![]() ![]() Optimization of soluble gamma-secretase modulators for the treatment of Alzheimer’s disease PDE4D allosteric modulators for treating cognitive impairment ![]() Small-molecule development of PrPc antagonists for the treatment of Alzheimer’s disease ![]() Triazine-based compounds to promote regeneration in optic neuropathies Targeting cytokine-mediated pathologies for neuroprotection in treatment of AMD Small-molecule drugs for treatment of dry age-related macular degeneration It should be noted that projects from academic institutions were highly represented throughout the stages of the program (60% of projects at the onset, 80% of projects reaching the preclinical safety stage) demonstrating the quality of the starting projects and success of our mentoring from our NIH staff and consultants. The regular interactions allowed for maximum benefit of the BPN infrastructure and consultants’ expertise to the grantees, as well as focusing efforts on critical path activities. Additionally, as projects progressed, Lead Discovery Teams met face-to-face at major transition points such as start of Lead Optimization, Start of Development and Investigational New Drug preparation. Formal milestone reviews with go/no go decisions for continued funding typically occurred once or twice a year depending on the stage of the program. Through these meetings, progress was measured against milestones, and scientific direction was altered collaboratively based on emerging data in order to give the teams the best chance at meeting their milestones and advancing further. The BPN formed customized Lead Discovery Teams around each of the grantees’ project needs and worked in a collaborative fashion, typically meeting every 2 weeks via web-enabled meetings. The BPN launched 15 projects over the period 2011 to 2013, directed at 13 different disease indications in the mission of 7 different BPN ICs (listed in Table Table1). In practice, each application round was reviewed by a National Institute of Neurological Disorders and Stroke Special Emphasis Panel consisting of members with disease expertise, as well as drug discovery and development experts with industry experience in multiple disciplines. Therefore, careful consideration was given in the program to ensure that intellectual property of the contributing academic institution or small business was protected and unencumbered by the NIH in order to simplify licensing discussions with pharma and venture capital investors.Īs a first-of-its-kind program at NIH, we projected prelaunch a 50% attrition at each stage considering an overall lower success rate for central nervous system drugs, limited NIH resources, and the average industry attrition rates. ![]() Another explicit goal of the BPN was to de-risk the development of new, impactful therapies that could attract commercial interest enabling a hand-off to industry for late-stage development and additional clinical trials. The BPN’s initial target was to start up to 20 milestone-driven projects and advance those projects with the most promise of obtaining Food and Drug Administration approval to enter and execute phase I clinical trials with BPN resources. NIH = National Institutes of Health PK/Tox = pharmacokinetics/toxicology The BPN is a milestone-driven cooperative agreement program bringing together a unique blend of grant dollars, industry-standard scientific expertise, and contract resources to foster drug development from the discoveries of academic and small businesses with the goal of advancing at least one compound into clinical trials by the end of the first 5 years. To foster small-molecule neurotherapeutic development, the NIH Blueprint Neurotherapeutics Network (BPN) ( ) was launched in 2011, creating a first-of-its-kind virtual pharma network at NIH (Fig. With many biopharmaceutical companies exiting or significantly downsizing their neuroscience efforts in the last decade, it highlighted the need for NIH to provide a catalyst for neuroscience drug discovery efforts. To address the need for crosscutting neuroscience research, the NIH established the NIH Blueprint for Neurological Research ( ) comprised of 15 separate NIH ICs whose missions have neuroscience components. Neuroscience encompasses a wide variety of diseases and spans the missions of many of the National Institutes of Health (NIH) Institutes and Centers (ICs). ![]()
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However, there are exceptions mixed flocks may occur in migration, being recorded with up to 10,000 birds in one instance at Fuerte Esperanza, Argentina. Migration normally occurs in groups of 20 to 30 birds. This species migrate to southern subtropical South America in the winter, mostly to Argentina and Brazil. ![]() As well, the territory has expanded westwards due to shelterbelts being planted in grassland habitats. Another pair was observed breeding in Ohio in 2007. Breeding territory has expanded in recent years and Mississippi kites have been regularly recorded in the southern New England states a pair has successfully raised young as far north as Newmarket, New Hampshire. The summer breeding territory of the Mississippi kite is in the central and southern United States the southern Great Plains is considered a stronghold for the species. The call is a high-pitched squeak, sounding similar to the noise made by a squeaky toy. The bird is 12 to 15 inches (30–37 cm) beak to tail