Miracle-dz/UniFAR-FTUs huggingface dataset:
Quantifying the unobserved protein-coding variants in human populations provides a roadmap for large-scale sequencing projects

As new proposals aim to sequence ever larger collection of humans, it is critical to have a quantitative framework to evaluate the statistical power of these projects. We developed a new algorithm, UnseenEst, and applied it to the exomes of 60,706 individuals to estimate the frequency distribution of all protein-coding variants, including rare variants that have not been observed yet in the current cohorts. Our results quantified the number of new variants that we expect to identify as sequencing cohorts reach hundreds of thousands of individuals. With 500K individuals, we find that we expect to capture 7.5% of all possible loss-of-function variants and 12% of all possible missense variants. We also estimate that 2,900 genes have loss-of-function frequency of less than 10-5 in healthy humans, consistent with very strong intolerance to gene inactivation.
Rapid Publication In Vivo Neutralization of Eosinophil-derived Major Basic Protein Inhibits Antigen-induced Bronchial Hyperreactivity in Sensitized Guinea Pigs

This study examines the effect of purified rabbit anti– guinea pig eosinophil-derived major basic protein (MBP) Ig on antigen-induced bronchial hyperreactivity to inhaled acetylcholine in aerosol-sensitized guinea pigs. Ovalbumin inhalation by sensitized guinea pigs induced a rise in the numbers of eosinophils and in the levels of MBP in the bronchoalveolar lavage fluid, which peaked at 24 h and resolved at 72 h. Antigen-challenged animals exhibited bronchial hyperreactivity to inhaled acetylcholine at 72 h, but not at 6 or 24 h. The intranasal administration of 200 m l of purified rabbit anti–guinea pig MBP Ig, at 2.5 mg/ml, but not of the control preimmune rabbit Ig, 1 h before and 5 h after ovalbumin inhalation suppressed bronchial hyperreactivity to acetylcholine at 72 h without affecting the number of eosinophils accumulating in the bronchoalveolar lavage fluid. These findings indicate that antigen challenge in sensitized guinea pigs is followed by early eosinophil infiltration and activation within the airways and by late bronchial hyperreactivity. Neutralization of endogenously secreted MBP by a specific antiserum prevented antigen-induced bronchial hyperreactivity, suggesting that eosinophil degranulation plays an important role in the alterations of bronchopulmonary function in the guinea pig. ( J. Clin. Invest. 1996. 97:1117– 1121.)
ect of Video-on-Demand on Piracy : Evidence From a Household Level Randomized Experiment ⇤

We partner with a major multinational telecommunications provider to analyze the e↵ect of Subscription Video-on-Demand (SVoD) services on digital piracy. For a period of 45 consecutive days, a group of randomly selected households who used BitTorrent in the past were gifted with a bundle of TV channels with movies and TV shows that could be streamed as in SVoD. We find that, on average, households that received the gift increased overall TV consumption by 4.6% and reduced Internet downloads and uploads by 4.2% and 4.5%, respectively. However, and also on average, treated households did not change their likelihood of using BitTorrent during the experiment. Our findings are heterogeneous across households and are mediated by the fit between the preferences of households in our sample for movies and the content available as part of the gifted channels. Households with preferences aligned with the gifted content reduced their probability of using BitTorrent during the experiment by 18% and decreased their amount of upload tra c by 45%. We also show using simulation that the size of the SVoD catalog and licensing window restrictions limit significantly the ability of content providers to match SVoD o↵erings to the preferences of BitTorrent users. Finally, we estimate that households in our sample are willing to pay at most $3.25 USD per month ⇤The authors thank Ricardo Guizado, Antonio Moreira, Filipa Reis and Chris Yang for excellent research assistantship. They thank Rodrigo Belo, Brett Danaher and Rahul Telang for valuable comments to earlier versions of this paper and for many brainstorming sessions. The authors thank the Industrial Partner for their support and they thank organizers and participants in the Workshop on Digitization and Economics of IT of the 2015 NBER Summer Institute for their comments and feedback. This research was partially funded by Carnegie Mellon University’s Initiative for Digital Entertainment Analytics (IDEA), which receives unrestricted (gift) funding from the Motion Picture Association of America. This research was conducted independently without any oversight or editorial control. All remaining errors are entirely our own. 1 to access a SVoD catalog as large as Netflix? s in the US. Together, our results show that, as a stand-alone strategy, using legal SVoD to curtail piracy will require, at the minimum, o↵ering content much earlier, and at much lower prices than those currently o↵ered in the marketplace ? changes that are likely to reduce industry revenue and may damage overall incentives to produce new content while, at the same time, might curb only a small share of piracy.
Structural brain and neuropsychometric changes associated with pediatric bipolar disorder with psychosis.

