, just like Jon Jones’ last (fight), not his last one against DC but their first fight against each other. I think it’s gonna go like that. They’re both gonna get rocked, they’re both gonna get taken down, they’re both gonna get cut and have bruises and what not, but I think Stipe’s length and his boxing (will be too much). “
The 27-year-old Blaydes revealed his experiences training with Miocic, and had some interesting insights on both the wrestling and striking battles they had when sparring with each other.
“I actually trained with him a couple of years ago, I wrestled with him,” Bl And I’m not gonna toot my own horn, but I think I’m one of the better wrestlers overall regardless of the weight class in the UFC right now, and his wrestling is legit. He is very good.
“On the feet he destroyed me. I was an amateur, this is back in 2013. I’m one of those guys, I’m not gonna lie to you when someone is better. Like, he was leaps and bounds better than me. He was supposed to be, like, at the time he was going up against Gabriel Gonzaga. So yeah, it would have been weird if they brought me in there and I just started picking him apart. That probably would have been a problem for Stipe. No, he handled me like he was supposed to. But when we wrestled, like I said, pretty back and forth. He would go, (in) I guess an hour practice, he would get two takedowns, I would get two takedowns, or maybe he would get one more, maybe I would get one more.”
As for Blaydes, he has his own big fight coming up on June 9th in his hometown of Chicago, Illinois, as he’ll be facing Alistair Overeem at UFC 225. That fight represents the last on his UFC contract, although if he re-signs, you would figure that a win over Overeem puts him in prime position for a title shot.
|
{
"pile_set_name": "OpenWebText2"
}
|
Holes a plenty: oral health status a major issue for newly arrived refugees in Australia.
Dental health needs of newly arrived refugees are much greater than for the wider Australian community. This paper identifies the disparities and highlights major dental health issues for Australia's growing and constantly changing refugee population. Using available data and the decayed, missing and filled teeth (DMFT) index as a measure of oral health, the reported oral health status of refugee groups in Australia was compared with that of the general population, Indigenous Australians, recipients of public dental services, special needs groups in Australia and other refugee groups outside Australia. The reported oral health status of Australian refugees compared poorly with the comparison groups. Of particular concern was the number of reported untreated decayed teeth (D). This ranged from a mean of 2.0 to 5.2 compared with 0.6 to 1.4 for the general Australian population. Refugee groups also reported fewer filled teeth (1.0 to 5.8) compared with the general population (4.1 to 9.3). Similar results were found when reported D, M and F teeth for refugees were compared to Indigenous Australians, public dental service recipients, immigrants and special needs groups in Australia. Dental health of refugees, particularly untreated decay, compared poorly to that of Indigenous Australians, and special needs populations in Australia who all have known worse dental health than the general population. There is an urgent need for the inclusion of this at risk population among targeted dental services. In addition, sources of health related data must clearly identify refugees to enable appropriate comparisons with other population groups. Recommendations for refugees are made regarding on-arrival dental assessment and treatment, and community based oral health programmes.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
1. Field of the Invention
The present invention relates to an apparatus and method for processing a packet in a voice and data integration system.
2. Description of the Related Art
Owing to today's rapid popularization of Internet and its accompanying request for various services, an Internet protocol (IP) network is being remarkably advanced in its performance and service. Accordingly, a request for more various services is continuously increased.
IP network-based voice transmission, one of such services, plays a great role in the IP network together with data transmission. Hence, a request for various voice transmission functions is also made together. Accordingly, terminals such as a digital telephone and a single telephone have been required to integrate voice IPs (VoIP: Voice over Internet Protocol).
Thus, a voice and data integration apparatus begins to be developed so that conventional terminals and Internet terminals can exchange data or voice with each other through the IP network.
Such a voice and data integration apparatus performs a gateway function of matching the IP network and each terminal, and performs a VoIP gateway function of decoding a voice packet received from the IP network into pulse code modulation (PCM) data and transmitting the decoded data to the terminal, or encoding the PCM data received from the terminal into the voice packet and transmitting the encoded data to the IP network.
Further, main factors deteriorating a quality of voice communication in a network such as an IP network include a loss of packet, a delay, and a jitter.
1) Loss of Packet: phenomenon in which a packet is lost during transmission on the network and thus not decoded in the voice and data integration apparatus, and thereby a quality of voice is remarkably deteriorated.
2) Delay: phenomenon in which a packet is temporally delayed when output, compared to when input, and each packet is differently delayed depending on a route along which the packet is transmitted on the network.
3) Jitter: phenomenon in which queuing and congestion occurring in network equipment due to a different rate of delay of each packet. Each piece of network equipment should include a jitter buffer in order to prevent this phenomenon, but the jitter buffer causes transmission delay.
Accordingly, in order to guarantee the quality of voice communication over the IP network, techniques such as dynamic jitter buffering for dynamically adjusting a size of the jitter buffer, Real-time Transport Protocol (RTP) compressing for compressing a Real-time Transport Protocol (RTP) packet as a voice packet, and Real-time Transport Protocol (RTP) multi-framing for splitting a voice packet have been utilized. See Network Working Group Request for Comments (RFC) 1889-RTP: A Transport Protocol for Real-Time Applications; Audio-Video Transport Working Group, H. Schulzrinne et al. January 1996 or Network Working Group Request for Comments (RFC) 3550-RTP: A Transport Protocol for Real-Time Applications; H. Schulzrinne et al. July 2003. However, a perfect quality of voice is not yet guaranteed.
Further, in the conventional voice and data integration apparatus, an algorithm for guaranteeing the quality of voice is processed only in a digital signal processing (DSP) manufactured in a manufacture company. Hence, the algorithm is not so good in extensibility and reliability.
|
{
"pile_set_name": "USPTO Backgrounds"
}
|
Scaled quantum chemical force fields for 1,1-difluorocyclopropane and the influence of vibrational anharmonicity.
Potential functions and harmonic (omega(i)) and anharmonic (nu(i)) fundamental frequencies have been calculated for 1,1-difluorocyclopropane (DFCP) and its d4 and d2 isotopomers using the program Gaussian 03. B3LYP and MP2 models were employed, each with the bases 6-311++G** and cc-pVTZ. Anharmonicity corrections Delta(i) = omega(i) - nu(i) are listed and shown to be different for symmetric and antisymmetric CH stretching modes in situations where Fermi resonance appears to be absent. The same effect is missing in C2H4, for which similar calculations were made. The quadratic force fields for DFCP have been scaled in symmetry coordinate space with 15 scale factors both to observed frequencies nu(obsd)and also to omega (obsd), where omega(obsd) = nu(obsd) + Delta. With nu(obsd) especially, different scale factors are needed for the symmetric and antisymmetric CH stretching force constants due to their differing anharmonicities. The source of the latter in the quartic and cubic force field is explored. MP2 calculations of valence interaction force constants involving the stretching of bonds on a common carbon atom are preferred to those from a B3LYP model. In either model, scaling to omega(obsd) rather than to nu(obsd) does not remove the necessity of varying scale factors for differing types of motion in the same group. Theoretical values of the five quartic centrifugal distortion constants are listed for the normal species and compared with new experimental data. The predictions are sufficiently good to be useful in fitting pure rotational transitions. A weakness is identified in the current Gaussian 03 code for the calculation of vibration-rotation quantities, and limitations are noted in the manner in which Fermi resonance is handled.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Q:
How to start process, then stop later in PHP, MySQL with AJAX
I want to send an AJAX call to a server that makes phone calls to our clients. However, I don't want the person who starts the process to have to leave their browser open. After some research, I've found that I can pass a header in php normally to allow the browser to disconnect without the php execution stopping. Will this work for AJAX as well? The relevent code is below.
//jQuery 1.8.10
$('#start').click(function(){
$.post('/startcalling', {
'time_limit': 0
});
});
$('#stop').click(function(){
$.post('/stopcalling');
});
The important PHP
function startCalling(){
echo "starting...";
header('Connection: close');
while(getFlagStatus()){
makeNextCall();
}
}
function stopCalling(){
if(!getFlagStatus()){
$query = "UPDATE cc_flags SET cc_on = 0";
mysql_query($query);
}
}
I could package this into a CLI command, and accomplish my goal, but I feel like there has to be an easier way. If I've been confusing, let me know and I'll edit.
EDIT: Does php execution stop after a user leaves the page?
Does this apply here?
A:
I looks like you want the behavior of ignore_user_abort($bool). But this alone won't help you much as PHP usually have a time limit of 30 seconds. set_time_limit($seconds) probably will help you with this.
Keep in mind that the script will run on your webserver and the user will not have any way to kill the script if they make a mistake, so don't forget to add extra checks so your users don't spawn the script 10 times and let it run, especially if it's making phone calls!
I'd suggest making a server script that runs outside of the web server, so you can communicate with the daemon and start/stop jobs on it. It's faily easy to do with simple sockets.
|
{
"pile_set_name": "StackExchange"
}
|
Why the British Are Hiding Information About Rudolf Hess.
The Russian scholar, Andrei Fursov, explains in this video the reason why the British authorities insisted to keep Rudolf Hess’s files classified until 2050. His theory is that Hess was indeed negotiating with the United Kingdom. On June 14th 1941, Hitler suspended the transfer of forces from the western front to the Soviet border. Meanwhile, the negotiations were progressing and the royal air force had even planned a raid on Soviet targets. However, the deployment of the German forces at the Soviet border resumed four days later, on June 18th 1941. Mr. Fursov claims that the negotiations failed after the US threatened UK to confiscate all of its gold if they agree to stop the war.
|
{
"pile_set_name": "OpenWebText2"
}
|
"use strict";
// This icon file is generated automatically.
// tslint:disable
Object.defineProperty(exports, "__esModule", { value: true });
var CaretLeftFilled = { "name": "caret-left", "theme": "filled", "icon": { "tag": "svg", "attrs": { "viewBox": "0 0 1024 1024", "focusable": "false" }, "children": [{ "tag": "path", "attrs": { "d": "M689 165.1L308.2 493.5c-10.9 9.4-10.9 27.5 0 37L689 858.9c14.2 12.2 35 1.2 35-18.5V183.6c0-19.7-20.8-30.7-35-18.5z" } }] } };
exports.default = CaretLeftFilled;
|
{
"pile_set_name": "Github"
}
|
Redox-linked structural changes associated with the formation of a catalytically competent form of the diheme cytochrome c peroxidase from Pseudomonas aeruginosa.
A recombinant form of the prototypic diheme bacterial cytochrome c peroxidase (BCCP) from Pseudomonas aeruginosa (PsaCCP) has been expressed in Escherichia coli and purified to homogeneity. This material was used to carry out the first integrated biochemical, spectroscopic and structural investigation of the factors leading to reductive activation of this class of enzymes. A single, tightly bound, Ca2+ ion (K = 3 x 10(10) M-1) found at the domain interface of both the fully oxidized and mixed-valence forms of the enzyme is absolutely required for catalytic activity. Reduction of the electron-transferring (high-potential) heme in the presence of Ca2+ ions triggers substantial structural rearrangements around the active-site (low-potential) heme to allow substrate binding and catalysis. The enzyme also forms a mixed-valence state in the absence of Ca2+ ions, but a combination of electronic absorption, and EPR spectroscopies suggests that under these circumstances the low potential heme remains six-coordinate, unable to bind substrate and therefore catalytically inactive. Our observations strongly suggest that the two mixed-valence forms of native PsaCCP reported previously by Foote and colleagues (Foote, N., Peterson, J., Gadsby, P., Greenwood, C., and Thomson, A. (1985) Biochem. J. 230, 227-237) correspond to the Ca2+-loaded and -depleted forms of the enzyme.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
298 So.2d 622 (1973)
Leonard Ray WILSON, Sr.
v.
Peggy Dickerson WILSON (York).
Civ. 173.
Court of Civil Appeals of Alabama.
December 12, 1973.
Rehearing Denied January 9, 1974.
*623 Hubert L. Taylor, Gadsden, for appellant.
Corretti, Newsom, Rogers & May, Birmingham, for appellee.
BRADLEY, Judge.
This is an appeal from a decree of the Walker County Circuit Court, in Equity, *624 granting and denying relief as requested by the parties in their respective petitions to modify a final decree of divorce.
The appellant, in his petition for modification of the divorce decree, requested that custody of a minor child of the marriage, Leonard Ray Wilson, Jr., now be vested in him on the grounds that the appellee was neglecting the child, mistreating it, and also attempting to alienate the child's affections for him. Further, it was stated that appellant had just discovered that his former wife had engaged in adulterous conduct prior to their divorce. It was also requested that the appellee be required to petition the Probate Court of Shelby County, Alabama for rescission of its order changing the name of the minor child in question from Leonard Ray Wilson, Jr. to Ray Frank York.
The appellee cross-petitioned for a modification of the same divorce decree and requested that the amount of child support be increased and that she be awarded attorney's fees. In support of her request for an increase in child support, the appellee pointed out that the divorce decree, which affirmed an agreement between the parties, awarded $50 per month for the child, Leonard Ray Wilson, Jr., and $50 per month for the unborn child. The pregnancy resulted in twins being born, and appellee asked for an increase in support payments for the additional child. She also sought additional support money due to increase in the cost of living.
The trial court's decree awarded $165 for child support, denied the request for change of custody, denied the request that appellee be required to initiate proceedings to rescind the order of the Shelby County Probate Court's changing the name of Leonard Ray Wilson, Jr. to Ray Frank York, and denied the request for an award of attorney's fee to appellee. From said decree an appeal has been perfected to this court.
The appellee in this cause has filed a motion to strike from the record an amendment to the petition filed by the appellant in the trial court. We believe that the motion is due to be granted. The transcript shows that the appellant filed that amendment in open court and that the appellee requested a continuance pending that motion. The trial judge said that it would be some time before the motion for the continuance could be heard. The attorney for appellant then made the following statement:
"MR. HARDWICK: Well, your Honor, insofar as this petition is concerned, I have it, and I have presented it to the Court as an aid, and I am willing at this time to withdraw the amendment that I have presented to the Court, and we will proceed accordingly as intended. I thought that this would be some assistance to Mr. Corretti and the Judge, but if it will cause problems, we won't file it, and we would like to proceed."
We believe that this statement constitutes a withdrawel of the proposed amendment and it is due to be stricken from the record.
Appellant filed nineteen assignments of error, only nine of which were argued. Those assignments not argued are deemed waived. Supreme Court Rule 9.
In assignment of error two, appellant contends that the decree of the trial court filed on January 9, 1973 is not final but is still in fieri. He argues that the language used in the first part of the decree to the effect, ". . . that . . . relief should be granted in part and denied in part in both petitions . . ." indicates that something remains to be done since he did not receive any relief in response to his petition for modification.
A decree in fieri will not support an appeal. But, the test of the finality of a decree which will support an appeal is *625 not whether the cause is in peri, but whether the decree rendered ascertains and declares the rights of the parties. Ex parte Elyton Land Co., 104 Ala. 88, 15 So. 939. It has also been held that a decree which declares the rights of the parties and settles the equities is final even though further proceedings by the court are envisioned so as to effectuate the decree. Newton v. Ware, 271 Ala. 444, 124 So.2d 664.
In the instant case, we believe that the rights and equities of the parties have been adjudicated. Custody of the children was denied to the father and left with the mother; support for the children was increased as requested by the mother and opposed by the father; attorney fees as requested by appellee and opposed by appellant were refused; and request by appellant to have the order of Shelby County Probate Court changing the name of the oldest son set aside was denied. As we view the request for relief as set out in the respective pleadings, nothing remains to be done by the trial court as regards the rights and equities of the parties; consequently the decree is final and supportive of the appeal taken.
In assignments of error three, four and five, appellant contends that the trial court erred in refusing to award custody of Leonard Ray Wilson, Jr. to him and in assignments of error seven, eight and nine, the contention is that the trial court erred in requiring him to pay increased child support. Both contentions are based on the lack of sufficient evidence to support the trial court's decree.
The testimony was taken orally before the court sitting without a jury, and it was conflicting. For example, there was testimony by appellant that the appellee had engaged in adulterous conduct prior to the divorce and he had just learned about it. The appellee denied ever having engaged in such conduct. The appellant and his mother testified that Leonard Ray Wilson, Jr. was dirty and ill-cared for, and had been mistreated by appellee and her new husband. Appellee denied that she or her husband had mistreated the child and she testified that the child was kept clean, provided with suitable clothes, dental and medical care and toys. Several witnesses confirmed that the child was clean, well-dressed, well-behaved and appeared to love its mother. These same witnesses stated that appellee appeared to be a loving and concerned mother.
There was evidence that the appellant had agreed in the divorce proceeding to pay $50 per month for Leonard Ray Wilson, Jr. and $50 per month for the unborn child. Instead of one child, there were two children born as a result of appellee's pregnancy. There was testimony from appellee and several of her witnesses that the cost of living had increased about twenty-five percent. The testimony from appellant and several of his witnesses was to the effect that the cost of living had increased anywhere from three to ten percent. There was evidence that appellant's income was about $1,000 per month and that his assets were in the neighborhood of $30,000 to $40,000. He was not married and lived alone. He did not have a regular job. Appellee was married, her husband worked and earned $3.50 per hour. Appellee was employed and earned $625 per month. She employed a maid to keep her house and care for the children and paid the maid $55 per week.
To authorize an equity court to modify a final divorce decree so as to alter the custody arrangements, the petitioner must show a change in the circumstances since that final decree. McBride v. McBride, 268 Ala. 619, 109 So.2d 718. Furthermore, where the evidence is heard ore tenus in a child custody case, the findings and conclusions of the trial court will not be changed unless they are deemed to be plainly and palpably wrong. Wilkes v. Wilkes, 270 Ala. 341, 118 So.2d 906.
As stated before, the evidence was in sharp conflict and it was the duty of the *626 trial court to resolve the conflicts and decide the matter and when it does so, unless it is plainly and palpably wrong, we have no authority to change its decree. And, in this instance, we are not so persuaded.
The same rules apply when examining a chancellor's decree for error in the award of increased child support, i. e., child support or an increase thereof will not be awarded unless there are changed circumstances warranting it. The evidence relating to the request for more support money for the children in question was in sharp conflict and was resolved by the court when it awarded more child support. After careful examination of the facts relating to this aspect of the case, we cannot say that the trial court abused its discretion by requiring appellant to increase the amount of support given to his children.
In assignment of error six, appellant says that the trial court erred in not requiring appellee to initiate proceedings to have rescinded the order of the Shelby County Probate Court changing the name of Leonard Ray Wilson, Jr. to Ray Frank York. The above allegation and request for relief was set out in appellant's petition for modification of the divorce decree wherein he sought custody of the child, Leonard Ray Wilson, Jr.
The context in which this allegation appears in the petition for modification persuades the court that the relief requested pertaining to the name change amounts to no more than a collateral attack on the order of the Shelby County Probate Court. Judgments or decrees of a probate court are not subject to collateral attack. Foxworth v. White, 72 Ala. 224; Edmondson et al. v. Jones, 204 Ala. 133, 85 So. 799. Such decrees, judgments or orders can be set aside only after a direct attack in a proper proceeding and in the applicable forum. Edmondson et al. v. Jones, supra.
Assignment of error fourteen is based on the contention that the trial court erred in refusing to allow a newspaper clipping to be admitted into evidence. The newspaper clipping was an announcement of the approaching marriage of the parties to this proceeding by the grandparents of appellee. Appellant argued that the purpose in attempting to admit the newspaper article was to show that appellee was not a fit and proper person to have custody of the child in question.
As has been stated many times by the appellate courts of this state, the only issue before the trial court on a petition to modify a divorce decree to change the custody of a minor child is whether or not there has been a sufficient change in circumstances since the final decree so as to warrant such relief. Parker v. Parker, 269 Ala. 299, 112 So.2d 467.
The newspaper clipping attempted to be placed into evidence related to an event that occurred prior to the marriage of the parties and obviously prior to the final decree of divorce. The remoteness in time of this event as it related to the issue before the trial court, i. e., changed conditions relating to custody since the final decree, would be of major concern as to its admissibility and we cannot say that the court erred in refusing to so admit it on that basis.
No reversible error having been argued, this case is affirmed.
Motion to strike granted.
Affirmed.
WRIGHT, P. J., and HOLMES, J., concur.
|
{
"pile_set_name": "FreeLaw"
}
|
Journalist Alan Cleaver reports on the impact of swine flu in the UK with a particular slant on how the media report the pandemic. The views expressed are his personal views only.
Wednesday, 5 August 2009
Northern Ireland's first swine flu fatality
How sad to learn of Northern Ireland's first swine flu death - Lee Porter was only 30 years old. Once again journalists are unquestioningly throwing in the line that he had "underlying health problems" as some sort of reassurance to the public. He was 30 years old, a bombardier in the Royal Artillery and also worked in the fire service. It's hard to see what underlying health problems someone that young and fit could have that would weaken him to the effects of swine flu. The BBC says he is the 28th person in England (surely United Kingdom?) to have died, plus three in Scotland.
On BBC4 tonight (Wednesday, August 5th) at 9pm there is a docu-drama on the Spanish flu of 1918 and that's followed by a documentary on how the world tries to cope with pandemics. Should be interesting if morbid viewing.
|
{
"pile_set_name": "Pile-CC"
}
|
Because of our unusual flexibility, Johnson offers individuals the opportunity to combine an MBA degree with advanced study in a huge array of fields.
If you have strong quantitative skills and proven leadership abilities, you may want to consider our One-Year MBA program. If your strengths are in other areas, you will still be able to shorten the amount of time required to complete our Two-Year MBA program by receiving advanced standing credits toward your MBA for the masters level program you are already pursuing.
Why pursue an MBA along with another graduate degree?
The reasons are as many and varied as the individuals who undertake them. Typically, however, they want to add an understanding of business and develop the leadership and management skills that enable them to do more with their other specialized knowledge.
If you want to develop entrepreneurial new ventures, our outstanding Entrepreneurship and Innovation Institute provides unique performance-learning opportunities to learn and practice this specialized knowledge.
If you are pursuing a degree in one of areas of sustainability, agriculture, power, or global organizations, will likely find that our Center for Sustainable Global Enterprise offers you a base of knowledge and skills perfectly suited to advancing your goals.
If you plan to pursue a career in a non-governmental organization or non-profit, you will likely benefit by developing knowledge of all the business functions and developing strong leadership skills.
These are just some of the reasons to pursue an MBA along with another graduate degree. You may have others. We would welcome a chance to explore them with you.
|
{
"pile_set_name": "Pile-CC"
}
|
// Copyright (c)2008-2011, Preferred Infrastructure Inc.
//
// 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 Preferred Infrastructure nor the names of other
// 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
// OWNER 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.
#ifndef INCLUDE_GUARD_PFI_NETWORK_CGI_SERVER_H_
#define INCLUDE_GUARD_PFI_NETWORK_CGI_SERVER_H_
#include "base.h"
#include "../../lang/shared_ptr.h"
#include "../../concurrent/thread.h"
namespace pfi{
namespace network{
namespace cgi{
class run_server{
public:
typedef pfi::lang::shared_ptr<server_socket> socket_type;
run_server(const cgi &cc, uint16_t port=8080, int thread_num=1, double time_out=10);
run_server(const cgi &cc, socket_type ssock, int thread_num=1);
run_server(const cgi &cc, int argc, char *argv[]);
~run_server();
void run(bool sync=true);
void join();
private:
void process(socket_type ssock,
pfi::lang::shared_ptr<cgi> cc);
void listen(uint16_t port, double time_out);
socket_type ssock;
std::vector<pfi::lang::shared_ptr<pfi::concurrent::thread> > ths;
int thread_num;
const cgi &c;
};
class run_server_or_cgi{
public:
run_server_or_cgi(const cgi &cc, int argc, char *argv[]);
void run();
private:
int argc;
char **argv;
cgi &c;
};
} // cgi
} // network
} // pfi
#endif // #ifndef INCLUDE_GUARD_PFI_NETWORK_CGI_SERVER_H_
|
{
"pile_set_name": "Github"
}
|
Asleep (poem)
"Asleep" is a poem by Wilfred Owen. It deals with the atrocities of World War I.
Category:Poetry by Wilfred Owen
Category:World War I poems
|
{
"pile_set_name": "Wikipedia (en)"
}
|
Platelet morphology, soluble P selectin and platelet P-selectin in acute ischaemic stroke. The West Birmingham Stroke Project.
The pathophysiology of ischaemic stroke involves the platelet. In this study, we hypothesised that abnormalities in platelet morphology, as well as soluble (sPsel) and total platelet P-selectin (pPsel) levels would be present in patients presenting with an acute ischaemic stroke, and that these changes would improve at > or = 3 months' follow-up. We studied 59 hypertensive patients (34 male; mean age 68 +/- 12 years) who presented with an acute ischaemic stroke (ictus < 24 hours), and compared them with 2 groups: (i) age-, sex- and ethnic- origin matched normotensive healthy controls; and (ii) uncomplicated 'high risk' hypertensive patients as 'risk factor control' subjects. Platelet morphology (volume and mass) was quantified, and sPsel (plasma marker of platelet activation) was measured (ELISA) in citrated plasma. The mass of P-selectin in each platelet (pPsel) was determined by lysing a fixed number of platelets and then determining the levels of P-selectin in the lysate. Results show that patients who presented with a stroke had significantly higher levels of sPsel and pPsel (both p < 0.001), compared to the normal controls and the hypertensive patients. Patients with an acute stroke had lower mean platelet mass (MPM) and mean platelet volume (MPV) as compared to the uncomplicated hypertensive patients, who had significantly higher mean MPM and MPV values, as compared to normal controls. On follow-up, the levels of both sPsel (p = 0.011), pPsel (< 0.001) and MPV (p = 0.03) were significantly lower. Mean MPM levels remained unchanged. We conclude that patients presenting with an acute ischaemic stroke have activated platelets, as evident by the increased levels of soluble and platelet P-selectin. Further study of platelet activation and the role of P-selectin is warranted.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Q:
Best way to compare input values to read values from files
I am relatively new to c++ programming and I have hit one of my first major snags in all of this..
I am trying to figure out how to read a value/character from a generic ".txt" file that is on notepad. With that comparison I want to determine whether or not to read that entire line, but I can't seem to just read the single one or two digit number, I got it to read the whole line using { 'buffername'.getline(variable, size) } but when I try to change the 'size' to a specific number it gives me a comparison error saying that its invalid to switch to 'int' or 'char' (depending on how I declare the variable).
Any help is appreciated.
Thanks
A:
int length = 2;
char * buffer;
ifstream is;
is.open ("test.txt", ios::binary );
// allocate memory:
buffer = new char [length];
// read 2 char
is.read (buffer,length);
//Compare the character and decide
delete[] buffer;
return 0;
|
{
"pile_set_name": "StackExchange"
}
|
The present invention is directed to a vertical lathe apparatus, although certain features of the invention may have applicability in other areas, as may be evident to persons skilled in the art. In a verticle lathe, the work to be machined is mounted upon a turntable, which is rotatable about a vertical axis. The machine is provided with one (usually) or a plurality (occasionally) of rams adapted interchangeably to receive and support cutting tools appropriate to the required machining operations. The rams are mounted for controlled vertical movement in ram support housings, and these in turn are mounted for controlled horizontal movement on a cross slide carried by the machine frame. In some cases, provision may be made for a vertical adjustment of the cross slide itself, in addition to providing for vertical movement of the rams, in order to provide for optimum initial positioning of the rams with respect to a given work piece.
In the machining of a work piece on a vertical lathe apparatus, as generally described above, the work piece is fixed upon and rotated by the turntable and machining operations are performed by cutting tools carried by the rams. The desired cutting operations are performed by manipulating the position of the cutting tools, through vertical motions of the rams and horizontal movements of the ram supports. In a typical machining operation, carried out on vertical lathe equipment, a wide variety of cutting tools may be necessary or desirable for effecting various types of machining operations. Frequently, this has been accomplished in the past through the use of turrets mounted on the machine rams and selectively indexable to bring any one of several cutting tools into operative position. The turret arrangements are limited, however, by their tool holding capability in relation to size. Thus, as a practial matter, not more than four or five tools can be conveniently carried on a single turret, necessitating changing of entire turrets where (as is frequently the case) the typical production requirements of the machine involve the use of a greater number of tools. In addition, the use of tool-mounting turrets carried by the machine ram presents certain problems with respect to the accuracy of machining, because the geometry of the turret necessitates a mounting of the cutting tools somewhat more eccentrically, relative to the ram axis, than is desired. The use of the turrets also tends to limit, to a somewhat greater degree than desired, the minimum size of opening that the turret-carrying ram may enter to carry out internal machining.
An overall objective of the invention is to provide a vertical lathe machine of the type described with a novel and advantageous form of automatic tool change system, providing for a high speed, versatile changing of individual tools. Of course, the provision of automatic tool change facilities in machine tools of all kinds is well known, in the general sense, and the present invention does not purport to be directed broadly to the concept of automatic tool change. Rather, it is directed to the provision of an automatic tool change system, adapted particularly for vertical lathe equipment, which incorporates a number of novel and highly advantageous features providing for a high degree of efficiency and versatility in effecting and changing of tools in the course of production operations.
In accordance with one feature of the invention, a novel tool transport arrangement is provided for conveying a new cutting tool from a stationary tool matrix or "library" over to a ready-to-load position adjacent the ram, during the course of a machining operation with the previous tool. Thus, when the time comes for effecting a change of tools, it is merely necessary to retract the ram vertically from its extended machining position to a predetermined loading position and effect a rapid loading of the waiting new tool into the ram, in exchange for the previously used tool. In addition, a novel arrangement is provided for effecting a simultaneous exchange of tools in the ram with a linear "flow through" movement of tool blocks, minimizing the time required to effect the exchange of tools from the "ready" position.
In accordance with another feature of the invention, provision is made in the ram and in the tool library for receiving "right hand" and "left hand" tool blocks, for use in performing internal or external machining operations as may be required. In this respect, a "left-hand" tool block desirably is mounted eccentrically to the left on the ram, while the "right hand" tool is mounted eccentrically to the right. To accommodate these possibilities, the tool transport system and the tool loading system incorporate selectively operable, automatic positioning means accommodating the various "left hand" and "right hand" tool blocks in their several (four) possible combinations. This arrangment permits the use of an advantageous highly simplified form of loading device having a pair of spaced tool engaging elements arranged simultaneously to engage the tool in use and the "ready" tool and with a controlled lateral movement slide the original tool out of position and the new tool into position with the proper right-side or left-side eccentricity. The apparatus of the invention also includes an improved carrousel-type system constituting a tool matrix or tool library for storing a plurality of tool blocks for eventual use. The general function of the carrousel is, of course, to bring the new tool blocks successively into position for transfer to the ram. In this respect, the equipment of the invention incorporates improved control facilities for reliably positioning the carrousel and for reliably retaining and releasing the various tool blocks as they are called for.
|
{
"pile_set_name": "USPTO Backgrounds"
}
|
<?php
/*
* This file is part of the Symfony package.
*
* (c) Fabien Potencier <fabien@symfony.com>
*
* For the full copyright and license information, please view the LICENSE
* file that was distributed with this source code.
*/
namespace Symfony\Component\HttpKernel\Tests\Fixtures;
use Symfony\Component\HttpKernel\Bundle\Bundle;
class FooBarBundle extends Bundle
{
// We need a full namespaced bundle instance to test isClassInActiveBundle
}
|
{
"pile_set_name": "Github"
}
|
Two Mama's, one Brat, and Porthos and Aramis but not D'artagnan. In NYC and dreaming all the while.
Wednesday, January 25, 2012
Closets of many a kind....
Umm.. does anyone know why my archive link is suddenly in Spanish? Did I do that?
So.. today I meant to blog about The Broom Closet and lost the wind in my sails. Now that they've picked up again, I figured I'd try to put my thoughts down, including ones about the many other closets I hide in.
You see, what I really wanted to do today was stay awake long enough to cook, take pictures of the process and share the recipe. Unfortunately, I just couldn't stay awake that long. My schedule is still all topsy turvy from a couple of bad nights. So now I wake up between 8 and 10 pm, and stay awake until noon.
Worst schedule ever. I feel like I miss the whole day. Case in point, I didn't get to cook. Punky did it. So of course my previously diagnosed Cleaver Syndrome kicked in. (Thank you Dr. Aine W.D.) I feel like it would have been stupid to blog about Turkeyroni. Who doesn't know how to make their own version? Psh.
Then I thought about blogging about my trials and tribulations in parenting and even about some of my wins.. but I got paranoid that I'd give away information that Satan would somehow pile up and take to court to take The Brat away from me with. Mind you.. there isn't anything I could say that would logically lead to that.. I'm just paranoid.
These are some of the many closets I hide in. Some of them are the results of pride. Actually, most of them are in one way or another. They come about from a worry that people won't see me as I want them to see me. I'm a person like any other, I've got about a hundred sides to me.. but I want people to see the right ones first. It's about pride, and control, and a bunch of other stuff too.
So... here's me making attempt number one at coming out of some of these.
I cook stupid things like Turkeyroni. I'm aware you can get Beefaroni in a can, I just like my version better. Also the yield by price is way more awesome. It's not gourmet, or even pretty, but it's delicious. My mom used to make it for me. I taught Punky to make it, and now we both make it for our kid. The next time I make it, I vow to take pictures and show them off. NO MORE TURKEYRONI SHAME.
Ahem.
I am an awesome and righteous parent. Righteous as in I'm cool as hell, not in the AND JESUS SAID.. kind of way.
Bratexander the Great is autistic. Boy, was I not prepared for that. Is anyone ever prepared for that bomb? I mean, by the time he was officially diagnosed, we had kind of figured it out at home, but the figuring out part was the shocker. What do you do with an autistic child? How special are his special needs? How far from normal are we talking?
I got lucky. We got lucky. The Brat is on the low end of the spectrum. Which basically means that if anyone of you happened upon him in a park or on the street, his only tell would be his speaking difficulty. Of course, it doesn't help that he's got a retainer now and goddamnit has that thing set him back eons.
Anywho... like the average parent, I educated myself to the best of my ability. Most of it was trial and error. I learned that the television turns the boy child into a zombie. I think I've mentioned it before. His brain melts and pours out of his ears. So for the past three years he just hasn't had one. There's only one tv in the house and it comes out of the closet for Thanksgiving and Christmas/New Years. We watch the parade on Thanksgiving, and the lighting of the tree. That's about it.
I will admit that we are slowly relaxing on the rule lately, and perhaps allowing a little bit of x-box time. He's coming up on his first decade of life soon. His friends all have one, or even more than one. Not to mention a whole library of games. I became torn about making him an outcast. I figure that anything I forbid is just going to be something that he runs to and loses himself in as soon as I let the reigns go. I don't want him to be a eighteen year old basement dweller obsessed with an x-box.
He can't play Monday thru Friday unless he saves some nuns from a burning building or something. I suppose that would earn him some x-box time. He has to earn play time. Thirty minutes of reading with no fussing earns him thirty minutes of game time. Miracle of miracles... he's not a little snot about it. He's not perfect, but not nearly as bad as I thought it was going to be.
So what does an autistic boy with no t.v. do when he's not in school? Time to come out of the internet anonymity closet.
He takes dorky web-cam pictures with his mamas. Hello world.
He cooks. One of his favorite pass times actually.
He takes over the world like a Bratexander should.
He goes to dance class.
He hangs out with toy soldiers.
And visits the elves.
He goes ice skating at Lasker Rink.
Tries his hand at being a mermaid display at the Museum of Natural History.
Measures up against tigers at the zoo.
Plus you know there's piano class. Aikido. Visits to Lela's house. Can you tell? This is a kid that doesn't know the meaning of sitting at home and doing nothing. He's always somewhere doing something. That right there is my greatest accomplishment as a parent.
So.. who am I?
I'm the rockstar mom in the Kim Kardashian shades.
Basking in the sunshine.
Trying to be a tiger.
And hopping out of the broom closet to try and find my witch-y path in nature. Horrible picture of me though.
The Broom Closet Miss Aine calls it. She's brilliant. I would have never thought to give it a name. I don't know that I've ever lingered in one for long. I think my relationship with my mother is the only one in which I'd still be in there. Only because I've never said to her, Mom, I'm a witch. Lord knows that we talk about witchcraft often enough. Miss Aine thinks my mom might even be one.
Hilarious because my mom is a hardcore talk to God about it Christian. But I see it too. My mom raised me to know that the events of a harvest could be read in spilled wine. She's got what I teasingly call Peruvian Voodoo in her. She'll even get close to admitting it some days. When and where she grew up, you didn't rely on doctors as much as you did on Shamans.
She knows how to make all matters of herbs and vegetables and fruits work for her. I wish I was half as talented, but I know that I'm not because I'm still warm. Neither Hot nor Cold, just suspended somewhere in the grey middle.
But I dream things that'll happen. I have since I was tiny. Good lord did that suck. Knowing how you were going to be bullied the next day didn't exactly inspire to get up and go to school in the morning. Of course, it's never like it is in the movies. You can't just ninja dodge whatever is coming to you just because you know it's there. At least it never worked that way for me.
These days I wake up and mutter lines from shows and movies that make no sense out of context. Weeks/months/days later, whatever I sleepily muttered to Punky plays in a trailer or something. Utterly useless to me because I didn't want to dream anymore. So I begged the God that I believe in to please make it stop.
At the time, I had a near and dear witchy friend who told me not to do it. She said it was bad news to turn away from a gift. Said it wouldn't go away anyway. To this day I can't tell if she was just being harsh on me, or if she was just plain right. Maybe both. Eventually the dreams stopped meaning anything.
And now my son sees things. AUGH. Damnit.Curse her and her witchy ways, but not really. That wasn't the sort of blowback I was expecting. I suppose that I should have been. So, I've been stuck lately. I don't have a community of witches that I belong to. I don't even have any more witchy friends as I used to, save for my bloggy godmother's Aine and Jeanne. Lord knows I bug them enough with all my endless questions. It sure feels like I'm in a broom closet.
Except for the part where I'm not. I live in the greatest city in the world. There isn't much you can do around here that'll shock anyone. Case in point, a neighbor came by months ago on a friendly visit and noticed that Punky had put some small storage containers she gave her to good use. So.. What was in them? Shepherd's purse. Without thinking twice about it, I just said it when she asked. Even went as far as to mention that it was for some spell work. She didn't blink twice, nodded along, and we carried on conversation until it was time for her to go.
That's my tale on the broom closet. I don't really live in one, and some days I even whip out the witch card that I may or may not be entitled to just to scare away the crazies.
So.. as I wrap it up.. I've got a question for you, my bloggy godmother. Though.. anyone with their own two cents can feel free to chime on in.
You define a witch as someone who does the magic. I think, I might be wrong, you've mentioned that he or she do it every day. It's just a part of life. How strict is the every day thing? Is it like cooking? I try to cook at home ninety to ninety-five percent of the time. Sometimes though, there's pizza. Or Chinese. Or bootlegg KFC. Does it make me less of a cook?
2 comments:
Magic is performed by the Witch everyday because it just becomes very natural to do so. For instance, when I have an issue that needs taking care of, I think about my everyday practical solution, but I also think about a magical one - because magic is such a part of my life and the magic empowers my own attempts at a solution. This magic, of course, does not always mean that I orchestrate a complicated spell every time. Sometimes it is kitchen magic, sometimes it's putting certain herbs in the bath water, lighting a candle, setting certain fruits in a bowl, etc. Many of us do this kind of magic without thinking that it's magic. But a Witch does it intentionally. When working in corporate, I placed many a black tourmaline on my desk and sprayed the room with that awesome spray sage!
You are always such help to me Aine. It's why you're my bloggy godmother. It's like having my very own fairy godmother on the internet.
I think my own definition of a witch will be much like yours with a small difference. I don't know if at the part of the path that I'm on, I can practice each day, even if the act of practicing is as you say. I think for me a witch will be someone who does the magic or experiences it, everyday.
I think there's tons of magic at work each day that I just walk into when I walk out of the house. The sun is magical to me. It's one of the deities I worship. I think that when I walk out of the building I live in, and that first burst of warmth and light hits my face, that's a good morning greeting from a far away friend.
Anywho.. We HAVE got to talk about kitchen magic one of these days. When I was younger, I heard the term kitchen witch and thought it was a witch who made magical food or something. xD Punky set me straight. Sort of. You know how her sort of evasive answers can go.
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
How to upload zip file to azure blob then unzip it there
I have lot of zip files, which will have few folders and 50+ files in it. How can I upload those zip files to azure blob then unzip it there.
Unzipping the file in server and uploading files in it one by one to azure blob will be a cumbersome process.
Does azure has any easy way to achieve this or is there any workaround?
I'm implementing this in PHP.
A:
Simple answer is Azure Blob Storage will not do the unzipping for you. This is something you would need to do on your own. How you do it is up to you.
One possibility is (like you mentioned) that you upload zip files on your server, unzip them there and then upload individual files.
Another possibility is to do this unzipping through a background process if you are concerned about the processing happening on the web server. In this approach, you will simply upload the zip files in blob storage. Then through some background process (could be WebJobs, Functions, Worker Roles, or Virtual Machines), you would download these zip files, unzip them and then re-upload these individual files.