and has a wingspan averaging 3 feet (91 cm). Young kites have banded tails and streaked bodies. Males and females look alike, but the males are slightly paler on the head and neck. Kites of all ages have red eyes and red to yellow legs. Description Īdults are gray with darker gray on their tail feathers and outer wings and lighter gray on their heads and inner wings. It is currently classified in the subfamily Buteoninae, tribe Buteonini. He had first observed the species in the Mississippi Territory, while the bird's long pointed wings and forked tail suggested that it was a type of kite. ![]() ![]() Wilson also gave the Mississippi kite its English-language common name. The genus name derives from the Greek iktinos, for "kite". The current genus of Ictinia originated with Louis Jean Pierre Vieillot's 1816 Analyse d'une nouvelle Ornithologie Elémentaire. Wilson gave the kite the Latin binomial name of Falco mississippiensis: Falco means "falcon", while mississippiensis means from the Mississippi River in the United States. The Mississippi kite was first named and described by the Scottish ornithologist Alexander Wilson in 1811, in the third volume of his American Ornithology. It is common to see several circling in the same area. Mississippi kites have narrow, pointed wings and are graceful in flight, often appearing to float in the air. The Mississippi kite ( Ictinia mississippiensis) is a small bird of prey in the family Accipitridae. ![]() ![]() ![]() When he is handed a financial lifeline, he gambles it away. ![]() He steals from his mother and forgets his daughter’s birthday. As we become invested in Gi-hun, we watch him as he lets us down over and over again. In Lee’s performance, we see all the big and small humiliations of capitalism: the feeling of your worth being tethered to your productivity the magical thinking that once you’re rich, you’ll be a different person the embarrassments we are willing to endure to afford what we think we deserve. It’s a villain viewers everywhere can identify.Īt the center of it all is Seong Gi-hun, a chauffeur addicted to gambling and self-sabotage, played brilliantly by Lee Jung-jae. Regardless of the country or language, capitalism is the shared villain in Netflix’s global successes. But these shows also share a common throughline: They all deal with inequality, capture the despair of poverty, and dissect class anxiety. The dizzying success of Squid Game and the triumph of other non-English shows may finally kill the unfounded idea that North American viewers - the largest share of Netflix’s audience - are not interested in watching foreign shows. Out of its top ten most viewed series, two of them are also not in English and boast no Hollywood megastars: the French Lupin sits in second place while the Spanish-language hit Money Heist occupies the sixth position. Earlier this week, Netflix released some of its viewing data. But zoom out more, and the picture becomes clearer. For one, the popularity of K-dramas has grown by 200% among Netflix subscribers in just the last two years. ![]() If the success of Squid Game is a surprise, it’s not exactly without precedent. In two short weeks, it has become a bonafide phenomenon. The internet is awash in Squid Game memes, games, and TikTok challenges. And yet it’s a megahit, with 95% of its audience outside Korea. More shocking still: It boasts no Hollywood megastars and it’s not based on any existing intellectual property that comes with a preloaded fanbase. It’s difficult enough for new shows to break through the noise with so much TV content, but Squid Game’s success is an astonishing feat for a show that was released on the platform less than two weeks ago, to little fanfare. At this point, we are deep in the Squid Game hype cycle, and for good reason: the Korean drama is not only the top show on Netflix in 90 countries, but this week Ted Sarandos, the streaming platform’s CEO, hypothesized that “it might be our biggest show ever.” That’s nuts. ![]() ![]() ![]() Adding some bling to the collection are the shimmery ankle boots that will make for the perfect partner to hit the clubs with. We have quilted boots, boots with embellishments and many other styles for you to choose from.įor your evening looks, our fab heeled shoes are sure to make a charming pick. Go for mid-calf length boots to get your style game going on casual dates and evenings with your friends. Choose your pick from zippered boots and lace ups. 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When in the agitated state, the bat will either pick up or swap what it currently carries with an object in the present room, eventually returning to the non-agitated state where it will not pick up an object. The bat's two states are agitation and non-agitation. An enemy bat can roam the kingdom freely, carrying an item or a dragon around the bat was to be named Knubberrub but the name is not in the manual. The kingdom is guarded by three dragons-the yellow Yorgle, the green Grundle, and the red Rhindle-that protect or flee from various items and attack the player's avatar. The kingdom is made of a total of thirty rooms, with various obstacles, enemies, and mazes located in and around the Golden, White, and Black Castles. In Adventure, the player's goal is to recover the Enchanted Chalice that an evil magician has stolen and hidden in the kingdom and return it to the Golden Castle. Gameplay The player with the White Key in the White Castle's catacombs, pursued by the green dragon, Grundle The game's prototype code was used as the basis for the 1979 Superman game, and a planned sequel eventually formed the basis for the Swordquest games. More than one million cartridges of Adventure were sold, and the game has been included in numerous Atari 2600 game collections for modern computer hardware. It is considered the first action-adventure and console fantasy game, and inspired other games in the genres. While not the first such Easter egg, Robinett's secret room pioneered this idea within video games and other forms of media, and since has transcended into popular culture, such as the climax of Ernest Cline's book and film adaption Ready Player One.