OBJECTIVES To identify neuropsychological and structural brain changes using a combination of high-resolution structural and diffusion tensor imaging in pediatric bipolar disorder (PBD) with psychosis (presence of delusions and or hallucinations). METHODS We recruited 15 patients and 20 euthymic age- and gender-matched healthy controls. All subjects underwent high-resolution structural and diffusion tensor imaging. Voxel-based morphometry (VBM), tract-based spatial statistics (TBSS), and probabilistic tractography were used to analyse magnetic resonance imaging data. RESULTS The PBD subjects had normal overall intelligence with specific impairments in working memory, executive function, language function, and verbal memory. Reduced gray matter (GM) density was found in the left orbitofrontal cortex, left pars triangularis, right premotor cortex, occipital cortex, right occipital fusiform gyrus, and right crus of the cerebellum. TBSS analysis showed reduced fractional anisotropy (FA) in the anterior corpus callosum. Probabilistic tractography from this cluster showed that this region of the corpus callosum is connected with the prefrontal cortices, including those regions whose density is decreased in PBD. In addition, FA change was correlated with verbal memory and working memory, while more widespread reductions in GM density correlated with working memory, executive function, language function, and verbal memory. CONCLUSIONS The findings suggest widespread cortical changes as well as specific involvement of interhemispheric prefrontal tracts in PBD, which may reflect delayed myelination in these tracts.
Muscarinic acetylcholine type-3 receptor desensitization due to chronic exposure to Sjögren's syndrome-associated autoantibodies.

OBJECTIVE Anti-muscarinic acetylcholine type-3 receptor (anti-M3R) autoantibodies have been shown to inhibit M3R-mediated responses by both in vitro contractility and fura-2 microfluorimetry analyses of intracellular calcium mobilization, suggesting an important role for anti-M3R autoantibody in secretory dysfunction. We investigated whether chronic stimulation of M3R by anti-M3R autoantibodies and/or the agonist pilocarpine results in a general M3R desensitization. METHODS Carbachol-evoked responses of mouse-bladder smooth muscle strips were measured following exposure to anti-M3R-positive and/or anti-M3R-negative sera from either NOD/Lt mice, a model of SS-like disease, or human patients with primary SS. RESULTS Bladder smooth muscle strips isolated from NOD/Lt mice with circulating anti-M3R autoantibodies exhibited lower carbachol-evoked responses than smooth muscle strips from anti-M3R autoantibody-negative NOD/Lt mice and control C57BL/6 mice. Repeated pilocarpine injections of NOD mice for 6 days also revealed M3R desensitization in the agonist-evoked contractile assay, whereas age and sex matched C57BL/6 mice injected with pilocarpine for the same period showed a 2-fold higher response. Incubation of smooth muscle strips with sera obtained from patients with primary SS resulted in both stimulated and inhibited responses. CONCLUSION These results support the hypothesis that chronic stimulation of membrane-bound M3R can result in receptor desensitization, and raise questions about repeated use of pilocarpine by patients positive for anti-M3R autoantibodies.
Enhanced islet expansion by β‐cell proliferation in young diabetes‐prone rats fed a protective diet