To trigger the background process on demand, once the zip file is uploaded you could simply write a message in a queue telling background process to download the zip file and start unzipping process.
A:
As you prob. already found all over the internet, it's no possible to run workloads INSIDE of the storage servers... but:
You can write a azure function to FileWatch your storage account, and unzip files for you, then upload them
|
{
"pile_set_name": "StackExchange"
}
|
Activities
Download files for this release
Release notes
Percona is glad to announce the release of Percona Server 5.1.67-14.3 on January 23rd, 2013 (Downloads are available here and from the Percona Software Repositories).
Based on MySQL 5.1.67, including all the bug fixes in it, Percona Server 5.1.67-14.3 is now the current stable release in the 5.1 series. All of Percona‘s software is open-source and free, all the details of the release can be found in the 5.1.67-14.3 milestone at Launchpad.
Bugs Fixed:
Fixed the upstream bug #68045 and ported a fix for the security vulnerability CVE-2012-4414 from the Percona Server 5.1.66-14.2. This bug fix replaces the upstream fix for the MySQL bug #66550. More details about this can be found in Stewart’s blogpost. Bug fixed #1049871 (Vlad Lesin).
|
{
"pile_set_name": "Pile-CC"
}
|
{
"CVE_data_meta": {
"ASSIGNER": "cve@mitre.org",
"ID": "CVE-2018-20698",
"STATE": "PUBLIC"
},
"affects": {
"vendor": {
"vendor_data": [
{
"product": {
"product_data": [
{
"product_name": "n/a",
"version": {
"version_data": [
{
"version_value": "n/a"
}
]
}
}
]
},
"vendor_name": "n/a"
}
]
}
},
"data_format": "MITRE",
"data_type": "CVE",
"data_version": "4.0",
"description": {
"description_data": [
{
"lang": "eng",
"value": "The floragunn Search Guard plugin before 6.x-16 for Kibana allows URL injection for login redirects on the login page when basePath is set."
}
]
},
"problemtype": {
"problemtype_data": [
{
"description": [
{
"lang": "eng",
"value": "n/a"
}
]
}
]
},
"references": {
"reference_data": [
{
"refsource": "CONFIRM",
"name": "https://docs.search-guard.com/latest/changelog-kibana-6.x-16",
"url": "https://docs.search-guard.com/latest/changelog-kibana-6.x-16"
},
{
"refsource": "CONFIRM",
"name": "https://github.com/floragunncom/search-guard-kibana-plugin/pull/140",
"url": "https://github.com/floragunncom/search-guard-kibana-plugin/pull/140"
}
]
}
}
|
{
"pile_set_name": "Github"
}
|
Machine Learning for Knowledge Extraction from PHR Big Data.
Cloud computing, Internet of things (IOT) and NoSQL database technologies can support a new generation of cloud-based PHR services that contain heterogeneous (unstructured, semi-structured and structured) patient data (health, social and lifestyle) from various sources, including automatically transmitted data from Internet connected devices of patient living space (e.g. medical devices connected to patients at home care). The patient data stored in such PHR systems constitute big data whose analysis with the use of appropriate machine learning algorithms is expected to improve diagnosis and treatment accuracy, to cut healthcare costs and, hence, to improve the overall quality and efficiency of healthcare provided. This paper describes a health data analytics engine which uses machine learning algorithms for analyzing cloud based PHR big health data towards knowledge extraction to support better healthcare delivery as regards disease diagnosis and prognosis. This engine comprises of the data preparation, the model generation and the data analysis modules and runs on the cloud taking advantage from the map/reduce paradigm provided by Apache Hadoop.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
From a10349f1710a11239c58da3a7e5b353c6b2070c2 Mon Sep 17 00:00:00 2001
From: Chaotian Jing <chaotian.jing@mediatek.com>
Date: Mon, 16 Oct 2017 09:46:32 +0800
Subject: [PATCH 153/224] mmc: mediatek: add pad_tune0 support
from mt2701, the register of PAD_TUNE has been phased out,
while there is a new register of PAD_TUNE0
Signed-off-by: Chaotian Jing <chaotian.jing@mediatek.com>
Tested-by: Sean Wang <sean.wang@mediatek.com>
Signed-off-by: Ulf Hansson <ulf.hansson@linaro.org>
---
drivers/mmc/host/mtk-sd.c | 51 ++++++++++++++++++++++++++++++-----------------
1 file changed, 33 insertions(+), 18 deletions(-)
--- a/drivers/mmc/host/mtk-sd.c
+++ b/drivers/mmc/host/mtk-sd.c
@@ -75,6 +75,7 @@
#define MSDC_PATCH_BIT 0xb0
#define MSDC_PATCH_BIT1 0xb4
#define MSDC_PAD_TUNE 0xec
+#define MSDC_PAD_TUNE0 0xf0
#define PAD_DS_TUNE 0x188
#define PAD_CMD_TUNE 0x18c
#define EMMC50_CFG0 0x208
@@ -303,6 +304,7 @@ struct msdc_save_para {
struct mtk_mmc_compatible {
u8 clk_div_bits;
bool hs400_tune; /* only used for MT8173 */
+ u32 pad_tune_reg;
};
struct msdc_tune_para {
@@ -364,21 +366,25 @@ struct msdc_host {
static const struct mtk_mmc_compatible mt8135_compat = {
.clk_div_bits = 8,
.hs400_tune = false,
+ .pad_tune_reg = MSDC_PAD_TUNE,
};
static const struct mtk_mmc_compatible mt8173_compat = {
.clk_div_bits = 8,
.hs400_tune = true,
+ .pad_tune_reg = MSDC_PAD_TUNE,
};
static const struct mtk_mmc_compatible mt2701_compat = {
.clk_div_bits = 12,
.hs400_tune = false,
+ .pad_tune_reg = MSDC_PAD_TUNE0,
};
static const struct mtk_mmc_compatible mt2712_compat = {
.clk_div_bits = 12,
.hs400_tune = false,
+ .pad_tune_reg = MSDC_PAD_TUNE0,
};
static const struct of_device_id msdc_of_ids[] = {
@@ -583,6 +589,7 @@ static void msdc_set_mclk(struct msdc_ho
u32 flags;
u32 div;
u32 sclk;
+ u32 tune_reg = host->dev_comp->pad_tune_reg;
if (!hz) {
dev_dbg(host->dev, "set mclk to 0\n");
@@ -665,10 +672,10 @@ static void msdc_set_mclk(struct msdc_ho
*/
if (host->sclk <= 52000000) {
writel(host->def_tune_para.iocon, host->base + MSDC_IOCON);
- writel(host->def_tune_para.pad_tune, host->base + MSDC_PAD_TUNE);
+ writel(host->def_tune_para.pad_tune, host->base + tune_reg);
} else {
writel(host->saved_tune_para.iocon, host->base + MSDC_IOCON);
- writel(host->saved_tune_para.pad_tune, host->base + MSDC_PAD_TUNE);
+ writel(host->saved_tune_para.pad_tune, host->base + tune_reg);
writel(host->saved_tune_para.pad_cmd_tune,
host->base + PAD_CMD_TUNE);
}
@@ -1226,6 +1233,7 @@ static irqreturn_t msdc_irq(int irq, voi
static void msdc_init_hw(struct msdc_host *host)
{
u32 val;
+ u32 tune_reg = host->dev_comp->pad_tune_reg;
/* Configure to MMC/SD mode, clock free running */
sdr_set_bits(host->base + MSDC_CFG, MSDC_CFG_MODE | MSDC_CFG_CKPDN);
@@ -1241,7 +1249,7 @@ static void msdc_init_hw(struct msdc_hos
val = readl(host->base + MSDC_INT);
writel(val, host->base + MSDC_INT);
- writel(0, host->base + MSDC_PAD_TUNE);
+ writel(0, host->base + tune_reg);
writel(0, host->base + MSDC_IOCON);
sdr_set_field(host->base + MSDC_IOCON, MSDC_IOCON_DDLSEL, 0);
writel(0x403c0046, host->base + MSDC_PATCH_BIT);
@@ -1261,7 +1269,7 @@ static void msdc_init_hw(struct msdc_hos
sdr_set_field(host->base + SDC_CFG, SDC_CFG_DTOC, 3);
host->def_tune_para.iocon = readl(host->base + MSDC_IOCON);
- host->def_tune_para.pad_tune = readl(host->base + MSDC_PAD_TUNE);
+ host->def_tune_para.pad_tune = readl(host->base + tune_reg);
dev_dbg(host->dev, "init hardware done!");
}
@@ -1404,18 +1412,19 @@ static int msdc_tune_response(struct mmc
struct msdc_delay_phase internal_delay_phase;
u8 final_delay, final_maxlen;
u32 internal_delay = 0;
+ u32 tune_reg = host->dev_comp->pad_tune_reg;
int cmd_err;
int i, j;
if (mmc->ios.timing == MMC_TIMING_MMC_HS200 ||
mmc->ios.timing == MMC_TIMING_UHS_SDR104)
- sdr_set_field(host->base + MSDC_PAD_TUNE,
+ sdr_set_field(host->base + tune_reg,
MSDC_PAD_TUNE_CMDRRDLY,
host->hs200_cmd_int_delay);
sdr_clr_bits(host->base + MSDC_IOCON, MSDC_IOCON_RSPL);
for (i = 0 ; i < PAD_DELAY_MAX; i++) {
- sdr_set_field(host->base + MSDC_PAD_TUNE,
+ sdr_set_field(host->base + tune_reg,
MSDC_PAD_TUNE_CMDRDLY, i);
/*
* Using the same parameters, it may sometimes pass the test,
@@ -1439,7 +1448,7 @@ static int msdc_tune_response(struct mmc
sdr_set_bits(host->base + MSDC_IOCON, MSDC_IOCON_RSPL);
for (i = 0; i < PAD_DELAY_MAX; i++) {
- sdr_set_field(host->base + MSDC_PAD_TUNE,
+ sdr_set_field(host->base + tune_reg,
MSDC_PAD_TUNE_CMDRDLY, i);
/*
* Using the same parameters, it may sometimes pass the test,
@@ -1464,12 +1473,12 @@ skip_fall:
final_maxlen = final_fall_delay.maxlen;
if (final_maxlen == final_rise_delay.maxlen) {
sdr_clr_bits(host->base + MSDC_IOCON, MSDC_IOCON_RSPL);
- sdr_set_field(host->base + MSDC_PAD_TUNE, MSDC_PAD_TUNE_CMDRDLY,
+ sdr_set_field(host->base + tune_reg, MSDC_PAD_TUNE_CMDRDLY,
final_rise_delay.final_phase);
final_delay = final_rise_delay.final_phase;
} else {
sdr_set_bits(host->base + MSDC_IOCON, MSDC_IOCON_RSPL);
- sdr_set_field(host->base + MSDC_PAD_TUNE, MSDC_PAD_TUNE_CMDRDLY,
+ sdr_set_field(host->base + tune_reg, MSDC_PAD_TUNE_CMDRDLY,
final_fall_delay.final_phase);
final_delay = final_fall_delay.final_phase;
}
@@ -1477,7 +1486,7 @@ skip_fall:
goto skip_internal;
for (i = 0; i < PAD_DELAY_MAX; i++) {
- sdr_set_field(host->base + MSDC_PAD_TUNE,
+ sdr_set_field(host->base + tune_reg,
MSDC_PAD_TUNE_CMDRRDLY, i);
mmc_send_tuning(mmc, opcode, &cmd_err);
if (!cmd_err)
@@ -1485,7 +1494,7 @@ skip_fall:
}
dev_dbg(host->dev, "Final internal delay: 0x%x\n", internal_delay);
internal_delay_phase = get_best_delay(host, internal_delay);
- sdr_set_field(host->base + MSDC_PAD_TUNE, MSDC_PAD_TUNE_CMDRRDLY,
+ sdr_set_field(host->base + tune_reg, MSDC_PAD_TUNE_CMDRRDLY,
internal_delay_phase.final_phase);
skip_internal:
dev_dbg(host->dev, "Final cmd pad delay: %x\n", final_delay);
@@ -1548,12 +1557,13 @@ static int msdc_tune_data(struct mmc_hos
u32 rise_delay = 0, fall_delay = 0;
struct msdc_delay_phase final_rise_delay, final_fall_delay = { 0,};
u8 final_delay, final_maxlen;
+ u32 tune_reg = host->dev_comp->pad_tune_reg;
int i, ret;
sdr_clr_bits(host->base + MSDC_IOCON, MSDC_IOCON_DSPL);
sdr_clr_bits(host->base + MSDC_IOCON, MSDC_IOCON_W_DSPL);
for (i = 0 ; i < PAD_DELAY_MAX; i++) {
- sdr_set_field(host->base + MSDC_PAD_TUNE,
+ sdr_set_field(host->base + tune_reg,
MSDC_PAD_TUNE_DATRRDLY, i);
ret = mmc_send_tuning(mmc, opcode, NULL);
if (!ret)
@@ -1568,7 +1578,7 @@ static int msdc_tune_data(struct mmc_hos
sdr_set_bits(host->base + MSDC_IOCON, MSDC_IOCON_DSPL);
sdr_set_bits(host->base + MSDC_IOCON, MSDC_IOCON_W_DSPL);
for (i = 0; i < PAD_DELAY_MAX; i++) {
- sdr_set_field(host->base + MSDC_PAD_TUNE,
+ sdr_set_field(host->base + tune_reg,
MSDC_PAD_TUNE_DATRRDLY, i);
ret = mmc_send_tuning(mmc, opcode, NULL);
if (!ret)
@@ -1581,14 +1591,14 @@ skip_fall:
if (final_maxlen == final_rise_delay.maxlen) {
sdr_clr_bits(host->base + MSDC_IOCON, MSDC_IOCON_DSPL);
sdr_clr_bits(host->base + MSDC_IOCON, MSDC_IOCON_W_DSPL);
- sdr_set_field(host->base + MSDC_PAD_TUNE,
+ sdr_set_field(host->base + tune_reg,
MSDC_PAD_TUNE_DATRRDLY,
final_rise_delay.final_phase);
final_delay = final_rise_delay.final_phase;
} else {
sdr_set_bits(host->base + MSDC_IOCON, MSDC_IOCON_DSPL);
sdr_set_bits(host->base + MSDC_IOCON, MSDC_IOCON_W_DSPL);
- sdr_set_field(host->base + MSDC_PAD_TUNE,
+ sdr_set_field(host->base + tune_reg,
MSDC_PAD_TUNE_DATRRDLY,
final_fall_delay.final_phase);
final_delay = final_fall_delay.final_phase;
@@ -1602,6 +1612,7 @@ static int msdc_execute_tuning(struct mm
{
struct msdc_host *host = mmc_priv(mmc);
int ret;
+ u32 tune_reg = host->dev_comp->pad_tune_reg;
if (host->hs400_mode &&
host->dev_comp->hs400_tune)
@@ -1619,7 +1630,7 @@ static int msdc_execute_tuning(struct mm
}
host->saved_tune_para.iocon = readl(host->base + MSDC_IOCON);
- host->saved_tune_para.pad_tune = readl(host->base + MSDC_PAD_TUNE);
+ host->saved_tune_para.pad_tune = readl(host->base + tune_reg);
host->saved_tune_para.pad_cmd_tune = readl(host->base + PAD_CMD_TUNE);
return ret;
}
@@ -1860,10 +1871,12 @@ static int msdc_drv_remove(struct platfo
#ifdef CONFIG_PM
static void msdc_save_reg(struct msdc_host *host)
{
+ u32 tune_reg = host->dev_comp->pad_tune_reg;
+
host->save_para.msdc_cfg = readl(host->base + MSDC_CFG);
host->save_para.iocon = readl(host->base + MSDC_IOCON);
host->save_para.sdc_cfg = readl(host->base + SDC_CFG);
- host->save_para.pad_tune = readl(host->base + MSDC_PAD_TUNE);
+ host->save_para.pad_tune = readl(host->base + tune_reg);
host->save_para.patch_bit0 = readl(host->base + MSDC_PATCH_BIT);
host->save_para.patch_bit1 = readl(host->base + MSDC_PATCH_BIT1);
host->save_para.pad_ds_tune = readl(host->base + PAD_DS_TUNE);
@@ -1873,10 +1886,12 @@ static void msdc_save_reg(struct msdc_ho
static void msdc_restore_reg(struct msdc_host *host)
{
+ u32 tune_reg = host->dev_comp->pad_tune_reg;
+
writel(host->save_para.msdc_cfg, host->base + MSDC_CFG);
writel(host->save_para.iocon, host->base + MSDC_IOCON);
writel(host->save_para.sdc_cfg, host->base + SDC_CFG);
- writel(host->save_para.pad_tune, host->base + MSDC_PAD_TUNE);
+ writel(host->save_para.pad_tune, host->base + tune_reg);
writel(host->save_para.patch_bit0, host->base + MSDC_PATCH_BIT);
writel(host->save_para.patch_bit1, host->base + MSDC_PATCH_BIT1);
writel(host->save_para.pad_ds_tune, host->base + PAD_DS_TUNE);
|
{
"pile_set_name": "Github"
}
|
Tag Archives: Connect the Dots
Truth Movement Godfather Jordan Maxwell relaxes in a cream colored easy chair and nonchalantly discusses everything from the hidden history of ancient Babylonian symbols in modern society, to his own experiences with UFO sightings, how his life work really began, … Continue reading →
Understanding Why a Historically Re-occurring Scientific Astronomical Event May Bring About A Pole Shift of the Earth and the Seven Last Plagues as Recorded in the Christian Holy Bible’s Book of Revelations Continue reading →
Americans are behaving generally in a somewhat similar fashion, post-Obama’s election, inauguration and general floundering about in six directions at once. It has been very unsettling to observe. Continue reading →
If you would like to get a real good look at how the Illuminati controlled USA media – along with the CDC, tries to INDUCE FEAR by lying openly (oh but I guess the polite phrase is “misrepresentation”) about Swine Flu, read the article below, then click the link above to see the number of actual confirmed swine flu cases here in the USA. Continue reading →
|
{
"pile_set_name": "Pile-CC"
}
|
Hermeneutic-phenomenology: providing living knowledge for nursing practice.
The phenomenological approach has gained popularity among nurse researchers as an alternative investigative method to those used in the natural sciences. As more nurse scholars and nurse researchers utilize phenomenology as a research approach, it becomes critical to examine the implications this may have for nursing knowledge development and for the utilization of that knowledge in practice. In this paper, an examination of the results of phenomenological inquiry is presented and compared with the types of knowledge considered important for nursing by Carper and White. It is clear that phenomenology contributes to empirical, moral, aesthetic, personal, and socio-political knowledge development. Its contribution is not in developing predictive and prescriptive theory, but in revealing the nature of human experience. Although interpretive inquiry, such as hermeneutic phenomenology, does not prescribe action for use in clinical practice, it does influence a thoughtful reflective attentive practice by its revealing of the meanings of human experience.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Hearts and Minds: Vietnam and Memory
By Peter Davis
Imagine yourself a Vietnamese veteran of the National Liberation Front or the North Vietnamese Army. Imbued with hopes of independence and the anti-imperialist ideal, you lost a leg in the war. But your side did win. You look around you now, and you see Coca-Cola and Exxon all over your country, and you see a U.S. defense secretary on a naval ship steaming into Cam Ranh Bay. You might be forgiven if you think to yourself, I lost my leg, and they cut that deal anyway. What was this about?
Meanwhile, have a look at your former enemy.
If the first casualty of war is truth, the last is memory. More than a generation after our helicopters retreated from the roof of the U.S. embassy in Saigon on April 30, 1975, over half of our population cannot remember the American loss in Vietnam, because they weren’t even born until the war was over. For many of the rest of us, memory is contaminated; our attitudes and anger hardened long ago like fists, and we have never unclenched them. In the imperial dream and anti-Communist nightmare that simultaneously gripped America after World War II, what we did in Vietnam was lose 58,000 dead, while the Vietnamese, North and South, were losing thirty times that number. A rampage, by any measurement. But what did our deeds in turn do to us?
No one doubts that our first lost war changed attitudes toward our own country and its leadership. Even before the war had quite ended, we turtled into ourselves and unprecedentedly drove out the last president, in midterm, who had led us to defeat. The book No More Vietnams was written, tellingly, not by Marcus Raskin or Noam Chomsky but by Richard Nixon.
The Vietnam War exploded the myth that because we elect a government it will tell us the truth. The myth of American invulnerability and perseverance was likewise a war casualty. We could and did lose; we could and did quit. We saw the limits of power, the failure of intervention, the strategic uselessness—not to mention cruelty—of bombing a country that didn’t want us there, hitting it with more tonnage than had been dropped in all previous wars combined, not because the country threatened us but simply because we did not agree with its government. We learned the contradiction in a policy that was willing to destroy a country in order to “save” it, as an American officer casually claimed he was doing when he leveled a village one day. We could and did destroy an economy and much of a countryside and still had to slink out of town, our choppers bringing up the rear.
Even now, haunted by Vietnam, we have not decided on the meaning of the war. For boomers, whether they were actually there or not, it was the Big Event, as World War II was for children of the Depression. What the war meant changes with your perspective. Was the war a crime (radicals), a mistake (liberals), a mistake not to win (conservatives), a crime not to win (hard right)?
As a result of losing, we had little choice but to see ourselves in the bright light of imperialists whose imperialism had failed. “The worst thing that could happen to our country,” Mary McCarthy wrote in 1967, “would be to win this war.” In the decade before Vietnam, the United States had mounted successful, relatively secret, low-cost operations to overthrow governments in Iran, Guatemala, and the newly independent Congo. In the following decades, the Vietnam War was a tempering influence. If there had been no Vietnam, who can doubt we’d have tried to conquer and garrison Nicaragua in the eighties instead of “only” illegally funding an incompetent insurgency; or completed the conquest of Iraq during the Gulf War of the nineties instead of stopping as soon as we restored the territorial integrity of Kuwait? If there had been no Vietnam, American youth might never have learned the power of a peace crusade. The civil rights movement was well under way before the war, but it was Martin Luther King Jr. himself who united the two causes of peace and racial reconciliation, each drawing strength from the other. Feminism, gay and lesbian rights, and other sequel movements were able to coalesce around the antiwar campaign. The young also learned they had the power to say no, as well as to say NOW. The famous desertion of LBJ by the so-called Wise Men of the foreign policy elite may have done more than any single act by the peace movement to convince the establishment it wouldn’t win the war, but the Wise Men had children and grandchildren in the streets, and the noise reached the upper floors.
Defeat had its uses, as well, in provoking a reexamination of war as an instrument of policy, a reexamination that could not have occurred after victory in World War II, which was far more devastating to far more people over a far greater area. World War II led to the United Nations and a resolve for peace, but its good-versus-evil climate did not lead to what today is frequently concluded by the young. They may not know the specifics of a particular conflict, but they have a seemingly innate skepticism about war. On some campuses, it is taken as a given that war is caused by a ruling clique acting in what they take to be their own interests, institutional violence promulgated by a hierarchy for personal gain. Our upper classes generally had an easy time avoiding service in Vietnam, yet a blue-collar war led to blue-collar conclusions, diffusing eventually through all classes, about the purpose of war.
Historically, we are not a people given easily to shame. Not only our winner’s sensibility but also our sunny view of inevitable progress have fenced us off from feelings of regret or remorse. Germany, darker and less optimistic about history in general, has been able to express far more shame—backed with cash reparations—over the Holocaust, which for all its horror lasted only a few years, than the United States has done in the century and a half since the end of slavery, which endured for more than two centuries. While we may look sheepishly now and then at Native Americans, a nation of immigrants has never sliced its victory over the original inhabitants into even one part guilt to ten parts pride. But Vietnam at last shamed us. And it’s easy to feel shame associated with any of the following: Guantanamo, Abu Ghraib, drones, black-op sites, extraordinary rendition, waterboarding. Vietnam opened the door to shame.
As an individual, I found the uses of defeat somewhat surprising. I had always figured that Communism as it developed in other countries was harsh and repressive mostly because of the history of those countries and because of our own implacable and menacing opposition to it. I should have known earlier, of course, but it was only after our loss in Vietnam—in other words, after the triumph of its revolution—and subsequent political developments there, that I understood the right was right about one big thing: the institutionalized absence of personal freedom in a Communist state. Calling freedom bourgeois is like calling ice cream fattening; you’re going to want it anyway. Regardless of Marxist economic aims, Communism has never been about individual freedom. This was hardly fresh news, but for the old as well as the new left, the conclusion was as inescapable as it was paradoxical that Communism killed socialism for a generation. I also realized after Vietnam, and after the clear evidence that our defeat did not lead to the sky falling (never mind dominoes), that there never was a threat to American democracy or capitalism, much less power, from either domestic or international Communism. I had once thought that there was, but there was not, and Vietnam proved that.
But nothing else Vietnam did or did not do was as crucial as the mirror it held up to all of us. Surely it changed the way we saw our national selves. Innocence is a strange word to use about Goliath prior to his encounter with David; it may, however, fit American attitudes toward the world before Vietnam. We were so sure our way was better than anyone else’s, that our civilization was the template for humanity, that our might was always right, so sure we couldn’t lose, that our very naïveté constituted a form of innocence. Vietnam repealed World War II assumptions of inherent virtue. Even our triumphalist boasting during the market boom of the nineties was principally economic rather than moral or political. In the mirror Vietnam provided us, we stopped being so sure about ourselves and our formerly wondrous ways.
Vietnam, specifically our loss there, kept us out of foreign interventions for most of a generation. We learned our lesson: don’t fight a country that doesn’t threaten us. Expensive lesson; nonetheless, lesson learned. But September 11, 2001, was like a hammer blow to our national head. Like many blows to the head, it caused a concussion, followed by amnesia. The result was we went to war against two countries that not only had not attacked us but had no designs on us or our resources. At the time I began making Hearts and Minds, the war in Vietnam had just surpassed the American Revolution as our longest war. But the war in Afghanistan surpassed the Vietnam War as our longest. As for Iraq, we flew into war there, as we had in Vietnam, on the wings of lies.
The lies worked. Polls showed that most Americans actually believed at the time that Saddam Hussein not only had weapons of mass destruction but also had been part of the planning for the 9/11 attacks on the United States. Iraqis had their own way of responding to the American invasion. In the enormous Shiite section of Baghdad called Sadr City, the main thoroughfare was renamed as American soldiers began what was supposed to be a “cakewalk” in Iraq. The new name for the boulevard was Vietnam Street.
When I covered the war in Iraq for The Nation in 2003, one could almost hear a sigh across the Mesopotamian desert from the ghost of the philosopher George Santayana: those who cannot remember the past are condemned to repeat it.
But we are learning new lessons from the inconclusive, costly (in blood and treasure), brutal wars in Afghanistan and Iraq. We have again hit the national pause button on intervention. What will happen that may cause the next amnesia?
Let us return to the Vietnamese veteran who lost his leg in the war. Imagine he has changed nationalities and is now a Vietnam veteran, one of ours. He looks down to where his leg once was, glances up at his television set, showing him the rain, and reign, of American products in Vietnam as well as the joint efforts of the U.S. and Vietnamese air forces to look for a vanished Malaysian Airlines plane. Peace makes strange bedfellows. The Vietnamese had to throw us out, had to decolonize, before they could be recolonized; had to find their independence before they could bring back the Western economies and aspire to become Vietnam Inc. Vietnamese Communists are business partners with American corporations. I lost my leg, our vet may be thinking, and they cut that deal anyway. Can we blame him if he wonders, What was this about?
An earlier version of this piece was published in the May 15, 2000, issue of The Nation. It has been updated by the author for this release.
Related Films
4 comments
By
Michael Benton
June 20, 201402:01 PM
Peter Davis thank you for this vivid reminder of the past and how it is being replayed now.
I'm teaching your great documentary in two college film course in the fall ("films of 1971-1975" and "peace & conflict studies") and look forward to using it to think through our militaristic policies of the past/present.
What a pile of revisionist dung. "We saw the limits of power, the failure of intervention, the strategic uselessness—not to mention cruelty—of bombing a country that didn’t want us there, hitting it with more tonnage than had been dropped in all previous wars combined, not because the country threatened us but simply because we did not agree with its government."
First, we didn't lose the war. We signed the Paris Peace Accords in 1973. South Vietnam didn't fall for two more years. It fell because Congress reneged on the United States pledge to support South Vietnam and withdrew military aid when they needed it most. There were NO US combat forces in Vietnam when South Vietnam fell.
Secondly, the South Vietnamese wanted us there. It was the North Vietnamese Communists who did not want us there, but they also wanted to take over South Vietnam, which they did after we abandoned a country we had promised to help.
Ask the millions of Vietnamese who escaped their country how they felt about being abandoned by a perfidious Congress. Ask them how they feel about the Communists who took over and slaughtered millions of them, not to even mention the 2+ million Cambodians and Laotians that died under their iron fist.
Then you follow up with the idiocy that Iraq and Afghanistan never attacked us. As if that's the metric by which we should judge "intervention". It's like claiming that the guy who drove the getaway car was not involved in the robbery because he never entered the bank, something only an idiot leftist would even posit.
Do you ever have a lucid thought?
Finally!!!!! It is nice to see some one with some common sense and an actual grasp on history. This movie is a pile of crap. My mother saw this while she was in high school just after she and her classmates attended a seminar on how to spot propaganda. She walked out of it feeling dumber just watching it (she knew it was propaganda) while her classmate left the theater kicking themselves saying they "felt bad about the war." Gag me. To me it felt very dishonest. It is overly emotionally manipulative and it seems to manipulate footage and facts about Vietnam to support it's goal. That is hardly the trademark of a good documentary. All I can say is she was right.
|
{
"pile_set_name": "Pile-CC"
}
|
NOT RECOMMENDED FOR FULL-TEXT PUBLICATION
File Name: 14a0823n.06
Case No. 13-2652 FILED
Oct 30, 2014
UNITED STATES COURT OF APPEALS DEBORAH S. HUNT, Clerk
FOR THE SIXTH CIRCUIT
THOMPSON I.G., LLC, )
)
Plaintiff-Appellant, )
) ON APPEAL FROM THE
v. ) UNITED STATES DISTRICT
) COURT FOR THE EASTERN
EDGETECH I.G. INC., ) DISTRICT OF MICHIGAN
)
Defendant-Appellee. )
)
____________________________________/ )
Before: KEITH, MOORE, and STRANCH, Circuit Judges
DAMON J. KEITH, Circuit Judge.
This case presents a commercial dispute arising from a contract for the sale of window
parts. Plaintiff-Appellant Thompson I.G., LLC (“Thompson”) is a Michigan company that
manufactures windows. Thompson bought foam “spacers” from Defendant-Appellee Edgetech
I.G., Inc. (“Edgetech”), an Ohio corporation, for use in its windows. Thompson sued Edgetech
based on allegations that the spacers were defective, asserting claims for breach of contract,
breach of express warranty, breach of implied warranty, and fraud. The district court dismissed
Thompson’s breach of implied warranty claim and granted summary judgment on the others.
Thompson appeals from the district court’s final judgment. For the reasons that follow, we
AFFIRM the judgment of the district court.
-1-
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
I. BACKGROUND
Thompson manufactures insulated glass (“IG”) units. IG units are large window parts
consisting of two panes of insulated glass. Edgetech manufactures smaller window parts called
spacers. Apparently, in 2003, Edgetech marketed a spacer called Super Spacer to Thompson.
Super Spacer maintains the glass panes in IG units at the desired air space, thus promoting
insulation. In contrast to traditional aluminum spacers, Super Spacer is made of foam. Although
Edgetech manufactures more than one type of Super Spacer, this case concerns the Super Spacer
whose foam contains ethylene propylene diene monomer (“EPDM”). Unless otherwise noted,
“Super Spacer” refers to the EPDM-type Super Spacer.
In January 2005, Thompson and Edgetech held a meeting at Edgetech’s Ohio facility.
There, Edgetech employee Larry Johnson made a PowerPoint presentation. Thompson’s former
president, Russell Manser, states that Johnson made a misrepresentation during the presentation.
Manser asserts that Johnson falsely stated that Super Spacer had passed testing standards of the
American Society for Testing and Materials. R. at 1767.1 Likewise, Thompson asserts that the
presentation’s slides show that Edgetech represented that Super Spacer had passed various tests
from other standards organizations. R. at 2083, 2093. But Gerhard Reichert, a former senior-
level Edgetech employee and coinventor of Super Spacer, states that Super Spacer had failed
some of these tests and that Edgetech knew so. R. at 2050–51. Reichert also states that, from
2004 to 2011, numerous Edgetech customers complained that Super Spacer had failed the
1
“R.” designates citations to the paginated record of the proceedings below. Thus, “R. at 1767” refers to
PageID 1767, “R. at 2083” refers to PageID 2083, and so on.
-2-
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
“fogging test,” which means that the window assemblies using the Super Spacer fogged up
during testing. R. at 2480.2
Manser adds that, during the same meeting, Johnson and another Edgetech representative
recommended that Thompson use Fenzi polysulfide (“polysulfide”) as a secondary sealant.
According to Thompson, one must use a secondary sealant with EPDM because EPDM
outgasses at or above 60°C and the secondary sealant prevents the outgassing.3 4 Manser further
asserts that the Edgetech representatives discussed using hot melt butyl or polyurethane as a
secondary sealant instead of polysulfide. The Edgetech representatives did not recommend hot
melt butyl. They knew that Thompson planned to install some of the IG units in RVs and
concluded that hot melt butyl would melt under the intense heat that the exposed RV windows
would experience. Manser does not explain why polyurethane was not selected. R. at 2495. For
his part, Reichert states that he knew that “EPDM was not designed for polysulfide” and that this
combination had failed industry standards in several countries. R. at 2479. Reichert adds that he
advised “countless” Edgetech customers over the years to use silicone spacers, not EPDM
spacers, with polysulfide. R. at 2482. Likewise, other Thompson witnesses suggested that EPDM
was incompatible with polysulfide. See, e.g., R. at 2487–88, 2499–2500.
In February 2005, the Parties entered into a Usage Purchase Agreement (“Contract”). R.
at 1815. Thereby, Thompson agreed to purchase a minimum of sixty million linear feet of Super
Spacer over approximately five years. R. at 1815–16. The Contract incorporated the terms of a
2
The parties dispute the cause of the windows’ fogging. Thompson argues that the windows fogged
because Edgetech’s Super Spacers were “outgassing,” meaning that they released gas that was trapped
between the two window panes in the assembly. Edgetech argues that the windows fogged because
Thompson assembled them poorly, which allowed moisture from outside to enter.
3
Although Thompson states on brief that EPDM and Super Spacer would outgas at 50°C, Thompson’s
expert testified that these products outgassed at or above 60°C. R. at 2462. Whether these products
outgassed at 50°C or 60°C is ultimately immaterial.
4
The distinction between a primary sealant and a secondary sealant is irrelevant to the analysis.
-3-
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
document titled Terms and Conditions of Sale (“Terms”). R. at 1814. Paragraph 4 of the Terms
is titled “Limited Warranty.” Under paragraph 4, Edgetech expressly guaranteed that the Super
Spacer would be “free of manufacturing defects at the time of shipping from Edgetech.” R. at
1814. For its part, paragraph 19 states that the Contract “shall be governed by the laws of the
State of Ohio.” R. at 1814.
According to Thompson engineer Ed Wilson, Thompson started receiving defective IG
units in February/March 2011.5 R. at 1458. Around that time, Wilson instructed Thompson
employees to preserve the returned IG units. R. at 1458. On or around March 31, 2011,
Thompson filed suit against Edgetech in Michigan state court. On June 30, 2011, Edgetech
removed the case on the basis of diversity jurisdiction. Thompson filed an amended complaint on
August 29, 2011. The amended complaint asserted claims for breach of contract, breach of
implied warranty, breach of express warranty, and fraud. For reasons irrelevant here, the district
court granted a motion to dismiss the implied warranty claim.
Edgetech moved to disqualify Reichert and Stephen H. Howes as Thompson’s experts.
The district court granted the motion to disqualify Reichert. Noting that Reichert had been a
“longstanding, high-ranking employee of Edgetech,” the district court reasoned that “[a]llowing
Reichert to serve as an expert is analogous to an expert switching sides mid-litigation.” R. at 549.
Yet the district court did not conclude that Reichert could not testify as a fact witness and
Edgetech has not so argued. For his part, Howes was not disqualified. Thompson tendered
Howes to testify that Super Spacer was incompatible with polysulfide and that this
incompatibility caused the windows in question to outgas. Howes intended to base his testimony
on testing he conducted “when trying to create a competitive product . . . .” R. at 2414.
5
It is unclear whether Thompson alleges to have received defective IG units before this date.
-4-
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
Thompson also proffered Howes’s opinion that five returned windows were defective because
their Super Spacers outgassed.6 Edgetech urged the district court to disqualify Howes because (1)
he failed to save any data or material from his tests supposedly showing that Super Spacer was
incompatible with polysulfide; and (2) he only visually examined the five returned windows and
failed to break them open and examine the actual fog. Although the district court noted that the
scientific basis of Howes’s opinion was “attenuated” and “[might] not withstand scrutiny on
cross-examination,” it declined to disqualify him. R. at 2416. The Parties do not contest the
district court’s disposition of the motions to disqualify.
Edgetech also moved for sanctions, alleging that Thompson spoliated evidence and
committed fraud on the district court. Edgetech argued that Thompson failed to preserve the
defective windows and obstructed the efforts of its expert, William Lingell, to inspect the five
windows that Howes visually examined. Thompson itemized the defective windows in a
“Warranty Report” purporting to show that its customers returned 277 windows due to defective
Super Spacer. Manser stated that the warranty report constituted Thompson’s “best guess” of all
the Super Spacer failures. R. at 1739. Manser acknowledged that the warranty report does not
show whether the windows had Super Spacers or metal (i.e., aluminum) spacers. R. at 1739–40.
Likewise, two Thompson customers stated that some of the claims in the report were for metal
spacers. R. at 1848–58, 1860. Another Thompson customer stated that it never submitted certain
claims in the report. R. at 1861. At any rate, it is undisputed that Thompson failed to produce
these windows. Thompson blamed this failure on the difficulty of removing the windows without
6
Howes originally stated that he examined six windows and later changed this number to five. Although
Thompson was supposed to make these windows available to Edgetech for inspection, some evidence
suggests that Thompson made only four windows available. But whether Howes examined four or five
windows is immaterial to the issues at hand. Consistent with Howes’s latest declaration, we assume that
he inspected five.
-5-
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
breaking their glass and at least two customers’ destruction of the units and/or failure to return
them. R. at 1398, 1402–03, 1408. Yet Manser stated that Thompson received defective IG units
in the 2004–2011 period and estimated that it discarded 375 such units at its Michigan facility. R.
at 1183. Although Manser later stated that the 375 estimate was “way off,” he did not disavow
his earlier statement that Thompson discarded some IG units. Paul Lewis, a Thompson sales
representative, also stated that Thompson discarded returned IG units. R. at 1431. Thompson
downplays the extent to which the discarded IG units contained Super Spacer. Thompson also
asserts that it notified its employees as early as May 2011 that the Super Spacer units needed to
be preserved. R. at 1492, 1494. But other evidence indicates that Thompson failed to notify some
of its employees to preserve the Super Spacer units and failed to institute a procedure to prevent
their disposal until some time between January and March 2013. R. at 1157, 1183, 1205.
Nonetheless, the district court denied Edgetech’s motion for sanctions. In reaching this
conclusion, the district court reasoned that (1) Thompson sought to safeguard the windows early
in the case; and (2) Thompson’s alleged spoliation did not preclude Lingell from forming his
opinion that poor workmanship by Thompson caused the failures.
Edgetech moved for summary judgment. Among other things, Edgetech argued that: (1)
Thompson could not demonstrate breach or causation on its breach of contract and breach of
express warranty claims; and (2) Michigan’s economic loss doctrine barred Thompson’s fraud
claim. On November 14, 2013, the district court entered an opinion and order granting
Edgetech’s summary judgment motion and dismissing the case. See R. at 2603. The district court
held that Thompson submitted insufficient evidence to show that the Super Spacers outgassed or
that any outgassing caused the damages detailed in the warranty report. R. at 2611–12. The
district court also held that Thompson’s fraud claim failed as a matter of law under Michigan’s
-6-
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
economic loss doctrine, which Thompson conceded barred said claim. The district court applied
Michigan law because Michigan was the forum state and it saw no rational reason to apply Ohio
law.
Thompson appealed. Thompson argues that the district court overlooked evidence
supporting its contract and warranty claims. For instance, Thompson customer Wynne stated that
it received claims for under one-half percent of its IG units with aluminum spacers for roughly
two decades, but that it received as many as 100 times more warranty claims for Super Spacer
units when it started using them. R. at 2533–54, 2536, 2538–39. Similarly, Thompson customer
Oxbowindo stated that its failure rate for aluminum IG units was “less than one percent.” R. at
2545. Two other Thompson customers stated that the outgassing in the Super Spacer units
primarily occurred in windows facing the sun. R. at 2527, 2544. According to Thompson, these
statements comport with Howes’s opinion that Super Spacer outgasses at or above 60°C.