Īdventure received mostly positive reviews at the time of its release and in the decades since, often named as one of the industry's most influential games and among the greatest video games of all time. As a result of conflicts with Atari's management which denied giving public credit for programmers, Robinett programmed a secret room that contained his name within the game, only found by players after the game shipped and Robinett had left Atari. ![]() ![]() Warren Robinett spent approximately one year designing and coding the game, while overcoming a variety of technical limitations in the Atari 2600 console hardware, as well as difficulties with management within Atari. The game was conceived as a graphical version of the 1977 text adventure Colossal Cave Adventure. Adventure introduced new elements to console games, including enemies that continue to move when offscreen. The game world is populated by roaming enemies: three dragons that can eat the avatar and a bat that randomly steals and hides items around the game world. ![]() The player controls a square avatar whose quest is to explore an open-ended environment to find a magical chalice and return it to the golden castle. Adventure is a video game developed by Warren Robinett for the Atari Video Computer System (later renamed Atari 2600) and released in 1980 by Atari, Inc. ![]() ![]() The green square-shapes are the Entropy values for p(28/70) and (12/50) of the first two child nodes in the decision tree model above, connected by a green (dashed) line. So, why is this happening? For an intuitive explanation, let’s zoom in into the Entropy plot: Thus, the splitting rule would continue until the child nodes are pure (after the next 2 splits). In contrast to the average classification error, the average child node entropy is not equal to the entropy of the parent node. Next, let’s see what happens if we use Entropy as an impurity metric: In this case, splitting the initial training set wouldn’t yield any improvement in terms of our classification error criterion, and thus, the tree algorithm would stop at this point (for this statement to be true, we have to make the assumption that neither splitting on feature x2 nor x3 would lead to an Information gain as well). Now, is it possible to learn this hypothesis (i.e., tree model) by minimizing the classification error as a criterion function? Let’s do the math:Īs we can see, the Information Gain after the first split is exactly 0, since average classification error of the 2 child nodes is exactly the same as the classification error of the parent node (40/120 = 0.3333333). Further, let’s assume that it is possible to come up with 3 splitting criteria (based on 3 binary features x1, x2, and x3) that can separate the training samples perfectly: Let’s consider the following binary tree starting with a training set of 40 “positive” training samples (y=1) and 80 training samples from the “negative” class (y=0). Here comes the more interesting part, just as promised. Or all non-empty classed p(i ❘ t) ≠ 0, where p(i ❘ t) is the proportion (or frequency or probability) of the samples that belong to class i for a particular node t C is the number of unique class labels.Īlthough we are all very familiar with the classification error, we write it down for completeness: (Note that since the parent impurity is a constant, we could also simply compute the average child node impurities, which would have the same effect.)įor simplicity, we will only compare the “Entropy” criterion to the classification error however, the same concepts apply to the Gini index as well. Impurity Metrics and Information Gainįormally, we can write the “Information Gain” as * This is the important part as we will see later. Splitting a note does not lead to an information gain*.Stop if leave nodes are pure or early stopping criteria is satisfied, else repeat steps 1 and 2 for each new child node.Assign training samples to new child nodes.Split the parent node at the feature x i to minimize the sum of the child node impurities (maximize information gain).Machine Learning FAQ Why are we growing decision trees via entropy instead of the classification error?īefore we get to the main question – the real interesting part – let’s take a look at some of the (classification) decision tree basics to make sure that we are on the same page. ![]() ![]() ![]() ![]() ![]() Aviv Kohavi and then to the security cabinet for approval. The military said the attack that killed St.-Sgt. Heavy barrages of rockets were fired at central and southern Israel Wednesday, 7 injured in Sderot due to direct hit, 5-year-old Ido Avigail has died from his wounds. The plans will be presented to IDF Chief of Staff Lt.