Type 1 diabetes is inhibited in diabetes‐prone BioBreeding (BBdp) rats fed a low‐antigen hydrolyzed casein (HC) diet. In cereal‐fed BBdp rats, islet expansion is defective accompanied by a futile upregulation of islet neogenesis without increased islet mass, due to a subtle blockage in islet cell cycle. We hypothesized that islet growth is enhanced before insulitis in HC‐fed young BBdp rats and that islet neogenesis could be stimulated by a trophic factor, islet neogenesis‐associated protein (INGAP). β‐Cell homeostasis was analyzed using immunohistochemistry, morphometry, laser capture microdissection and RT‐PCR in BBdp rats fed HC or cereal diets. β‐cell proliferation in small and medium islets, and the number and area fraction of medium and large islets were increased in HC‐fed animals. In situ islet cell cycle analysis revealed an increased proportion of proliferating S + G2 cells in medium and large islets of 25–45 day HC‐fed rats. Expression of the cell cycle inhibitor, p16INK4a correlated with islet size and the percentage of p16INK4a+ β‐cells increased in HC‐fed BBdp rats, likely reflecting an increase in large islet area fraction. In HC‐fed rats, extra‐islet insulin+ clusters (EIC), insulin+ duct cells, large islet area fraction, and β‐cell mass were increased. Neurogenin‐3 and Pdx‐1, markers of β‐cell progenitors, were increased in EIC of weanling HC‐fed rats. Daily injection of INGAP (30–45 days) increased the number of small islets, total islets, and insulin+ cells in small ducts. Thus, in BBdp rats fed a protective HC diet, β‐cell expansion is enhanced through increased β‐cell proliferation and stimulation of islet neogenesis. J. Cell. Physiol. 224: 501–508, 2010. © 2010 Wiley‐Liss, Inc.
Total Hip Arthroplasty in Mucopolysaccharidosis Type IH

Children affected by mucopolysaccharidosis (MPS) type IH (Hurler Syndrome), an autosomal recessive metabolic disorder, are known to experience a range of musculoskeletal manifestations including spinal abnormalities, hand abnormalities, generalised joint stiffness, genu valgum, and hip dysplasia and avascular necrosis. Enzyme therapy, in the form of bone marrow transplantation, significantly increases life expectancy but does not prevent the development of the associated musculoskeletal disorders. We present the case of a 23-year-old woman with a diagnosis of Hurler syndrome with a satisfactory result following uncemented total hip arthroplasty.
Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10−8) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.
On the complexity of nash dynamics and sink equilibria

Studying Nash dynamics is an important approach for analyzing the outcome of games with repeated selfish behavior of self-interested agents. Sink equilibria has been introduced by Goemans, Mirrokni, and Vetta for studying social cost on Nash dynamics over pure strategies in games. However, they do not address the complexity of sink equilibria in these games. Recently, Fabrikant and Papadimitriou initiated the study of the complexity of Nash dynamics in two classes of games. In order to completely understand the complexity of Nash dynamics in a variety of games, we study the following three questions for various games: (i) given a state in game, can we verify if this state is in a sink equilibrium or not? (ii) given an instance of a game, can we verify if there exists any sink equilibrium other than pure Nash equilibria? and (iii) given an instance of a game, can we verify if there exists a pure Nash equilibrium (i.e, a sink equilibrium with one state)? In this paper, we almost answer all of the above questions for a variety of classes of games with succinct representation, including anonymous games, player-specific and weighted congestion games, valid-utility games, and two-sided market games. In particular, for most of these problems, we show that (i) it is PSPACE-hard to verify if a given state is in a sink equilibrium, (ii) it is NP-hard to verify if there exists a pure Nash equilibrium in the game or not, (iii) it is PSPACE-hard to verify if there exists any sink equilibrium other than pure Nash equilibria. To solve these problems, we illustrate general techniques that could be used to answer similar questions in other classes of games.
LAYSTREAM: Composing standard gossip protocols for live video streaming