Additionally, Thompson argues that Ohio law applies to its fraud claim and that Ohio’s
economic loss doctrine does not bar said claim. We have jurisdiction pursuant to 28 U.S.C. §
1291 (2012).
II. STANDARD OF REVIEW
We review a district court’s grant of summary judgment de novo. Pinney Dock & Transp.
Co. v. Penn Cent. Corp., 838 F.2d 1445, 1472 (6th Cir. 1988) (citations omitted). Summary
judgment is proper “if the movant shows that there is no genuine dispute as to any material fact
and the movant is entitled to judgment as a matter of law.” Fed. R. Civ. P. 56(a). A disputed fact
is “material” if it “might affect the outcome of the suit under the governing law . . . .” Anderson
v. Liberty Lobby, Inc., 477 U.S. 242, 248 (1986). A dispute about a material fact is “genuine” if
“the evidence is such that a reasonable jury could return a verdict for the nonmoving party.” Id.
-7-
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
In determining whether a reasonable jury could return a verdict for the nonmoving party, we
“view the evidence and draw all reasonable inferences in favor of the nonmoving party.” Sec’y of
U.S. Dep’t of Labor v. Gilley, 290 F.3d 827, 829 (6th Cir. 2002) (citing Matsushita Elec. Indus.
Co. v. Zenith Radio Corp., 475 U.S. 574, 587 (1986)). The nonmoving party cannot create a
genuine dispute of material fact through “mere speculation, conjecture, or fantasy.” Lewis v.
Philip Morris Inc., 355 F.3d 515, 533 (6th Cir. 2004) (citation omitted) (internal quotation marks
omitted).
III. ANALYSIS
A. Breach of Contract and Breach of Warranty
The district court held that Thompson submitted insufficient evidence to show that the
Super Spacers outgassed or that any outgassing caused the damages detailed in the warranty
report. Thompson contends that its circumstantial evidence creates genuine disputes of material
fact on the issues of breach and causation. Edgetech responds that Thompson’s evidence is
insufficient in this regard.
The district court applied Ohio law to Thompson’s breach of contract and warranty
claims. The Parties agree that Ohio law applies to these claims. Unless otherwise indicated, we
treat these claims in tandem as they present overlapping issues.
Under the Ohio version of the Uniform Commercial Code, to prevail on a breach of
express warranty claim, the plaintiff must show that: (1) an express warranty exists; (2) the
product under warranty is defective; (3) the plaintiff provided the defendant with reasonable
notice of the defect; and (4) the plaintiff suffered an injury as a result of the defect. See Litehouse
Prods., Inc. v. A.M.I. Int’l, Ltd., No. 46834, 1984 WL 4539, at * 3 (Ohio Ct. App. Mar. 8, 1984);
McKinney v. Bayer Corp., 744 F. Supp. 2d 733, 753 (N.D. Ohio 2010) (citations omitted); cf.
-8-
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
Ohio Rev. Code Ann. § 1302.27 cmt. 13 (LexisNexis 2012) (“In an action based on breach of
warranty, it is of course necessary to show not only the existence of the warranty but the fact that
the warranty was broken and that the breach of the warranty was the proximate cause of the loss
sustained.”); Drayton v. Jiffee Chem. Corp., 591 F.2d 352, 359 (6th Cir. 1978) (stating that
“breach of an express warranty, if causally related to the injury, [is] actionable” under Ohio law).
In this case, Thompson’s evidence was insufficient for a reasonable juror to conclude that
the Super Spacer units were defective. Manser conceded that the warranty report was only his
best guess as to the identity and number of the defective Super Spacer windows. Furthermore,
Manser acknowledged that the report did not show whether the listed windows had foam or
aluminum spacers, and Thompson’s customers stated that some of the listed windows had
aluminum spacers. Therefore, although some of the windows in the report could have contained
defective Super Spacer, a juror would have to rely on “mere speculation, conjecture, or fantasy”
to so conclude. See Lewis, 355 F.3d at 533.
The evidence was also inadequate to reasonably conclude that Super Spacer caused the
windows to outgas. Thompson failed to preserve the windows in the warranty report and the
report does not list the five windows that Howes visually examined and determined failed due to
outgassing. R. at 1458, 1821. Consequently, Thompson failed to present expert testimony on
(1) whether the windows in the report outgassed and (2) whether Super Spacer caused the
alleged outgassing. Although Ohio law does not always require expert testimony to prove that a
design is defective, the causation issues here are too complex for the jury to decide without the
help of expert testimony. Compare Grover Hill Grain Co. v. Baughman-Oster, Inc., 728 F.2d
784, 793–94 (1984), with Newell Rubbermaid, Inc. v. Raymond Corp., 676 F.3d 521, 529 (6th
Cir. 2012). Even Howes stated that he did not know why the windows in the report failed. R. at
-9-
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
2269. Furthermore, although Howes visually examined five other windows and concluded that
Super Spacer caused them to outgas, he stated that determining whether the fog was outgassing
or mere “water fog” required a “destructive” test. R. at 1285, 1364, 1867. Heather Abbas,
Thompson’s director of quality, agreed that a destructive test was required. R. at 1891–92.
Hence, it is unclear how a rational juror could conclude that Super Spacer caused the five
visually examined windows to outgas.
Thompson contends that its circumstantial evidence creates triable issues on breach and
causation. To that end, Thompson points to evidence purporting to prove that: (1) both EPDM
and Super Spacer outgas; (2) Super Spacer field failures were heat-related as Howes predicted;
(3) Super Spacer units failed much more than aluminum units; (4) Super Spacer was
incompatible with polysulfide; and (5) Thompson has sound workmanship. We recognize that
circumstantial evidence may suffice in some cases to show that a defective product caused a
given injury. Rayco Mfg., Inc. v. Deutz Corp., 497 F. App’x 515, 518 (6th Cir. 2012) (citing
State Farm Fire & Cas. Co. v. Chrysler Corp., 523 N.E.2d 489, 493–94 (Ohio 1988)). However,
we disagree that Thompson’s circumstantial evidence creates genuine issues for trial.
Thompson’s counterargument overlooks the obvious. There is not enough evidence to reasonably
conclude that the windows Thompson designates as defective contained Super Spacer. In any
event, evidentiary items (1) – (3) share an infirmity: Thompson’s and Howes’s failures to
preserve pertinent evidence and data preclude meaningful comparative analysis. It is unclear that
the properties of the EPDM and Super Spacer that Howes tested are comparable to the Super
Spacer at issue; that the Super Spacer units and aluminum units were alike in all material
respects; that the sunny conditions under which the Super Spacer at issue failed were similar to
Howes’s laboratory conditions; and so on. Cf. Glastetter v. Novartis Pharms. Corp., 252 F.3d
- 10 -
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
986, 990 (8th Cir. 2001) (citation omitted) (stating that “[e]ven minor deviations in molecular
structure can radically change a particular substance’s properties and propensities”). As to item
(4), although there may be evidence supporting the inference that Super Spacer is incompatible
with polysulfide, Thompson opted to use polysulfide as a secondary sealant and applied it to the
IG units itself. Thus, item (4) does not indicate that the Super Spacer at issue was defective when
Edgetech shipped it. Concerning item (5), while Thompson arguably submitted evidence from
which one could infer that it had sound workmanship overall, sound workmanship alone is
generally insufficient to show breach of express warranty by a parts supplier. Therefore, the
evidence was insufficient for a rational juror to conclude that the Super Spacer windows were
defective or that Super Spacer caused any observed outgassing. Accordingly, the district court
did not err in granting summary judgment on Thompson’s interrelated claims for breach of
warranty and breach of contract.
B. Fraud
Thompson asserts a fraud claim based on Edgetech’s alleged misrepresentation that
polysulfide was a suitable secondary sealant to use with Super Spacer. The district court applied
Michigan law to Thompson’s fraud claim and concluded that Michigan’s economic loss doctrine
barred it. Thompson concedes that Michigan law would bar its fraud claim. Appellant’s Br. at
37; R. at 1977. Thus, we have no occasion to address this issue. Nevertheless, Thompson argues
that the district court should have applied Ohio law to its fraud claim and that Ohio’s economic
loss doctrine does not bar said claim. We review a district court’s choice-of-law determination de
novo. Performance Contracting Inc. v. DynaSteel Corp., 750 F.3d 608, 611 (6th Cir. 2014)
(citing Mill’s Pride, Inc. v. Cont’l Ins. Co., 300 F.3d 701, 704 (6th Cir. 2002)).
- 11 -
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
“Federal courts sitting in diversity must apply the choice-of-law rules of the forum state.”
Muncie Power Prods., Inc. v. United Techs. Automotive, Inc., 328 F.3d 870, 873 (6th Cir. 2003)
(citations omitted). Michigan courts “apply Michigan law unless a ‘rational reason’ to do
otherwise exists.” Sutherland v. Kennington Truck Serv., Ltd., 562 N.W.2d 466, 471 (Mich.
1997) (quoting Olmstead v. Anderson, 400 N.W.2d 292, 302, 305 (Mich. 1987)). Michigan
courts employ a two-step approach to determine whether there is a rational reason to displace
Michigan law. Id. First, the court “must determine if any foreign state has an interest in having
its law applied.” Id. “If no state has such an interest, the presumption that Michigan law will
apply cannot be overcome.” Id. But if a foreign state has an interest in applying its law, the court
“must then determine if Michigan’s interests mandate that Michigan law be applied[] despite the
foreign interests.” Id. “Although this balancing approach most frequently favors using [Michigan
law], Michigan courts nonetheless use another state’s law where the other state has a significant
interest and Michigan has only a minimal interest in the matter[.]” Hall v. Gen. Motors Corp.,
582 N.W.2d 866, 868 (Mich. Ct. App. 1998). The following nonexhaustive list of considerations
informs this determination: (1) whether the injury occurred in the state whose law a party seeks
to apply, see Standard Fire Ins. Co. v. Ford Motor Co., 723 F.3d 690, 695, 698 (6th Cir. 2013);
Radeljak v. Daimlerchrysler Corp., 719 N.W.2d 40, 46 (Mich. 2006) (“‘[There] is a local interest
in having localized controversies decided at home.’” (quoting Gulf Oil Corp. v. Gilbert, 330 U.S.
501, 509 (1947))); (2) the extent to which the relevant commercial activity took place in the state
whose law a party seeks to apply, see Standard Fire, 723 F.3d at 699; (3) whether a party seeks
to defeat the application of the law of its home state, Olmstead, 400 N.W.2d at 304 (“Since
defendant is a citizen of Michigan, there can be no serious argument that applying Michigan law
will defeat his expectations.”); (4) the forum state’s interest in applying its own law, Radeljak,
- 12 -
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
719 N.W.2d at 46 (“‘[There] is an appropriateness . . . in having the trial . . . in a forum that is at
home with the state law that must govern the case . . . .’” (quoting Gilbert, 330 U.S. at 509)); (5)
whether the law of the foreign state would entitle the party to greater relief than the law of the
party’s home state, cf. Standard Fire, 723 F.3d at 698 (“Michigan was deemed to have no
interest in affording greater rights of tort recovery to a Tennessee resident than would Tennessee
law.”); Frydrych v. Wentland, 652 N.W.2d 483, 486 (Mich. Ct. App. 2002) (citation omitted)
(“Michigan has little or no interest in affording greater rights of tort recovery to a foreign state
resident than those afforded by the foreign state.”); and (6) whether courts in the foreign state
whose law the party seeks to apply would apply Michigan law, Sutherland, 562 N.W.2d at 473.
To be expeditious, we go directly to step two.
Here, Michigan’s interests in applying its law to Thompson’s fraud claim dwarf any
countervailing interests on Ohio’s part. Although Edgetech made the alleged misrepresentation
in Ohio, the vast bulk of the outgassing (i.e., the alleged injury) took place in Michigan.
Likewise, while Edgetech manufactured the Super Spacer in Ohio, the other relevant commercial
activity primarily took place in Michigan. For instance, Thompson relied on the alleged
misrepresentation in Michigan by entering into the Contract at its Fenton office, see R. at 1816,
issued purchase orders and payment in Michigan, and manufactured the defective IG units in
Michigan. Furthermore, most of Thompson’s customers are located in Michigan, the units failed
largely in Michigan, and Thompson’s remedial efforts took place in Michigan. As to factors
(3) and (4), Michigan’s interests outweigh Ohio’s because Thompson is a Michigan company
and the district court had a general interest in applying Michigan law. Regarding factor
(5), Thompson seeks the application of Ohio law to obviate an unfavorable outcome under
Michigan law. Although Thompson could counter that Edgetech also seeks a favorable outcome
- 13 -
Case No. 13-2652
Thompson I.G., LLC v. Edgetech I.G., Inc.
under the law of another state, Edgetech is a foreign defendant seeking the application of the law
of the forum state. Thus, Edgetech’s conduct does not suggest “law shopping.” Cf. Ferens v.
John Deere Co., 494 U.S. 516, 539 (1990) (Scalia, J., dissenting). As for factor (6), Ohio
conflict-of-law rules would mandate the application of Michigan law. Under Ohio law, “a
presumption is created that the law of the place of the injury controls unless another jurisdiction
has a more significant relationship to the lawsuit.” Morgan v. Biro Mfg. Co., Inc., 474 N.E.2d
286, 289 (Ohio 1984) (citing Restatement (Second) of Conflicts of Laws § 146 (1971)). Where,
as here, the alleged tort occurred in more than one state, “the place of the wrong is the state
where the last event necessary to make the actor liable took place.” Bailey v. Chattem, Inc.,
684 F.2d 386, 392 (6th Cir. 1982) (applying Tennessee law) (citation omitted) (internal quotation
marks omitted). “Under this lex loci delicti approach, ‘[when] a person sustains loss by fraud, the
place of wrong is where the loss is sustained, not where fraudulent representations are made.’”
Id. (quoting Restatement (First) of Conflicts of Laws § 377 n.4 (1934)). Thus, because
Thompson sustained the alleged loss in Michigan, Michigan law applies to Thompson’s fraud
claim. Accordingly, the district court did not err in granting summary judgment on Thompson’s
fraud claim.7
IV. CONCLUSION
For the foregoing reasons, we AFFIRM the judgment of the district court.
7
Thompson also suggests that the Contract contains a choice-of-law clause requiring the application of
Ohio law to its fraud claim. However, choice-of-law clauses are not invariably enforceable under
Michigan law. See Johnson v. Ventra Grp., Inc., 191 F.3d 732, 739 (6th Cir. 1999) (citation omitted).
Moreover, under the circumstances of this case, the provision that the Contract “shall be governed by the
laws of the State of Ohio” appears to be sufficiently narrow to exclude Thompson’s fraud claim, which
lacks a sufficiently close relationship to the Contract.
- 14 -
|
{
"pile_set_name": "FreeLaw"
}
|
Insulin receptor knock-out mice.
Targeted mutagenesis of the insulin receptor gene in mice has yielded unexpected results. This article reviews recent findings and analyzes this animal model can further our understanding of the mechanism of insulin action and its impairment in non-insulin-dependent diabetes mellitus is analyzed. (Trends Endocrinol Metab 1997;8:101-104). Published 1997 by Elsevier Science Inc.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Over the past five years, this Purdue University team has been collaborating with colleagues at Rutgers University to investigate the computational and experimental infrastructure for continuous manufacturing (CM) of solid oral dosage products. This work has built on a decade of research under the NSF supported Center for Structured Organic Particulate Systems. In parallel, the PI and Purdue co-workers have investigated CM approaches to small molecule API manufacture at micro and intermediate scales. This work has demonstrated the essential roles of process modeling, process analytical technology, active process control, intelligent process monitoring, material tracking and real time risk assessment. Moreover, current work is showing how these components must be linked through an integrated data management and informatics infrastructure in order to achieve the desired Industry 4.0 functionalities. While CM is an important development for the pharmaceutical industry, it is not a universal solution that meets all manufacturing needs, either technically or economically: often hybrid batch-continuous or fully batch modes can be advantageous. Moreover, given the major investment in existing batch facilities in the generic \manufacturing sector, there is an unmet need to bring Industry 4.0 functionalities to those manufacturers and thus significantly improve quality and reduce cost of medicines. The goal of this proposal is to expand the research on CM to develop and demonstrate a framework for the design and operation of batch and hybrid small molecule manufacturing systems. This will be achieved through five aims: Aim 1: Development of Pharmaceutical Model Library for small molecule and oral drug product manufacture Aim 2: General framework for the optimal synthesis of processes for small molecule-based API and product manufacture, encompassing the spectrum from batch to fully continuous processes Aim 3: Development of an Industry 4.0 real-time process management framework (RTPM). Aim 4: Demonstration of these technologies using several case-studies including high cost/low volume and high volume/low cost generic drugs at three different scales (lab, pilot and industrial) Aim 5: Development of instructional modules for conducting training programs for both FDA staff and industry as well as web-based access to tools and cases studies via pharmaHUB. This work will result in the development of the tool set necessary to implement Industry 4.0 across the pharmaceutical sector as well as the demonstration of the framework for systematic design and operation of processes for several specific drugs, including the effects of scale. The case studies will serve to inform and promote innovative manufacturing practices across the numerous batch and hybrid batch-continuous facilities existing worldwide. Moreover, by complementing the progress made in CM, it will enable the FDA to develop effective guidelines on the application of Industry 4.0 functionalities across the industry.
|
{
"pile_set_name": "NIH ExPorter"
}
|
Q:
c++ one solution two projects (exe & dll) linking error
I have one Visual Studio solution which consists of two win32 projects: 1) application (.exe) 2) functions wrapper (.dll).
The solution is in prototyping stage so all classes/functionality are implemented under (.exe) project - dirty but quick and easy for debugging/testing.
I've started to write a DLL wrapper to "play" with functionality in MSExcel/VBA and faced linking error
error LNK2019: unresolved external symbol "public: __thiscall Date::Date(int,int,int)" (??0Date@@QAE@HHH@Z) referenced in function addNumbers
DLL header file:
#ifdef LIBRARYWRAP_EXPORTS
#define LIBRARYWRAP_API __declspec(dllexport)
#else
#define LIBRARYWRAP_API __declspec(dllimport)
#endif
LIBRARYWRAP_API int _stdcall addNumbers(int a, int b);
DLL source file:
#include "..\applicationProject\Date.h"
class Date;
LIBRARYWRAP_API int _stdcall addNumbers(int a, int b){
Date dummyDate(12,1,2014); // <- Linker error LNK2019.
return (a+b);
}
Class Date and constructor Date::Date(int,int,int) are defined in application project(.exe) within Date.h, Date.cpp.
What I've tried to do already:
for librarywrap project added new reference. Project -> Properties -> Common -> Add New Reference. Selected "applicationProject".
added additional include directories: $(SolutionDir)\applicationProject
Two questions:
First, Is that legal/achievable what I'm trying to do? DLL links to application project, whereas usually it should be other way round - application links to DLL. Hypothetically if i have two application projects (.exe) & (.exe) will it be possible to link one to another?
Second, If answer for first question is positive what should I add/change to make it work?
Thanks very much!
Nicholas
A:
Technically, it is possible to make a DLL to call all needed functions from another modules (even from .exe ones - LoadLibrary can do this), but it would be a great pain: you will have to export all needed methods explicitly in the .EXE (just like you export DLL functions) and import them into your DLL. So the answer to the first question is yes, but if the DLL wants to use a lot of entry points from the EXE then probably it is not the best option.
I'd suggest a different approach: having a common code base for both .exe (application) and .dll projects. Then you will be able to test your code by running the application, and to use the functionality from other apps through the DLL (the DLL will contain all the necessary code itself).
|
{
"pile_set_name": "StackExchange"
}
|
Q:
Input and Output symbols in EAGLE (perhaps with Labels and XREF)
I'd like to create arrows in my schematic. The solution (using XREF) to an older, related post gets me most of the way there:
Arrows on connections in schematics
BUT, with that approach, the net always connects to the pointy part of the label symbol, effectively making all labels look like inputs. Mirroring the label, or rotating it 180 degrees does not solve this problem. Does anybody have a work-around? e.g. is it possible to make a set of devices (INPUT, OUTPUT, INOUT, etc.) that have symbols and a pin to tie to a net, but no associated packages?
Here is an example of what I'd like to have:
And here is what I can do in EAGLE so far (notice that my OUTPUT is a mirrored version of the input, but the net is drawn through the label in order to connect to the vertex. What I'd like is for the net to connect to flat side of the output label (i.e. on the left side of the label, near the letter "O" in the example below, and as in the CE, CSN, MOSI and SCK labels in the image above).
A:
Just drag the output label over. It doesn't need to be touching the net at the label origin.
Note: To remove those little origin markers, use the set Option.ShowTextOrigins 0; command. Also note that this does not disconnect the label from the net, they are still associated (renaming the net will change the label). This simply moves the origin to not be on top of the net, so the two must be selected with the selection tool before being moved.
|
{
"pile_set_name": "StackExchange"
}
|
FILED
NOT FOR PUBLICATION
FEB 18 2020
UNITED STATES COURT OF APPEALS MOLLY C. DWYER, CLERK
U.S. COURT OF APPEALS
FOR THE NINTH CIRCUIT
NATIONAL UNION FIRE INSURANCE No. 17-35404
COMPANY OF PITTSBURGH, PA,
D.C. No. 2:16-cv-01461-JLR
Plaintiff-Appellee,
v. MEMORANDUM*
ZILLOW, INC.,
Defendant-Appellant.
Appeal from the United States District Court
for the Western District of Washington
James L. Robart, District Judge, Presiding
Argued and Submitted February 6, 2020
Seattle, Washington
Before: M. SMITH and N.R. SMITH, Circuit Judges, and TUNHEIM,** District
Judge.
Zillow, Inc. appeals the district court’s order entering judgment on the
pleadings in favor of National Union Fire Insurance Company of Pittsburgh, Pa.
*
This disposition is not appropriate for publication and is not precedent
except as provided by Ninth Circuit Rule 36-3.
**
The Honorable John R. Tunheim, United States Chief District Judge
for the District of Minnesota, sitting by designation.
(“National Union”) and dismissing Zillow’s counterclaims. We have jurisdiction
under 28 U.S.C. § 1291, and we reverse in part, affirm in part, and remand for
further proceedings.
1. Zillow challenges the district court’s declaration that Zillow’s professional
liability insurance policy (“Policy”)—which provided coverage “solely with
respect to Claims first made against an Insured during the Policy Period . . . and
reported to the Insurer”—did not cover a copyright-infringement lawsuit brought
against Zillow by VHT, Inc. during the Policy Period (“VHT Action”). The district
court determined that, because the VHT Action was “based on the same wrongful
conduct” as that alleged by VHT, Inc. in a demand letter sent to Zillow prior to the
Policy Period (“VHT Demand Letter”), the VHT Demand Letter and the VHT
Action comprised “a single Claim that was first made” prior to the Policy Period,
and thus was not covered by the Policy.
The district court’s interpretation finds no support in the plain language of
the Policy. Instead, the Policy defines a “Claim” as either “(1) a written demand
for money, services, non-monetary relief or injunctive relief; or (2) a Suit.” A
“Suit” is further defined as “a civil proceeding for monetary, non-monetary or
injunctive relief, which is commenced by service of a complaint or similar
2
pleading.” The VHT Action falls squarely within the definition of a “Suit,” and is
therefore a “Claim,” which was made during the Policy Period.
National Union nevertheless maintains that the Policy’s use of the phrase
“Claims first made” implicitly requires that the VHT Demand Letter and the VHT
Action be treated collectively as a single Claim for purposes of coverage, because
both Claims are based upon the same wrongful conduct. But, unlike a number of
other claims-first-made policies cited by both parties, the Policy does not contain a
provision expressly providing for the integration of factually related Claims. Had
National Union wanted factually similar Claims to be integrated under the Policy’s
coverage provision, it could have easily drafted the Policy to include such a
requirement. See Queen City Farms, Inc. v. Cent. Nat’l Ins. Co. of Omaha, 882
P.2d 703, 713 (Wash. 1994) (“As [the insured] correctly notes, if the insurers
wanted an objective standard to apply, they could easily have drafted language to
that effect.”).
As Zillow argues, several other provisions in the Policy underscore that
factually related Claims are not necessarily integrated under the coverage
provision. Overton v. Consol. Ins. Co., 38 P.3d 322, 325 (Wash. 2002)
(“Interpretation of insurance policies is a question of law, in which the policy is
construed as a whole and each clause is given force and effect.”). For example, the
3
Policy includes an exclusion from coverage for Claims “alleging, arising out of,
based upon or attributable to any Wrongful Acts, or any Related Acts thereto,
alleged or contained in any Claim which has been reported, or in any
circumstances of which notice has been given, under any [prior policy].” If
National Union were correct that factually related Claims were integrated under the
Policy’s “Claims first made” provision, this exclusion would be rendered
meaningless, because any Claim involving the same Wrongful Act as that alleged
in an earlier Claim made under a prior policy would already fall outside of the
Policy’s coverage provision. See Kut Suen Lui v. Essex Ins. Co., 375 P.3d 596, 602
(Wash. 2016) (refusing to interpret an insurance policy in a manner that would
cause language to become superfluous and without meaning).
However, while the Policy does not expressly require the integration of
factually related Claims, neither does it unambiguously resolve the coverage issue
before us. Zillow maintains that, under the Policy’s disjunctive definition of a
Claim, the VHT Demand Letter (i.e., “a written demand”) and the VHT Action
(i.e., “a Suit”) must be considered “separate and distinct” Claims for coverage
purposes. While we do not agree with the district court’s reasoning that the
Policy’s use of the word “or” in the definition of a “Claim” was merely “required
by basic grammatical considerations,” we do not find the Policy’s coverage
4
provision as unambiguous as Zillow contends. In particular, the Policy’s use of the
term “Claims first made” suggests that—under circumstances unclear from the
language of the Policy—a Claim made against Zillow might be the reassertion of a
prior unreported Claim. A contrary conclusion would render superfluous the
Policy’s use of the word “first.” See Kut Suen Lui, 375 P.3d at 602.
Because the Policy “is fairly susceptible to two different interpretations, both
of which are reasonable,” we find the Policy’s “Claims first made” coverage
provision ambiguous. See Quadrant Corp. v. Am. States Ins. Co., 110 P.3d 733,
737 (Wash. 2005) (quoting Weyerhaeuser Co. v. Commercial Union Ins. Co., 15
P.3d 115, 122 (Wash. 2000)). Under Washington law, “[i]f a clause is ambiguous,
[a court] may rely on extrinsic evidence of the intent of the parties to resolve the
ambiguity. Any ambiguity remaining after examination of the applicable extrinsic
evidence is resolved against the insurer and in favor of the insured.” Id. (citation
omitted). We therefore reverse and remand to the district court for consideration of
any admissible extrinsic evidence of the parties’ intent to resolve the ambiguity in
the coverage provision. After considering the extrinsic evidence, any remaining
ambiguity relating to the coverage issue must be resolved in favor of Zillow.
2. Zillow also argues that the district court erred in dismissing its breach-of-
contract counterclaim, which alleges that National Union breached its duty to
5
defend under the Policy “by failing to pay or reimburse any of Zillow’s defense
costs.” Zillow maintains that National Union’s duty to defend was triggered by
notice of the VHT Action, and that National Union cannot be relieved of that duty
until it is clear that the VHT Action is not covered by the Policy. See Am. Best
Food, Inc. v. Alea London, Ltd., 229 P.3d 693, 696 (Wash. 2010).
Even assuming, for the sake of argument, that National Union had a duty to
defend Zillow in the VHT Action, Zillow failed to plausibly allege that National
Union breached its duty by not paying Zillow’s defense costs. See Nw. Indep.
Forest Mfrs. v. Dep’t of Labor and Indus., 899 P.2d 6, 9 (Wash. Ct. App. 1995).
Under the plain language of the Policy, “[f]ees, costs, charges, billings and any
other expense incurred through any law firm” not selected in accordance with the
procedures set forth in Endorsement #5 “shall not be recoverable under this policy
as Defense Costs or otherwise.” Zillow does not allege that its defense counsel in
the VHT Action were selected in accordance with Endorsement #5’s procedures. In
fact, the record reflects the contrary.
Accordingly, because Zillow does not allege that National Union breached
its duty to defend by failing to pay or reimburse defense costs recoverable under
the Policy, Zillow has failed to state a plausible claim for relief. Therefore, the
district court properly dismissed Zillow’s breach-of-contract counterclaim. See
6
Cassirer v. Thyssen-Bornemisza Collection Found., 862 F.3d 951, 974 (9th Cir.
2017) (“[I]f the district court’s order can be sustained on any ground supported by
the record that was before the district court at the time of the ruling, we are obliged
to affirm the district court.” (quoting Jewel Cos., Inc. v. Pay Less Drug Stores Nw.
Inc., 741 F.2d 1555, 1564–65 (9th Cir. 1984))).
3. Although the district court properly dismissed Zillow’s breach-of-contract
counterclaim, Zillow argues that the district court erred in denying it leave to
amend on grounds of futility. In particular, Zillow maintains on appeal that
“[q]uestions of fact exist as to whether National Union waived any condition or
requirement in the Policy on selection of counsel.” Because we do not find that “it
is clear, upon de novo review, that the [counterclaim] could not be saved by any
amendment,” we reverse and remand to the district court to reconsider whether
amendment is appropriate. See Curry v. Yelp Inc., 875 F.3d 1219, 1228 (9th Cir.
2017) (quoting Zucco Partners, LLC v. Digimarc Corp., 552 F.3d 981, 1007 (9th
Cir. 2009)).
Each party shall bear its own costs on appeal.
REVERSED in part, AFFIRMED in part, and REMANDED for further
proceedings.
7
|
{
"pile_set_name": "FreeLaw"
}
|
The Inhibitory Effect of Abietic Acid on Melanoma Cancer Metastasis and Invasiveness In Vitro and In Vivo.
Melanoma cell metastasis is the primary cause of patient death. Thus, various treatment strategies have been developed to prevent metastasis. Abietic acid (AA) is an organic compound commonly found in trees. This study is aimed to investigate the antimetastatic activity of AA in B16F10-xenografted C57BL/6 mice and assess the anticancer activity of AA in combination with Taxol in melanoma cells. AA effectively reduced the formation of lung metastases by approximately 92.8%. AA treatment inhibited migratory potential (p < 0.001), invasion (p < 0.001), and motility (p < 0.001) of highly metastatic B16F10 melanoma cells in vitro. Zymography revealed that AA reduced the proteinase activities of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Molecular analyses showed that AA reduced Akt phosphorylation and activating protein-1 DNA-binding activity by Western blot and electrophoretic mobility shift assay (EMSA), respectively. In summary, AA effectively inhibited B16F10 lung metastasis, and 50[Formula: see text][Formula: see text]M AA did not affect the viability of B16F10 cells. AA improved the efficacy of Taxol and demonstrated strong anticancer activity on melanoma cells. These results suggested that AA could be used as an antimetastatic agent or as an adjuvant for anticancer therapy.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
using System.Reflection;
using System.Runtime.CompilerServices;
using System.Runtime.InteropServices;
// General Information about an assembly is controlled through the following
// set of attributes. Change these attribute values to modify the information
// associated with an assembly.
[assembly: AssemblyTitle("Budget2.Reports")]
[assembly: AssemblyDescription("")]
[assembly: AssemblyConfiguration("")]
[assembly: AssemblyCompany("Microsoft")]
[assembly: AssemblyProduct("Budget2.Reports")]
[assembly: AssemblyCopyright("Copyright © Microsoft 2010")]
[assembly: AssemblyTrademark("")]
[assembly: AssemblyCulture("")]
// Setting ComVisible to false makes the types in this assembly not visible
// to COM components. If you need to access a type in this assembly from
// COM, set the ComVisible attribute to true on that type.
[assembly: ComVisible(false)]
// The following GUID is for the ID of the typelib if this project is exposed to COM
[assembly: Guid("f227c302-3a75-4f3e-90f1-6426f3fa625c")]
// Version information for an assembly consists of the following four values:
//
// Major Version
// Minor Version
// Build Number
// Revision
//
// You can specify all the values or you can default the Build and Revision Numbers
// by using the '*' as shown below:
// [assembly: AssemblyVersion("1.0.*")]
[assembly: AssemblyVersion("1.0.0.0")]
[assembly: AssemblyFileVersion("1.0.0.0")]
|
{
"pile_set_name": "Github"
}
|
Tennessee state legislators on Wednesday advanced a bill to make the Bible the official state book, a measure the state attorney general said would be unconstitutional and Republican Governor Bill Haslam has called disrespectful.
The Republican-controlled state House of Representatives voted 55-38 to approve the Bible as state book. A companion bill could be considered as soon as Thursday in the state Senate, where Republicans hold 28 seats to five for Democrats.
ADVERTISEMENT
Representative Bud Hulsey, a Republican, told colleagues in support of the bill it is worth the fight “now more than ever.”
Other Republican representatives opposed the bill, citing concerns about how Tennessee might be perceived and the cost of defending it against legal challenges.
“The controversy will not end in this chamber,” Representative Martin Daniel said. “If we pass this, we’re going to be ridiculed.”
Representative Marc Gravitt said the attorney general’s legal opinion made it clear Tennessee could spend millions of dollars in a losing effort to defend the measure if it becomes law.
Other representatives said recognizing the Bible as the state book and putting it alongside the official state tree, song or dance would trivialize it.
ADVERTISEMENT
Representative Patsy Hazlewood, a Republican, said “To Kill a Mockingbird” and “The Pilgrim’s Progress” are books and calling the Bible a book is in itself wrong.
The bill also has drawn criticism from religious leaders and others – including Tennessee Attorney General Herbert Slatery III – who say it violates the separation of church and state under the U.S. Constitution and Tennessee’s constitution.
A spokesman has said the governor sees the bill as disrespectful of what the Bible is.
ADVERTISEMENT
(Reporting by Tim Ghianni; Editing by David Bailey and Bill Trott)
|
{
"pile_set_name": "OpenWebText2"
}
|
Атомная электростанция «Пакш». Фото: REUTERS / Laszlo Balogh
Нежданно-негаданно и почти бесшумно Россия вдруг решила одарить энергетику Восточной Европы чуть ли не крупнейшей инвестицией со времен соцлагеря. Выдать венграм каких-то 10 млрд евро, чтобы они купили у «Росатома» пару энергоблоков для своей АЭС «Пакш». Для сравнения: на «Северный поток» ушло 9 млрд евро, на «Южный поток», если он вообще случится, планируется потратить около 15 млрд евро. И тот и другой затрагивают десяток стран, годами гремят в СМИ по всей Европе и обсуждаются на куче международных встреч. А тут вдруг из ниоткуда сразу 10 млрд евро и одной Венгрии – как-то вечером премьер Орбан заскочил в Кремль подписать бумажки.
Мастер-класс для Лукашенко
Чтобы лучше представить, что такое 10 млрд евро для Венгрии – это по тысяче с лишним евро на каждого венгра, включая стариков и младенцев. Население там не дотягивает до 10 млн. Ну или более практичное сравнение – без малого четверть годовых расходов венгерского госбюджета. Или 13,5% совокупного госдолга. Или в два с половиной раза больше, чем суммарный размер субсидий, которые Венгрия получает из бюджета ЕС за год.
Вот такую сумму должна получить Венгрия из российского бюджета в виде долгосрочного кредита, чтобы потратить ее на покупку у «Росатома» двух новых энергоблоков по 1,2 ГВт каждый для своей единственной АЭС «Пакш». Сейчас эта АЭС, которую в рамках интернационального долга строили советские специалисты в 80-х, выдает около 2 ГВт и обеспечивает 40% всего энергопотребления в стране. А так как особого экономического роста в Венгрии в ближайшее время не предвидится, то нетрудно подсчитать, что к 2023 году, когда проект должен быть завершен, АЭС «Пакш» сможет практически полностью покрыть потребности венгров в электроэнергии.
Раздобыть в кризис долгосрочный кредит размером 11% ВВП страны – это, конечно, удивительная победа новой внешней политики венгерского премьера Виктора Орбана. После того как он разругался на Западе со всеми, с кем только можно, из-за чрезвычайных налогов на иностранные корпорации и национализации пенсионных накоплений, ему пророчили судьбу второго Лукашенко. Обещали превращение в диктатора-популиста из страны-изгоя, которому никто не захочет подавать руки.
Однако на деле оказалось, что быть вторым Лукашенко не так уж и плохо. Из Евросоюза Венгрию все равно не выгонят – там такая процедура не предусмотрена в принципе. А статусом государства – члена ЕС можно очень успешно торговать на мировом рынке, не заморачиваясь излишней принципиальностью и чистоплюйством, потому что на Западе терять уже нечего. Так, в 2012 году Орбан продал Азербайджану азербайджанского офицера, осужденного за убийство своего армянского коллеги во время учений НАТО в Будапеште. На родине убийцу тут же освободили как героя, а в качестве благодарности купили у Венгрии облигаций на 2 млрд евро.
Венгры стали любимым партнером Китая в Восточной Европе. За время правления Орбана, то есть с 2010 года, размер китайских инвестиций в Венгрии утроился, достигнув $2,5 млрд. Но все это меркнет на фоне роскошного подарка от России. Даже прожженный попрошайка Лукашенко смог добиться от Москвы всего 7,5 млрд евро на строительство АЭС в Белоруссии. Украине – архистратегическому братскому партнеру – обещают всего 4,5 млрд евро кредитов на ее атомную энергетику. А тут какой-то Орбан, который в Москве был всего пару раз в жизни, – и сразу 10 млрд евро.
Последний в ЕС
С таким кредитом и с расширяющейся АЭС Орбан легко сможет выполнить свое главное предвыборное обещание – понизить цены на электроэнергию. Это позволит ему переизбраться на следующий срок, выиграв парламентские выборы весной этого года. А если повезет, то положительного эффекта может вполне хватить и до следующих выборов, в 2018 году. Так что то, о чем думал венгерский премьер, когда соглашался на эту сделку, понять не трудно. Труднее понять, о чем думала российская сторона. Бюджет без дефицита свести не можем, собственные инфраструктурные проекты сворачиваем, а вот найти 10 млрд евро для Венгрии – это легко.
Как обычно, стратегические интересы оказались для Кремля дороже денег. За последние десять лет «Росатом» успел почти полностью растерять ту огромную атомную империю в Восточной Европе, которую он унаследовал от СССР. Когда-то почти в каждой стране бывшего соцлагеря было по АЭС, и все обслуживались советскими специалистами. Сейчас не осталось почти ничего. Правда, дело здесь не только в кондовых и неповоротливых методах «Росатома» – некоторые страны Восточной Европы настолько уверовали в националистические и экологические утопии, что сами охотно бросились выкалывать себе глаза назло теще и добровольно позакрывали еще вполне жизнеспособные АЭС, лишив свои экономики дешевой и обильной электроэнергии.
В любом случае список потерянных рынков у «Росатома» получился огромный. Накануне вступления в ЕС свои атомные станции полностью закрыли Литва и Словакия. Болгария остановила часть энергоблоков, много лет вела переговоры с Москвой о строительстве новой АЭС в Белене, но в 2012 году соскочила с проекта окончательно, несмотря на гигантские убытки. Польша уже много лет планирует построить свою первую АЭС, но работы пока не начались, и Россию туда вряд ли возьмут. Чехия не стала отказываться от ядерной энергетики, несмотря на давление ЕС, но контракт «Росатома» на поставку топлива чешской АЭС «Темелин» истекает в 2020 году, а тендер на строительство там двух новых энергоблоков, в котором участвует и Россия, постоянно откладывается все дальше и дальше в будущее.
В итоге Венгрия осталась для «Росатома» последней возможностью хоть как-то закрепиться на рынке Восточной Европы. Ведь людям хочется работать не только в Иране или Индии. Для хорошего международного имиджа нужны проекты в более респектабельных странах, в таких, которые не станут бросаться на что угодно ради одной только низкой цены. И Восточная Европа, которая теперь оказалась частью такой уважаемой организации, как Евросоюз, подходит для этих целей лучше всего. Вот в Москве и решили выбрать в регионе самое слабое звено и удержать его всеми силами.
Заемщик мечты
То, что «Росатому» удалось сохранить свое присутствие хотя бы в Венгрии, само по себе замечательно. Вопрос только в том, во сколько это обойдется российским налогоплательщикам. Насколько надежны и перспективны такие гигантские инвестиции в венгерскую энергетику? И вот здесь возникают большие сомнения.
Россия собирается одолжить 10 млрд евро одному из самых неблагонадежных заемщиков в Европе. Это только так говорится, что Венгрия – член Евросоюза. А на самом деле Орбан настолько испортил отношения и с европейскими, и с международными институтами, что, случись чего, там никто пальцем не пошевелит, чтобы помочь тонущей в долгах Венгрии. Наоборот, будут только злорадствовать.