-Gen. The IDF used artificial intelligence and supercomputing during the last conflict with Hamas in the Gaza Strip. Sergeant Omer Tabib, 21, was identified as the IDF soldier who was killed. Hidai Zilberman said that a ground invasion remained a viable option. Leaves have been suspended in the combat units in preparation for a possible ground operation, for which troops have been redeployed to the Gaza border from the Paratroopers Brigade, Golani Infantry Brigade and 7th Armored Brigade. Omer Tabib of the Nahal Brigade, was killed this morning by an Anti-Tank missile fired by Hamas from Gaza into Israel. Doctors, paramedics, intelligence and other combat units were included in the call-up. Omar Tene, The Right to Privacy Following the Basic Law of Human Dignity: A Conceptual. Can someone fact check it This reminds me of the one shot two kills t-shirt by idf mocking shooting pregnant women. Iran’s Supreme Leader Ayatollah Ali Khamenei incited the Arab masses in Jerusalem, Judea, and Samaria in the weeks leading up to the war, calling upon Palestinian Arabs to defend the al. The Israeli military derives its powers in the West Bank from. The soldiers will be sent to artillery units and to man the Iron Dome Missile Defense System, which will be adding another battery. So about the recently dead idf soldier omar tahib Saw a tweet about him bragging about raping a palestinian woman and smoking.I just put it up on me profile. (Omri Stein/Flash90)Īs terrorist groups in Gaza continued to fire barrages of rockets at southern and central Israel on Thursday evening, the IDF has called up 7,000 reservists to bolster its response. 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The resurgence in the popularity of cigars is continuing unabated, and we are pleased to be on the forefront of bringing world-class cigars to the public at very affordable prices. ![]() ![]() ![]() Photosweeper has a lot of settings, all of which seem straightforward. I tested Photosweeper with an enormous set of images stored on an external drive connected to a Mac mini via USB 3, and it performed extremely well, scanning over 200GB of images (nearly 50,000) in several minutes, generating previews as it went.Īt that point, you can view images as in a photo browser, but you click the Compare button to engage the real functionality. You can also use a Media Browser option that lets you drag any of those library types into a window and then look through them. The app starts by having you pick locations to scan, and it automatically recognizes libraries for iPhoto, Photos, Aperture, and Adobe Lightroom, allowing it to parse the storage format and look inside packages, instead of indexing endless thumbnails and other files that are used directly by those apps. IDGĪ Media Browser lets you examine images stored in iPhoto, Photos, Aperture, or Lightroom libraries, and then add them to compare. The developers promise eternal free upgrades to new releases, which is a bonus. Depending on how many systems you have and photos you take, you might wind up using it every few months. But with Photosweeper’s modest cost and laser focus, it’s worth the price. Some other software, especially disk uncluttering packages, include image-duplication scanning. ![]() So, w/ stricter recognition it’s a byte for byte comparison? no possibility of error? In any case, a 3rd party app would give me more options like deleting only from certain folders or multiple versions of photos, etc.App Store is a well-updated version of software designed to solve this problem with a high degree of customization and specificity. ![]() For non-exact copies I need a quick way to make decisions and delete or I’ll be at it till 2032. I just want to clean it all up, but there are thousands of duplicates and I need to find a faster way to be sure they are exact copies. Add to that importing files from various old drives (again to be sure I had everything), and now I’m left w/ a huge regrettable mess. I experimented w/ index vs non-indexed databases and because I couldn’t be sure if I had deleted something accidentally (something I actually did a couple times and couldn’t figure out exactly which files), I kept them all to be sure. This article talks about doing this before importing, but the files are already imported: DEVONtechnologies DEVONtechnologies | How to Find and Remove DuplicatesĭEVONtechnologies develops DEVONthink, DEVONagent, and other Mac and iOS apps for document and information management and web research. Thoughts on using a 3rd party application? Sadly, I have thousands of duplicates/triplicates and need to speed up the process. In general, I’m nervous to delete duplicates in DT as I had the experience of deleting things that weren’t duplicates even after selecting stricter recognition of duplicates. A duplicate detector can give me more precise control over differences in files and photos, but I’m not sure if it would corrupt a non-indexed database somehow to delete them on the file level instead of via the DT interface. I actually have a lot of versions of docs that I do need to differentiate, as well as images that might be slightly different (not sure how DT handles that). I read that the DT duplicate detection is not byte for by, giving the example that the difference of only a comma would make the file essentially the same. ![]() |
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