Gossip-based live streaming is a popular topic, as attested by the vast literature on the subject. Despite the particular merits of each proposal, all need to implement and deal with common challenges such as membership management, topology construction and video packets dissemination. Well-principled gossip-based protocols have been proposed in the literature for each of these aspects. Our goal is to assess the feasibility of building a live streaming system, LAYSTREAM, as a composition of these existing protocols, to deploy the resulting system on real testbeds, and report on lessons learned in the process. Unlike previous evaluations conducted by simulations and considering each protocol independently, we use real deployments. We evaluate protocols both independently and as a layered composition, and unearth specific problems and challenges associated with deployment and composition. We discuss and present solutions for these, such as a novel topology construction mechanism able to cope with the specificities of a large-scale and delay-sensitive environment, but also with requirements from the upper layer. Our implementation and data are openly available to support experimental reproducibility.
PENGARUH PROFESIONALISME, MOTIVASI, INTEGRITAS, DAN INDEPENDENSI SATUAN PENGAWASAN INTERNAL DALAM MENCEGAH KECURANGAN (FRAUD) DI LINGKUNGAN PERGURUAN TINGGI NEGERI

Penelitian ini bertujuan untuk menguji dan menganalisis pengaruh profesionalisme, motivasi, integritas, dan indpendensi Satuan Pengawasan Internal dalam mencegah kecurangan ( fraud ). Populasi dalam penelitian ini adalah seluruh Satuan Pengawasan Internal yang ada di 5 Perguruan Tinggi Negeri. Teknik sampling yang digunakan dalam penelitian ini adalah teknik total sampling dimana teknik penentuan sampel dengan mengambil seluruh anggota populasi sebagai atau sampel. Hasil penelitian ini membuktikan bahwa, profesionalisme berpengaruh signifikan dalam mencegah kecurangan ( fraud ) dengan koefisien negatif. Motivasi, integritas, dan independensi berpengaruh positif signifikan dalam mencegah kecurangan ( fraud ) dengan koefisien positif.
Are There Qualitative Differences between Face Processing in Photographic Positive and Negative?

The question whether face recognition in photographic negative relies more on external features and pictorial cues than in photographic positive was studied in five experiments. Recognition of whole faces as well as both external and internal features of the faces was compared in experiments 1 and 2. The conditions in which views of faces between learning and test were either identical (hence providing maximum pictorial cues) or different (hence reducing such cues) were compared in experiments 3, 4, and 5. The results showed that recognition of internal features in two-tone and multi-tone images suffered more from use of photographic negatives than recognition of external features. Testing with both multi-tone and two-tone images revealed that the deficit caused by view changes between learning and test was no more severe with negatives than with positives. Finally, removing external features made recognition of different views equally more difficult for positives and negatives. Overall, these results point to a qualitative rather than quantitative difference between processing face images in photographic positive and negative.
Predictors of Decline in Medication Adherence: Results From the Cohort Study of Medication Adherence Among Older Adults

Few data are available on the predictors of decline in antihypertensive medication adherence and the association of decline in adherence with subsequent blood pressure (BP) control. The current analysis included 1965 adults from the Cohort Study of Medication Adherence Among Older Adults recruited between August 2006 and September 2007. Decline in antihypertensive medication adherence was defined as a ≥2-point decrease on the 8-item Morisky Medication Adherence Scale assessed during telephone surveys 1 and 2 years after baseline. Risk factors for decline in adherence were collected using telephone surveys and administrative databases. BP was abstracted from outpatient records. The annual rate for a decline in adherence was 4.3% (159 participants experienced a decline). After multivariable adjustment, a decline in adherence was associated with an odds ratio (OR) for uncontrolled BP (≥140/90 mm Hg) at follow-up of 1.68 (95% CI: 1.01–2.80). Depressive symptoms (OR: 1.84 [95% CI: 1.20–2.82]) and a high stressful life events score (OR: 1.68 [95% CI: 1.19–2.38]) were associated with higher ORs for a decline in adherence. Female sex (OR: 0.61 [95% CI: 0.42–0.88]), being married (OR: 0.68 [95% CI: 0.47–0.98]), and calcium channel blocker use (OR: 0.68 [95% CI: 0.48–0.97]) were associated with lower ORs for decline. In summary, a decline in antihypertensive medication adherence was associated with uncontrolled BP. Modifiable factors associated with decline were identified. Further research is warranted to determine whether interventions can prevent the decline in antihypertensive medication adherence and improve BP control.
Permissivity of primary hepatocytes and hepatoma cell lines to support hepatitis C virus infection