А случиться может запросто. Венгрия и без российского кредита бесспорный чемпион Восточной Европы по соотношению госдолга с ВВП – около 80%. Про экономический рост венгры забыли задолго до кризиса, еще в 2006 году. За последние 10 лет ВВП соседней Словакии или Польши вырос примерно в полтора раза, ВВП Венгрии – всего на 8%. Страна давно впала в затяжную экономическую стагнацию, и оживить ее не могут даже самые причудливые реформы Виктора Орбана.
Кроме того, из-за постоянных экономических проблем политическая жизнь в Венгрии поляризировалась гораздо сильнее, чем у соседей. Никакой преемственности, каждый следующий лидер обещает избирателям не меньше чем новую эпоху. Сам Орбан, придя к власти, радикально пересмотрел чуть ли не все решения своих социал-демократических предшественников. И нет никаких гарантий, что если оппозиция вдруг выиграет, то она не поступит точно так же. Венгерские левые уже сейчас называют атомную сделку с Россией энергетическим рабством, новой советской оккупацией и угрозой всему живому в стране. Они считают, что это соглашение недействительно, потому что Орбан не провел тендер, а это противоречит венгерскому законодательству. И вообще такие важные решения можно принимать только на референдуме.
Поэтому гораздо надежнее было бы заключить атомные соглашения с Польшей или Чехией, где правительства не в пример адекватнее, а экономические перспективы намного радужнее, чем у Венгрии. Но странам с адекватными правительствами и радужными перспективами делают предложения получше российских. А России приходится брать, что осталось, утешая свой неконкурентоспособный бизнес особым распределением: гарантированный доход – госкорпорациям, риски и убытки – налогоплательщикам.
|
{
"pile_set_name": "OpenWebText2"
}
|
//
// JPSImagePickerControllerDemoTests.m
// JPSImagePickerControllerDemoTests
//
// Created by JP Simard on 1/31/2014.
// Copyright (c) 2014 JP Simard. All rights reserved.
//
#import <XCTest/XCTest.h>
@interface JPSImagePickerControllerDemoTests : XCTestCase
@end
@implementation JPSImagePickerControllerDemoTests
- (void)setUp
{
[super setUp];
// Put setup code here. This method is called before the invocation of each test method in the class.
}
- (void)tearDown
{
// Put teardown code here. This method is called after the invocation of each test method in the class.
[super tearDown];
}
- (void)testExample
{
XCTFail(@"No implementation for \"%s\"", __PRETTY_FUNCTION__);
}
@end
|
{
"pile_set_name": "Github"
}
|
Online Tutoring
During this period of transition to online learning, the university continues to expand resources and support to help make sure everyone can make the most of available tools.
STEM tutoring information: Tutoring Summer 2020
Free online Mathematics tutoring: MAC Online Tutoring Summer 2020
Monday through Thursday: 9:00 a.m. – 7:00 p.m. & Friday: 9:00 a.m. – 4:00 p.m.
*Weekend tutoring will be available as well.
To get help, visit the website GSU.TUTOROCEAN.COM
Create an account using your Georgia State University email address Search for the course you need help with today Check “Downtown Stem Center” for Atlanta campus tutors
Schedule View makes it easier to see which time slots are available
*Disregard “Perimeter College” on the homepage, TutorOcean is open to all Georgia State University students.
We can help with the following Courses:
MATH Course Name 0999 Support for College Algebra* 1101 Mathematical Modeling 1111 College Algebra 1113 Precalculus 1220 Survey of Calculus 2201 Calculus for Life Sciences I 2202 Calculus for Life Sciences II 2215 Multivariate Calculus 2420 Discrete Mathematics 3050/7050 Geometry and Spatial Sense 3070/7070 Introduction to Probability and Statistics 3090/7090 Algebraic Concepts*** 4547/6547 Introduction to Statistical Methods 4751/6751 Mathematical Statistics I
* Online Section only.
*** Task from the book are often assigned to be handed in for a grade and hence are excluded in MAC.
Helpful TutorOcean Tutorials
Contacts
Mrs. Sutandra Sarkar (ssarkar@gsu.edu)
Mr. Martin Crowe (mcrowe2@gsu.edu)
Helpful Links
Math Tutorials
PatrickJMT — This is a YouTube channel which many students turn to for help in math. Many concepts are covered in this collection of short videos.
Khan Academy — This website is extremely helpful for all levels of math and numerous other subjects.
Hippo Campus — Contains comprehensive lessons on Calculus, Statistics, Algebra and Geometry
Paul’s Online Math Notes — Provides topic-oriented help with calculus
Study Tips, Math Anxiety, etc…
Practical Study Strategies — From the University of Illinois-Chicago’s Center for Academic Excellence.
Sheila Tobias’ Math Anxiety Page — Although it’s mostly an advertisement for her books, it does include detailed summaries of each chapter of her books Overcoming Math Anxiety, Breaking the Science Barrier, and Succeed with Math, as well as some frequently asked questions about math anxiety.
General Math Help
|
{
"pile_set_name": "OpenWebText2"
}
|
The present invention relates to a developer transportation device for supplying a sheet and an image forming apparatus having the developer transportation device.
In a conventional image forming apparatus such as a printer, a copier, a facsimile, and the likes, a charge roller charges a surface of a photosensitive drum, and an LED (Light Emitting Diode) head exposes the surface of the photosensitive drum to form a static latent image thereon. Then, a developing roller attaches a thin layer of toner to the static latent image through static electricity, thereby forming a toner image. A transfer roller transfers the toner image to a sheet, and a fixing device fixes the toner image to the sheet, thereby forming an image on the sheet. After the transfer roller transfers the toner image to the sheet, a cleaning blade scrapes off toner remaining on the photosensitive drum, so that toner is collected as waste toner.
When the cleaning blade collects waste toner, a toner transportation device as a developer transportation device transports waste toner to a waste toner box, so that waste toner can be discarded externally. The toner transportation device includes a transportation spiral as a transportation member having a coil shape. When the transportation spiral rotates, the transportation spiral transports waste toner (refer to Patent Reference). Patent Reference: Japan Patent Publication No. 2006-58729
|
{
"pile_set_name": "USPTO Backgrounds"
}
|
/*
Simple DirectMedia Layer
Copyright (C) 1997-2018 Sam Lantinga <slouken@libsdl.org>
This software is provided 'as-is', without any express or implied
warranty. In no event will the authors be held liable for any damages
arising from the use of this software.
Permission is granted to anyone to use this software for any purpose,
including commercial applications, and to alter it and redistribute it
freely, subject to the following restrictions:
1. The origin of this software must not be misrepresented; you must not
claim that you wrote the original software. If you use this software
in a product, an acknowledgment in the product documentation would be
appreciated but is not required.
2. Altered source versions must be plainly marked as such, and must not be
misrepresented as being the original software.
3. This notice may not be removed or altered from any source distribution.
*/
#include "../../SDL_internal.h"
#if SDL_VIDEO_DRIVER_ANDROID
#include "SDL_androidvideo.h"
#include "SDL_androidclipboard.h"
#include "../../core/android/SDL_android.h"
int
Android_SetClipboardText(_THIS, const char *text)
{
return Android_JNI_SetClipboardText(text);
}
char *
Android_GetClipboardText(_THIS)
{
return Android_JNI_GetClipboardText();
}
SDL_bool Android_HasClipboardText(_THIS)
{
return Android_JNI_HasClipboardText();
}
#endif /* SDL_VIDEO_DRIVER_ANDROID */
/* vi: set ts=4 sw=4 expandtab: */
|
{
"pile_set_name": "Github"
}
|
Cut some prices, Mr. Cook! Justin Sullivan/Getty Images Third quarter global smartphone sales came out earlier this week.
The message was clear:
Apple is getting its clock cleaned by Samsung, which is now by far the dominant smartphone maker in the world. (Samsung had 32% of the global market in Q3, the same share as a year ago. Apple, meanwhile, had only 12% of the market, down from 14% a year ago.)
Yes, both companies sold more smartphones this year than last year. But Apple's sales badly lagged both Samsung and, importantly, the broader smartphone market.
Apple's sales increased 23%. Samsung's increased 46%. The smartphone market as a whole, meanwhile, grew 46%.
In other words, Apple's smartphone sales grew at only half the rate of the market.
Apple fans have developed excuses for Apple's lagging sales. The most popular is that Apple is a "premium" gadget maker, not a hoi polloi gadget maker, and it only wants to sell its phones (and tablets) to people who can afford to pony up for them. Apple, in other words, is like BMW, not Ford.
There are two big problems with this analogy. First, unlike cars, smartphones are a "platform market" — third parties build products and services that run on top of smartphones — and in platform markets, market share is a huge competitive advantage. Second, in emerging markets, which is where most of the growth in smartphones and tablets now is, there just aren't that many people who want to buy BMWs when many very high-quality gadgets are available for much lower prices.
The actual reason that Apple's gadget sales are now so badly underperforming the market is that Apple no longer sells products at price points that appeal to the growth segment of the market.
Apple fans can keep telling themselves that this is just fine, that Apple doesn't want or need to sell gadgets to earthlings of more average wealth, but what these fans need to recognize is that this is effectively a major change in Apple's pricing strategy.
In the first few years after the iPhone and iPad launched, Apple led the market not just in product quality but in product price. The iPhone and iPad were not just way better than the competition, they also cost the same or less.
Now, Apple may still have an edge in product quality (this is debatable and a matter of personal preference), but in most countries, its gadgets are considerably more expensive than the alternatives. And those alternatives — from Samsung, Google, Amazon, and many other vendors — are getting better and better.
If gadgets were not a platform market, this wouldn't matter. But they are. And the more market share Apple surrenders in China, Brazil, India, et al, the less chance it will have to become the leading platform in these countries. (In fact, in many of them, it's probably already too late.)
The simple answer is NOT for Apple to make low-end gadgets that it considers crappy. It is for Apple to use its phenomenal profitability as a competitive weapon. Specifically, the answer is for Apple to sell some of its gadgets -— not the latest, greatest ones, but some — at prices that are highly competitive with local alternatives.
Now that Apple has "forked" its iPhone product line into the 5S and 5C, for example, it could sell the 5C at a sharply lower price point. Instead, Apple is still charging almost as much for the 5C as the 5S. (Yes, Apple is selling the iPhone 4 at a significantly lower price than the 5s, but this phone is now old, weak, and small.)
Similarly, in iPads, Apple is selling its "Mini" at prices that are radically higher than high-quality alternatives. Instead, it could sell the latest, greatest version of the Mini at a high price and other recent models at a very competitive price.
Importantly, this would cost Apple nothing more than some near-term profits. And Apple has plenty of profit to spare. (In fact, it has so much profit to spare that it has no idea what to do with the cash piling up on its balance sheet.)
Significantly increasing its market share in key markets around the world would make Apple's long-term competitive position much stronger. It would help Apple increase the value of its content and app "ecosystem" in these countries and, thereby, strengthen the "lock-in" of its products and services.
But, instead, Apple is being shortsighted and choosing to maintain its already fantastically high profit margins at the expense of market share.
Let's go to the charts:
(These charts are all from BI Intelligence, our premium industry research service. You can sign up for a free trial here >)
First, as you can see, the global smartphone and tablet markets are still growing like mad. Here's smartphones:
Business Insider
And here's tablets:
Business Insider
And now look at Apple's growth in these markets.
First, as the line in the chart below shows, Apple's iPhone sales have slowed sharply:
Business Insider
Apple's tablet sales, meanwhile, have hit a wall. (Yes, the new iPads will help. But it is going to be very hard for Apple to make up this lost ground.)
Business Insider
When confronted with these statistics, Apple fans generally point out that Apple still has a very strong position in the U.S. market and that Americans keep scarfing up Apple's top-of-the-line iPhones.
That's true.
Apple's market share in the United States is indeed strong, as the following chart shows:
Business Insider
But the U.S. is an anomaly. In most other countries, Apple is losing share fast. And that means that, at best, Apple is missing a massive opportunity.
The bottom line is that, by trying to maintain its price points and super-high profit margin, Apple has radically underperformed the market for the past couple of years, especially in tablets. Because of the importance of the platform and ecosystem for long-term value, this is a shortsighted decision.
Meanwhile, Google's Android has become the world's dominant smartphone and tablet platform:
Business Insider
Business Insider
Business Insider
If Apple continues to pursue its current pricing and maximize-short-term profit strategy, it may continue to increase its profits for the next couple of years. (BlackBerry and Nokia grew earnings for a couple of years after some analysts began seeing the writing on the wall.)
But Apple will also continue to lose platform and ecosystem share in most of the world.
Apple fans can talk all they want about how Apple is "like BMW," but in a couple of key competitive respects, it isn't. And if the gadget platform market behaves the way other platform markets have (think Windows), Apple and its fans may come to regret this short-term thinking in the end.
SEE ALSO: The Future Of Digital [SLIDES]
Disclosure: I'm an Apple shareholder.
|
{
"pile_set_name": "OpenWebText2"
}
|
PET imaging study of brown adipose tissue (BAT) activity in mice devoid of receptor for advanced glycation end products (RAGE).
Brown adipose tissue (BAT) is responsible for adaptive thermogenesis. We previously showed that genetic deficiency of receptor for advanced glycation end products (RAGE) prevented the effects of high-fat diet (HFD). This study was to compare BAT activity in RAGE knock out (Ager-/-, RKO) and wild-type (WT) mice after treated with HFD or LFD. [18F]FDG PET-CT imaging under identical cold-stimulated conditions and mean standard uptake values (SUVmean), ratio of SUViBAT/SUVmuscle (SUVR, muscle as the reference region) and percentage ID/g were used for BAT quantification. The results showed that [18F]FDG uptake (e.g., SUVR) in WT-HFD mice was significantly reduced (three-fold) as compared to that in WT-LFD (1.40 +/- 0.07 and 4.03 +/- 0.38; P = 0.004). In contrast, BAT activity in RKO mice was not significantly affected by HFD, with SUVRRKO-LFD: 2.14 +/- 0.10 and SUVRRKO-LFD: 1.52 +/- 0.13 (P = 0.3). The uptake in WT-LFD was almost double of that in RKO-LFD (P = 0.004); however, there was no significant difference between RKO-HFD and WT-HFD mice (P = 0.3). These results, corroborating our previous findings on the measurement of mRNA transcripts for UCP1 in the BAT, suggest that RAGE may contribute to altered energy expenditure and provide a protective effect against HFD by Ager deletion (Ager -/-).
|
{
"pile_set_name": "PubMed Abstracts"
}
|
If Bernie runs, it looks like the progressive left flank is ready to mobilize on his behalf.
Recent signals by Vermont's Independent Senator Bernie Sanders that he would consider a run for president in 2016 in order to "take on Wall Street, address the collapse of the middle class, tackle the spread of poverty... and address global warming," perked the ears of progressives who look out at the Democratic Party and see no other candidate—especially the presumed frontrunner Hillary Clinton—likely to speak for them on a core set of issues.
And now, a survey prompted by Sanders' comments shows that among those who closely identify as "progressive" support for his candidacy is at more than 80 percent.
Conducted by RootsAction.org—a progressive online activism, advocacy and lobbying organization—the survey asked the group's members to offer their opinion on a Sanders run for the nation's highest office.
Asked if he should run, 81 percent said 'Yes.' Only 9 percent said 'No,' and the remaining 10 percent were unsure.
“Nearly 20,000 people responded to our survey, from every state in the nation,” said RootsAction.org co-founder Jeff Cohen. “Though not a scientific sampling, it reflects Bernie Sanders’ huge popularity among progressives. And that there’s a ready-made base for him – or perhaps another progressive candidate – in a campaign that challenges the Democratic establishment and ostensible frontrunner Hillary Clinton.”
SCROLL TO CONTINUE WITH CONTENT Never Miss a Beat. Get our best delivered to your inbox.
In the letter sent to members that accompanied the survey, RootsAction told its members:
[We] rarely focuses on elections because, quite frankly, few politicians make us enthusiastic. But Bernie Sanders is different. He has long been a strong advocate of enhanced Medicare for all, taxing Wall Street, cutting the military, opposing corporate trade pacts, etc. In 2010, he touched a national nerve when he filibustered against the Obama-GOP deal extending Bush-era tax cuts for the rich. Bernie told Politico: “Obviously if I did not think I had a reasonable chance to win I wouldn’t run . . . It is not my intention to be some kind of spoiler and play the role of just draining votes away to allow my voice to be heard.”
In addition to whether or not he should run, respondents were also asked to offer input on strategy. As a follow-up question, they were asked: “Would you be more likely to support a Bernie presidential campaign if he were to run inside Democratic caucuses and primaries -- or, if he ran outside as an independent ‘3rd-party’ candidate?”
On that question there was a clear majority which thought he should challenge Democrats from within (45 percent) and much a smaller number who thought running as an outside candidate would be good (24 percent). Those who remain unsure of the best strategy actually came in second place with 31 percent.
As Cohen commented: “While a spectrum of our country’s progressive base represented in our online membership is overwhelmingly supportive of a Sanders campaign, there’s less of a consensus on strategy – with those favoring an inside the Democratic caucuses and primaries approach about 2 to 1 over those wanting an outside approach.”
____________________________________________
|
{
"pile_set_name": "OpenWebText2"
}
|
Q:
In C++, how to declare a data structure in header file , while it is defined in source file?
Say I want to use typedef to define a new set MyTypeSet with customized hash and comparator functions in a source file. I want to hide all the implementation details in the source file.
typedef std::unordered_set<MyType, MyTypeHash, MyTypeKeyEqual>
MyTypeSet;
Then I want to declare MyTypeSet in header file for other modules to use. But I do not want to expose MyTypeHash and MyTypeKeyEqual
Just can not figure out the right syntax.
A:
This can't be done with typedef. The user of MyTypeSet needs to be able to see complete definitions for MyType, MyTypeHash, and MyTypeKeyEqual in order to know how to compile MyTypeSet.
There are a few approaches in use to demarcate the public interface of templated code from the implementation details:
Put the implementation details in another header ("MyTypeImpl.hpp") that is included in the public header.
Put the private implementation types in a namespace named detail, private, or similar.
Mangle the private names with underscore characters, as in MyTypeHash_. (This can be seen a good bit in the MSVC standard library).
If it is absolutely imperative to keep MyTypeHash and MyTypeKeyEqual secret, then one could declare MyTypeSet as a class that only has the methods needed by the end user. Then MyTypeSet could use the pImpl idiom to have a std::unordered_set as a member variable visible only in the source file. All of the methods of MyTypeSet would be implemented by calling into the std::unordered_set.
Such a MyTypeSet cannot have exactly the same public interface as std::unordered_set, because std::unordered_set exposes its hash and key types as member types.
|
{
"pile_set_name": "StackExchange"
}
|
Thermodynamics of catalytic formation of dimethyl ether from methanol in acidic zeolites.
We present a theoretical study of the formation of the first intermediate, dimethyl ether, in the methanol to gasoline conversion within the framework of an ab initio molecular dynamics approach. The study is performed under conditions that closely resemble the reaction conditions in the zeolite catalyst including the full topology of the framework. The use of the method of thermodynamic integration allows us to extract the free-energy profile along the reaction coordinate. We find that the entropic contribution qualitatively alters the free-energy profile relative to the total energy profile. Different transition states are found from the internal and free energy profiles. The entropy contribution varies significantly along the reaction coordinate and is responsible for stabilizing the products and for lowering the energy barrier. The hugely inhomogeneous variation of the entropy can be understood in terms of elementary processes that take place during the chemical reaction. Our simulations provide new insights into the complex nature of this chemical reaction.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Five years ago, the UK funding body Research England, then known as the Higher Education Funding Council for England, announced an ambitious policy designed to speed up the transition to open-access publishing. To become eligible for a slice of billions of pounds of government money distributed to UK universities, academics would have to post their research on free-to-access websites such as preprint servers and institutional repositories within three months of acceptance by a journal. Though the policy took effect in 2016, it has been difficult to judge its efficacy.
Now an analysis shows that researchers in the UK are indeed posting their papers online earlier, as are their colleagues all over the world. The time researchers are taking to post papers online shrunk by an average of 472 days per country between 2013 and 2017, finds a study published on 17 April and to be presented at the ACM/IEEE Joint Conference on Digital Libraries in June. Though the authors can’t definitively say what’s behind the trend, they suggest that the Research England policy and other funding eligibility requirements recently announced worldwide are pushing academics to rapidly make their work freely available.
Drahomira Herrmannova, Nancy Pontika, and Petr Knoth at the Open University in Milton Keynes, UK, evaluated the time it took for academics to deposit some 800 000 papers—including more than 90 000 from the fields of physics and astronomy—in repositories beginning in 2013. They compared the date on which each study was posted to a repository with the journal publication date. The bibliometric data came from CORE, a website that aggregates data about scholarly publications from online repositories, including preprint servers such as arXiv and institutional servers like White Rose Research Online, a collection of work from the UK’s Universities of Leeds, Sheffield, and York.
The authors found that in 2017, researchers took an average of 135 days following publication to deposit their papers in an online repository. Since 2016, UK-based scientists have been posting their papers online more quickly than those in the other four nations with the highest number of papers in the dataset: the US, the Netherlands, Italy, and Switzerland. All five countries have rapidly decreasing deposition times, the study suggests, with Italy making the largest improvement, from an average of 706 days in 2013 to 48 days in 2018.
In 2014 “there was a big change in behavior, and suddenly the deposit time lag starts going down,” says Herrmannova. The shift is less pronounced for physicists and astronomers, but that’s because many of them were already religiously posting to arXiv.
Academics from five countries with high research output have been taking less and less time to post their journal papers in open-access repositories. Source: D. Herrmannova, N. Pontika, P. Knoth, Open University (2019); created with Flourish
The authors speculate that researchers have been motivated to more quickly post their work by new funding policies. By following the 2016 Research England policy, UK researchers make themselves eligible for Research Excellence Framework 2021, a system designed to evaluate the quality of research to guide government funding. In Italy, legislation passed in 2013 requires that all research receiving at least 50% of its funding from public sources be made freely available. Other policy shifts toward open access are reflected in the US Public Access Plan, which was introduced in 2013, and Europe’s Plan S, due to take effect in 2020.
It’s surprising that open access didn’t take over sooner, considering the financial burdens placed on universities by the cost of journal subscriptions, says Tom McLeish, a polymer physicist at the University of York, who was not involved in the work. In February the University of California system announced that it had canceled its subscription contract with Elsevier.
Daniel Himmelstein, a data scientist at the University of Pennsylvania, says it’s possible the new study has a large selection bias, since it doesn’t consider papers that weren’t deposited at all.
The authors found many repositories where more than 90% of the material had been posted within three months of publication in a journal, but they also found many sites with less than 50% compliance with the Research England policy. (Because of data limitations, the authors defined compliance as posting within three months of the publication date rather than the acceptance date.) It’s up to institutions to remind their staff to make sure their studies are compliant, Knoth says. “This is not a game of medicine versus physics or mathematics,” he notes. “This is a game of institutional policies and practices.”
The study’s finding that institutional culture seems to affect how quickly researchers deposit papers is a novel one, says Vincent Larivière, an information scientist at the University of Montreal. Last year, Larivière and Cassidy Sugimoto of Indiana University Bloomington reported that up to one-third of the 1.3 million papers subject to open-access mandates from 12 major funders were not free to read. Funder policies that allowed depositing to be delayed had lower compliance rates than those that required immediate deposit.
Editor’s note, 7 May: The article and graph were corrected to state that Switzerland, not China, was among the five countries analyzed in the study.
|
{
"pile_set_name": "OpenWebText2"
}
|
Background {#Sec1}
==========
Nature exploits specific proteolytic cleavage as a mechanism to transform inactive precursor proteins into active enzymes. Numerous examples of this exquisite biological strategy can be found, for instance in: the enzymes of the intrinsic and extrinsic coagulation pathways \[[@CR1]\]; the fibrinolytic precursor-enzyme combination of plasminogen and plasmin \[[@CR2]\]; and in the proteins of the complement and caspase cascades \[[@CR3], [@CR4]\]. Enzyme activation by specific proteolytic cleavage allows for tight regulation of the timing, location, and extent of enzymatic activity. From a biotechnological perspective, attempts have been made to emulate this approach, to produce novel proteins with potential therapeutic applications. Dawson et al. mutated the unique activation site of plasminogen, ordinarily cleaved by tissue-type (tPA) or urokinase-type plasminogen activators, to the thrombin recognition site in coagulation factor XI (FXI) \[[@CR5]\]. This change accelerated plasmin formation at the site of pathological blood clots, and the engineered plasminogen was shown to be a superior thrombolytic agent to tPA in dog or rabbit thrombosis models \[[@CR6]\]. Other examples of conceptually related approaches include single chain variable fragment (ScFv) antibody-interleukin 12 (IL-12) chimeric proteins in which the ScFv component blocks biological activity of IL-12 until tumour-enriched proteases release IL-12 \[[@CR7]\], and coagulation factor IX- (FIX-) albumin fusion proteins that circulate together until FIX is activated and released from albumin via a repetition of its natural activation sites \[[@CR8]\].
Hirudin is a small protein found in medicinal leech secretions that potently inhibits the key coagulation enzyme thrombin \[[@CR9]\]. Early in the biotechnological production of recombinant hirudin, it was noted that much of its activity was lost if its N-terminus was blocked, even by small peptides \[[@CR10], [@CR11]\]. This observation was supported and rationalized by the co-crystallization of hirudin with thrombin, which showed the N-terminus of the small protein inserted into the active site canyon of the enzyme \[[@CR12]\]. These findings prompted efforts to engineer a protease-activated "switch" into hirudin, to create a specific way of activating the thrombin inhibitor. Peter et al. fused an anti-fibrin-ScFv to hirudin, separating the fusion protein components with a factor Xa (FXa) cleavage site \[[@CR13]\]. Our laboratory fused human serum albumin (HSA) to hirudin, separating the components with a plasmin cleavage site \[[@CR14]\]. Zhang et al. capped the N-terminus of hirudin with small peptides cleavable by thrombin, FXa, or FXIa \[[@CR15]\].
There is considerable current interest in FXI(a) as a target for antithrombotic therapy \[[@CR16]\]. Existing antithrombotic agents come with bleeding risks. Both mice and human patients deficient in FXI are protected from thrombosis, and do not appear to suffer a strong bleeding tendency \[[@CR17]\]. Pharmacological down-regulation of FXI mRNA by specific antisense oligonucleotides has been shown to be superior to an existing antithrombotic agent in a phase II clinical trial \[[@CR18]\]. For these reasons, in this study we returned to the concept of an activatable hirudin-albumin fusion protein, substituting an FXIa cleavage site N-terminal to the hirudin moiety, and positioning HSA either C-terminal or N-terminal to the FXIa-removable hirudin activity blocking group. We tested the hypothesis that FXIa-activatable hirudin-albumin fusion protein would diminish thrombosis in vivo without promoting bleeding, while maintaining a circulating reserve of latent protein due to the slowly cleared phenotype of HSA. In this study, we found that FXIa-activatable hirudin-albumin had a superior benefit/risk profile to constitutively active hirudin-albumin, but one inferior to our previously reported plasmin-activatable counterpart \[[@CR14], [@CR19]\].
Methods {#Sec2}
=======
Construction of expression plasmids and transformation of *Pichia pastoris* {#Sec3}
---------------------------------------------------------------------------
Oligonucleotides were obtained through the Institute for Molecular Biology and Biotechnology (MOBIX) at McMaster University (Hamilton, ON). DNA sequencing to confirm the coding sequences of all plasmids was performed by the same facility. Three of four novel expression plasmids were constructed as follows. Plasmid pPICZ9ssHV3HSAH~6~ \[[@CR20], [@CR21]\] was DNA-amplified using sense and antisense paired oligodeoxyribonucleotide primers in reactions catalysed by heat-stable Phusion DNA polymerase (Thermo Fisher Scientific, Waltham, MA, USA). Primer sequences for each construct are given in Table [1](#Tab1){ref-type="table"}. Following PCR, products were restricted with XhoI and XbaI, gel-purified, and ligated to the 5237 bp XhoI-XbaI double digestion fragment of pPICZ9ssHV3HSAH~6~. Following transformation of competent *E. coli* DH5α subclones with appropriate restriction profiles were verified by DNA sequencing. Clones of correct sequence were designated pPICZ9ss(protein), where (protein) was either EPR-HV3HSA, mycEPR-HV3HSA, or mycHV3HSA, as they were designed to direct the synthesis and secretion of these proteins (see Fig. [1](#Fig1){ref-type="fig"}). Note that EPR is tripeptide Glu-Pro-Arg in single letter amino acid code, and that myc is EQKLISEEDL in the same notation. The fourth novel expression plasmid, pPICZ9ssHSAEPR-HV3, was constructed in a similar manner, except that the template was pPICZ9ssHSACHV3H~6~ \[[@CR14]\], and the PCR product produced using the specific primer pair in Table [1](#Tab1){ref-type="table"} was restricted with SnaBI and XbaI and ligated to the major restriction endonuclease digestion product of pPICZ9ssHSACHV3H~6~ \[[@CR14]\] to yield pPICZ9ssHSAEPR-HV3. Each sequence-verified plasmid described above was linearized via SacI digestion and was then used to transform *Pichia pastoris* strain X33 to Zeocin (Invitrogen) resistance as previously described \[[@CR14], [@CR19]--[@CR21]\].Table 1Oligonucleotide sequences. Oligonucleotide primers used in expression plasmid construction. The unique order number, short name, DNA sequence, and purpose is shown. Sense EPR, myc, and mycEPR oligonucleotides were separately paired with antisense myc/EPR oligonucleotide for amplification and restriction with XhoI and XbaI. HSA sense and antisense clEPRHV3 were paired for amplification and restriction with SnaBI and XbaI. Additional details are provided in the Materials and MethodsNumberNameSequencePurpose123,620,623Sense EPR5'-TCTCTCGAG AAAAGAGAGC CTAGAATCAC CTACACAGAC TGC-3'Mutate and amplify codons to alter HV3HSA cDNA to EPR-HV3HSA, provide XhoI site123,620,624Sense myc5'-TCTCTCGAGA AAAGAGAACA AAAACTCATC TCAGAAGAGG ATCTGATCAC CTACACAGAC TGC-3′Mutate and amplify codons to alter HV3HSA cDNA to myc-HV3HSA, provide XhoI site123,620,625Sense mycEPR5'-TCT CTC GAG AAA AGA GAA CAA AAA CTC ATC TCA GAA GAG GAT CTG GAG CCT AGA ATC ACC TAC ACA GAC TGC-3′Mutate and amplify codons to alter HV3HSA cDNA to myc-EPRHV3HSA, provide XhoI siteML-08-6225Antisense myc/EPR5′- CTCTCCAAGC TGCTCGAAAA GCTC-3'Anchor 3′ end of amplification in all 3 cases above, allow inclusion of XbaI site in amplicon890,140,002HSA sense5'-AGGCATCCTGA TTACTCTGTC GTGCTGCTG-3'Anchor 5′ end of amplification for HSAEPR-HV3 construct, allow inclusion of XbaI site in amplicon161,722,273Antisense clEPRHV35' TGTGTACGTAA TTCTAGGCTC GGATCCTAAG GCAGC-3'Mutate and amplify codons specifying EPR cleavage site for HSAEPR-HV3 construct, allow inclusion of SnaBI site in ampliconFig. 1Schematic representation of recombinant proteins employed in this study. All polypeptides contained human serum albumin (HSA) sequences, were expressed in *Pichia pastoris,* and were purified from media conditioned by methanol-induced cultures. Polypeptides are shown in linear format, amino- to carboxyl-terminus, to emphasize their modular design. Protein segments are shown in black boxes (HSA, 585 amino acids), while small proteins (HV3, hirudin variant 3, 66 amino acids, or KPI, the Kunitz Protease Inhibitor domain of protease nexin 2, 57 amino acids) are shown in grey, and peptides (G6, hexaglycine spacer, H6, hexahistidine affinity tag, EPR, FXIa-cleavable tripeptide (i.e. Glu-Pro-Arg, and myc, myc oncoprotein epitope tag, EQKLISEEDL) in white. From top to bottom, the following recombinant, His-tagged proteins are depicted, with their length in amino acids (\[a.a.\], at right of linear depiction): EPR-HV3HSA; HSA-EPRHV3; mycEPR-HV3HSA; mycHV3HSA; KPIHSA; and HSA
Expression and purification of albumin fusion proteins {#Sec4}
------------------------------------------------------
Clonal *Pichia pastoris* cell lines transformed with expression plasmids described above, or pPICZ9ssHSACHV3, pPICZ9ssHSAH~6~ \[[@CR14]\], or pPICZ9ssKPIHSA \[[@CR22]\], were used to condition buffered minimal medium supplemented with methanol for 72 h. Following neutralization, clarification and ultrafiltration, albumin fusion proteins were purified from concentrated conditioned media by nickel-chelate affinity chromatography as previously described \[[@CR14], [@CR21]\].
Prothrombin time assays {#Sec5}
-----------------------
Prothrombin times (PT) were determined using an STA 4 coagulation analyzer (Diagnostica Stago, Asnières-sur-Seine, France). Citrated normal human pooled plasma (\[NHPP\], Precision Biologic, Dartmouth, NS, Canada) or NHPP immunodepleted of Factors VIII, IX, XI, or XII (Haematologic Technologies, Essex Junction, VT, USA) was combined with purified fusion proteins (45:5 μl by volume) in saline, or saline alone, and incubated at 37 °C for 2 -- 240 min prior to initiation of PT measurement through addition of 50 μl Thromborel S PT reagent containing human placental thromboplastin and calcium chloride (Siemens Healthcare Diagnostics, Oakville, ON, Canada). In some experiments, citrated CD-1 mouse pooled plasma was substituted for NHPP.
Two-stage activation and thrombin activity assays {#Sec6}
-------------------------------------------------
To determine if albumin fusion proteins possessed latent antithrombin activity, a two-stage assay was employed as previously described \[[@CR14], [@CR19]\]. Briefly, albumin fusion proteins (400 nM) were combined with 300 nM purified protease in PPNE buffer (20 mM sodium phosphate, pH 7.4, 0.1% polyethylene glycol 8000, 100 mM NaCl, 0.1 mM EDTA) for varying times. Purified proteases included FXIa, Factor Xa (FXa), Factor XIIa (FXIIa), plasmin (Enzyme Research Laboratories (South Bend, IN, USA)) and recombinant FVIIa (Niastase, Novo Nordisk Canada, Mississauga, ON, Canada). First-stage reaction products were combined 1:1 with 10 nM thrombin in PPNE for 1 min, and then diluted 10-fold into 100 μM S2238 chromogenic substrate (Chromogenix, Lexington, MA, USA). Colour generation from the amidolysis reaction was followed for 5 min to determine the reaction velocity. In some reactions HEPES-buffered saline (HBS; 25 mM HEPES, pH 7.4, 100 mM NaCl) supplemented with 5 mM calcium chloride was substituted for PPNE.
Electrophoresis and immunoblotting {#Sec7}
----------------------------------
SDS polyacrylamide gel electrophoresis was carried out under denaturing and reducing conditions using a Mini-PROTEAN III electrophoresis system following the manufacturer's instructions (BioRad Laboratories, Mississauga, ON, Canada). Replica gels were transferred to nitrocellulose using an iBlot Gel Transfer Device as specified by the manufacturer (Invitrogen, Carlsbad, CA, USA). Immunoblotting was as previously described, using Tris-buffered saline/0.02% Tween 20 (TBST) for washing and 3% BSA in TBST for antibody incubations. Primary antibodies were all monoclonal: mouse anti-HSA (Genway Biotech, San Diego, CA; mouse anti-polyhistidine (Sigma-Aldrich, Oakville, ON, Canada); and mouse anti-myc (Thermo Fisher Scientific, Mississauga, ON, Canada). The secondary antibody was goat anti-mouse IgG, alkaline phosphatase- (AP-) conjugated. Blots were visualized through colour development resulting from the action of AP on substrate nitro blue tetrazolium chloride/5-bromo-4-chloro-3-indolyl-phosphate, toluidine salt (NBT/BCIP).
Murine carotid artery thrombosis model {#Sec8}
--------------------------------------
The time to occlusion (TTO) of the ferric-chloride treated carotid artery was assessed by Doppler ultrasound as previously described \[[@CR14], [@CR23]--[@CR26]\]. Briefly, CD-1 mice were anesthetized, the carotid artery was exposed surgically, and thrombosis was induced by topical application of a 1 mm^2^ patch of Whatman paper soaked in 10% (*w*/*v*ol) ferric chloride for 3 min. Two min prior to patch application, purified EPR-HV3HSA or mycHV3HSA in saline, or saline vehicle, were injected intravenously at 120 or 40 mg/kg body weight. Arterial blood flow was monitored after patch removal and the TTO defined as the time until flow dropped below 0.1 ml/min. Vessels not occluded at the end of the 60 min observation period were scored with a TTO of 60 min. These and all other experiments with mice were carried out under the terms of an Animal Utilization Protocol (AUP) approved by the Animal Research Ethics Board of the Faculty of Health Sciences of McMaster University. At the close of all experiments, anesthetized mice were euthanized by cervical dislocation as stipulated in the approved AUP.
Murine LPS/L-NAME fibrin deposition thrombosis model {#Sec9}
----------------------------------------------------
The deposition of fibrin in the heart and kidney of CD-1 mice treated with lipopolysaccharide (LPS, serotype 0127:B8, Sigma-Aldrich) and vasoconstrictor nitro-L-arginine methyl ester (L-NAME, Alexis, Nottingham, UK) \[[@CR27], [@CR28]\]was assessed using radiological methods as previously described \[[@CR23]\]. Briefly, L-NAME was given intraperitoneally (IP) (50 mg/kg body weight) at 0, 30, 120, and 240 min; the second injection also contained 2 mg/kg body weight LPS. One minute prior to the first IP injection, albumin fusion proteins in saline or saline vehicle were given at 40 mg/kg body weight with 30 million cpm ^125^I-human fibrinogen labeled using the Iodogen method \[[@CR29]\]. Five hours after the first IP injection, mice were euthanized, and hearts and kidneys were excised, washed in ice-cold saline, and organ-associated radioactivity was determined by γ-counting.
Murine bleeding models {#Sec10}
----------------------
Blood loss subsequent to injury was determined in two previously described models: liver laceration \[[@CR19]\]; and tail transection model \[[@CR14]\]. In the first model, CD-1 mice were anesthetized and a standard, 5 mm perforating incision was made through an exteriorized liver lobe placed on a tared weigh boat. Shed blood was captured in the weigh boat and combined with shed blood clotted on the lobe surface 15 min after injury. Albumin fusion proteins or saline vehicle were injected intravenously (IV) two minutes prior to injury. In the second model, anesthetized CD-1 mice were also injected IV with albumin fusion proteins or saline vehicle just prior to injury, but the injury in this case was tail transection at a point 1.0 cm from the tip. Shed blood was collected on Whatman paper for 15 min, and subsequently eluted in water. Blood loss was quantified by determining the optical density of the hemolysate at 492 nm wavelength and determined using a standard curve generated from hemolysed whole blood from the same mouse, taken as a terminal sample.
Statistical Analysis {#Sec11}
--------------------
A *p* value \< 0.05 was considered significant throughout this study. Statistical analysis was performed using computer software (InStat, Version 3.06, GraphPad Software, San Diego, CA, USA). Comparisons between two data sets were made using Student's paired test. For multiple comparisons, one way Analysis of Variation (ANOVA) was employed, with post-tests. Normally distributed data sets with similar standard deviations were assessed with Tukey's post-test, while data sets failing either criterion were assessed using non-parametric (Kruskal-Wallace) ANOVA with Dunn's post-test. Data sets were logarithmically transformed if this transformation allowed them to meet the two criteria above.