The major cell type supporting hepatitis C virus (HCV) infection is the hepatocyte; however, most reports studying viral entry and replication utilize transformed hepatoma cell lines. We demonstrate that HCV pseudoparticles (HCVpp) infect primary hepatocytes with comparable rates to hepatoma cells, demonstrating the limited variability in donor hepatocytes to support HCV receptor-glycoprotein-dependent entry. In contrast, we observed a 2-log range in viral replication between the same donor hepatocytes. We noted that cell proliferation augments pseudoparticle reporter activity and arresting hepatoma cells yields comparable levels of infection to hepatocytes. This study demonstrates comparable rates of HCVpp entry into primary hepatocytes and hepatoma cells, validating the use of transformed cells as a model system to study HCV entry.
Patient and Provider Reported Reasons for Lost to Follow Up in MDRTB Treatment: A Qualitative Study from a Drug Resistant TB Centre in India

Introduction Multidrug-resistant Tuberculosis (MDR TB) is emerging public health concern globally. Lost to follow-up (LTFU) is one of the key challenge in MDRTB treatment. In 2013, 18% of MDR TB patients were reported LTFU in India. A qualitative study was conducted to obtain better understanding of both patient and provider related factors for LTFU among MDR TB treatment. Methods Qualitative semi-structured personal interviews were conducted with 20 MDRTB patients reported as LTFU and 10 treatment providers in seven districts linked to Nagpur Drug resistant TB Centre (DRTBC) during August 2012–February 2013. Interviews were transcribed and inductive content analysis was performed to derive emergent themes. Results We found multiple factors influencing MDR TB treatment adherence. Barriers to treatment adherence included drug side effects, a perceived lack of provider support, patient financial constraints, conflicts with the timing of treatment services, alcoholism and social stigma. Conclusions Patient adherence to treatment is multi-factorial and involves individual patient factors, provider factors, and community factors. Addressing issue of LTFU during MDRTB treatment requires enhanced efforts towards resolving medical problems like adverse drug effects, developing short duration treatment regimens, reducing pill burden, motivational counselling, flexible timings for DOT services, social, family support for patients & improving awareness about disease.
The Effects of Methylphenidate on Cognitive Function in Children with Attention–Deficit/Hyperactivity Disorder

Abstract Focusing on behavioral criteria for attention–deficit/hyperactivity disorder (ADHD) diagnosis leads to considerable neuropsychological profile heterogeneity among diagnosed children, as well as variable response to methylphenidate (MPH) treatment. Documenting “cold” executive working memory (EWM) or “hot” self–regulation (SR) neuropsychological impairments could aid in the differential diagnosis of ADHD subtypes and may help to determine the optimal MPH treatment dose. In this study, children with ADHD inattentive type (n = 19), combined type (n = 33), and hyperactive–impulse type (n = 4) underwent randomized controlled MPH trials; neuropsychological, behavioral, and observational data were collected to evaluate the children's responses. Those with moderate or significant baseline EWM/SR impairment showed robust MPH response, whereas response for those with lower baseline impairment was equivocal. Implications for medication use and titration, academic achievement, and long–term treatment efficacy are examined.
European Modernity and beyond: The Trajectory of European Societies 1945-2000

PART ONE: THEORY AND HISTORY Structure, Culture and Modernity Europe in Modern History PART TWO: STRUCTURATIONS The Boundaries and the Peopling of Europe Tasks Divisions of Labour Rights to Claim Membership and Welfare Rights to Act Politics, Sex and Property Means 'The Glorious Years' Risks and Opportunities PART THREE: SPACING Cities and States The European Economic Space Europe's Cultural Space PART FOUR: ENCULTURATIONS Issues of Identity Horizons of Knowledge and Times of Belief Values of Contemporary Modernity PART FIVE: COLLECTIVE ACTION AND SOCIAL STEERING Civil Societies and Collective Action Eastern Socialism and Western Union Two Processes of Social Steering PART SIX: MODERNITY AND EUROPE: SIX QUESTIONS AND THEIR ANSWERS