Results {#Sec12}
=======
Recombinant protein design and expression {#Sec13}
-----------------------------------------
Novel albumin fusion proteins were designed to test the effects of transient blockade of hirudin activity as shown in Fig. [1](#Fig1){ref-type="fig"}. The N-terminus of HV3 was blocked using a variety of different groups including: the FXIa-cleavable tripeptide EPR (in EPR-HV3HSA); its extended triskaidecapeptide counterpart mycEPR (in mycEPR-HV3HSA); the entire coding sequence of HSA (in HSAEPR-HV3); and noncleavable control decapeptide myc (in mycHV3HSA). Other proteins depicted in Fig. [1](#Fig1){ref-type="fig"} have been previously described, including KPIHSA \[[@CR22]\], a direct FXIa inhibitor-albumin fusion, His-tagged unfused HSA \[[@CR14]\], and constitutively active HV3HSA (also called HV3HSAH~6~) \[[@CR21], [@CR30]\]. All proteins were expressed at similar levels and were purified from conditioned *P. pastoris* media; as shown in Fig. [2a](#Fig2){ref-type="fig"}, they demonstrated relative electrophoretic mobilities consistent with their predicted length in amino acids, given that aberrant migration of HV3-containing polypeptides relative to molecular mass standards has been previously noted and arises from clustered negative charges in the HV3 C-terminal dodecapeptide \[[@CR14], [@CR20], [@CR21]\]. Immunoblotting revealed that all *P. pastoris*-derived fusion proteins reacted with anti-HSA (Fig. [2b](#Fig2){ref-type="fig"}) and anti-hexahistidine monospecific polyclonal antibodies (Fig. [2c](#Fig2){ref-type="fig"}), while only mycEPR-HV3HSA and mycHV3HSA reacted with anti-myc monoclonal antibodies (Fig. [2d](#Fig2){ref-type="fig"}). Immunoblotting results were supported by immunoreactivity with positive controls (e.g. anti-H6 antibodies reacted with recombinant API but not plasma-derived thrombin B chain, Fig. [2c](#Fig2){ref-type="fig"}).Fig. 2Electrophoretic and immunological characterization of fusion proteins.Panel **a** depicts a 10% SDS-polyacrylamide gel electrophoresed under reducing conditions and stained with Coomassie Brilliant Blue (Gel). Lanes contain markers (MW) or pre-stained markers (PS) or 500 ng of purified proteins (identified above the lanes). Recombinant His-tagged Alpha-1 Protease Inhibitor (API) (purified from transformed *E. coli* Top10 as described \[[@CR39]\]), or human plasma-derived α-thrombin B chain (IIa B) served as non-HSA-related or non-HSA, non-His tagged controls. Panels **b**-**d** depict immunoblots of replicate gels identical to that shown in Panel **a**, except that 250 ng of purified proteins were used per lane, and gels were transferred to nitrocellulose and probed with antibodies specific to HSA, the hexahistidine tag, or the myc epitope (Anti-HSA, Anti-H6, or Anti-myc respectively). PS markers were (in kDa): 180; 130; 95; 72; 55; 43; 34; and 26. MW markers were (in kDa): 200; 150; 120; 100; 85; 70; 60; 50 (greater intensity); 40; 30; 25; and 20
Initial screening of FXIa-activatable albumin fusion proteins {#Sec14}
-------------------------------------------------------------
We sought an FXIa-activatable, slowly cleared form of hirudin. As in our previous work with plasmin-activatable hirudin and hirudin-albumin fusion proteins, we selected hirudin variant 3 (HV3), one of the most potent known variants of hirudin \[[@CR21], [@CR30]\]. We chose to assess all activatable and non-activatable forms of HV3 as albumin fusion proteins, to ensure slow clearance and an extended time of pharmacodynamic action. To assess if FXIa recognized the EPR-I cleavage site differently if it was positioned N- or C-terminal to HSA, we compared EPR-HV3HSA and HSAEPR-HV3 with respect to FXIa reactivity. We employed a two-stage assay, first challenging the EPR or HSAEPR blocking groups with FXIa, then diluting the first reaction products into a thrombin S2238 chromogenic activity assay. That FXIa in the first stage of the reaction had no effect on S2238 amidolysis was shown by the lack of difference between its presence or absence on the thrombin-catalysed initial rates (see Fig. [3a](#Fig3){ref-type="fig"}) and also by the lack of reaction of S2238 when FXIa was substituted for thrombin (data not shown). As shown in Fig. [3b](#Fig3){ref-type="fig"}, exposure of EPR-HV3HSA, but not HSAEPR-HV3, to FXIa conferred antithrombin activity on the first, but not the second preparation. We next compared two small N-terminal HV3 blocking groups, tripeptide EPR and triskaidecapeptide mycEPR, to determine if one was more readily recognized by FXIa than the other. Fig. [3c](#Fig3){ref-type="fig"} shows that FXIa preincubation did not activate control protein mycHV3HSA, and exposed greater antithrombin activity for EPR-HV3HSA than for mycEPR-HV3HSA (compare middle and lower progress curves in Fig. [3c](#Fig3){ref-type="fig"}). Activation appeared to be specific to FXIa, as it alone, among 5 coagulation or fibrinolytic enzymes that were tested, released antithrombin activity from EPR-HV3HSA (Fig. [3d](#Fig3){ref-type="fig"}; note that the buffer employed in this experiment differed from those shown in the other panels of Figure [3](#Fig3){ref-type="fig"} to accommodate calcium sensitive proteases FVIIa and FXa). In each case, control experiments in which the protease (FVIIa, FXa, FXIIa, Plasmin, or FXIa) was introduced into the S2238 reaction without addition of albumin fusion proteins showed no difference compared to buffer only, activation protease-free results (data not shown). Accordingly, we selected EPR-HV3HSA over mycEPR-HV3HSA and HSAEPR-HV3 for further study.Fig. 3Activation of latent antithrombin activity in fusion proteins. Purified albumin fusion protein preparations were first reacted with specific purified proteases, then diluted into the presence of thrombin and its chromogenic substrate S2238, and the velocity of the thrombin-catalysed amidolysis reaction was measured and expressed as a percentage of the uninhibited control reaction. Panel A: EPR-HV3HSA was reacted with FXIa for zero (open squares) or 60 min (closed triangles) prior to dilution into the S2238 reaction and measurement of the rate of coloured product formation by thrombin over time. Buffer controls introduced phosphate buffer PPNE (see Materials and Methods) and FXIa (open circles) but no fusion protein into the S2238 reaction**.** Data represents the mean ± SEM, *n* = 7. Panel **b**: As in Panel **a**, EPR-HV3HSA or HSAEPR-HV3 proteins were incubated for zero (0′, white bars) or 60 min (60′, black bars) prior to dilution into S2238 reactions and determination of the rate of thrombin-mediated amidolysis. EPR-HV3HSA reactions are the slope of the same progress curves shown in Panel **a** as a percentage of the Buffer control; HSAEPR-HV3 reactions were determined analogously. Panel **c**: The mean (*n* = 6 ± SEM) of thrombin reaction velocities supplemented with activation reactions of the three fusion proteins labelled to the right of the progress curves with FXIa is shown, at six time points, in PPNE buffer as in Panels **a** and **b**. Panel **d**: As in Panel **a** and **b**, except that HBS / 5 mM CaCl~2~ was used as the buffer instead of PPNE and except that EPR-HV3HSA was combined with the proteases identified on the x axis prior to determination of second stage thrombin-mediated reaction velocity (white bars, FVIIa, FXa, FXIIa, or Plasmin; black bars FXIa). Control reaction "FXIa + No EPR-HV3HSA" contained FXIa but no EPR-HV3HSA in the activation reaction. Buffer reaction contained only HBS / 5 mM CaCl~2~ Data represents the mean ± SEM, *n* = 7
Antithrombotic activity of EPR-HV3HSA in the ferric chloride-treated murine carotid artery model {#Sec15}
------------------------------------------------------------------------------------------------
FXIa-activatable EPR-HV3HSA and its non-activatable counterpart, mycHV3HSA, were compared in the ferric chloride-treated thrombosis model in the topically treated murine carotid artery, at two doses. Fig. [4](#Fig4){ref-type="fig"} shows that EPR-HV3HSA administration prior to ferric chloride exposure lengthened the TTO of the artery four-fold versus vehicle, to 44 ± 16 min at 120 mg/kg body weight, and 2.6-fold versus vehicle, to 22 ± 3 min at 40 mg/kg body weight. In contrast, mycHV3HSA administration elicited TTO values that did not differ statistically from saline vehicle at both doses. We selected the lower dose of 40 mg/kg for further experimentation.Fig. 4Time to occlusion of murine ferric chloride-treated carotid arteries. The time to occlusion (TTO) of surgically exposed carotid arteries treated by topical application of 10% (*w*/*v*ol) ferric chloride, for CD-1 mice receiving saline vehicle (circles) or the two albumin fusion proteins identified on the x axis, in saline (EPR-HV3HSA, squares, and mycHV3HSA, triangles). Mice were injected intravenously with protein doses of 120 mg/kg (Panel **a**) or 40 mg/kg (Panel **b**) two minutes prior to application of a ferric chloride-saturated patch (for three minutes). After patch removal blood flow through the artery was monitored for 60 min using ultrasound. Vessels not occluding during the observation period had their TTO recorded as 60 min. Each point in the scatter plots reflects results from a single mouse of a group of 7. Horizontal lines indicate the mean for each group. Lines above groups show statistical significance between groups as determined by ANOVA with post-tests (*p* \< 0.5, \*, *p* \< 0.01, \*\*, *p* \< 0.001, \*\*\*)
Antithrombotic activity of EPR-HV3HSA in a mouse model of inflammatory thrombosis {#Sec16}
---------------------------------------------------------------------------------
We next examined the ability of EPR-HV3HSA to modulate thrombosis in a murine endotoxemic model, in which co-administration of bacterial LPS and the nitric oxide antagonist L-NAME promotes fibrin deposition in organs \[[@CR23]\]. We monitored ^125^I-labeled fibrin(ogen) in the heart and kidneys of treated mice. Mice treated with saline vehicle just prior to initiation of LPS/L-NAME demonstrated a significant, 4.3-fold elevation in heart fibrin(ogen) relative to mice not receiving LPS/L-NAME, one that was unaltered by administration of mycHV3HSA, but was significantly reduced, by on average 40%, by dosing with EPR-HV3HSA (Fig. [5a](#Fig5){ref-type="fig"} and [c](#Fig5){ref-type="fig"}). The same pattern of results was observed in the kidneys of the same cohorts of mice; the 3-fold elevation in fibrin(ogen) deposition elicited by LPS/L-NAME administration was significantly, albeit partially, reduced, by on average 37%, by treatment with EPR-HV3HSA but not with mycHV3HSA (Fig. [5b](#Fig5){ref-type="fig"} and [d](#Fig5){ref-type="fig"}). In contrast, treatment with 1.0 mg/kg KPIHSA, a fusion protein that inhibits FXIa with inhibitory constants in the low nM range \[[@CR22]\], did not affect the LPS/L-NAME-mediated increases in fibrin(ogen) deposition(data not shown).Fig. 5Deposition of ^**125**^I-fibrin(ogen) in organs of mice treated with LPS and L-NAME. Mice were treated with or without (No LPS/L-NAME) multiple intraperitoneal (IP) injections of LPS and L-NAME. Immediately prior to the IP injection, all mice were injected intravenously with ^**125**^I-fibrinogen in saline vehicle, alone (Vehicle) or combined with 40 mg/kg body weight EPR-HV3HSA or mycHV3HSA. Five hours later, mice were euthanized and the radioactivity present in excised hearts (panels **a** and **c**) or kidneys (panels **b** and **d**) was determined and expressed as the % of the injected dose (panels **a** and **b**) or normalized to the mean of the % of the injected dose in the No LPS/L-NAME cohort (panels **c** and **d**). Bars depict the mean of 5 determinations, each in a separate mouse, ± SD. Lines above bars show statistical significance between groups as determined by ANOVA with post-tests (*p* \< 0.5, \*, *p* \< 0.01, \*\*, *p* \< 0.001, \*\*\*). Scatter plots (**c** and **d**) show the same data as in **a** and **b**, except that each point corresponds to data from a single mouse, normalized to the "No LPS/L-NAME" control
Effects of EPR-HV3HSA in murine bleeding models {#Sec17}
-----------------------------------------------
Having demonstrated antithrombotic activity of EPR-HV3HSA in two murine models of thrombosis, we next addressed the issue of whether EPR-HV3HSA promoted bleeding. In the liver laceration model, administration of constitutively active HV3HSA just prior to injury resulted in severe bleeding approaching 50% of the murine blood volume (600 ± 150 mg). In contrast, administration of EPR-HV3HSA or mycHV3HSA was associated with statistically indistinguishable post-injury blood losses of 220 ± 60 mg and 140 ± 90 mg, respectively (Fig. [6a](#Fig6){ref-type="fig"}). Similar results were obtained in the tail transection model, which constitutes a less severe hemorrhagic insult; EPR-HV3HSA was associated with significantly lower blood losses than HV3HSA (130 ± 40 μl versus 230 ± 100 μl) which did not differ significantly from those associated with mycHV3HSA administration (54 ± 40 μl) (Fig. [6b](#Fig6){ref-type="fig"}). In the same mice, no significant difference between bleeding times from the transected tail, as opposed to volumes of shed blood from that site, was found between mice treated with HV3HSA or EPR-HV3HSA, while mice treated with mycHV3HSA ceased to bleed significantly earlier than the other two groups (Fig. [6c](#Fig6){ref-type="fig"}). The proportion of mice still bleeding at the end of the observation period was 8/10 and 9/10 for the EPR-HV3HSA and HV3HSA groups, respectively, compared to only 3/10 for the mycHV3HSA-treated group (Fig. [6c](#Fig6){ref-type="fig"}).Fig. 6Blood losses or bleeding time in mice subjected to liver laceration or tail transection. Mice were subjected to liver laceration (Panel **a**) or tail transection protocols (Panels **b** and **c**). Blood losses were measured by weighing shed and/or clotted blood (**a**) or collecting shed blood into water and quantifying hemolysis (**b**). Continuing bleeding from the transected tail was assessed visually every 30 s for 15 min (**c**). Mice were injected intravenously with 40 mg/kg body weight of the purified proteins identified on the x axis of each panel. Scatter plots show each data point from a separate mouse in groups of 5 (panel **a**) or 10 (panels **b** and **c**) mice. Horizontal lines depict the mean for each group. Lines above bars show statistical significance between groups as determined by ANOVA with post-tests (*p* \< 0.5, \*, *p* \< 0.01, \*\*, *p* \< 0.001, \*\*\*)
Stability of EPR-HV3HSA in human and murine plasma {#Sec18}
--------------------------------------------------
To gain additional insights as to the potential fate of injected EPR-HV3HSA in vivo, we examined its stability in plasma. Using normal human pooled plasma, we compared the PT in the presence of 13.3 μM albumin fusion proteins (the theoretical peak plasma concentration of the fusion proteins following a 1 mg/kg body weight intravenous dose to mice). As shown in Fig. [7a](#Fig7){ref-type="fig"}, plasma samples supplemented with HV3HSA failed to clot during the 400 s observation period in the assay. Mean PTs for plasma samples supplemented with saline, mycHV3HSA, or HSACHV3 were below 25 s, but the corresponding EPR-HV3HSA-containing samples exhibited PT values in excess of 60 s. A concentration curve of HV3HSA PT times after two minutes' preincubation of chelated NHPP with the fusion protein (Fig. [7b](#Fig7){ref-type="fig"}) illustrated that HV3HSA had only a modest effect on the PT until concentrations in excess of 1.5 μM were exceeded; plasma supplemented with 2.5 μM HV3HSA failed to clot. By extrapolation, this finding suggests that 1.5 to 1.75 μM of the total 13.3 μM EPR-HV3HSA became activated within two minutes of exposure to calcium-chelated human plasma, or 11-13% of the administered dose. Fig. [7c](#Fig7){ref-type="fig"} shows PT values for saline and albumin fusion proteins (excepting HV3HSA, to enhance visibility in the \< 80 s PT range). Inclusion of EPR-HV3HSA significantly prolonged the PT by 4-fold, while mycHV3HSA had no significant effect. A modest but significant elevation resulting from HSACHV3 inclusion in the PT was also observed. When we substituted mouse normal pooled plasma for NHPP in PT assays (Fig. [7d](#Fig7){ref-type="fig"}), similar results were observed. Inclusion of 13.3 μM HV3HSA in murine plasma PT assays eliminated clotting, while EPR-HV3HSA significantly increased the PT by 3- to 4- fold, while HSACHV3-containing assays did not differ from saline controls. The 6-fold prolongation in human plasma PT arising from inclusion of 13.3 μM EPR-HV3HSA was retained when pooled plasma depleted of Factor VIII, Factor IX, Factor XI, or Factor XII were substituted for NHPP (5- to 7- fold observed prolongation, data not shown).Fig. 7Stability of albumin fusion proteins in plasma**.** Panel **a**: Prothrombin times (PT) were measured for reactions containing 13.3 μM fusion protein in saline vehicle, or saline alone. Test samples were combined with human normal pooled plasma (NHPP) and preincubated at 37 °C prior to addition of calcium and PT reagent containing tissue factor for times indicated on the x axis. The mean of 12 determinations ± SD is shown for reactions containing test proteins or solutions shown in the legend at right, Panel **b**: As in Panel **a**, but for varying concentrations of purified HV3HSA preincubated with NHPP prior to PT initiation for two minutes. Data points are the mean of seven determinations ± SEM. Note y axis break. Panel **c**: As in Panel **b**, but for reactions supplemented with the proteins or solutions specified below the x axis. \*\*\*, *p* \< 0.001 versus Saline by non-parametric ANOVA with Dunn's post-tests. Panel **d**: As in Panel **c**, but mouse pooled plasma was substituted for NHPP. Note y axis break. \*\*, *p* \< 0.01, and \*\*\*, *p* \< 0.001 versus Saline by non-parametric ANOVA with Dunn's post-tests. Note that results of \> 400 s mean that no clotting was detected at the end of the observation period
Discussion {#Sec19}
==========
Our initial preferred strategy in this study was to modify the previously described fusion protein HSACHV3 as little as possible, simply substituting a FXIa cleavage site for the plasmin cleavage site GSGIYR- that we had previously positioned between HSA and HV3 \[[@CR14]\]. This geometry would have recreated the hypothetical situation whereby HSACHV3, encountering an activating enzyme in the local environment of a thrombus, released HV3 not only from inhibition by the polypeptide blocking its N-terminus, HSAC, but also physically released HV3 from union with albumin, restoring rapid clearance of the small protein. The only difference would have been substitution of FXIa for plasmin as the putative thrombus-localized activator. However, we found that positioning the EPR cleavage site between HSA and HV3 in fusion protein HSAEPR-HV3 prevented its recognition by FXIa. In contrast, the alternative geometry, represented by fusion protein EPR-HV3HSA, was recognized by FXIa, at least to the extent that detectable antithrombin activity could be liberated in vitro. For in vivo applications, however, we were aware that EPR-HV3HSA activation would liberate HV3HSA, a constitutively active hirudin-albumin fusion protein that would perpetuate or conceivably worsen the narrow therapeutic window of hirudin \[[@CR31]\]. Our ability to activate EPR-HV3HSA was entirely consistent with the findings of Zhang et al., who reported that hirudin variant 2 (HV2) activity was liberated by FXIa cleavage of recombinant protein EH, in which EPR was positioned on the N-terminus of HV2 \[[@CR15]\]. These investigators also noted no activation of EH by FXa or thrombin; we extended this finding to include a lack of reactivity with plasmin, FVIIa, FXa, or FXIIa, supporting the specificity of the EPR hirudin "switch".
EPR is nevertheless a very small blocking group, comprising a mere three amino acid residues highly exposed on the N-terminus of both EPR-HV3HSA and EH. To provide additional insulation of the HV3 domain from plasma, we produced fusion protein mycEPR-HV3HSA, expanding the blocking group to 13 amino acids. However, this protein was recognized less effectively by FXIa than EPR-HV3HSA; under conditions in which detectable antithrombin activity was liberated from EPR-HV3HSA in 20 min, 200 min of digestion was required to liberate similar amounts of functional HV3HSA from mycEPR-HV3. We cannot exclude the possibility that another blocking group of the same size, perhaps one with a lesser density of negatively charged residues than the myc epitope (sequence EQKLISEEDL) might be better recognized by FXIa.
The FXIa-dependent activation of HV3HSA that we observed in vitro was similar to that we previously observed for HSACHV3 by plasmin \[[@CR14]\] in that high nM concentrations and minutes of incubation were required to generate measurable release of active HV3HSA or HV3. Both for plasmin and for factor XIa, it is difficult to predict what local concentrations might be generated in a thrombus. Free plasmin is generally not detectable in plasma, in part due to the efficiency with which it is incorporated into plasmin-antiplasmin complexes \[[@CR32]\]; and free FXIa has been reported to be present in picomolar concentrations in the plasma of healthy individuals \[[@CR33]\]. Plasma concentration data is not necessarily predictive of local concentrations that could be generated in a thrombus. In the case of HSACHV3, it was possible to show a favourable profile of antithrombotic activity with minimal bleeding risk when in vitro studies were extended into murine in vivo studies \[[@CR19]\]; given this precedent, we decided to examine EPR-HV3HSA activities in vivo, even though the plasmin precursor plasminogen is present in approximately 20-fold excess over factor XI in plasma \[[@CR34]\].
Fusion protein EPR-HV3HSA showed antithrombotic activity in two models of thrombosis in mice, one dependent on ferric chloride, and one independent of this agent. Ferric chloride, although widely used as a prothrombotic treatment, is a potent antioxidant with pleiotropic effects, and it has been suggested that its use should be accompanied in rigorous experimental studies with data from another model \[[@CR35]\]. EPR-HV3HSA, at 120 mg/kg or 40 mg/kg, prolonged the TTO in the ferric chloride-treated carotid artery, while mycHV3HSA had no greater effect than saline vehicle. These results are consistent with the findings of Zhang et al. \[[@CR15]\], who noted a significant increase in the TTO in a rat carotid artery model in which thrombosis was initiated by application of an electrical current, and animals were treated with 4 mg/kg body weight EH, an equimolar dose to the larger EPR-HV3HSA protein at 40 mg/kg. In the LPS/L-NAME model, in which more physiologically relevant thrombotic triggers of inflammation and nitric oxide antagonism are employed, EPR-HV3HSA reduced fibrin deposition in the heart and kidneys. Interestingly, a direct FXIa inhibitor, KPI, also administered as an albumin fusion protein at an identical dose by weight, was without effect. This finding suggests that although FXIa is generated in the LPS/L-NAME model, its inhibition is insufficient to prevent thrombosis, while its use to trigger HV3 liberation and thrombin inhibition was effective. A possible explanation of this effect is that the affinity of KPI for FXIa is much less than that of HV3 for thrombin, with binding constants for the former reported in the nM range \[[@CR36]\] and for the latter interaction in the sub-pM range \[[@CR31]\], a difference of more than three orders of magnitude. While EPR-HV3HSA reduced intra-organ fibrin deposition in the LPS/L-NAME setting, it did not eliminate it; in this regard it was less effective than recombinant activated protein C in our previous use of this model \[[@CR23]\].
EPR-HV3HSA clearly promoted bleeding to a lesser extent than constitutively active HV3HSA, as shown by significantly lower blood losses than those elicited by that protein in both liver laceration and tail transection models. However, mean blood losses were greater in EPR-HV3HSA-treated mice than in mycHV3HSA-treated mice in both models, although the differences did not reach statistical significance. Bleeding times in the tail transection model were significantly lower in mycHV3HSA-treated mice than in HV3HSA- or EPR-HV3HSA-treated mice; therefore this bleeding parameter was not reduced versus constitutively active HV3HSA. In our previous studies with HSACHV3, blood losses were more convincingly reduced to baseline in both bleeding models than in the current study with EPR-HV3HSA \[[@CR19]\]. These observations could reflect the relatively small number of mice that we tested, or they could indicate that FXIa was a less appropriate trigger for HV3 liberation than plasmin, or they could point to instability of the small EPR blocking group in plasma. To distinguish among these possibilities, we examined the stability of EPR-HV3HSA and, to a lesser extent, that of HSACHV3 in plasma.
At a fusion protein concentration equivalent to the peak concentration expected in the murine circulation following intravenous injection of 40 mg/kg body weight doses, HV3HSA eliminated the ability of human or murine plasma to clot in the PT assay, while HSACHV3 had no effect in murine plasma and a modest, less than 2-fold prolongation in human plasma. In contrast, EPR-HV3HSA, after only two minutes' exposure to chelated plasma, prolonged the PT by five-fold in human plasma, and four-fold in mouse plasma. Prolonging the incubation in plasma increased the PT, but loss of clotting factor activities over time would also be expected to contribute to such an effect. Comparison to a calibration curve with HV3HSA suggested that approximately 10 -- 15% of EPR-HV3HSA was behaving as if its EPR blocking group had been removed, in both species' plasma. The trivial explanation that proteolysis had taken place during purification of EPR-HV3HSA could be eliminated because EPR-HV3HSA had no antithrombin activity without exposure to purified FXIa or plasma.
While we cannot eliminate all proteases specifically involved in coagulation or fibrinolysis in this unexpected activation, its detection in chelated plasma renders their involvement unlikely. Moreover, unexpected activation of EPR-HV3HSA was also noted in plasma depleted of Factor VIII, Factor IX, Factor XI, or Factor XII, and EPR-HV3HSA also showed no sensitivity to purified FVIIa or plasmin. A more likely explanation for these findings is that EPR-HV3HSA, at μM concentrations, lost its EPR blocking group through the action of plasma endopeptidases or exopeptidases unrelated to coagulation or fibrinolysis. Proteomic studies of human plasma have shown that 28% of 722 unique N-terminal blood protein peptides had characteristics consistent with their having arisen through aminopeptidase action, such as laddering \[[@CR37]\]. In future experiments, this problem could conceivably be avoided by rendering EPR more accessible to FXIa in an internal location in a fusion protein like HSAEPR-HV3, either by separating EPR from HSA structures using an optimized polyglycine linker, or by using a different FXIa cleavage site (like TSKTLR in coagulation factor IX \[[@CR38]\]), or both.
Conclusions {#Sec20}
===========
Fusion protein EPR-HV3HSA's latent antithrombin activity was released by FXIa in vitro to a greater extent than mycEPR-HV3HSA; moving the EPR FXIa cleavage site to the C-terminus of HSA, in HSAEPR-HV3, abrogated FXIa recognition. EPR-HV3HSA was recognized and activated in vivo in mice, as shown by its antithrombotic activity in carotid artery and intra-organ thrombosis models, and the lack of activity of noncleavable mycHV3HSA. EPR-HV3HSA elicited less blood loss than constitutively active HV3HSA in lacerated liver and transected tail mouse models, but failed to attenuate the elevated bleeding time associated with HV3HSA administration. The partial overlap in bleeding promotion with HV3HSA is likely due to the partial instability of EPR-HV3HSA in murine and human plasma. Activation of EPR-HV3HSA in plasma was not due to any of seven tested coagulation or fibrinolytic proteases, but may have arisen due to the action of plasma exopeptidases on the N-terminally exposed EPR tripeptide. Only modest activation of plasmin-activatable HSACHV3 was observed. Although our results supported the use of FXIa as a thrombosis-specific fusion protein activator, N-terminally positioned EPR is a suboptimal biochemical "switch" compared to the internal plasmin-dependent switch in HSACHV3.
The authors wish to thank Sharon Gataiance for technical assistance, and Dr. David A. Donkor and Dr. Syed M. Qadri for helpful discussions.
Funding {#FPar1}
=======
This work was made possible by Grant-In-Aid G-15-0009117 from the Heart and Stroke Foundation of Canada. WPS and VB are members of the Centre for Innovation of Canadian Blood Services, which receives funding from Health Canada. Accordingly, this article must contain the obligatory statement, and "The views expressed herein do not necessarily represent the views of the federal government \[of Canada\]". No funding body had any role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Availability of data and materials {#FPar2}
==================================
Any datasets used or analyzed for the current study which are not included in this published article are available from the corresponding author on reasonable request.
Author's contributions {#FPar3}
======================
WPS designed the study, directed experiments, analyzed data, and wrote and revised the manuscript. LJE-S and VB performed all experiments and analyzed data. All authors edited and revised the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate {#FPar4}
==========================================
All experiments with mice in this study were carried out under the terms of an Animal Utilization Protocol approved by the Animal Research Ethics Board of the Faculty of Health Sciences of McMaster University (AUP 16-04-13).
Consent for publication {#FPar5}
=======================
Not applicable.
Competing interests {#FPar6}
===================
The authors declare that they have no competing interests.
Publisher's Note {#FPar7}
================
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
|
{
"pile_set_name": "PubMed Central"
}
|
Introduction {#S1}
============
Efficient sensory decision-making in a constantly changing environment requires neuronal circuits to be plastic and rapidly modify their activity. Cortical and subcortical processing are influenced substantially by feedback and neuromodulatory afferents eliciting experience-induced modulation of neuronal excitability lasting from milliseconds to hours ([@B31]; [@B10]; [@B52]; [@B58]; [@B1]). It has been suggested that simultaneous neuromodulation of neural circuits that process sensory, cognitive, and motor information is required to maintain neuronal dynamics for proper decision-making ([@B29]). Therefore, the brain region(s) acting as a modulator should innervate most if not all sensory processing regions. In addition, the brain region should exhibit the ability to modulate neuronal excitability dynamically allowing rapid context-dependent changes in information processing to elicit adequate behavioral outputs. The basal forebrain (BF) emerges as a good candidate to participate as an integrator and neuromodulator source for behavior since it is one of the most important and widely projecting neuromodulatory circuits in the mammalian brain ([@B26]) reaching the entire cortical mantle, hippocampus, and the olfactory system among others ([@B43]; [@B73]; [@B72]). Functionally, it has been linked with attention ([@B34]), arousal ([@B5]), and learning and memory ([@B20]; [@B34]). Specifically, its subnuclei have been proposed to play important roles in components of goal-directed behaviors such as motivational saliency ([@B38]), sensory discrimination ([@B38]; [@B16]; [@B50]; [@B53]; [@B17]), and cortical control ([@B52]).
The wide array of neurophysiological and cognitive functions that the BF is involved in correlates with the neuronal complexity found in the region. Among the variety of neuronal types found in the BF ([@B74]), the cholinergic corticopetal projecting neurons have been extensively studied due to the important and dense top--down coordination role acetylcholine plays in cognitive functions such as attention. This idea arose from studies where pharmacological blockade or selective lesions of cholinergic neurons (CNs) in BF produced impairments in attention, memory, and operant conditioning performance ([@B70]; [@B13]; [@B46]; [@B34]; [@B16]; [@B52]; [@B42]; [@B14]; [@B55]). Moreover, in attention-demanding tasks, cholinergic release enhances cue detection and sensory discrimination ([@B59]).
Here, we ask whether BF neurons are involved in the decision-making process in a non-cued olfactory-based self-initiated task. We addressed this question by recording the neural activity of the BF while the animals were freely engaged in a go/no--go task with voluntary trial start. Moreover, using optogenetic tagging, we identified CNs among the recorded units offline.
Results {#S2}
=======
The Firing Rate of Basal Forebrain Neurons Changes Before Initiation of the Trial {#S2.SS1}
---------------------------------------------------------------------------------
To study the dynamics of recruitment of BF neurons in animals engaged in a self-initiated decision-making task, we implanted a multielectrode device in the horizontal diagonal band of Broca/magnocellular preoptic (HDB/MCPO) nuclei and proximity in the BF of trained adult mice ([Supplementary Figures S1A,B](#FS1){ref-type="supplementary-material"}). We recorded from HDB/MCPO because these are the only BF nuclei that send projections to the olfactory bulb and olfactory cortex ([@B73]). Animals were trained in a go/no--go olfactory discrimination associative learning task ([@B62]). This task studies the ability of a thirsty rodent to lick to obtain water in response to a rewarded conditioned stimulus (CS^+^) and refrain from licking in response to an unrewarded stimulus (CS^--^) ([Figure 1A](#F1){ref-type="fig"}). The CS^+^ and CS^--^ were odors randomly chosen from an odor set known to elicit neuronal response in the olfactory system ([@B18]) (see section "Materials and Methods"). Each trial is self-initiated 1--1.5 s after the computer detects the mouse entering the odor port.
{#F1}
We recorded neuronal activity during 200 trial sessions in animals proficient in differentiating between the two odorants (percent of correct responses, ≥80%). We found that single units responded with increases or decreases in firing rate (FR) during trial initiation (tstart). [Figure 1B](#F1){ref-type="fig"} shows examples of scatterplots of spike firing and peristimulus histograms (PSTHs) for two single BF units aligned to trial initiation (tstart) (top, increase in FR; bottom, decrease in FR).
We analyzed the time course of FR changes aligned to tstart in 153 units total. A unit was categorized as responsive if the changes in FR assessed for 1 s after tstart were statistically significantly different from the basal FR assessed 1.3--0.3 s before tstart tested with a paired *t* test corrected for multiple comparisons using the false discovery rate (FDR) ([@B12]). We choose this time range to calculate the basal FR, since there appeared to be a change in FR just before the animal entered the port (see below). We found that a substantial fraction of BF neurons (53 out of 153 or 34.6%) exhibited significant increases (43 out of 153 or 28.1%) or decreases (10 out of 153 or 6.5%) in FR when the animal initialized a trial (*p* \< *p*FDR, *p*FDR, the FDR critical significance level per animal, ranged from 0.006 to 0.03; *n* = 153 units, 141 single units and 12 multiunits from 8 mice and 10 sessions). [Figure 1C](#F1){ref-type="fig"} shows on the left side a heatmap illustrating the FR time course for the 53 units that were significantly responsive and on the right side the time when the FR changed by 2 × SD above or below basal FR. Interestingly, for most of the units, the change in FR took place before the animal entered the odor port (mean onset time −260 ms with a 95% bootstrapped confidence interval ranging from −168 to −350 ms) suggesting that BF neurons are involved in behavioral functions associated with trial preparation and anticipation.
We found that the number of BF neurons that exhibited a significant change in FR at the start of correct response trials (hits, 36 out of 149 units, −29 or 19.5% increase and 7 or 4.7% decrease their FR; and correct rejections, CR, 38 out of 150 total units recorded on those trials, −30 or 20% increase and 8 or 5.4% decrease their FR) is larger than the number of responsive units in false alarm trials (FA, licking in response to the CS^--^; 4 of 67 total units recorded during FA trials were responsive, 1 unit or 1.5% increase and 3 or 4.4% decrease their FR, [Figures 1D,E](#F1){ref-type="fig"}). A chi-squared test indicated that the difference in the number of responsive units between FA trials and correct trials is significant (*p* \< *p*FDR = 0.05). This shows that engagement of BF neurons during the precue epoch reflects the behavioral outcome of the trial, suggesting that activity of these neurons may play a role in successful discrimination.
To further test the relationship between BF neural activity at trial initiation and behavioral outcome, we asked whether the change in BF neuronal activity is affected by engagement in sensory discrimination of rewarded vs. unrewarded odorants. We recorded neuronal activity of animals trained in a go/go task where the mouse is rewarded randomly for 70% of the trials regardless of the identity of the odorant. The key difference with go/no--go is that, in the go/go task, both odorants are rewarded and no sensory discrimination is required to receive the reward. We found that the number of units responsive at port entry was significantly lower in the go/go task compared to the go/no--go task ([Figure 1Eii](#F1){ref-type="fig"} and [Supplementary Figure S2](#FS2){ref-type="supplementary-material"}, chi-squared test *p* \< *p*FDR = 0.05, go/no--go = 53 responsive out of 153 or 34.6%), go/go = 8 responsive out of 44 or 18.2%, all of which increased their FR, suggesting that BF neuronal recruitment before trial initiation may play a role in adequate stimulus discrimination. In the go/go task, the units that responded to trial initialization also exhibited a change in FR before the animal entered the port (mean onset time −175 ms with a 95% bootstrapped confidence interval ranging from 167 ms to −517 ms). We also compared the change in FR after the start of the trial between units that responded to correct and incorrect trials. [Figure 1F](#F1){ref-type="fig"} shows the relationship between change in FR for incorrect trials and the change in FR for correct trials. The data are fit with a line with a slope significantly smaller than one, suggesting that engagement of BF neurons reflects correct behavioral performance ([Figure 1F](#F1){ref-type="fig"}; ANCOVA, *F* = 16.6, Tukey's *post hoc*, *p* = 0.0004, *n* = 19). To further determine whether recruiting BF neurons during trial initiation relates to animal behavior, we calculated *d*′, defined as the difference in the change in FR upon trial initiation normalized by the standard deviation of basal FR (*d*′) per trial. [Figure 1Gi](#F1){ref-type="fig"} shows no difference for *d*′ for hit vs. CR for the go/no--go task ([Figure 1G](#F1){ref-type="fig"}, KS test *p* = 0.11, *n* = 6,289 trials for hit and 6,649 responsive units for CR). In contrast, [Figure 1Gii](#F1){ref-type="fig"} shows a significant difference in *d*′ curves of hit trials in the go/no--go task vs. hit trials in the go/go task (KS test *p* = 3.6 × 10^--8^, *n* = 1,266 trials units for go/go). These data indicate that neurons responded similarly during correct responses that required sensory discrimination but responded differently when no discrimination was required. To study how effective the change in FR during trial initiation is at classifying correct vs. incorrect behavioral outcome, we used the receiver operant characteristic (ROC) analysis ([@B21]) and measured the area under the curve (AUC) for each unit. The higher the AUC (maximum 1), the better the unit differentiates between correct and incorrect responses (AUC of 0.5 indicates no differentiation). We found that units in the go/no--go task were a more effective classifier than in the go/go scenario ([Figure 1Gii](#F1){ref-type="fig"}, *t* test *p* = 0.03, *n* = 153 for go/no--go and 44 for go/go), suggesting that BF neuron activity is related to adequate decision-making in sensory discrimination.
Basal Forebrain Neurons Exhibit Changes in Firing Rate When Conditioned Stimulus or Reinforcement Are Delivered {#S2.SS2}
---------------------------------------------------------------------------------------------------------------
To determine whether BF neuronal activity is recruited during other epochs of the behavioral trial in our experimental design, we aligned the normalized FR of the recorded units either to delivery of the conditioned stimulus (CS or odor) or the reward. [Figure 2](#F2){ref-type="fig"} shows changes in FR aligned to odor delivery ([Figure 2A](#F2){ref-type="fig"}) or reward delivery ([Figure 2B](#F2){ref-type="fig"}) for mice performing \>80% in the go/no--go task. As described in previous studies ([@B38]; [@B68]; [@B17]), we found that neurons either increase ([Figures 2Ai](#F2){ref-type="fig"}, [iii](#F2){ref-type="fig"}; 12/153 or 7.8%) or decrease ([Figures 2Aii](#F2){ref-type="fig"}, [iii](#F2){ref-type="fig"}, 31/153 or 20.3%), their FR in response to the stimulus. Specifically, 21 out of 150 units (14%) recorded were recruited during CS^+^ delivery and 45 out of 150 (30%) during CS^--^ (*t* test *p* \< *p*FDR, *p*FDR per session ranged from 0.02 to 0.01, 0.003 to 0.04, 0.02 to 0.01 for odor, CS^--^ and CS^+^ and reward, respectively). As shown in the heat map of [Figure 2Aiii](#F2){ref-type="fig"}, some units responded transiently, while others responded with slow sustained changes in FR.
{#F2}
In addition, units were also recruited during water (reward) delivery (22/148 or 14.9% increase and 8/148 or 5.4% decrease their FR, [Figure 2B](#F2){ref-type="fig"}, *t* test *p* \< *p*FDR, *p*FDR per session ranged from 0.003 to 0.03). Units that responded to reward in this self-initiated task also tended to respond to the conditioned stimulus as described by [@B38] in rodents trained in a cue-oriented task ([Supplementary Figure S2D](#FS2){ref-type="supplementary-material"}).
Supporting the idea that the BF could play a role in stimulus discrimination and reward association, the percent of units that responded during odor or reward delivery in the go/go task (when regardless of the odorant 70% of the trials are rewarded) are significantly smaller than the responses in the go/no--go task (28.1% go/no--go vs. 9.1% go/go and 20.3% go/no--go vs. 4.8% go/go during stimulus presentation and water delivery, respectively, [Supplementary Figures S2B,C](#FS2){ref-type="supplementary-material"}; chi-squared test, *p* \< *p*FDR = 0.05, two pairwise comparisons).
Basal Forebrain Neurons Become More Responsive to the Stimulus as the Animal Learns to Differentiate Odorants in the Go/No--Go Task {#S2.SS3}
-----------------------------------------------------------------------------------------------------------------------------------
Our data suggest that neurons from the BF are required for adequate decision-making and stimulus discrimination in proficient animals, raising the question whether the number of neurons coding for information during the different epochs of the behavioral trial increased as the animal learned to discriminate between rewarded and non-rewarded odors. We compared the change in FR during the different epochs of the trial when the animal was learning to discriminate (= 50% correct trials) and when the animal was proficient in their response to the rewarded odorant (\>80% correct trials). A representative learning curve is shown in [Figure 2C](#F2){ref-type="fig"}. It starts with 50% correct responses, while the mouse gradually becomes proficient until reaching criteria (\>80% correct responses, hits and CRs) within a session. We observe that the number of BF-responsive neurons during trial initialization does not increase as the animals learn to associate the stimulus with the reward ([Figure 2D](#F2){ref-type="fig"}, chi-squared test *p* = 0.37 \> *p*FDR = 0.016, 10 out of 27 units or 37% were responsive during learning and 21 out of 44 or 47.7% were responsive when the animal was proficient). These units are likely engaged during the instrumental shaping of the task that occurs before animals are trained in the go/no--go task and could reflect the motivation and initial attention required to start the trial.
After that initial training, animals are trained to lick in response only to the rewarded stimulus that has no hedonic value at the beginning of the session. The number of responsive units when FR is aligned to odorant onset increased dramatically with learning ([Figure 2D](#F2){ref-type="fig"}, 7.4 vs. 38.6%; chi-squared test, *p* = 0.004 \< *p*FDR = 0.016). In contrast, for the reward epoch, we found no statistical difference between the number of responsive neurons before and after the animal became proficient (7.6 vs. 14.6%; chi-squared test, *p* = 0.39 \> *p*FDR = 0.016). Taken together, our results suggest that BF neurons play a role in actively engaging the animal in the task (trial start epoch), in correct odorant discrimination (odor epoch), and responding to the reward (reward epoch) and that learning increases the number of neurons engaged in the odor epoch.
A Subset of the Basal Forebrain Cholinergic Neurons That Are Responsive During Trial Initiation or Conditioned Stimulus Epochs Are Cholinergic {#S2.SS4}
----------------------------------------------------------------------------------------------------------------------------------------------
The neuronal makeup of the BF is heterogeneous with glutamatergic, GABAergic, and cholinergic projection neurons, among others ([@B19]; [@B72]). The cholinergics have granted particular attention since they project to the whole cortical mantle and actively participate in cortical plasticity ([@B11]) and sensory processing ([@B39]; [@B53]). This motivated us to determine whether BF CNs were responsive in any epochs of our self-initiated task in proficient animals. To identify CNs, we used optogenetic tagging ([@B30]). We used mice expressing ChR2-EYFP under control of the choline acetyl transferase (ChAT) promoter. Once the behavioral session concluded, we delivered light stimulation (10 trials of 10 50-ms pulses at 5 Hz) through the optic fiber of the optetrode implanted in the BF of mice expressing ChR2-EYFP selectively in CNs (ChR2^+^ neurons, [Figure 3A](#F3){ref-type="fig"}, see section "Materials and Methods"). The pronounced increase in spiking frequency in a subset of units was not observed in control ChAT-Cre animals ([Figure 3B](#F3){ref-type="fig"}) regardless of the frequency of stimulation (1 or 5 Hz), discarding the possibility that light delivery could generate false spikes due to thermal stimulation ([@B28]).
{#F3}
The BF, however, exhibits intricate local circuitry with abundant cholinergic collaterals terminating in non-cholinergics ([@B19]), raising the possibility that light-responsive neurons *in vivo* might not express ChR2. We confirmed the local connectivity by performing *in vitro* whole-cell patch clamp recordings in acute brain slices from the BF. In the voltage clamp mode, we found that brief light stimulation always elicited inward currents in ChR2^+^ neurons ([Figure 3C](#F3){ref-type="fig"}). In contrast, non-CNs (identified by their lack of ChR2-EYFP fluorescence, ChR2^--^ neurons) located in close proximity to a neuron expressing ChR2-EYFP (ChR2^+^) exhibited an array of responses after being transsynaptically activated by optogenetic activation of CNs. A small number of non-CNs (*n* = 1/10) exhibited an outward current after the cholinergic ChR2^+^ neurons were activated; some (*n* = 3/10) exhibited an inward current or a biphasic response (2/10), and most of them (*n* = 4/10) showed no change ([Figure 3C](#F3){ref-type="fig"}).
To obtain information relevant to the correct identification of CNs *in vivo*, we studied the latency for light activation of cholinergic ChR2^+^ and non-cholinergic ChR2^--^ neurons through *in vitro* current clamp ([Figure 3D](#F3){ref-type="fig"}). We found that there was a clear and significant difference in latency of responses between these neurons (18.1 ± 3.5 ms, *n* = 3/9 responded for ChR2^--^ vs. 4.1 ± 0.4 ms, *n* = 7/7 for ChR2^+^, respectively, *t* test, *p* \< 0.001) allowing us to establish 10 ms as a cutoff for maximum latency for neurons that were directly activated by light ([Figure 3E](#F3){ref-type="fig"}), in accordance with [@B30]. Only three out of nine non-cholinergics exhibited action potential generation after activating neighboring ChR2^+^ neurons, while all nine ChR2^+^ neurons responded.
*In vivo*, we found that 15 out of 186 units (from go/no--go and go/go tasks) exhibited latency \<10 ms ([Figure 3E](#F3){ref-type="fig"}). In addition, we used two other properties to classify a neuron as cholinergic: (1) it had to exhibit a statistically significant increase in FR after light stimulation in a paired *t* test with correction for multiple comparisons, and (2) it had to display a reliability of response of 100% (they had to spike within 200 ms after light stimulation in all 10 trials; [Figure 3F](#F3){ref-type="fig"} and [Supplementary Figures S3A--C](#FS3){ref-type="supplementary-material"}). CNs, despite their wide and critical role in brain function, are sparsely distributed and account for only 5% of the BF neurons ([@B26]). With our conservative criteria, we classified 6 out of 186 (3.2%) units as cholinergic in accordance with the numbers found in other studies ([@B38]; [@B30]). We found that three of these six optogenetically tagged CNs responded with a significant change in their FR when the mouse decided to enter the port (3/6 units or 50% of responsiveness, paired *t* test *p* \< *p*FDR = 0.025; mean onset latency of FR change, 100 ms ± 100) and when presented with the CS (67% of responsiveness, paired *t* test *p* \< *p*FDR = 0.033, [Figure 4](#F4){ref-type="fig"} and [Supplementary Figure S3D](#FS3){ref-type="supplementary-material"}). We did not find responses to reward in these six neurons ([Figure 4](#F4){ref-type="fig"} and [Supplementary Figure S3E](#FS3){ref-type="supplementary-material"}). Therefore, although CNs are sparse, yielding recording from a small number of units, the changes in FR are clear and consistent from trial to trial, indicating that these neurons are engaged in trial initiation and CS discrimination.
{#F4}
Discussion {#S3}
==========
On the basis of *in vivo* electrophysiological recordings in freely moving and behaving animals, we demonstrated that neurons from the BF are engaged throughout the decision-making process in a goal-directed task. Transient changes in the activity of BF, specifically the HDB/MCPO and proximity, were found during trial initialization anticipating the stimulus, stimulus discrimination, and in reward association in the go/no--go odor discrimination task. Importantly, the number of units displaying changes in FR increased for the stimulus discrimination epochs as the animal learned to discriminate the odorants. Furthermore, the changes in FR were found to be related to correct outcome in the trial, and the number of units that displayed a change in FR decreased in a go/go task where animals receive reward regardless of the odorant, indicating that BF activity plays a role in correct outcome of the trial. Finally, through optogenetic tagging, we found that BF CNs are involved in this processes.
Basal Forebrain and Anticipatory Activity {#S3.SS1}
-----------------------------------------
The capacity of the brain to correctly respond to environmental cues has been linked in recent years to its ability to predict future outcomes. The anticipatory behavior has been described to improve performance not only by enhancing motor preparedness and reaction time but also by improving perception ([@B48]) and more efficiently processing the upcoming sensory input ([@B2]; [@B32]). Specifically, baseline rates of neurons in HDB/MCPO BF has been shown to be higher during the acquisition phase of an odor--reward association than during spontaneous investigation or the recall phase of an odor reward association ([@B17]). Furthermore, neurons in other nucleus of the BF, the nucleus basalis, responded before stimulus onset and continued for seconds after reward delivery in a whisker-dependent tactile discrimination two-alternative forced choice task ([@B68]). Interestingly, [@B68] observed that the anticipatory modulation in neuronal FR began ∼1 s before the onset of the mechanical deflection of the whiskers, similar to our results, where we observed anticipatory changes in FR of the BF before the animal enters the odor port. They hypothesized that neurons of the nucleus basalis participated in the circuit defining animal's expectations in the task ([@B68]). In addition, neuronal responses with onsets before the first lick were reported in the olfactory tubercle in a self-initiated water-motivated dry lick instrumental task ([@B23]) and an intermodal selective attention task ([@B6]). They found that neurons of the olfactory tubercle fired in anticipation of the expected reward probably to invigorate instrumental training in states of reduced motivation. Finally, in primates, the anticipatory activity of neurons in the caudate nucleus correlates with reward association, expectation, and response latency, probably reflecting the animal's motivational state ([@B35]; [@B71]).
In conclusion, there is evidence of anticipatory neuronal activity in different brain regions, suggesting that neuronal activity linked to expectation might play an important role in behavior.
Interestingly, we also found that this anticipatory activity was correlated with behavioral performance, supporting an additional role of early neuronal activity in attaining correct stimulus discrimination. This idea follows the line of evidence suggesting that top--down modulation might be as important as the external stimulus information in sensory processing and perception in the visual system ([@B25]) or other sensory-motor modalities, like the tongue--jaw motor cortex, which anticipatory prestimulus activity can be predictive of licking direction in a somatosensory detection task ([@B45]). A recent article found that inhibition of the neuronal activity of the BF using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) interrupted the ability of rats in increasing their discrimination accuracy in a sustained attention task in response to a high reward probability trials ([@B67]), further suggesting that the BF could play a role in sensory discrimination. In humans, electroencephalogram (EEG)/magnetoencephalogram (MEG) studies have suggested that anticipatory attention could promote desynchronization of oscillatory brain activity ([@B2]; [@B56]), which would enhance perception. Future studies with electrophysiology or imaging of neural activity imaging are necessary to determine the role of neuronal dynamics of the BF in sensory discrimination during reward expectation.
Cholinergic Neurons and Anticipatory Activity {#S3.SS2}
---------------------------------------------
As mentioned before, the neuronal population of the BF is an intricate heterogeneous network with glutamatergic, GABAergic, and cholinergic projection neurons, among others ([@B19]; [@B72]). Using optogenetic tagging, we identified CNs from our recorded units and found that the activity of CNs were also engaged and modulated during trial initialization, which could participate in the preparation of the decision-making process.
The role of slow changes in ACh concentration, in time scales from minutes to hours, is well established based on the finding that CNs are recruited during arousal ([@B5]) and that ACh is slowly released and diffuses through the cortical mantle ([@B47]). However, recent evidence suggests that fast transient changes (milliseconds to seconds) in ACh may regulate neuronal processes affecting decision-making and behavioral performance in instrumentally cued tasks ([@B51]; [@B38]; [@B53]; [@B47]; [@B30]; [@B27]). Here, we found that, in a more naturalistic scenario, where the cholinergic system is not permanently engaged, such as a self-initiated (not-instrumentally cued) behavior in freely moving animals, CNs are also transiently engaged. Our data agree with precue changes in cholinergic release that had been directly measured in the prefrontal cortex using choline-sensitive electrode at the millisecond scale, changes that had been directly correlated with sensory cue detection ([@B51]). Hence, BF with cholinergic and non-cholinergic-projecting neurons might be an important region to participate in anticipatory behavior and improve animal performance.
Basal Forebrain and Stimulus Discrimination {#S3.SS3}
-------------------------------------------
In addition to the stimulus anticipatory response, we found that BF neurons (including cholinergics) changed their activity when the CS or odor was presented. Afferents from the HDB/MCPO project to the whole olfactory system ([@B72]) and has been proposed that GABAergic and CNs are required for proper stimulus discrimination. GABA released from BF projecting neurons into the olfactory bulb (the first brain region involved in the processing of olfactory information) is required to discriminate between similar olfactory cues, in part by inhibiting local inhibitory neurons in the bulb ([@B50]). On the other hand it has also been proposed through *in vitro* and *in vivo* electrophysiology that ACh is required for olfactory sensory discrimination and odor memory formation ([@B22]; [@B7]; [@B63]). At the circuitry level, it is believed that acetylcholine regulates olfactory information processing by sharpening the olfactory receptive fields of the output neuron of the olfactory bulb ([@B8]; [@B44]) and increasing their firing frequency ([@B57]). At the level of the olfactory cortex, acetylcholine has been implicated in increasing pattern separation ([@B7]) and increasing synchronization in the neuronal output of the bulb, which could lead to a more robust and stable learned olfactory representations in the olfactory cortex ([@B15]). Supporting this idea, we found that when animals were trained in a go/go task, it engaged significantly lower BF neurons during the start of the trial and CS presentation.
In other brain regions, cortically implanted choline-sensitive electrode recording in animals performing instrument-initiated detection of a light cue demonstrated that cholinergic neurotransmission is regulated with transient increase within seconds following cue detection superimposed over slower changes in cholinergic activity ([@B51]). These transients are thought to be required for proper cue detection and behavioral output ([@B27]). For instance, optogenetic regulation of BF CNs elicits fast modulation of neuronal activity in visual cortex, enhancing perception in mice responding to grating orientation ([@B53]). Interestingly, in a cue-initiated auditory detection task, optogenetically identified CNs in the BF responded with changes in neuronal activity a few ms after receipt of reward or punishment ([@B30]) and not to any other epoch of the behavioral trial, such as stimulus discrimination. Therefore, depending on the behavioral context, there appears to be differences in the dynamics of cholinergic release.
Finally, we found that a substantial number of non-cholinergic BF neurons, but not CNs, responded to water reinforcement. Our finding is consistent with a study that showed that primary reinforcement elicited robust bursting in non-CNs in a go/no--go task initiated by a tone where the animals were freely moving ([@B38]).
In summary, we found that in a self-initiated task, BF cholinergic and non-CNs play a role in decision-making and stimulus discrimination. The behavioral response is in part correlated with BF anticipatory precue activity, which opens new targets and time windows to modulate attention. Finally, our data position the BF as a potential information integrator and a common neuronal pathway to elicit a context-adequate behavioral response.
Speculation on the Role of Basal Forebrain Modulation on Selective Attention in Olfaction and Vision {#S3.SS4}
----------------------------------------------------------------------------------------------------
What is the role of BF neuron modulation of early sensory processing in the olfactory and visual systems? In the visual system, optogenetic activation of BF CNs increases behavioral performance for mice engaged in the discrimination of vertical vs. horizontal drifting gratings ([@B53]). Interestingly, cholinergic BF stimulation decreases neuronal synchronized of low-frequency oscillations (1--5 Hz) and increases the power of high-frequency gamma oscillations (60--100 Hz). In the olfactory system, chemogenetic inhibition of GABAergic BF modulation of granule cells in the olfactory bulb produced a reversible impairment in the discrimination of structurally similar odors ([@B50]). Optogenetic stimulation of GABAergic BF inputs to olfactory bulb granule cells produces reliable inhibition of these interneurons ([@B50]) that are key in generating gamma frequency oscillations generating synchronized gamma bursts that efficiently stimulate piriform cortex recurrent circuits that transmit the olfactory information in concentration-invariant odor coding ([@B60]; [@B54]; [@B3]). The regulation of gamma oscillations by BF input in these sensory systems raises the question whether BF regulates transmission of information through phase amplitude coupling (PAC) mediating selective attention to specific stimuli ([@B49]).
Phase amplitude coupling is defined as gamma bursts of information firing at specific phases of low-frequency theta oscillations (4--12 Hz) ([@B64]; [@B40]; [@B9]). Theta are the most global oscillations in the brain that act as a timekeeper ([@B61]) and are coherent across numerous cortical and subcortical structures arguing for its role in transfer of discrete chunks of information ([@B4]; [@B69]). In the olfactory bulb, contextual odorant identity (is the odorant rewarded?) can be decoded from peak theta-phase referenced power of gamma oscillations in animals proficient in odorant discrimination in the go/no--go task but not in mice that have not learned to discriminate the odorants ([@B41]) arguing for selective attention filtering of information on relevant stimuli through PAC. In the visual system of the macaque monkey, the strength of theta and of theta-rhythmic gamma modulation was markedly reduced by selective attention-altering information transfer through PAC ([@B65]). The engagement of changes in BF activity in different epochs of trials in associative learning tasks shown in this and other studies ([@B38]; [@B53]; [@B30]; [@B17]; [@B23]), and the fact that BF activity modulates oscillatory activity in olfactory bulb ([@B50]) and visual cortex ([@B53]), raises the question whether BF modulates selective attention within sensory systems or intermodally ([@B49]) through modulation of PAC. Whether this is the case requires future studies in the visual and olfactory system of BF regulation of PAC, stimulus decoding by phase-referenced power, and changes in behavioral accuracy by alteration of PAC by modulation of BF activity.
Materials and Methods {#S4}
=====================
Animals {#S4.SS1}
-------
All procedures and experiments were approved by the Institutional Care and Use Committee at the University of Colorado Anschutz Medical Campus in accordance with NIH standards. We used 2- to 6-month-old mice from the Jackson Laboratories bred in-house. Mice were kept with water and food *ad libitum* in a reversed 12 h light cycle, except that, when they were trained for awake behaving recording, they were water restricted (below). To selectively express ChR2 in CNs, we used ChAT-EYFP-ChR2 mice generated by crossing ChAT-Cre mice \[B6;129S6-*Chat*^*TM*\ 2(cre)Lowl^/J, [RRID:IMSR_JAX:006410](https://scicrunch.org/resolver/RRID:IMSR_JAX:006410)\] with Rosa26-floxed-ChR2-EYFP animals \[B6;129S-*Gt(ROSA) 26Sor*^*TM*32(CAG--COP4\*H134R/EYFP)Hze^/J, [RRID:IMSR_JAX:012569](https://scicrunch.org/resolver/RRID:IMSR_JAX:012569)\]. The generated mouse selectively expresses channelrhodopsin 2 (ChR2) under the control of the ChAT promoter.
Optetrode Building {#S4.SS2}
------------------
Optetrodes were built as previously shown with custom modifications described in [@B36]. Briefly, four tetrodes consisting of four polymide-coated nichrome wires (diameter, 12.5 μm; Sandvik) were connected to a 16-channel interface board (EIB-16, Neuralynx) and fed through a housing glued to the board. An optic fiber (105 μm diameter, Thor Labs) was also fed through the housing, and the tetrode tips were glued maximizing the distance between them to the end of the bare fiber. Immediately before implantation, the tetrodes were gold plated to an impedance of 200--350 MΩ.
Surgery {#S4.SS3}
-------
Adult mice were anesthetized with an intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg). Mice were implanted in the BF at coordinates of anterior--posterior (AP) of 0.02 mm and medial--lateral (ML) of −1.625 mm, or AP of 1 mm and ML of −1.500 mm with respect to bregma. On the day of the surgery, the optetrode was implanted 200 μm above the final location, and every day, it was lowered to 50 μm until reaching a final depth of dorsal--ventral (DV) of 5 and 4.9 mm, respectively. A screw was also implanted in the skull in the opposite hemisphere (1 mm right and 2 mm posterior of bregma) to serve as ground connector. Light was delivered through the fiber, and recordings were made in order to verify neuronal light responses. The animals were allowed to recover at least 1 week before experiments were performed. Implant location was corroborated through CT scan imaging.
Non-invasive Micro-CT Imaging {#S4.SS4}
-----------------------------
All CT imaging protocols were developed at the Animal Imaging Shared Resources (AISR) supported by the University of Colorado Cancer Center (NCI P30CA046934) and the Colorado Clinical and Translational Sciences Institute (NIH/NCATS UL1TR001082). Mice were anesthetized with 2% isoflurane, placed on a warming pad, and inserted into a Siemens Inveon micro-CT scanner (Siemens Preclinical Solutions). A single 3-dimensional (3D) micro-CT image set was acquired for each mouse using Inveon Acquisition Workstation software (IRW v1.5) with the following parameters: 270\_ rotation; 240 rotation steps; charge-coupled device (CCD) readout of 2,304/2,048; 4 binnings for matrix size reduction; exposure time of 30 ms with 80 kV voltage and 450 mA current; with a field of view (FOV) of 30 mm. The 6-min acquisition with middle-to-high magnification resulted in effective isotropic resolution of 54 μm (after the Shepp--Logan reconstruction algorithm). Animals were monitored during recovery from the anesthesia and returned to their cages. The images were read with the RadiAnt DICOM Viewer 1.9.16, and measurements were made from the tip of the electrode to the dorsal, ventral, and medial aspect of the skull, taken in the coronal, sagittal, and horizontal view. With this measurements, the CT scan images were registered into an MRI atlas (AtlasView 1.0, Radiology Department Johns Hopkins University) and finally into the Paxinos Mouse Brain Atlas ([@B24]). Eight out of 14 animals with correct implant locations were considered in the study.
Behavior {#S4.SS5}
--------
We used instrumental conditioning in freely moving mice in the Slotnick olfactometer ([@B62]; [@B18]). Animals were trained in the go/no--go and go--go behavioral task as explained in detail in [@B18] and [@B37]. Briefly, thirsty animals were trained to discriminate between a rewarded (CS^+^) and unrewarded (CS^--^) odor. Each trial was freely initiated by the mouse entering the odor port and breaking a photodiode beam. Once the trial was started (tstart) 1--1.5 s later, the CS was presented for 2.5 s ([Figure 1A](#F1){ref-type="fig"}). After CS delivery, the animal had to stay in the odor port for at least 500 ms for a trial to be considered completed. If not, it was considered a premature exit, and the trial had to be started again. During CS presentation, the animal learned to lick onto the water port at least once in four 0.5-s segments in response to CS^+^ for a 10-μl water reward. They quickly learned to refrain from licking in response to CS^--^ since no water was rewarded. The animal's performance was evaluated in blocks (maximum of 10 blocks) of 20 trials (10 rewarded and 10 unrewarded, presented at random). Each block's percent correct value represents the percent of trials in which the odors were correctly discriminated and associated with the appropriate behavioral action. Each session included 4--10 blocks of 20 trials. Electrophysiological recordings of the segments where the animal reached criteria (80% of correct responses) were considered in this study. For the go--go task, mice were rewarded at random in 70% of the trials regardless of which of the two odors was presented. The odors used were isoamylacetate, phenylacetate, 2-butatnone, ethyl propionate, ethyl butyrate, and mineral oil, all diluted at 1% in mineral oil. Experiments were performed in the afternoon (1[--]{.smallcaps}5 [PM]{.smallcaps}) under the "light on" cycle.
Electrophysiological Recordings and Spike Clustering {#S4.SS6}
----------------------------------------------------
The output of the tetrodes was connected to a 16-channel amplifier (A-M Systems 3500) through a 1× gain headstage (Tucker-Davis Technologies). The signal was amplified 1,000× and was recorded digitally at 24 kHz with a Data Translation DT3010 A/D card in a PC computer controlled with a custom MATLAB (Mathworks) program. Behavioral epochs or events (tstart, CS presentation, water delivery) were also recorded by the A/D board in real time.
The spike clustering method was explained in detail in [@B37] Briefly, data were filtered digitally between 300 and 3,000 Hz. With custom-written MATLAB programs, each of the 16 channels was thresholded at three times the standard deviation of the mean. Every spike with amplitude bigger than the threshold was imported into a second program (1 ms record per spike) that performed superparamagnetic clustering and wavelet decomposition of the spikes using 13 different wavelets and three principal components for the analysis and previously described ([@B18]; [@B37]). A single unit was defined as a unit with a refractory period of 1 ms ([@B33]; [@B66]) and a violation \<2% in the inter spike interval (ISI). Data for multi- and single units were used for analysis. For the go/no--go task, we found that out of 156 total units, 141 were single units. In the case of the go--go task, we registered from 1 multiunit and 43 single units. Identified CNs were all single units ([Supplementary Figure S1](#FS1){ref-type="supplementary-material"}).
Confocal Imaging {#S4.SS7}
----------------
To visualize ChR2-EYFP expression, mice were intracardially perfused with 4% paraformaldehyde and the brains postfixed overnight in the same fixative at 4°C. Thereafter, the brains were placed in a sucrose solution \[30% in phosphate-buffered saline (PBS)\] until they sank in the solution. Subsequently, they were frozen in dry ice and stored at −80°C. The brains were sliced at 40 μm in a cryostat, mounted on slides, and visualized with a Leica SP5 X confocal microscope.
Delivery of Light Stimulus {#S4.SS8}
--------------------------
A light pulse protocol was delivered to ChAT-ChR2 mice after a successful behavioral session for optogenetic tagging of CNs. A 473-nm blue laser (Shanghai Laser) was used with a maximal power of 5.3 mW (66.3 mW/mm^2^) measured at the end of the fiber under steady illumination. In the same chamber where the behavior was performed, we delivered 10 pulses of 50-ms duration at a frequency of 5 Hz. The light delivery protocol was repeated 10 times, and only the first pulse on each trial was considered for analysis.
Slice Preparation for *in vitro* Whole Cell {#S4.SS9}
-------------------------------------------
Choline acetyl transferase-ChR2 mice (2--3 months old) were anesthetized by CO~2~ inhalation and decapitated. Brains were quickly removed and placed in ice-cold oxygenated sucrose slicing solution composed of (in mM): 234 sucrose, 11 glucose, 26 NaHCO~3~, 2.5 KCl, 1.25 NaH~2~PO~4~ 10, MgSO~4~, and 0.5 CaCl~2~ (equilibrated with 95% O~2~ and 5% CO~2~, pH 7.4). Coronal brain slices (300-μm thickness) were prepared using a Leica VT1200S vibratome (Leica Biosystems). Coronal slices were incubated in prewarmed (36°C), oxygenated artificial cerebrospinal fluid (ACSF; in mM): 126 NaCl, 26 NaHCO~3~, 10 glucose, 2.5 KCl, 1.25 NaH~2~PO~4~, 2 MgCl~2~, and 2 CaCl~2~ for at least 30 min before being transferred to the recording chamber, where they will be continuously perfused with ACSF (32°C).
Whole Cell Recording {#S4.SS10}
--------------------
Positive and negative ChAT-ChR2 neurons in the BF (HDB/MCPO) were visually identified by EYFP expression and differential interference contrast (DIC) on a modified Olympus upright microscope (Scientifca, East Sussex, United Kingdom). Whole cell recording was performed with a Multiclamp 700B amplifier (Molecular Devices Corp.), using recording pipettes with resistance of 3--5 MΩ pulled on a PC10 vertical puller (Narishige International) and filled with intracellular solution containing the following (in mM): 135 potassium gluconate, 20 KCl, 10 HEPES, 0.1 ethylene glycol tetraacetic acid (EGTA), 2 MgATP, and 0.3 NaGTP. Recordings were low-pass filtered at 4 kHz (Bessel filter) and digitized at 10 kHz (Digidata 1440) using pClamp 10.3 software (Molecular Devices Corp.). Series resistances were monitored throughout each voltage-clamp recording with 50 ms and −10 mV steps, and if it changed by \>20%, the data were discarded. Evoked synaptic responses were recorded from ChAT^+^ and ChAT^--^ neurons, and these responses were triggered by light stimulation directly onto the BF area. Light stimulation was evoked by a single mercury-free LED illumination system (CoolED pE-100 series) at 470 nm for 5 ms between 1 and 5% of the maximal intensity of the system. Latencies of evoked responses were analyzed using prewritten code routines in Axograph-X.
Data Analysis {#S4.SS11}
-------------
To determine the responsiveness of the units to the different events, we aligned all trials to the starting point of the event and calculated the average FR (in Hz). We performed a paired *t* test between the FR 1 s before and after the event and corrected the *p* value for multiple comparisons using the false discovery rate ([@B12]). To display the results, the FR was calculated in 0.1-s bins and normalized per unit to the mean FR, 1.2 s before the beginning of the event for 1 s. To calculate the first bin of responsiveness, we determined the first bin that exhibited a change in normalized FR (either increase or decrease) two times above or below the standard deviation of the mean with a sliding window of six bins used as a baseline.
To determine the latency of the response *in vitro* in current clamp mode, the mean latency between the beginning of the light pulse to the peak of the voltage change was measured for 15 trials. For *in vivo* recordings, the mean latency was calculated for 10 trials and defined as the time a spike was detected after the light stimulation and before 200 ms (were another light pulse was given). To identify CNs, the recordings obtained during the behavior and light delivery were processed in batch, and the same units were identified in both recordings. We calculated the latency of the first spike after the first light pulse with a custom program written in MATLAB (Mathworks), with the average of 10 trials defined as the light latency for the unit. To calculate the reliability of the response, a spike had to occur at least once 200 ms before the light was applied, and for 100% reliability, it had to spike during that period of time on each of the 10 trials. To calculate the changes in FR, we calculated the peristimulus time histogram (PSTH) of the 10 trials and performed a pairwise *t* test between baseline (500 ms--1 s) and 30 ms postlight application. The *p* value obtained for all the units was corrected for multiple comparisons ([@B12]). Extracellular recording from the electrodes was used to calculate the local field potential (LFP) in the frequency range from 1 to 100 Hz. Time--frequency power decomposition of the LFP was obtained by means of MATLAB's spectrogram.m function with a 1-s window and 90% overlap. To compare LFP power between genotypes, we utilized Mann--Whitney *U* test with false discovery rate correction for multiple comparisons ([@B12]).
Data Availability Statement {#S5}
===========================
The datasets generated for this study are available on request to the corresponding author.
Ethics Statement {#S6}
================
The animal study was reviewed and approved by the Institutional Animal Care and Use Committee University of Colorado Anschutz Medical Campus.
Author Contributions {#S7}
====================
AN-P and DR designed the *in vivo* experiments. AN-P, CC-DR, and MH designed the *in vitro* experiments. AN-P performed the *in vivo* experiments. CC-DR performed the *in vitro* experiments. AN-P and DR performed the data analysis. All authors wrote the manuscript.
Conflict of Interest {#conf1}
====================
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
**Funding.** This study was funded by the NIH grants R01 DC00566 (DR), DC008855 (DR), and NS095311 (MH), CONICYT REDES140231 (DR), and Fondecyt 11150897 (AN-P).
We thank Nicole Arevalo and Anan Li for their technical help and Gidon Felsen, Robert Freedman, Abigail Pearson, and E. Mae Guthman for their insightful comments on the manuscript.
Supplementary Material {#S10}
======================
The Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fncel.2020.00141/full#supplementary-material>
######
**(A)** Implant location was determined through CT scan imaging (Siemens Inveon animal CT scanner) and posterior electrode registration onto the Paxinos Mouse Brain Atlas **(B)**. The tetrodes can be observed in the BF in the coronal (white arrow) and sagittal CT images (bottom). The resolution of the horizontal CT allows to individually identify single tetrodes (top inset). 10 out of 16 animals were correctly implanted in the BF and included in this study. **(C)** Example of cluster analysis of one tetrode and one session. The spikes features, waveform, cluster size and inter spike interval (ISI) can be observed for a multi-unit (red) and a single unit (blue). **(D)** Bar histogram for all the units recorded in the go/no--go task *in vivo*. Top, single units, bottom, multi units.
######
Click here for additional data file.
######
**(A)** Heatmap of the normalized FR of all the units recorded during a Go/noGo task sorted by the delta FR between 1 s before and 1 s after trial start. During a Go/noGo task 24.2 and 25.3% of units responded to tstart during HIT and CR trials, respectively. Out of the 67 units that were recorded during FA trials, only 5,9% changed their FR in response to the tstart. **(B)** Heat map of the normalized FR of all the neuronas recorded in the Go/Go task. Units that responded to tstart = 18.2%, CS presentation = 9.1% and reward = 4.8% (Chi squared, *p* \< 0.05, corrected for multiple comparisons). **(C)** Comparison of the percentage of neurons responding to tstart, CS and reward presentation between the Go/noGo and Go/Go task. Statistical significance was determined by a Chi squared corrected for multiple comparisons (*p* \< pFDR = 0.0278, the correction was applied at the same time to the graph in [Figure 1E](#F1){ref-type="fig"}). **(D)** Table depicting the responsiveness of all the neurons recorded in the Go/noGo task, sorted by the change in FR exhibited during tstart. Notice that a large percentage of these cells (44.9%) did not change their FR significantly in any of the trial epochs, while 6.1% exhibited responses in all epochs. Out of the 31 units that exhibited a statistical decrease in FR during the stimulus presentation, 14 showed a previous increase during trial initialization, suggesting that previous neuronal activity could affect changes in FR later in the trial. However, 15 additional units showing an increase in FR during the odor epoch, exhibited no change in FR during tstart and two had a decrease in FR in response to trial initialization. In the other hand, out of the 12 units that exhibited an increase in FR during the stimulus presentation, 4 also showed an increase during trial initialization, three a decrease during trial initialization, and 5 had no change during this epoch.
######
Click here for additional data file.
######
**(A)** Cholinergic units exhibited, in addition to a latency of the first spike after light stimulation smaller than 10 ms, a significant increase in FR after light stimulation (*t*-test, *p* \< pFDR = 0.0062, corrected for multiple comparisons) and a reliability of response of 100% **(B)**. **(C)** Cholinergic neurons also exhibited low jitter (mean 4.9 ms). **(D)** Example of a cholinergic neuron responding at trial initialization (tstart). All the trials are aligned to tstart (time = 0 s, dashed black line) and sorted by odor presentation (orange line). **(E)** Top: Example of a cholinergic neuron that did not respond to reward. The PSTH was aligned to reward. Bottom: summary of the normalized FR responses to reward of all the identified cholinergic neurons (*n* = 6). Even though there appears to be a disturbance in the FR a few ms after time = 0, the changes are not statistically significant.
######
Click here for additional data file.
[^1]: Edited by: Debra Ann Fadool, Florida State University, United States
[^2]: Reviewed by: Daniel W. Wesson, University of Florida, United States; Ricardo C. Araneda, University of Maryland, College Park, United States
[^3]: This article was submitted to Cellular Neurophysiology, a section of the journal Frontiers in Cellular Neuroscience
|
{
"pile_set_name": "PubMed Central"
}
|
LLVM Weekly - #135, Aug 1st 2016
Welcome to the one hundred and thirty-fifth issue of LLVM Weekly, a weekly newsletter (published every Monday) covering developments in LLVM, Clang, and related projects. LLVM Weekly is brought to you by Alex Bradbury. Subscribe to future issues at http://llvmweekly.org and pass it on to anyone else you think may be interested. Please send any tips or feedback to asb@asbradbury.org, or @llvmweekly or @asbradbury on Twitter.
News and articles from around the web
LLVM/Clang 3.9.0-rc1 has been tagged. It's time to get testing.
Swift 3 is nearing completion and Chris Lattner has shared some thoughts looking ahead to Swift 4.
The first LLVM Cauldron will be held on September 8th in Hebden Bridge, UK. Registration to attend is open, and you have a week to submit your talks. Also consider the 2016 US LLVM Developers' Meeting, to be held November 3rd-4th in San Jose, California.
On the mailing lists
Renato Golin has shared a proposed LLVM target acceptance policy.
The discussion about a potential move from SVN to Git continues with most of it focused on the pros and cons of a single monolothic repo for all LLVM subprojects. Mehdi Amini has really helpfully collected links to various workflows people have shared and other concrete reasoning for or against monorepos that people have shared. Chris Bieneman has shared his concerns about a monorepo and is keen to point out that lack of dissent in this particular thread doesn't mean consensus - as others have pointed out, the discussion has become rather too unwieldy for many people to follow.
Christopher Bergström is interested in organising an LLVM social in Asia and want to gauge interest.
Michael Lewis wonders if there's interest in generating PDB from LLVM-backed languages. The reason to ask is actually as he's done rather a lot of work on it for his own language and wonders if others may benefit. A number of responders suggest looking at the PDB writing support that is being done in-tree.
LLVM commits
A massive, target-independent MachinePipeliner pass has landed which implements Swing Modulo Scheduling. r277169.
bugpoint has been modified to use a simpler control-flow graph simplification routine that results in faster runtime and more minimal test cases. r277063.
llvm-cov learned to export coverage data to JSON. r276813.
GlobalISel now has an instruction selector. r276875.
Clang commits
A simple analyzer was added to detect copy and pasted code. r276782.
The web manual for Clang checker developers has been updated with a much expanded section on debugging. r277029.
Other project commits
|
{
"pile_set_name": "OpenWebText2"
}
|
Long-distance motorcycle riding
Long-distance riding is the activity of riding motorcycles over long distances, both competitively and as a pastime. A goal of long-distance riding is to explore one's endurance while riding a motorcycle, sometimes across several countries.
Non-competitive forms of long-distance riding are typically a form of motorcycle touring, sometimes as part of an organised rally. Competitive long-distance motorcycle riding consist in riding in endurance events such as the French Bol d'Or and the 24 Heures du Mans, with a popular target being to cover 1,000 miles in a day.
Events
Long-distance riders may participate in a number of structured and unstructured events.
Rallies
Endurance riders sometimes engage in endurance events known as rallies. Rallies take on a multitude of formats, differing in duration (anywhere from 8 hours to 11 days), style, types of roads ridden and so forth. Some rallies have been referred to as "advanced scavenger hunts" and require participants to locate specific locations (a series of "Little House on the Prairie" locations, for instance), perform specific tasks (take a Polaroid photograph of a giant baseball bat, write down time, date and mileage and so forth), and sundry other items during the duration of the rally.
Iron Butt Rally
The 'Olympics' of all endurance rallies is the Iron Butt Rally (also known as the IBR, the Big Show, or the Butt). This event takes place over eleven days, usually in late August, on odd numbered years, and is run by the Iron Butt Association. In the early years this was an obscure event with only a dozen or so riders. Over the past decade or so, as distance riding has gained in popularity, the event has become so crowded that the IBA has imposed a limit of 125 riders. Entry is via lottery and discretion of the rallymasters. The basic concept is a lap around the lower 48 United States, with possible diversions into Canada and Alaska. There are interim checkpoints, at which the rider must appear within a brief time window or forfeit any bonus points acquired on that leg. The Iron Butt Rally, like all endurance rallies, is not a race. There is no advantage to arriving early at a checkpoint. The goal is to earn the most points, which are not directly related to number of miles traveled. The winning rider may not be the one with the most miles ridden.
Other endurance rides recognized by the Iron Butt Association are not competitions, but are documented rides (such as the Saddlesore 1000, the BunBurner 1500, the BunBurner Gold 1500, the 100 Coast-to-Coast-to-Coast insanity) that require the rider to meticulously record mileage, fuel taken on and other factors in order to complete a documented ride.
Other rallies
There are plenty of other rallies, shorter and easier to get into, available to the competitive and fun-seeking long-distance rider. Some popular 24-hr rallies are the Utah 1088, Minuteman 1000, Land of Enchantment 1000, Mason Dixon 20-20, Not Superman Rally, Texas Two Step, Cal 24, Minnesota 1000, and many others. For those looking for an IBR-like event, there are multi-day rallies such as the Butt Lite, Northwest Passage, and newcomers Spank and Ten 'N Ten. These rallies are all put on by rallymasters and volunteers who devote countless unpaid hours to their events. The riders themselves are competing for nothing more than bragging rights and the personal challenge. These rallies are also viewed as training grounds for the 11-day Iron Butt Rally.
Notable long-distance riders
Dave Barr — Vietnam veteran who became the first double-amputee to circumnavigate the world on a motorcycle
Ewan McGregor and Charley Boorman — riding for the books and TV series Long Way Round and Long Way Down
Simon and Monika Newbound — world record for motorcycle endurance
Neil Peart — drummer of rock band Rush, who undertook a long-distance ride from his home in Quebec, Canada, across Canada to Alaska and then down to Mexico and Belize after the deaths of his daughter and wife—a ride that was later documented in the book Ghost Rider: Travels on the Healing Road
Paul Pelland — riding to raise money for multiple sclerosis charities
Benka Pulko — Slovenian motorcyclist who holds two Guinness World Records for her 5.5 year, 7 continent trip
Nick Sanders — Guinness World Record for fastest circumnavigation of the world by motorcycle in 1997
Kevin and Julia Sanders — broke Nick Sanders' record in 2002 and broke the record for the Pan American Highway in 2003
Ted Simon — ride through 45 countries was documented in his books Jupiter's Travels and Riding High
Kane Avellano — Guinness World Record for youngest person to circumnavigate the world by motorcycle (solo and unsupported) at the age of 23 in 2017.
References
External links
AREM/IBA Mexico Asphalt Rats Endurance Motorcycling (location: Mexico)
Bracebridge Native takes Motorcycle Ride to the ‘End of the World’ by Karen Longwell, July 8, 2009
List of long-distance motorcycle riders
|
{
"pile_set_name": "Wikipedia (en)"
}
|
Q:
adding four lines before last line of the file in gvim
IS there a way to add 4 lines before the last line of the file in vim?
I'm new to vim and recently found out that vim does multiline search which is awesome. Now only if I could find how to add 4 lines before the last line in the file I would totally save immense amount of time
A:
G 4 O Esc
|
{
"pile_set_name": "StackExchange"
}
|
Recently, there has been interest in the use of resilient coating materials for areas which are subject to mechanical shock, such as automobile bumpers, moldings and front ends. To maintain the desired appearance for a protective coating on a motor vehicle body panel or like application, any such coating must have certain properties, such as a high degree of extensibility, impact resistance, and resistance to cracking and degradation under severe environmental conditions such as low temperature and high humidity. Conventional coatings, including those heretofore employed on rubber and similar extensible objects, do not have the required combination of properties. Generally, compositions that are flexible enough to be applied over both metal and plastic substrates have rather poor weatherability, appearance, and/or overall durability.
U.S. Pat. Nos. 3,882,189 and 3,962,522 are exemplary of numerous patents which describe flexible coating compositions, wherein the resin comprises polyurethane modified polyesters formed by reacting polyisocyanate with polyester polyols. These resins are cured with amine-aldehyde crosslinkers. It is taught therein, that the presence of the urethane groups in the polymer significantly contributes to the flexibility as well as improved weathering properties, gloss, and abrasion resistance of the coating. Such coatings, however, are not of an overall quality to meet certain applications, particularly automotive applications. Accordingly, it is an object of the present invention to provide novel polysiloxane graft copolymers and solvent based, thermosetting coating compositions comprising same, suitable to produce flexible cured coatings with good adhesion over diverse substrates including metal and plastic. In this regard, it is a particular object of the invention to provide such flexible coating compositions at sufficiently low Volatile Organic Content (VOC) to aid in meeting governmental emissions guidelines and yet which can be applied to a substrate by spraying or other known methods. It is another object of the invention to provide a composition which will form a coating on a substrate, which coating has advantageous physical properties including, for example, humidity and solvent resistance, flexibility and corrosion protection for the underlying substrate.
Additional aspects and advantages of the invention will be apparent from the following description thereof.
|
{
"pile_set_name": "USPTO Backgrounds"
}
|
Adjust watering schedule for autumn, winter
Even though winter is here and plants are dormant they still need winter watering in our high desert climate.
We recommend thoroughly watering trees, shrubs, lawns and perennial beds at least once a month. Remember to water when temperatures are above 40 degrees, and with enough time for the water to fully soak into the soil.
Added water, along with a thick bed of mulch, will help protect plants throughout the harsh winter months.
Newly planted trees, shrubs and perennials are the most at risk. Try to water these 2-3 times a month. Fall-laid sod will also need extra moisture.
Seasonal Tips for Winter
Have you noticed an annoying visitor that you haven’t been able to get rid of? We’re not talking about a relative that’s overstayed their holiday welcome … we’re talking fungus gnats. These small black flies live and breed in the soil of houseplants. With each watering, more gnats are given a warm, moist incubator for […]
Winter Tips
As heavy winter snow melts away, you may discover large patches of your lawn that are matted down and appear straw-colored or gray. This is caused by gray snow mold, a fungus. Cause of Snow Mold Snow Mold occurs when snow or leaves cover lawns for a prolonged period through the winter, especially in shady areas. […]
|
{
"pile_set_name": "Pile-CC"
}
|
Paimpol–Bréhat tidal farm
The Paimpol–Bréhat tidal farm is an 8 MW tidal turbine demonstration farm off Île-de-Bréhat near Paimpol, France. It is developed by Électricité de France (EdF). The project was initiated in 2004 and work began in 2008.
The tidal farm will consist of four turbines, 2 MW each. Turbines are assembled by DCNS and installed by OpenHydro. The first turbine was installed in August 2011. According to EdF, when completed it will be the world's largest tidal array and the world's first grid-connected tidal energy farm.
The two turbines were retrieved from the seabed in 2017 for replacement of components that threatened the turbine’s resistance to corrosion. These turbines were never redeployed and the project was subsequently cancelled by EdF in 2018.
References
Category:Energy infrastructure completed in 2012
Category:Tidal power stations in France
Category:Électricité de France
|
{
"pile_set_name": "Wikipedia (en)"
}
|
Q:
Unable to send Email through GoDaddy SMTP
I am working on an ASP .Net MVC website and I've to send email through Godaddy smtp, Previously my site was developed in classic ASP and it was hosted on godaddy's web hosting (then it was working fine) but now I am hosting this site on IIS,
I am using following code to send email but it is not working
MailMessage msg = new MailMessage();
msg.From = new MailAddress(model.From);
msg.To.Add(model.To);
msg.Body = model.Body;
msg.Subject = model.Subject;
SmtpClient smtp = new SmtpClient("relay-hosting.secureserver.net",25);
smtp.Credentials = new NetworkCredentials("support@{myCompanyName}.com",{password});
smtp.EnableSsl = False;
smtp.Send(msg);
I have also used dedrelay.secureserver.net instead of relay-hosting.secureserver.net host (as mentioned at https://pk.godaddy.com/help/what-is-my-servers-email-relay-server-16601) but both are not working
A:
GoDaddy does not allow relaying through their server unless you are on one of their hosting plans that includes SMTP.
|
{
"pile_set_name": "StackExchange"
}
|
HVWG 2016 Year-End Membership Report
At the end of 2016, the Hudson Valley Writers Guild had 133 “active” members, people who had paid their membership dues within the past two years. Of those, 98 (74%) paid their 2016 dues and 35 (26%) did not. Therefore, we start 2017 with 98 “active” members, the first time in three years the Guild’s membership has dipped below 100. The 98 dues payers were composed of 21 new members (7 fewer than last year) and 77 renewing members, contributing a total of $3,450, a decrease of $365 from 2015.
Generally speaking, it was a challenging year for membership at the Writers Guild after we’d enjoyed three years of growth. But in 2016 we saw a slight contraction that was reflected broadly throughout the membership. For example, this year five people renewed for two years, half of last year’s number. Similarly, this year’s Writing Contest contributed one-third the number of people who joined or renewed their membership compared to last year. Hopefully, this modest contraction will be short-lived, a one-year “correction” that will turn back around in 2017.
The Guild’s membership effort was carried out in 2016 through 190 mailings, composed of 92 Renewal Requests, 77 Thank You letters, and 21 New Member Welcome Letters. The direct cost of the 2016 membership effort was $219. Therefore, when compared to the $3,450 in revenues, we can say that the 2016 administrative expense for membership was 6.3%, well below average for similarly-sized non-profit organizations.
The Hudson Valley Writers Guild had an Honor Role of six members who made extra contributions in 2016 in addition to their membership dues. The following people are called out for special recognition:
Lann Bell
Anne Decker
Phyllis Hillinger
Bernadette Moran
Kathleen O’Brien
Dan Wilcox
The Guild’s Board is most grateful for the confidence expressed by the ongoing support of new and renewing members for the Hudson Valley Writers Guild and the work it does on behalf of writers living in New York’s Hudson River Valley. Thank you!
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
stack overflow code in c for writing exploit
I am attempting to launch a shell in my Linux environment (BT3) but it keeps seg faulting. The method that I'm using is out of The Shellcoder's HandBook. Note that all of this is straight out of the text.
For more reference: http://www.backtrack-linux.org/forums/old-pentesting/15508-stuck-eip-buffer-overflow.html
A:
Many buffer overflow exploits have been fixed in modern operating system patches. It's likely you're seg faulting because the operating system is detecting a buffer overrun and killing your process.
|
{
"pile_set_name": "StackExchange"
}
|
A viable alternative to Basel III prudential rules
Stefano Micossi
Global banking regulation is undergoing a massive reform, known as Basel III. This column argues that the proposed reforms will fail to correct flaws in the old system. The new rules are even more complicated, opaque and open to manipulation. What is needed is a radical shift to prudential rule based on a straight capital ratio.
There is something surreal in the process for the implementation of the new Basel capital framework for banks in the EU and US. The new rules, known as Basel III, have the full support of financial officialdom (see BCBS 2013b for the latest official update by Basel Supervisors). Implementation is a different story. Implementation appears fraught with frictions and resistances, while the system is by now utterly discredited in the eyes of financial markets and academia (e.g. Dewatripont et al. 2010, Goodhart 2013, Admati and Hellwig 2013).
Radical criticism has been voiced also by top regulators (e.g. Hoenig 2013, Haldane and Madouros 2012, and Tarullo 2008 on Basel II). In recent research, I propose shifting to a prudential rule based on a straight capital ratio (Micossi 2013 ). My work also argues that the often-rehearsed arguments against this solution are plain wrong.
What’s wrong with Basel rules?
My main criticism concerns the continuing reliance – for the determination of capital requirements – on banks’ risk-weighted assets calculated with unwieldy probabilistic econometric models of dubious analytical foundation that leave ample room for gaming the system and, more importantly, that are by construction unable to deal with systemic shocks hitting the banking and financial system (IMF 2009, FSA 2010, Haldane 2011, Carmassi and Micossi 2012).
After ignoring the issue almost entirely during the negotiations leading to the Basel III Accord, Basel supervisors have awoken to the reality of wide divergences in risk-weighted asset ratios to total assets for individual banks and are studying the issue as part of their new Regulatory Consistency Assessment. Their January 2013 report finds that ample risk-weighted asset variations can only in part be explained by differences in business models and risk management techniques, and reflect to a considerable extent “elements of the flexibility provided to banks and supervisors within the Basel framework” (BCBS 2013). Similar exercises undertaken by the European Banking Authority have come to similar conclusions (EBA 2013).
In this context, the new Liquidity Coverage and Net Stable Funding ratios are but another manifestation of Basel rules’ inability to protect financial stability. However, far from responding to a clear rationale, they have added new patches on a crumbling construction. Their costs and impact on banks’ operations have not been evaluated but may be substantial; and fierce industry lobbying, already under way, is likely to lead over time to their emasculation. As if this were not enough, important jurisdictions are also intervening directly to prohibit trading on one’s own account (the Volcker rule in the US) or impose structural separation between commercial (‘utility’) and investment banking (the Vickers ringfencing in the UK). In the EU, the Liikanen Report has brought up for consideration the possibility of segregating banks’ trading activities into a separate legal entity – with tortuous decision procedures to ensure that it doesn’t happen in practice.
The Basel system has also failed to create a level playing field for ‘internationally active’ banks as divergent implementation by national supervisors has increasingly ‘balkanised’ it across the main jurisdictions – a process that Basel III special treatments will worsen.
Finally, Basel rules made it possible for the banking system as a whole to operate with a very thin capital cushion and a very high aggregate leverage, laying the basis for the subsequent implosion of credit when the financial crisis struck. The problem has not been resolved by Basel III, which will permit individual banks to keep a capital buffer as low as 3% of total assets – corresponding to a total leverage ratio above 33.
In sum, Basel III has to provide banking supervisors and markets with a readable metric of banks’ strength. Piecemeal fixtures won’t suffice; a complete overhaul of the system is in order.
A fresh start
In our Centre for European Policy Studies (CEPS) paper, Jacopo Carmassi and myself (2012) have outlined a logical and complete prudential system for banking that is much simpler and less distortive, entailing five components:
First, capital requirements set as a straight ratio between common equity and total assets.
Its level should be (gradually) raised to between 7% and 10% of total assets, based on systemic stability considerations. The new capital ratio, with equity valued at market rates, would be used as a reference in both Pillar 2 (supervisory review) and Pillar 3 (market discipline).
Second, under Pillar 2, prudential capital ratios would be used to trigger enhanced supervisory review and bind supervisors to a set of predetermined corrective actions of increasing severity, when the bank’s capital ratio falls below certain pre-specified thresholds, as under the current US FDIC system of PCA.
Third, in order to eradicate moral hazard, the system must be ‘closed’ by a procedure for bank resolution, to be triggered when a bank’s capital falls beyond repair.
Resolution costs would fall primarily on shareholders and unsecured creditors but even secured creditors and uninsured depositors would not be sure to escape.
Fourth, the correction for risk-taking by individual banks would be entrusted to deposit insurance, that would cover retail depositors and only up to a maximum amount.
Fees would be determined on the basis of banks’ overall risk profile and systemic relevance, as will be described below.
Fifth, under Pillar 3 (market discipline), solvency rules would be completed by the obligation for banks to issue a substantial amount of contingent capital (Co.Co.), i.e. debentures convertible into equity;
It is important that conversion be triggered automatically upon crossing certain market-based capital indicators and not be left to supervisory discretion (as in a misguided proposal by the Commission, 2012).
Under this system, there would be no need for special rules on liquidity or funding structures, whose adequacy would be concretely verified within the supervisory review of the banks covering the overall business model, its riskiness and its sustainability. There would also be no need for special restrictions on particular activities and operations, since supervisors would be able to penalise risk-taking as needed with deposit insurance fees.
Mimicking the Federal Deposit Insurance Corporation deposit insurance system
The system just outlined places a special burden on deposit insurance, that which becomes the sole instrument for charging individual banks for the risk they pose for the deposit insurance fund and financial stability in general. Therefore, it seems useful to recall that this approach already has an important precedent in the system of deposit insurance developed by in the US by the Federal Deposit Insurance Corporation, under the Federal Deposit Insurance Act, based on the so-called ‘CAMELS’ ratings system (that is, a ratings system based on capital, assets, management, earnings, liquidity and sensitivity to market risks).
Deposit insurance fees are determined based on the probability that an institution may cause a loss to the deposit insurance fund due to the ‘compositions and concentration’ of the institution’s assets and liabilities, and seeks to price all aspects of risk-taking by an individual institution and their systemic relevance. The system is open to periodic adaptations to the evolving banking business; apart from this, it seems to require no complements in the form of ad hoc capital surcharges or special constraints on banking activities and legal structure.
The ‘arbitrage’ objection to a straight prudential capital ratio
A main objection to this approach is that the elimination of all risk adjustment in the determination of prudential capital ratios would create fresh opportunities for regulatory arbitrage by banks seeking to maximise their returns on equity. This is an old argument that played a paramount role in the demise of Basel I and the adoption of risk-based capital ratios in Basel II (Tarullo 2008). It also happens to be groundless.
Indeed, the arbitrage objection assumes that the bankers’ only goal is to maximise returns on equity regardless of risk. Unless we believe that bankers’ utility function is characterised by zero risk-aversion – a rather worrisome presumption, which, to my knowledge, has no empirical confirmation – the only explanation for that kind of behaviour can be perverse incentives created by regulation and systematically encouraging bankers to take reckless risks.
And indeed there is plenty of evidence that legal rules and financial-market regulations have created moral hazard by shielding bankers form the consequences of their mistakes (or reckless gambles). This is, for instance, a straight consequence of the legal provision of limited liability; of the promise that, in case of difficulty, the bank will enjoy special access to the central-bank liquidity facilities; of the implicit promise that the bank will not be allowed to fail.
Far from creating new opportunities for regulatory arbitrage, the shift to a straight, risk-unadjusted capital ratio would reduce them, relative to the present system, as current incentives to manipulate internal risk management models, in order to reduce capital absorption, would disappear.
Conclusions
The Basel framework for bank prudential requirements is deeply flawed; the Basel III revision has failed to correct these flaws and in the main has made the system even more complicated, opaque and open to manipulation. In practice, the present system does not offer regulators and financial markets a reliable capital standard for banks; its divergent implementation in the main jurisdictions of the EU and the US has broken the market into special fiefdoms governed by national regulators in response to industry interests. The time is ripe to stop tinkering with minor adjustments and radically change the system.
References
Admati A and M Hellwig (2013), The Bankers’ New Clothes, Princeton University Press.
Basel Committee on Banking Supervision (BCBS) (2013), “Regulatory consistency assessment programme (RCAP) – Analysis of risk-weighted assets for market risk”, Basel, January (revised in February).
Carmassi, J and S Micossi (2012), “Time to Set Banking Regulation Right”, CEPS Paperback, Brussels, March.
Dewatripont, M, JC Rochet and J Tirole (2010), Balancing the banks: global lessons from the financial crisis, Princeton, NJ, Princeton University Press.
European Banking Authority (EBA) (2013), “Interim results of the EBA review of the consistency of risk-weighted assets. Top-down assessment of the banking book”, London, 26 February.
European Commission (2012), “Proposal for a Directive of the European Parliament and of the Council establishing a framework for the recovery and resolution of credit institutions and investment, COM(2012) 280 final, Brussels, 6 June.
Financial Services Authority (FSA) (2010), “Results of 2009 hypothetical portfolio exercise for sovereigns, banks and large corporations”, March.
Goodhart, CAE (2013), “Ratio Controls need Reconsideration”, Journal of Financial Stability, 20 February.
Haldane, AG (2011), “Capital discipline”, speech to the American Economic Association, Denver, CO, 9 January.
Haldane, AG and V Madouros (2012),”The dog and the frisbee”, paper presented at the Federal Reserve Bank of Kansas City’s 36th economic policy symposium, “The Changing Policy Landscape”, Jackson Hole, Wyoming, 31 August.
Hoenig, T (2013), “Basel III Capital: A Well-Intended Illusion”, remarks to the International Association of Deposit Insurers 2013 Research Conference, Basel, 9 April.
IMF (2009), Detecting Systemic Risk, Global Financial Stability Report, Washington, DC, April.
Micossi S (2013), “A Viable Alternative to Basel III Prudential Capital Rules”, Ceps Policy Brief No. 291, Brussels, 30 May, available at http://www.ceps.eu/book/viable-alternative-basel-iii-prudential-capital-....
Tarullo, D K (2008), “Banking on Basel. The future of international financial regulation”, Peterson Institute for International Economics, Washington DC.
|
{
"pile_set_name": "OpenWebText2"
}
|
Q:
Single summation with two variables
Disclaimer: This is for homework, but I'm just stuck on this one small part of a larger problem.
I'm having trouble figuring out how to get the following summation in closed form.
$$\sum_{j=1}^i 4ij$$
Since the index is j, am I able to move the i out of the summation as a constant the way I am with the 4? If I do that, do I need to square the i because it is the stopping point of the summation?
Am I able to separate the summation into two, like this?
$$\left(\sum_{j=1}^i 4i\right)\left(\sum_{j=1}^i j\right)$$
A:
The $i$ is indeed a constant, so you treat it exactly as like the $4$:
$$\sum_{j=1}^i4ij=4i\sum_{j=1}^ij=4i\left(\frac{i(i+1)}2\right)=2i^2(i+1)\;.$$
It might help you to write out some terms: the sum is
$$4i\cdot1+4i\cdot2+4i\cdot3+\ldots+4i\cdot i\;,$$
which clearly has a factor of $4i$ in each term that can be factored out to yield
$$4i(1+2+3+\ldots+i)\;.$$
|
{
"pile_set_name": "StackExchange"
}
|
Canada University of Toronto Mississauga-Award over 3,600 African/ International Students For Free Loan To Study And Work Immediately | Register Here.
We generally provide genuine, 100% genuine JOBs, we Do Broad Search And bring you best jobs insurance from gulf countries for better future, you do not have to pay to apply this job, it is always free. If you are tired of searching and applying for fake jobs, don’t stress, you are in the right place for job opening vacancies in the gulf and other countries.
FULL SCHOLARSHIPS TO STUDY IN CANADA 2019Application Title: Canada scholarships
At the University of Toronto, we grant more than 3,600 undergrad confirmation grants every year. This year alone, UTM granted over $1.6 million in passage grants and more through in-course grants.
The University of Toronto Mississauga, normally known by its initials UTM, is a satellite grounds of the University of Toronto situated in the neighboring city of Mississauga, Ontario, Canada. Opened in 1967 as Erindale College, UTM’s grounds is determined to the valley of the Credit River (around 33 km west of Downtown Toronto) and is the bigger of the University of Toronto’s two satellite grounds.
When you are admitted to the University of Toronto Mississauga, you are naturally qualified for a few grants, in light of scholastic greatness and other criteria. You are informed of your qualification of a passageway grant on your offer letter.
You can likewise apply to some application-just grants, which are additionally dominatingly dependent on scholastic greatness, however numerous likewise think about extracurricular exercises, require references, or require selection.
Application process is entirely online for believability so all intrigued and qualified candidates Should apply Now.
To Register undergrad affirmation grants 2018 In University Of Toronto For Student Application Form just, you should pursue the straightforward strides underneath.
David Chisomeje Is A Graduate From The National Open University Nigeria, He Holds His BSc In International Relations, He Is Also A Political Analyst, Social Media Enthusiast And Anchor On Lifestylenaija TV.
|
{
"pile_set_name": "Pile-CC"
}
|
Automounter Question - Summary & Thanks
- A Few days ago I posted an automounter-related question (see below)
and I have been flooded with answers.
- Thanks for all those who answered so far.
- I'll summarize below. I tried to reply to each person, but some mails bounced,
so I'll honor all of them below.
- I apologize again for putting a 'tar'-realted question on sun-nets.
- BTW, only one person (so far) has answered question 2 below (antwerp@tpdsun.tno.nl) -
He says it can be done.
------------------- the question: --------------------
I have a tar tape (a poor copy of MIT X11R4) which was prepared in the dumbest way possible:
(well, maybe there are dumber ways, but I have not seen them yet...)
Previously I dealt with it by taking down the automounter, create a real
directory 'hostile' under /net and extract the stuff that I needed.
I was wondering whether I can fake a machine in the YP hosts map with the
above name, but with an ethernet address of my (real) machine and then create 'mit'
under the root and thus when extracting to /net/hostile it will actually go
to /net/friendly.
However, I'm loath to try it before I'm sure it'll work (a little wimpy, I admit).
My questions are:
1. Will it work?
2. Do YP/NFS/automounter care if there >1 host with the same address?
3. Unrelated to networking, is there a nicer way to override dump tar files like that?
I tried GNU tar 1.08. It worked for a while, then crashed with 'bus error'.
I then opted for Hans Buurman's 'chroot' solution which worked like a charm.
It does require superuser permission.
I have tried neither setting up symbolic links nor 'pax' of 'fixtar'.
Thanks for all who responded and tell your friends never to use absolute
files names when using 'tar'.
|
{
"pile_set_name": "Pile-CC"
}
|
Q:
MongoDB hosted in Azure Cosmos DB: Sharding vs partitioning
We want to use MongoDB for our database, and we want to use the MongoDB API to avoid to be "locked in" to Azure Cosmos DB hosting.
We use .Net Core and the MongoDB.Driver package (to be able to easily switch between on-prem, Atlas, Azure Cosmos hsoting etc.) to communicate with the MongoDB instance, so far so good.
To be able to handle future growth of data volumes (size and performance) I want to have my collections sharded. As I understand the strategy Cosmos DB use is partitioning with partition keys, but since we use the MongoDB.Driver I can not find anyway to specify partitionkeys in my queries.
"Plain" MongoDB use sharding instead, and you can set up a document property that should be used as a delimiter for how your data should be sharded.
So, my guess is that sharding is the way to go (since partionkeys is a Cosmos feature) but I can not manage to get it working.
The "MongoDB shell" in Azure Portal do not understand the sh.shardCollection command and if I connect with a MongoDB shell from my client I get the following error:
globaldb:PRIMARY> use sampledatabase
switched to db sampledatabase
globaldb:PRIMARY> sh.shardCollection("sampledatabase.Event", { TenantId: 1 } )
2018-06-21T12:03:06.522+0200 E QUERY [thread1] Error: not connected to a mongos :
How do I proceed to get sharding up and running in a MongoDB instance hosted in Azure Cosmos?
A:
The CosmosDB Mongo api endpoint exposes a MongoD interface with replica-set enabled instead of a MongoS interface. Hence, you will need to use db.runCommand instead of the "sh" sharding commands to create a sharded collection.
You can find more details at https://docs.microsoft.com/en-us/azure/cosmos-db/partition-data#mongodb-api
|
{
"pile_set_name": "StackExchange"
}
|
Q:
Swapping the text with the function
I am still a newbie with javascript and I wanted to know how to make it so that the function appears and the text next to that,
What I mean by that is, it is now show loading and next to it the variable text but I what I want is that the variable text is in front of the static 'loading' text
loader.text('Loading '+$(this).text()).show();
Thanks in advance
A:
It might be a good idea for you to check out some beginner Javascript resources. What you're trying to do is very basic, and is called "string concatenation". Best of luck.
|
{
"pile_set_name": "StackExchange"
}
|
9 So.3d 585 (2007)
FERNANDO LOURENCO MILINER
v.
STATE.
No. CR-06-0759.
Court of Criminal Appeals of Alabama.
May 11, 2007.
Decision of the Alabama Court of Criminal Appeal Without Opinion. Affirmed.
|
{
"pile_set_name": "FreeLaw"
}
|
Introduction {#Sec1}
============
Competition is one of the fundamental ecological interactions between species^[@CR1]^. We can observe that coexisting species are competing for the same resources^[@CR2]^. A typical resource competition model which has been recognized widely is the Classical Lotka-Volterra competition^[@CR1],[@CR2]^. The analyses of this equation show that coexistence of two or more species becomes only possible if intraspecific competition is stronger than interspecific competition^[@CR3]^. Otherwise, dynamics leads to the exclusion of one species among *n* species, known as the competitive exclusion principle^[@CR1],[@CR4]^. However, in natural communities many competing species have been coexisting in the same habitat over time, resulting in a high species diversity. Hence, we suspect that there should be some mechanisms for coexistence of competitive species, e.g., spatial structures^[@CR5],[@CR6]^. These models, however, introduce an additional complexity into the mathematical models of classical LV systems. Compared with these complex models, coexistence of multiple species in natural communities seems to be far more ubiquitous. Therefore, a more universal explanation may be worth considering.
Crowding effect is considered as one of the ubiquitous mechanisms in any biological populations^[@CR7]--[@CR16]^. A nonlinear density effect at high densities is called crowding effect, while that at low densities, Allee effect^[@CR7]--[@CR17]^. Unlike this nonlinear density effect, in the traditional mathematical models of population dynamics, density effect is usually treated as constant (i.e., linear), and crowding effect is not included. To consider the nonlinear density effects, aggregation models have been developed and studied extensively introducing 'mean crowding'^[@CR8]--[@CR10],[@CR15],[@CR16]^. These models show the coexistence of a few species, but not many species. The 'mean crowding' is a statistical feature of crowding affecting population growth rate (both birth rate and mortality). Here, we develop a simple LV type competition model with crowding effect on mortality only. We assume that the mortality rate of an individual increases with the density of a population. Moreover, using our modified LV competition model with nonlinear crowding effect, we show that multiple species are generally possible to coexist using LV system with crowding effect. This coexistence dynamics should be applicable to insect or animal species.
Results {#Sec2}
=======
We consider the LV competition system where all interspecific competition rates are unity, i.e., *α*~*ij*~ = *α*~*ji*~ = 1∀*i*. Setting *dx*~*i*~/*dt* = 0, we obtain the zero isoclines for the modified Lotka-Volterra (LV) competition equations with nonlinear crowding effect rate *m*~*i*~. These isoclines are straight lines in the classical LV competition equation when we sketch the graph of the population density 1 with respect to the population density 2 (Fig. [1](#Fig1){ref-type="fig"}, dotted lines). However, we observed that these isoclines turn out to be curved when we include a nonlinear crowding effect *m*~*i*~ (Fig. [1](#Fig1){ref-type="fig"}, solid lines). All four cases of Lotka-Volterra model show convergent-stable coexistence by adding a crowding effect, where an inferior (superior) species always increases (decreases) in densities (Fig. [1](#Fig1){ref-type="fig"}). The equilibrium point is moving from *E*~1~(*d*~*i*~ = 0.0) to *E*~2~(*d*~*i*~ = 0.5) which is also caused by the inclusion of a crowding effect *m*~*i*~, irrespective of other constant parameters (Fig. [1](#Fig1){ref-type="fig"}).Figure 1The zero isoclines and the long-term variation density of the classical LV competition equation with the inclusion of crowding effect for the four classical cases. Crowding effects (Solid line: *d*~*i*~ = 0.5, equilibrium: *E*~2~) enable coexistence in all four cases of classical LV system (Broken line: *d*~*i*~ = 0.0, equilibrium: *E*~1~). (**a**) $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$({K}_{2} < \frac{{K}_{1}}{{\alpha }_{12}},{K}_{1} > \frac{{K}_{2}}{{\alpha }_{21}})$$\end{document}$, (**b**) $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$({K}_{2} > \frac{{K}_{1}}{{\alpha }_{12}},{K}_{1} < \frac{{K}_{2}}{{\alpha }_{21}})$$\end{document}$, (**c**) $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$({K}_{2} < \frac{{K}_{1}}{{\alpha }_{12}},{K}_{1} < \frac{{K}_{2}}{{\alpha }_{21}})$$\end{document}$, and (**d**) $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$({K}_{2} > \frac{{K}_{1}}{{\alpha }_{12}},{K}_{1} > \frac{{K}_{2}}{{\alpha }_{21}})$$\end{document}$. Colors indicate *x*~1~(red) and *x*~2~ (blue). *K*~*i*~: carrying capacity of species *i*, and *α*~*ij*~: competition coefficient from species *j* to species *i*. Parameters value: *b*~*i*~ = 1.0, *d*~*i*~ = 0.5, *m*~*i*0~ = 0.1, 0 ≤ *δ* ≤ 5. (**a**) *α*~12~ = 0.8, *α*~21~ = 1.2. (**b**) *α*~12~ = 1.2, *α*~21~ = 0.8. (**c**) *α*~12~ = 0.5, *α*~21~ = 0.4. (**d**) *α*~12~ = 1.2, *α*~21~ = 1.3. Initial density *x*~1~ = 0.5, *x*~2~ = 0.2. We used Anaconda package of the software Python 3.6 for our simulation analysis^[@CR22]^.
Curved lines in the $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${x}_{1}-{x}_{2}$$\end{document}$ plane imply that coexistence only take place when the value of *δ* → 1.0 for all *d*~*i*~ \> 0 (Fig. [2](#Fig2){ref-type="fig"}). However, by increasing *δ*, the competitive exclusion reappears in all exclusion cases, where the equilibrium state in $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${x}_{1}-{x}_{2}$$\end{document}$ plane is strongly curved to return to the originated axis (Fig. [2](#Fig2){ref-type="fig"} except 2c). In contrast, an isocline is straight in $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${x}_{1}-{x}_{2}$$\end{document}$ plane, where the two species coexist without crowding effects, such that $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${K}_{2} < \frac{{K}_{1}}{{\alpha }_{12}}$$\end{document}$ and $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${K}_{2} < \frac{{K}_{2}}{{\alpha }_{12}}$$\end{document}$ (Fig. [2c](#Fig2){ref-type="fig"}). Furthermore, Fig. [3a](#Fig3){ref-type="fig"} shows that two competing species can coexist for any small positive value of *δ* for all *d*~*i*~\> 0. Moreover, small positive real number *δ* will make coexistence possible but bigger value indicates the competitive exclusion principle again (Fig. [2](#Fig2){ref-type="fig"} except 2c and Fig. [3](#Fig3){ref-type="fig"}). Figure [4](#Fig4){ref-type="fig"} shows many-species Lotka-Volterra competition dynamics with crowding effects. Temporal dynamics of all species becomes convergent stable by adding crowding effects (Fig. [4a,b](#Fig4){ref-type="fig"}). The effect of *δ* in 5 or 10 species (Fig. [4c,d](#Fig4){ref-type="fig"}) is qualitatively same with the case of two species competition (Fig. [3b](#Fig3){ref-type="fig"}). Thus, many-species LV competition model with crowding effects leads to the stable coexistence of all species (Fig. [4](#Fig4){ref-type="fig"}).Figure 2Modified LV competition system with nonlinear crowding effect using the four possible cases of isoclines for the crowding strength factor *δ*. All non-coexistence patterns (**a,b,d**) move to coexistence as *δ* → 1.0 and return to competitive exclusion as *δ* → 5.0. The right column figures show the equilibrium points in the *x*~1~ − *x*~2~ phase plane. (**a**) $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$({K}_{2} < \frac{{K}_{1}}{{\alpha }_{12}},{K}_{1} > \frac{{K}_{2}}{{\alpha }_{21}})$$\end{document}$, (**b**) $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$({K}_{2} > \frac{{K}_{1}}{{\alpha }_{12}},{K}_{1} < \frac{{K}_{2}}{{\alpha }_{21}})$$\end{document}$, (**c**) $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$({K}_{2} < \frac{{K}_{1}}{{\alpha }_{12}},{K}_{1} < \frac{{K}_{2}}{{\alpha }_{21}})$$\end{document}$, and (**d**) $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$({K}_{2} > \frac{{K}_{1}}{{\alpha }_{12}},{K}_{1} > \frac{{K}_{2}}{{\alpha }_{21}})$$\end{document}$. Colors indicate *x*~1~(red) and *x*~2~ (blue). Parameter value and software used: see Fig. [1](#Fig1){ref-type="fig"}.Figure 3The effects of *δ* on population density in LV competition model with crowding effect. (**a**) Density ratio (*x*~1~/*x*~2~) of species 1 and 2 plotted on the crowding strength factor *δ* and the basic crowding component constant assuming equal between species 1 and 2 (*d*~1~ = *d*~2~). (**b**,**c**) Density of two species (*x*~1~: red, *x*~2~: blue) plotted against *δ*, where (**b**) 0 ≤ *δ* ≤ 1, (**c**) 0 ≤ *δ* ≤ 5, and *d*~*i*~ = 0.3. Parameters value: *b*~1~ = 1.0, *b*~2~ = 1.8; *α*~*ij*~ = 1.0; *m*~*i*0~ = 0.1. Initial density *x*~*i*~ = 0.5. See Fig. [1](#Fig1){ref-type="fig"} for software.Figure 4Long-term dynamics of many-species LV competition model with crowding effect. (**a**,**b**) Temporal dynamics with the basic crowding component constant (solid line: *d*~*i*~ = 0.3; dotted line (no crowding): *d*~*i*~ = 0.0) and the crowding strength factor *δ* = 0.3, (**c**,**d**) the equilibrium (final) states plotted against the effects of crowding strength factor *δ* (0 ≤ *δ* ≤ 1). (**a**,**c**) 5 species (birth rate: *b*~*i*~ = 1.0 + 0.1(*i* − 1)); (**b**,**d**) 10 species (birth rate: *b*~*i*~ = 1.0 + 0.05(*i* − 1)). Density of *i*-species: *x*~*i*~ (*i* = 1, 2, ..., *n*). Parameter value: *α*~*ij*~ = 1.0; *m*~*i*0~ = 0.1. Initial density *x*~*i*~ = 0.5. See Fig. [1](#Fig1){ref-type="fig"} for software.
We also build LV competition models with aggregation effects on mortality that are qualitatively equivalent to the aggregation model of Hartley and Shorrocks^[@CR8]^. We compare them with the current crowding models using the same parameter conditions (Fig. [5](#Fig5){ref-type="fig"}). In the 2-and 5-species dynamics, all species survive and converge to a stable equilibrium in both the crowding model (Fig. [5a,c](#Fig5){ref-type="fig"}) and aggregation model (Fig. [5b,d](#Fig5){ref-type="fig"}). In the 10-species dynamics, all species survive and converge to stable equilibrium in the crowding models (Fig. [5e](#Fig5){ref-type="fig"}), while only five species in the aggregation model.Figure 5Long-term dynamics of 2-, 5- and 10-species LV competition models with two types of nonlinear density effects. (**a**,**c**,**e**) Crowding effect (Eq. [1](#Equ1){ref-type=""}; *d*~*i*~ = 0.3, *δ* = 0.4); (**b**,**d**,**f**) aggregation effect (Eq. [3](#Equ4){ref-type=""}; ε = 0.01). (**a**,**b**) 2 species (*m*~*i*0~ = 0.3); (**c,d**) 5 species (*m*~*i*0~ = 0.3); (**e,f**) 10 species (*m*~*i*0~ = 0.1). Parameter value: *α*~*ij*~ = 1.0; *b*~*i*~ = 1.0 + 0.01(*i* − 1). Initial density: (**a**,**b**) *x*~1~ = 0.15, *x*~2~ = 0.25, (**c**,**d**) *x*~3~ = 0.2, *x*~4~ = 0.12, *x*~5~ = 0.18, (**e**,**f**) *x*~6~ = 0.19, *x*~7~ = 0.22, *x*~8~ = 0.14, *x*~9~ = 0.13, *x*~10~ = 0.26. See Fig. [1](#Fig1){ref-type="fig"} for software.
We also consider the effect of nonlinear competition terms^[@CR21]^ with or without crowding effect. We compare them with the current crowding models using the same parameter conditions (Fig. [6](#Fig6){ref-type="fig"}). In their original model, Taylor and Crizer consider a modified Lotka-Volterra model introducing the effect of nonlinear competition on growth rate. Here, we introduce the nonlinear competition on birth rate alone, since crowding effect is introduced only on mortality rate. In this manner, we can compare the effect of these changes separately. In the 2-species dynamics, both species survive and converge to a stable equilibrium in the crowding model with linear or nonlinear competition terms (Fig. [6a,c](#Fig6){ref-type="fig"}). In the current parameter conditions, the LV competition model with nonlinear competition terms lead to the extinction of one species (Fig. [6b](#Fig6){ref-type="fig"}). Note that by changing the conditions, this model lead to the coexistence of the two species^[@CR21]^. In the 5-species dynamics, all five species survive and converge to a stable equilibrium (Fig. [6d,e and f](#Fig6){ref-type="fig"}). Interestingly, the model with nonlinear competition terms converges to the same density for all five species (Fig. [6e](#Fig6){ref-type="fig"}), while the crowding effect lead to different densities among all species (Fig. [6d,f](#Fig6){ref-type="fig"}). In the 10-species dynamics, seven species survive and converge to stable equilibrium in the crowding models (Fig. [6g](#Fig6){ref-type="fig"}). In contrast, all ten species in the LV competition model with nonlinear terms lead to the coexistence of all species with an equal density (Fig. [6h](#Fig6){ref-type="fig"}). By combining the nonlinear competition and the crowding effect, all ten species survive and converge to different densities (Fig. [6i](#Fig6){ref-type="fig"}).Figure 6Long-term dynamics of 2-, 5- and 10-species LV competition models with crowding effect and/or nonlinear competition term. (**a**,**d**,**g**) Crowding effect (Eq. [1](#Equ1){ref-type=""}); (**b**,**e**,**h**) nonlinear competition term; (**c**,**f**,**i**) combination of both (Eq. [3](#Equ4){ref-type=""}). Parameter value: *α*~*ij*~ = 1.0; *b*~*i*~ = 1.0 + 0.1(*i* − 1). (**a,c,d,f,g,i**) *d*~*i*~ = 0.3, *δ* = 0.4. (**a--f**) *m*~*i*0~ = 0.3; (**g--i**) *m*~*i*0~ = 0.1. Initial density: (**a--c**) *x*~1~ = 0.15, *x*~2~ = 0.25, (**d--f**) *x*~3~ = 0.2, *x*~4~ = 0.12, *x*~5~ = 0.18, (**g--i**) *x*~6~ = 0.19, *x*~7~ = 0.22, *x*~8~ = 0.14, *x*~9~ = 0.13, *x*~10~ = 0.26. All simulations run for the same time steps. See Fig. [1](#Fig1){ref-type="fig"} for software.
Discussion {#Sec3}
==========
Many species compete for precisely the same limited resources to survive^[@CR1],[@CR2]^. Gause's exclusion principle show that multiple competing species cannot coexist in natural communities^[@CR1],[@CR4],[@CR18],[@CR19]^. Only one species, the superior competitor, will survive and other competitors will eventually become extinct. We should note that frequency dependence does not promote the coexistence of multiple species^[@CR20]^. Niche theory suggested that it will only become possible for the competing species to coexist if they have different niche^[@CR2],[@CR3]^. Linear density effects show that coexistence becomes possible under very limited conditions. Hence, we search for mechanisms that will enable coexistence of competitive species^[@CR5],[@CR6]^. As a universal and more biologically founded solution, we consider crowding effect, nonlinear density effects at high densities, in the LV competition systems.
Classical LV competition model shows that it is only possible for two species to coexist together if intraspecific competition is stronger than interspecific competition^[@CR3]^. However, our results have shown that inclusion of crowding effect to the classical Lotka-Volterra competition system guarantees the coexistence of two or more species. We have investigated that two species can coexist when we include crowding effect to the classical LV competition system (Fig. [1](#Fig1){ref-type="fig"} (solid lines), Fig. [2](#Fig2){ref-type="fig"} as *δ* → 1.0, Fig. [3a](#Fig3){ref-type="fig"} as *δ* → 1.0, and Fig. [4a,b](#Fig4){ref-type="fig"} (solid lines)) compare to the results of the classical LV competition model which show the competitive exclusion principle (Fig. [1](#Fig1){ref-type="fig"} (dotted lines) and Fig. [4a,b](#Fig4){ref-type="fig"} (dotted lines)).
Crowding effect has been recognized in many natural and experimental populations^[@CR7]--[@CR16]^. Note that if the density of population is increased a lot more than the carrying capacity, then crowding effect will kill all competing individuals. We here, introduced the intraspecific crowding effect into the Lotka-Volterra competition model. We have shown that a weak crowding effect make it possible to achieve a stable coexistence of multiple species. Our analysis implies that increased mortality under high density works as elevated intraspecific competition leading to the coexistence. This may be another ubiquitous mechanism for the coexistence of multiple species leading species diversity in nature.
We compare the current model with the aggregation model of coexistence^[@CR8]^ (Fig. [5](#Fig5){ref-type="fig"}). Unlike the original aggregation model of Hartley and Shorrocks in which the aggregation reduces growth rates, we only include the aggregation effect on mortality rate. These examples show that the aggregation model becomes difficult to maintain the coexistence of all or many species when the number of species is increased. In contrast, the coexistence of all or many species can be easily achieved in the current crowding model even when the number of species is increased (Fig. [5a,c and e](#Fig5){ref-type="fig"}). The reason why the coexistence becomes difficult when the number of species increased in the aggregation model seems to depend on the combination of the parameters, where the coexistence region is expressed as a polygon in the *n*-species parameter space which can disappear easily when the number of species is increased. The logic is same with linear programming in *n*-dimensional space. In contrast, in the crowding model, the mortality rate of any species increases when its density approaches its carrying capacity. Because of this, increasing mortality rate near carrying capacity will keep all the species at the densities much below their carrying capacity. Thus, the intraspecific competition becomes most severe at or near carrying capacity, resulting in the stable coexistence of all species.
We also compare the effects of the nonlinear competition terms with the current crowding effects (Fig. [6](#Fig6){ref-type="fig"}). Unlike the LV model with nonlinear competition effects on growth rates^[@CR21]^, we only include the nonlinear competition effects on birth rate alone since crowding effect is included only on mortality rate, so that these effects can be easily distinguished. In the current parameter conditions, the 2-species model results in the exclusion of one species (Fig. [6b](#Fig6){ref-type="fig"}). However, when the number of species is increased, LV model with nonlinear competition terms will lead to the coexistence of all species with an equal density regardless of the parameter combinations (Fig. [6e,h](#Fig6){ref-type="fig"}). It is not sure whether the stability can be achieved easily when the number of species increased in the nonlinear competition model. However, the equilibrium density is identical for all coexisting species in the model with nonlinear competition terms. This means that the effects of other species-specific parameters are completely cancelled by the introduction of nonlinear competition effect. In contrast, the coexistence of all or many species can be easily achieved in the current crowding model even when the number of species is increased (Fig. [6a,d and g](#Fig6){ref-type="fig"}). By combining the nonlinear competition and the crowding effect, many species survive and converge to different densities (Fig. [6c,f and i](#Fig6){ref-type="fig"}). Thus, both mechanisms can promote the coexistence of many species differently.
The most important assumption in our model of crowding effect is the increase in mortality rate at high density. Here, *d*~*i*~ represents the proportion of crowding mortality contribution and *δ* is the power of crowding effect. Therefore, when *d*~*i*~ = 0, this model reduces to the classical LV competition model. This assumption should be one natural way to include the crowding effect. However, there may be many other natural ways to include crowding effect, e.g., the aggregation model of Hartley and Shorrocks^[@CR8]^. We have to wait for empirical studies to verify which way is actually functioned in a natural ecosystem. Note that these functional mechanisms are not exclusive of each other. Thus, the valid mechanisms may be different depending on a natural ecosystem. We should also note that the nonlinearity in the functional responses should be an important factor driving population dynamics and resulting evolution. The nonlinearity in density effect may be biologically inherent and appears as crowding effect at high densities and as Allee effect at low densities. Our studies thus show that the real competitive communities have a much more complicated dynamical system than the classical LV competition system.
Methods {#Sec4}
=======
Mathematical models {#Sec5}
-------------------
We consider the modified Lotka-Volterra (LV) competition equations with crowding effect rate ***m***~***i***~ for species *i*. In our model, we only consider competition between two species. In addition, carrying capacity ***K***~***i***~ is set to be equal to 1, i.e., *K*~*i*~ = 1. The modified LV competition model is shown on the following equations:$$\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$\{\begin{array}{c}\frac{d{x}_{1}}{dt}={b}_{1}{x}_{1}(1-{x}_{1}-{\alpha }_{12}{x}_{2})-{m}_{1}{x}_{1},\quad {b}_{1}\,{\rm{and}}\,{\alpha }_{12}\,{\rm{are}}\,{\rm{constant}}\\ \frac{d{x}_{2}}{dt}={b}_{2}{x}_{2}(1-{x}_{2}-{\alpha }_{21}{x}_{1})-{m}_{2}{x}_{2},\quad {b}_{2}\,{\rm{and}}\,{\alpha }_{21}\,{\rm{are}}\,{\rm{constant}}\end{array}$$\end{document}$$where ***x***~***i***~ represents the population density of species *i* where *i* = 1, 2. In this model, parameter ***b***~***i***~ represents the birth rate of species *i* while ***α***~***ij***~ represents the effect of species *j* on *i* where *i*,*j* = 1, 2 and *i* ≠ *j*. The crowding effect rate *m*~*i*~ is given by$$\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${m}_{i}={m}_{i0}+{d}_{i}{x}_{i}^{\delta },\quad \delta \in (0,\infty )\forall i$$\end{document}$$where parameter ***m***~***i***0~ represents the initial mortality factor of species *i*. Parameter ***d***~***i***~ represents the density-dependent factor of species *i*. In addition, the sum of the initial mortality and density-dependent factor of species *i* must be greater than 0 but less than or equal to 1, i.e.,0 \< *m*~*i*0~ + *d*~*i*~ ≤ 1. Note that, if the initial mortality factor *m*~*i*0~ is zero then nonlinear crowding effect rate *m*~*i*~ will imply that the intraspecific competition is perfectly density-dependent. In addition, if *d*~*i*~ = 0 $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${\rm{\forall }}i$$\end{document}$ then *m*~*i*~ = *m*~*i*~0 $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${\rm{\forall }}i$$\end{document}$ which will imply that the modified LV competition model is the same with the classical LV competition model.
Following equations 4 and 11 in the paper of Hartley and Shorrocks^[@CR8]^, we arrived with the Lotka-Volterra competition model adding the effect of a few more individuals, shown on the following equations:$$\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$\{\begin{array}{c}\frac{d{x}_{1}}{dt}={b}_{1}{x}_{1}(1-{x}_{1}-{\alpha }_{12}{x}_{2})-{m}_{10}{{x}_{1}}^{1+\varepsilon }\,,\quad {b}_{1}\,{\rm{and}}\,{\alpha }_{12}\,{\rm{are}}\,{\rm{constant}}\\ \frac{d{x}_{2}}{dt}={b}_{2}{x}_{2}(1-{x}_{2}-{\alpha }_{21}{x}_{1})-{m}_{20}{{x}_{2}}^{1+\varepsilon },\quad {b}_{2}\,{\rm{and}}\,{\alpha }_{21}\,{\rm{are}}\,{\rm{constant}}\end{array}$$\end{document}$$where *ε* is any positive real number and $\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${m}_{i0}{{x}_{i}}^{1+\varepsilon }$$\end{document}$ is the effect of a few more individuals for all species *i*. Note that, we do not include the crowding effect on birth rates unlike the aggregation model of Hartley and Shorrocks^[@CR8]^.
In addition, we also used the modified LV competition model of Taylor and Crizer^[@CR21]^ with the inclusion of nonlinear crowding effect for two species. In their model, they add nonlinear competition terms to prevent the population of species 2 to have a smaller effect on the population of species 1 when the population density of species 1 is very small compare to the population density of species 2 and vice versa. Taylor and Crizer's competition model with nonlinear crowding effect is shown on the following equations:$$\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$$\{\begin{array}{c}\frac{d{x}_{1}}{dt}={b}_{1}{x}_{1}(1-{x}_{1}-{\alpha }_{12}{{x}_{2}}^{2})-({m}_{10}+{d}_{1}{{x}_{1}}^{\delta }){x}_{1}\,,\quad {b}_{1}\,{\rm{and}}\,{\alpha }_{12}\,{\rm{are}}\,{\rm{constant}}\\ \frac{d{x}_{2}}{dt}={b}_{2}{x}_{2}(1-{x}_{2}-{\alpha }_{21}{{x}_{1}}^{2})-({m}_{20}+{d}_{2}{{x}_{2}}^{\delta }){x}_{2},\quad {b}_{2}\,{\rm{and}}\,{\alpha }_{21}\,{\rm{are}}\,{\rm{constant}}\end{array}.$$\end{document}$$
Numerical simulations {#Sec6}
---------------------
In order to determine the impact of the inclusion of nonlinear crowding effects to the classical Lotka-Volterra equation we simulate the modified LV competition equations using Anaconda package of the software Python 3.6^[@CR22]^. Initially, we determine its effect if there are two competing species in a community and later extend it up to 10 competing species. We also determine the effect when we use small and large values of δ. Moreover, we identify the right combination of *d*~*i*~ and δ that will allow competing species to coexist. Without losing essential qualitative dynamics, we considered the following parameter ranges in our numerical simulations:0 ≤ Initial of *x*~*i*~ ≤ 1 for all *i*;0 \< *α*~*ij*~ ≤ 1 for all *i*, *j*;1 ≤ *b*~*i*~ ≤ 2 for all *im*~*i*0~ = 0.1 or 0.3 for all *i*;*d*~*i*~ = 0,0.1,0.3 or 0.5 for all *i*;0 ≤ δ ≤ 5; and*K*~*i*~ = 1
In addition, we compare the results of the LV competition equation ([1](#Equ1){ref-type=""}) with nonlinear crowding effect ($\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${m}_{i}={m}_{i0}+{d}_{i}{x}_{i}^{\delta }$$\end{document}$) and without nonlinear crowding effect (*m*~*i*~ = *m*~*i*0~) using the four possible cases of isoclines. The four isocline cases are:$\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${K}_{1} < \frac{{K}_{2}}{{\alpha }_{21}},{K}_{2} < \frac{{K}_{1}}{{\alpha }_{12}}$$\end{document}$$\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${K}_{1} < \frac{{K}_{2}}{{\alpha }_{21}},{K}_{2} > \frac{{K}_{1}}{{\alpha }_{12}}$$\end{document}$$\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${K}_{1} > \frac{{K}_{2}}{{\alpha }_{21}},{K}_{2} < \frac{{K}_{1}}{{\alpha }_{12}}$$\end{document}$$\documentclass[12pt]{minimal}
\usepackage{amsmath}
\usepackage{wasysym}
\usepackage{amsfonts}
\usepackage{amssymb}
\usepackage{amsbsy}
\usepackage{mathrsfs}
\usepackage{upgreek}
\setlength{\oddsidemargin}{-69pt}
\begin{document}$${K}_{1} > \frac{{K}_{2}}{{\alpha }_{21}},{K}_{2} > \frac{{K}_{1}}{{\alpha }_{12}}$$\end{document}$
where *K*~*i*~ is the carrying capacity of species *i* and *α*~*ij*~ represents the effect of species *j* on *i* where *i*, *j* = 1, 2 and *i* ≠ *j*.
Maica Krizna A. Gavina and Takeru Tahara contributed equally to this work.
**Publisher\'s note:** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This work was partly supported by grants-in-aid from the Japan Society for Promotion of Science (nos 22255004, 22370010, 26257405 and 15H04420 to JY; no. 26400388 to SM; nos 14J02983, 16H07075, 17J06741 and 17H04731 to HI; nos 25257406 and 16H04839 to TTo); and the Mitsubishi Scholarship (MISTU1722) to MKAG.
M.K.A.G., T.T.a., T.N. and J.Y. conceived the study. M.K.A.G., T.T.a., T.N. and J.Y. built and analyzed the model. M.K.A.G. and T.T.a. built a program and ran the numerical simulations. H.I., S.M., G.I. and T.O. verified the mathematical properties of the models. H.I., T.T.o. and J.Y. developed biological interpretations of the model. M.K.A.G., T.T.a. and J.Y. wrote the manuscript. M.K.A.G. and T.T.a. as the lead authors. All authors reviewed the manuscript and gave final approval for publication.
Competing Interests {#FPar1}
===================
The authors declare that they have no competing interests.
|
{
"pile_set_name": "PubMed Central"
}
|
Henry Allan (painter)
Henry Allan (18 June 1865 – 1912) was an Irish painter.
He was born at Retreat House, Dundalk, County Louth, Ireland, the youngest son of William Allan and his wife Anne. He studied art in Belfast and Dublin, and continued his art education in Antwerp, alongside contemporary Richard Moynan. He won multiple prizes at the Antwerp Academy as well as the Taylor Prize at the Royal Dublin Society.
He returned to Ireland in 1889 and lived for a year or two in Downpatrick, County Down, before moving to Dublin. He began exhibiting at the Royal Hibernian Academy (RHA) in 1889 with a painting entitled Country Road near Antwerp. His work, The Little Matchseller, was awarded the Albert Prize at the RHA in 1893. He also painted local scenes around Dublin and County Down as well as portraits, studio pieces and figure studies.
Allan's work is extremely rare on the market today and it may be that most of his work has been destroyed. The National Gallery of Ireland holds one example, A Dutch Interior, which was included in 'The Irish Impressionists' exhibition in 1984. The gallery's website notes that the style of this work, shows the influence of his training in Antwerp, "but the earthy colour range also invites comparison with the work of The Hague School".
References
Category:1865 births
Category:1912 deaths
Category:19th-century Irish painters
Category:20th-century Irish painters
Category:Irish male painters
Category:People from Dundalk
Category:Royal Academy of Fine Arts (Antwerp) alumni
|
{
"pile_set_name": "Wikipedia (en)"
}
|
Epilepsy
Epilepsy
The brain is a complex organ. It is made up of billions of nerve cells, each with a precise role to play in the functioning of the brain. Some of those functions include: controlling movements (voluntary and involuntary), sensations, emotions, memory and thought. The nerve cells communicate with one another through electrical signals. A change in regular brain electrical activity can result in a seizure. Epilepsy is not a mental illness, but rather a neurological disorder. Epilepsy affects 1 in every 100 Canadians.
Causes
In most cases, there is no identifiable cause for the onset of seizures. We do know however, that certain factors can trigger epileptic seizures, including:
Head trauma
Severe brain infection (e.g. meningitis)
Stroke
Substance abuse
Brain tumour
Problems with foetal brain development during pregnancy
Symptoms
There are several types of epileptic seizures. The kind of seizure depends on which part of the brain is affected. If the entire brain is involved, it is a generalized seizure. If only part of the brain is affected, it is known as a partial seizure. The characteristics of seizures vary greatly from one person to another. It is possible for a person with epilepsy to experience more than one type of seizure. The table below presents different types of seizures and some of the related symptoms. There are many more.
Partial (focal) Seizures
Generalized Seizures
Simple
No alteration of awareness
Unusual sensations (visual, olfactory, auditory, gastric, fear, etc.)
Sudden movements
Absence (petit mal)
Unresponsiveness
Blank stare, dazed appearance
Can be mistaken for inattentiveness (daydreaming)
Complex
Unresponsiveness
Automatisms or repeated motions
Tonic-clonic (grand mal)
Loss of consciousness
Generalized convulsion (muscle spasms)
Some persons with epilepsy experience auras or warnings that alert them to an impending seizure. This warning is, in itself, a simple partial seizure.
Status epilepticus is defined as a potentially life-threatening event whereby epileptics experience a series of recurring seizures from which they do not regain consciousness or a seizure that lasts long enough. If left untreated, status epilepticus can lead to severe brain damage.
Diagnosis
When diagnosing epilepsy, the physician will want to gather as much information about the seizure as possible. An exact description of the symptoms will help identify the affected area of the brain. He/she will also want to know whether it was an isolated occurrence or if there have been additional seizures. Another important point will be whether there were trigger factors (fever, infection) or if a medical condition is to blame. The physician will most likely order blood tests, medical imaging and an EEG (electroencephalograph) to rule out certain possibilities.
Treatment
To date, there is no curative drug on the market. There are however, certain medications known as anticonvulsants that allow persons with epilepsy to lead active lives by controlling and preventing seizures. Treatment generally involves taking only one type of anticonvulsant. Some people nevertheless, require a combination of drugs to keep their seizures under control. Finding the right medication or combination of medications and the ideal dose may take some time. Also, finding the dose that will prevent seizures and cause the least amount of side effects is also vital. It is important to note the frequency of seizures, accompanying symptoms and circumstances surrounding the event. Do not suddenly stop taking your medication.
Anticonvulsants can have an effect on the efficacy of many drugs. Always consult your physician or pharmacist before taking any other medication (prescription or over-the-counter). Avoid alcohol.
Certain measures can be taken to help limit seizures. These include avoiding triggers such as lack of sleep, the use of recreational drugs and drinking too much alcohol.
First Aid
Onlookers cannot do much more than wait for the seizure to stop and try to prevent the person from injuring themselves.
There is no need for special precautions or care when dealing with a person having a partial simple or generalized absence seizure.
As for partial complex seizures, stay close to the person and calmly reassure them.
Here are a few recommendations to follow when witnessing a tonic-clonic seizure:
Stay calm and reassure onlookers
Remove any objects that could harm the person
Do not put anything in the person's mouth
Do not move (except if there is imminent danger) or hold the person down
Gently turn unconscious persons onto their side to clear the airway
Place something soft under their head to protect it
Once the individual regains consciousness, gently reassure them. Most people with epilepsy can, after a seizure, resume their normal activities once they have rested.
If a seizure lasts (generally more than five minutes) or if seizures are recurrent and the person does not regain consciousness, immediately call for help to prevent status epilepticus, which could cause irreparable damage. Also, if the person is diabetic, pregnant or if the seizure occurs in water, it is recommended that you call an ambulance.
The patient information leaflets are provided by Vigilance Santé Inc. This content is for information purposes only and does not in any manner whatsoever replace the opinion or advice of your health care professional. Always consult a health care professional before making a decision about your medication or treatment.
|
{
"pile_set_name": "Pile-CC"
}
|
Left Coast Lion's Den
Main menu
Tag Archives: Western-attitudes
This column was published on UPI’s ReligionandSpirituality.com on October 30, 2006. It also headlined the UPI webpage’s religion section that day.
Americans have a problem when we talk about religion. Most of us think we’re more knowledgeable than actually we are, and, as a result, the plague of stereotypes traps us in our ignorance and foments enmity between religious communities.
Allow me to illustrate the American attachment to religious stereotypes by inviting you, esteemed reader, to play a game of “Religion Trivia:”
Thanks to my friend Randy Shadoe for passing along the video of Kyra Phillips and for our many enjoyable conversations and correspondences that keep me on my toes!
You too may have seen this one. The President is giving a speech to mark the first anniversary of Hurricane Katrina, and something goes terribly wrong in the CNN sound department. Suddenly we, the viewing audience, are hearing CNN anchor Kyra Phillips in the bathroom. We hear the zip of a garment, the flush of a toilet, and a conversation in which Ms. Phillips dishes some dirt on her sister-in-law.
It wasn’t long before this behemoth of a technical blunder was a momentary cultural sensation as video of the mishap bounced around cyberspace. To her great credit, Kyra Phillips went on Letterman to read a self-deprecating top ten list of excuses for what went wrong.
When I first saw the clip with Kyra Phillips’ private moment drowning out the President’s somber platitudes I laughed. It was great fun until the rusty cog wheels of my recollection began to turn, and through the fog of nearly twenty years of memory I recovered a bit of forsaken knowledge: I went to college with Kyra Phillips. Continue reading →
On June 22, The Pew Global Attitudes Project published the results of an extensive study called The Great Divide: How Westerners and Muslims View Each Other. One of the poll’s findings, which the study’s authors called “striking,” is that significant portions of the Muslim world believe the Bush Administration, the government of Israel, or both, conspired to carry out the September 11 attacks.
A few commentators, including Daniel Pipes have suggested that this proclivity to believe outlandish conspiracy theories is evidence of how different are the Muslim and non-Muslim worlds, but the results of another study conducted in July, suggest that a tendency to lend credence to bizarre beliefs about what happened on September 11 is something that the Muslim and non-Muslim worlds have in common.Continue reading →
|
{
"pile_set_name": "Pile-CC"
}
|
A second person in Pima County has been "presumptively diagnosed" with COVID-19 and is being treated at a local hospital, officials said.
How the patient contracted coronavirus is under investigation and that person's "household contacts are under observation in home isolation," officials said.
From Pima County:
A presumptive diagnosis was made March 13th at the Arizona State Public Health Laboratory in Phoenix. A sample will be sent to the Centers for Disease Control and Prevention in Atlanta, GA., for confirmation. The Health Department was notified Friday afternoon and is working hard to learn more about this individual’s potential exposure to the virus. At this time there is no clear link between this case and the presumptive case identified in Pima County on March 9. PCHD is working to identify additional close contacts that may have been exposed while the person was infectious. Any individuals who have been identified as having been exposed will be contacted directly. These individuals will be monitored for fever and respiratory symptoms in collaboration with PCHD and medical providers. This individual had recently traveled to another U.S. state, however, investigators are still working to identify whether or not this person contracted the virus during this travel.
"This new case highlights the importance of hospitals, doctors, public health, and the general public working closely together," said Dr. Bob England, director of the Pima County Health Department. "Our disease investigators have been working day and night to protect public health, and are in the process of identifying and reaching out to any people who may have been in contact with the case while infectious."
Cases tested in Arizona and other states are being deemed "presumptively positive," with test samples being sent to the CDC for further confirmation.
England said Friday evening that "there doesn't appear to be any link between" the two Pima cases. "Again, if you've got a disease where you're only able to test the sickest folks and you've got a lot of mild cases for each really sick person then you could have transmission from person to person to person, that you don't see, that links the two cases. But, we have no way of knowing that at this point."
Monday, officials announced that one other Pima County resident had been presumptively diagnosed with COVID-19. The patient, who had recently traveled to an area with "community spread," is "not severely ill" and is recovering at home.
"The patient is a resident of unincorporated Pima County. This individual is not severely ill, is currently recovering at home in isolation, and has been fully cooperative with public health monitoring," officials said.
Pima officials declined again Friday to release any details about the two COVID-19 patients here.
As of Friday morning, 143 people in Arizona have been tested for COVID-19 — the novel coronavirus that was first diagnosed in people late last year — with three confirmed positive cases and six "presumptive positive" cases the only ones in the state. Friday afternoon's announcement adds to that total. Another 40 tests were pending results, and 94 people have been ruled out, officials said.
The virus has caused the deaths of at least 47 people in the United States, with more than 2,000 people diagnosed as having the virus. There have been more than 4,000 deaths worldwide, with the World Health Organization declaring a pandemic Wednesday.
County officials refused to give any other details about the first person here who tested "presumptively" positive, only saying that they lived in unincorporated Pima County and had returned from traveling from an area known to be infected with COVID-19.
"We're keeping the details close because we don't want people to suspect their neighbor," England said.
'Common sense' urged
Earlier Monday, local officials urged residents to use "common sense" solutions against the COVID-19 virus, reminding people to wash their hands regularly, and stay home when they're sick. At that point, no positive tests had been announced in Pima County, but cases in Pinal County were evidence of "community transmission" there.
Tests still limited
Dr. Cara Christ, director of the Arizona Department of Health Services, said that state health authorities have a limited number of testing kits available.
"I understand and my numbers may be a little but outdated, we had enough to run 225 samples, we have not reached that capacity and we are expecting if we haven't already gotten another test kit in for another 150," she said Wednesday.
Tests are being limited because of the small supply, Gov. Doug Ducey and Christ said, despite President Trump's statement earlier this week that anyone who wants a test can get it.
"If you're symptomatic and you're in a position where you're part of the vulnerable population, that's where you would qualify for the test," the governor said.
Christ said that some patients require multiple test kits. "It's hard to determine how many patients that is because there's so many different factors that play a role in how many samples are getting utilized for each patient," she said.
Monday, Dr. England told TucsonSentinel.com that up to eight control tests are required for some individuals who are tested.
Arizona health emergency declared
Wednesday afternoon, Gov. Ducey declared a "public health emergency" prompted by the COVID-19 outbreak, allowing the state to request federal funds and deal with medical price-gouging.
"While our state is not currently facing the number of cases we've seen in some other states, we are anticipating additional positive cases — and we're not taking any chances," Ducey said in announcing his emergency declaration. "Arizonans should not panic — our approach will be calm and steady."
Ducey also ordered insurance companies to cover out-of-network providers and cover 100 percent of the cost for coronavirus care. He also announced that nursing homes and elder care facilities will begin implementing new visitor policies and enhanced symptom checks for staff members and visitors.
Ducey and Christ, speaking at a news conference Wednesday afternoon, downplayed suggestions that large gatherings be banned.
"At this time we are not recommending canceling mass gatherings in Arizona," Christ said. "So we are working right now with the CDC on brand-new community mitigation guidance that they just put out and we are not at a point where we would recommend those type of things, but we are constantly evaluating to see if those measures do take sense, but at this time we're not."
'Focus on protecting the vulnerable'
"I want you to think about three things that are our most important messages," county Chief Medical Officer Dr. Francisco Garcia said Monday. "Number one, this is the time to optimize your health and the health of your family. People who are healthy get over this virus, people who are unhealthy, or who are frail, who are elderly may have a harder time and it may have a more serious consequence," he said.
And, he said that people need to "focus on protecting the vulnerable."
"The vulnerable are the same vulnerable that are impacted every year during the flu season — these are our elders and medically frail individuals," he said, adding that they should stay our from crowds, including cruise ships and airplanes. "These folks need to be cocooned so that we can maintain their health," he said.
Garcia also said that the city and county should "settle-in for a long-term response," which includes making sure that employers allow people to stay home when they're sick.
England who also dealt with the county's response during the H1N1 outbreak in 2009, said that there hadn't been a positive result in Pima County, "but it really doesn't matter because it's going to be here, and it's going to transmit locally," he said. "and we need to begin treating it in that way as if we're expecting it."
"This is probably going to feel to us like a bad flu season, so just as we lose tens of thousands of Americans each and every year to the flu," COVID-19 "will tragically kill many people," said England. "There's no getting around that, but that' going to be something that we've all experienced every year because we go through the flu season every year," he said.
England said that while the illness might be deadly, testing in South Korea showed that COVID-19 might have a lower mortality rate than expected, running about 0.6 percent, or roughly one-fifth of the "often quoted figure that you see in the news."
"I'm sure we're much of the mild illnesses," he said, noting that cases from cruise ships showed that people were often "asymptomatic" and showed no signs of the disease, dragging the mortality rate down to the range of the flu. "We've got a lot to learn," he said, but he added that there were "good indications" for county and city officials to treat this in the same way that they treat influenza.
"So, I cannot foresee a circumstance under which we would close a school, or more the point all the schools," he said. "That would be terribly disruptive and the data just doesn't support it." He added that kids often have a less severe illness, and are often less likely to be infected by COVID-19.
- 30 -
|
{
"pile_set_name": "OpenWebText2"
}
|
Ion signalling in eukaryotic cells is essential for numerous physiological processes, including regulation of exocytosis, contraction, gene transcription and fertilization, as well as maintenance of cell membrane potential. Ion signalling is equally important in prokaryotic cells, e.g. in osmoregulation. Ion signalling in cells may be affected by alteration of extracellular and intracellular concentration of ions. Such alterations result in intracellular concentration changes in the forms of i) rapid increase followed by a rapid decrease (termed spikes), ii) a sustained, elevated concentration, or iii) repetitive spikes that produce an oscillation of characteristic frequency and amplitude. Due to technical limitations of available methods to decipher these complex signalling pathways, very little is known about the molecular and physiological effects on cells. A limitation of certain concern is the inability of available methods to provide controlled ion fluxes to cells to be studied.
Presently, transport of ions from, to or between electrolytes, such as from a stock solution to a cell culture medium, is performed by manual or automated use of e.g. pipettes, pumps or membranes. Such techniques result in unspecific delivery of ions to a cell culture medium as such only, whereas further diffusion to cells cultured in the medium is uncontrollable and unpredictable. Furthermore, said techniques require the use of expensive equipment. Examples of present methods for transport of ions are given below.
U.S. Pat. No. 6,780,584 discloses a device for the modulation of a reaction comprising: a first buffer reservoir containing a first buffer and a first charged entity, wherein the first buffer has an initial conductance less than 1000 μS/cm; a second buffer reservoir separated from the first buffer reservoir containing a second buffer comprising a second charged entity, wherein the second charged entity has a charge opposite that of the first charged entity, the second charged entity modulates the specific reaction between the specific binding entity and the first charged entity; a conductive semi permeable matrix contained in a non-conductive support material, the conductive semi permeable matrix disposed between and fluidically connecting the first buffer reservoir and the second buffer reservoir; a first electrode linked to a power source and located in the first buffer reservoir and contacting the first buffer; and a second electrode linked to the power source and located in the second buffer reservoir and contacting the second buffer; and a specific binding entity which reacts specifically with the first charged entity and which is physically fixed on, in, or adjacent to the semi permeable matrix.
U.S. Pat. No. 5,776,325 discloses a method of inducing mono-directional transport of ions between electrolyte solutions comprising separating the electrolyte solutions with a conducting polymer membrane and creating a potential gradient across said membrane wherein the potential gradient is created by using the conducting polymer membrane as a shared working electrode.
|
{
"pile_set_name": "USPTO Backgrounds"
}
|
Q:
Difference between symbolic execution and reachability analysis
Now I am confused about symbolic execution (SE) and reachability analysis (RA). As I know, SE uses symbols to execute some code to reach each branch with branch conditions. And RA can be used to find the reachability of each branch, right? When RA is used, we can extract the branch condition for each branch. If so, what's the difference between them? Can they be swift? Are they all static analysis?
A:
Generally, reachability analysis is a goal (determine which points in the code are reachable), whereas symbolic execution is a specific algorithmic technique (a tool for analyzing code). You can use symbolic execution for reachability analysis, or for other goals. Conversely, you can use other algorithms for reachability analysis.
Classically, symbolic execution was a static analysis. However, recently it has been widely used in a hybrid static-dynamic analysis: see, e.g., concolic execution. These hybrid methods seem to be very effective, but they are not purely static.
|
{
"pile_set_name": "StackExchange"
}
|
The influence of femoral technique for graft placement on anterior cruciate ligament reconstruction using a skeletally immature canine model with a rapidly growing physis.
The purpose of this study was to evaluate 3 different femoral techniques of anterior cruciate ligament (ACL) reconstruction using a skeletally immature canine model. A soft-tissue autograft ACL reconstruction was performed in 25 ten-week-old canines via a central transphyseal tibial tunnel and 1 of 3 femoral techniques: epiphyseal, over the top, or transphyseal. The contralateral hind limbs served as controls. The canines were killed at 16 weeks postoperatively and evaluated by gross inspection, plain radiographs, photography, magnetic resonance imaging, and histomorphometry. There were no significant differences in femoral longitudinal growth; however, tibial growth was significantly greater on the experimental side relative to controls (P = .001). Angular and rotational deformities were noted on the femoral side but not on the tibial side. The epiphyseal technique resulted in less angular deformity and most closely maintained the anatomic position of the ACL graft with growth; however, this technique exhibited increased femoral rotational deformity. All techniques exhibited a high rate of graft failure. Magnetic resonance imaging revealed chondral and subchondral injuries to the lateral femoral condyle, most frequently in the epiphyseal group. From the results of our study, we cannot advocate any single femoral reconstructive technique. An epiphyseal femoral technique may reduce the risk of angular deformity and allow a more optimal femoral graft position after growth as opposed to transphyseal and over-the-top techniques. However, the epiphyseal technique may possess an increased risk for rotational deformity, physeal injury, and articular surface injury. Metaphyseal fixation of ACL grafts traversing rapidly growing physes may be responsible for the observed abnormalities in graft integrity, femoral graft position, and femoral angulation and rotation. ACL reconstruction in the skeletally immature individual is complicated by the presence of active physeal and epiphyseal cartilage surrounding the growing knee, the pathophysiologic consequences of injury to these developing structures, and the final effect on the anatomy and function of the graft, bone, and articular surface. Animal models can provide insight and direction as we develop and evaluate our treatment methods for this clinical problem, but these animal models have anatomic and physiologic differences that limit direct comparison to humans.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
Endometrial cancer, obesity, and body fat distribution.
A case-control study was undertaken to evaluate the roles of obesity and body fat distribution in the etiology of endometrial cancer. The study also included an evaluation of the associations of serum estrone, estradiol, and androstenedione with obesity, body fat distribution, and endometrial cancer risk. The study included 168 cases and 334 control subjects identified at an optometry clinic. A strong, positive relationship between overall obesity and endometrial cancer was found. The relative rate of endometrial cancer for women in the upper 90th percentile of a body mass index compared to those below the median was estimated as 5.5 with 95% confidence limits of 3.2-9.6. There was no association between endometrial cancer and the waist to hip ratio, an index of upper versus lower body fat distribution. A statistical test of trend across the four quartiles of the waist to hip ratio yielded a P value of 0.45 after adjustment for confounding by the body mass index. On the other hand, there was a statistically significant, independent positive effect of a high subscapular to tricep skinfold ratio, a measure of central versus peripheral obesity, on endometrial cancer risk. The relative rates of endometrial cancer for the second, third, or fourth quartile compared to the first quartile of this index were 1.5, 1.9, and 2.7, respectively (P = 0.007), after adjustment for the body mass index. Serum estrone and estradiol, but not androstenedione, were statistically significantly correlated with the body mass index among control subjects (r = 0.37 and 0.40 for estrone and estradiol, respectively). On the other hand, each of the sex hormones was uncorrelated with the waist to hip ratio after adjustment for body mass. The correlations between each of the three hormones and the subscapular to tricep skinfold ratio among controls were weak and were not statistically significant (0.10, 0.10, and 0.14 for estrone, estradiol and androstenedione, respectively). Cases had statistically significantly higher mean serum estrogen and androstenedione levels than did controls and these elevations did not simply reflect a higher prevalence of obesity among them. The findings are equivocal with respect to fat patterns and endometrial cancer. We suggest that future epidemiological studies of cancer and body fat distribution more carefully distinguish among the various types of fat patterns.
|
{
"pile_set_name": "PubMed Abstracts"
}
|
/*******************************************************************************
* Copyright (c) Microsoft Open Technologies, Inc.
* All Rights Reserved
* Licensed under the Apache License, Version 2.0.
* See License.txt in the project root for license information.
******************************************************************************/
#import "MSOrcEntityFetcher.h"
#import "MSOrcBaseContainer.h"
#import "MSOrcOperations.h"
#import "MSOrcObjectizer.h"
#import "api/MSOrcRequest.h"
#import "api/MSOrcURL.h"
@interface MSOrcEntityFetcher()
@property (copy, nonatomic, readonly) NSString *select;
@property (copy, nonatomic, readonly) NSString *expand;
@end
@implementation MSOrcEntityFetcher
@synthesize operations = _operations;
- (instancetype)initWithUrl:(NSString *)urlComponent
parent:(id<MSOrcExecutable>)parent asClass:(Class)entityClass {
if (self = [super initWithUrl:urlComponent parent:parent asClass:entityClass]) {
_operations = [[MSOrcOperations alloc] initOperationWithUrl:@"" parent:parent];
_expand = nil;
_select = nil;
}
return self;
}
- (void)orcExecuteRequest:(id<MSOrcRequest>)request
callback:(void (^)(id<MSOrcResponse> response, MSOrcError *error))callback {
id<MSOrcURL> url = request.url;
[url appendPathComponent:self.urlComponent];
if (self.select != nil) {
[url addQueryStringParameter:@"$select" value:self.select];
}
if (self.expand != nil) {
[url addQueryStringParameter:@"$expand" value:self.expand];
}
[MSOrcBaseContainer addCustomParametersToOrcURLWithRequest:request
parameters:self.customParameters
headers:self.customHeaders
dependencyResolver:super.resolver];
return [super.parent orcExecuteRequest:request callback:^(id<MSOrcResponse> r, MSOrcError *e) {
callback(r,e);
}];
}
- (void)update:(MSOrcBaseEntity <MSOrcInteroperableWithDictionary> *)entity callback:(void (^)(id updatedEntity, MSOrcError *error))callback {
NSDictionary *updatedValues = [entity toUpdatedValuesDictionary];
NSString *payload = [MSOrcObjectizer deobjectizeToString: updatedValues];
return [self updateRaw:payload callback:^(NSString *response, MSOrcError *e) {
if (e == nil) {
id entity = [MSOrcObjectizer objectizeFromString: response toType: self.entityClass];
callback(entity, e);
}
else {
callback(nil, e);
}
}];
}
- (void)updateRaw:(NSString*)payload
callback:(void (^)(NSString *entityResponse, MSOrcError *error))callback {
id<MSOrcRequest> request = [self.resolver createOrcRequest];
[request setContent:[NSMutableData dataWithData:[payload dataUsingEncoding:NSUTF8StringEncoding]]];
[request setVerb:HTTP_VERB_PATCH];
return [self orcExecuteRequest:request callback:^(id<MSOrcResponse> response, MSOrcError *e) {
if (e == nil) {
callback([[NSString alloc] initWithData:response.data encoding:NSUTF8StringEncoding], e);
}
else {
callback(nil, e);
}
}];
}
-(void)deleteWithCallback:(void (^)(int statusCode, MSOrcError *error))callback {
id<MSOrcRequest> request = [self.resolver createOrcRequest];
[request setVerb:HTTP_VERB_DELETE];
return [self orcExecuteRequest:request callback:^(id<MSOrcResponse> r, MSOrcError *e) {
callback(r.status, e);
}];
}
- (void)readRawWithCallback:(void (^)(NSString *entityString, MSOrcError *error))callback {
id<MSOrcRequest> request = [self.resolver createOrcRequest];
return [self orcExecuteRequest:request callback:^(id<MSOrcResponse> response, MSOrcError *e) {
if (e == nil) {
callback([[NSString alloc] initWithData:response.data encoding:NSUTF8StringEncoding], e);
}
else {
callback(nil, e);
}
}];
}
- (void)readWithCallback:(void (^)(id result, MSOrcError *error))callback {
return [self readRawWithCallback:^(NSString *r, MSOrcError *e) {
if (e == nil) {
id entity = [MSOrcObjectizer objectizeFromString: r toType: self.entityClass];
callback(entity, e);
}
else {
callback(nil, e);
}
}];
}
- (MSOrcEntityFetcher *)select:(NSString *)params {
_select = params;
return self;
}
- (MSOrcEntityFetcher *)expand:(NSString *)value {
_expand = value;
return self;
}
+ (void)setPathForCollectionsWithUrl:(id<MSOrcURL>)url
top:(int)top
skip:(int)skip
select:(NSString *)select
expand:(NSString *)expand
filter:(NSString *)filter
orderby:(NSString *)orderBy
search:(NSString *)search {
if (top > -1) {
[url addQueryStringParameter:@"$top" value:[[NSString alloc] initWithFormat:@"%d", top]];
}
if (skip > -1) {
[url addQueryStringParameter:@"$skip" value:[[NSString alloc] initWithFormat:@"%d", skip]];
}
if (select != nil) {
[url addQueryStringParameter:@"$select" value:select];
}
if (expand != nil) {
[url addQueryStringParameter:@"$expand" value:expand];
}
if (filter!= nil) {
[url addQueryStringParameter:@"$filter" value:filter];
}
if (orderBy != nil) {
[url addQueryStringParameter:@"$orderBy" value:orderBy];
}
if (search != nil) {
[url addQueryStringParameter:@"$search" value:search];
}
}
@end
|
{
"pile_set_name": "Github"
}
|
NEON COLLEGE ON STA TEE
￥7,344
http://zozo.jp/shop/bapeland/goods/11829173/?did=27311914
BATHING APE LOGO TEE
￥7,344
BY BATHING TEE
￥7,344
http://zozo.jp/shop/bapeland/goods/11861912/?did=27362912
MILO COLLEGE TEE
￥7,344
MILO ON BIG APE HEAD TEE
￥7,344
http://zozo.jp/shop/bapeland/goods/11786830/?did=27260982
MULTI LOGO TEE
￥8,640
http://zozo.jp/shop/bapeland/goods/11786695/?did=27260288
TROPICAL CAMO TANK TOP
￥7,560
http://zozo.jp/shop/bapeland/goods/11786698/?did=27260299
1ST CAMO COLLEGE TEE
￥10,800
http://zozo.jp/shop/bapeland/goods/11786701/?did=27260324
CREWNECK SS
￥13,824
http://zozo.jp/shop/bapeland/goods/11786708/?did=27260367
BAPE STA POLO
￥12,960
http://zozo.jp/shop/bapeland/goods/11786703/?did=27260329
LARGE APE HEAD CHAMBRAY BD SHIRT
￥21,384
http://zozo.jp/shop/bapeland/goods/11732292/?did=27170484
COLLEGE SNAP BACK CAP
￥8,640
http://zozo.jp/shop/bapeland/goods/11861827/?did=27362440
APE HEAD CAP
￥8,640
http://zozo.jp/shop/bapeland/goods/11829130/?did=27311724
TYPE 1 BAPEX
￥49,464
http://zozo.jp/shop/bapeland/goods/11786716/?did=27260393
TYPE 1 BAPEX
￥52,704
http://zozo.jp/shop/bapeland/goods/11786712/?did=27260386
http://zozo.jp/shop/bapeland/goods/11786687/?did=27260250
￥7,344￥7,344￥7,344￥7,344￥7,344￥8,640￥7,560￥10,800￥13,824￥12,960￥21,384￥8,640￥8,640￥49,464￥52,704
Listed prices are Japan retail in Yen (￥).Japan retail is 40-50% less than US, UK and EU stores.We highly recommend you order from Japan if the item is still available.Ordering is easy! Our guide will walk you through the process, step-by-step.~~~~If you can't find it on Bape.com, then it's currently sold out.If no Zozo link has been posted, check back the following day.~~
|
{
"pile_set_name": "OpenWebText2"
}
|
Vince,
I spoke with Whalley at the SA offsite and he mentioned that had (or knew of)
a person that could bring some talent to the evaluation of an Enron merchant
business in Japan. I am in Sydney today, but will be in Tokyo next week. I
would like to speak more about this. What time might you be available? My
Japan mobile number is 81 90 4073 6761.
regards,
Joe
|
{
"pile_set_name": "Enron Emails"
}
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.