Miracle-dz/UniFAR-FTUs huggingface dataset:
Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour

Wilms tumour (WT) is an embryonal tumour of the kidney that occurs in 1 in 10 000 children. Familial clusters are rare and account for only 1–3% of cases. Mutations in WT1 account for a minority of WT families and two autosomal dominant familial WT predisposition genes have been mapped to chromosomes 17q21 and 19q13.1–3 However, a considerable proportion of familial WT pedigrees are not attributable to any of these loci.4 Fanconi anaemia (FA, MIM 227650) is a rare autosomal recessive condition affecting ∼1 in 300 000 children. FA is characterised by variable congenital abnormalities, short stature, bone marrow failure, hypersensitivity to DNA crosslinking agents, and a predisposition to haematological malignancies such as acute myeloid leukaemia in childhood.5 FA is heterogeneous and consists of at least 11 complementation groups, A, B, C, D1, D2, E, F, G, I, J, and L.6–8 Eight FA genes have been cloned and at least six FA proteins, FANCA, FANCC, FANCE, FANCF, FANCG, and FANCL, form a nuclear complex required for monoubiquitination of FANCD2. This modification promotes translocation of FANCD2 to DNA repair foci that also contain BRCA1, BRCA2, and RAD51.9 In 2002, Howlett and colleagues reported biallelic BRCA2 mutations in individuals with Fanconi anaemia D1 (FA-D1). Subsequently, additional FA-D1 and unclassified FA cases were examined and cases with BRCA2 mutations and WT and/or brain tumours were reported.10–13 These data prompted us to investigate BRCA2 in a familial WT pedigree, WILMS2, which includes siblings with both WT and brain tumours.4,14,15 ### Family report WILMS2 was ascertained as part of our research on susceptibility to WT, which is approved by the London Multicentre Research Ethics Committee. The family includes two affected brothers with WT. The elder child first came to attention when his cryptorchidism was corrected at …
Expectations of brilliance underlie gender distributions across academic disciplines

Women's participation and attitudes to talent Some scientific disciplines have lower percentages of women in academia than others. Leslie et al. hypothesized that general attitudes about the discipline would reflect the representation of women in those fields (see the Perspective by Penner). Surveys revealed that some fields are believed to require attributes such as brilliance and genius, whereas other fields are believed to require more empathy or hard work. In fields where people thought that raw talent was required, academic departments had lower percentages of women. Science, this issue p. 262; see also p. 234 General opinions about talent versus effort hold sway over representation of women in academic departments. [Also see Perspective by Penner] The gender imbalance in STEM subjects dominates current debates about women’s underrepresentation in academia. However, women are well represented at the Ph.D. level in some sciences and poorly represented in some humanities (e.g., in 2011, 54% of U.S. Ph.D.’s in molecular biology were women versus only 31% in philosophy). We hypothesize that, across the academic spectrum, women are underrepresented in fields whose practitioners believe that raw, innate talent is the main requirement for success, because women are stereotyped as not possessing such talent. This hypothesis extends to African Americans’ underrepresentation as well, as this group is subject to similar stereotypes. Results from a nationwide survey of academics support our hypothesis (termed the field-specific ability beliefs hypothesis) over three competing hypotheses.
Coordination in multiagent reinforcement learning: a Bayesian approach

Much emphasis in multiagent reinforcement learning (MARL) research is placed on ensuring that MARL algorithms (eventually) converge to desirable equilibria. As in standard reinforcement learning, convergence generally requires sufficient exploration of strategy space. However, exploration often comes at a price in the form of penalties or foregone opportunities. In multiagent settings, the problem is exacerbated by the need for agents to "coordinate" their policies on equilibria. We propose a Bayesian model for optimal exploration in MARL problems that allows these exploration costs to be weighed against their expected benefits using the notion of value of information. Unlike standard RL models, this model requires reasoning about how one's actions will influence the behavior of other agents. We develop tractable approximations to optimal Bayesian exploration, and report on experiments illustrating the benefits of this approach in identical interest games.
Molecular Basis of 9 G 4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

Christopher Richardson, University of Rochester School of Medicine Asida Seema Chida, Emory University Diana Adlowitz, University of Rochester School of Medicine Lin Silver, University of Rochester School of Medicine Erin Fox, University of Rochester School of Medicine Scott A. Jenks, Emory University Elise Palmer, University of Rochester School of Medicine Youliang Wang, Emory University Jamie Heimburg-Molinaro, Emory University Quan-Zhen Li, University of Texas Southwestern Medical Center
Monetary Integration, Partisanship, and Macroeconomic Policy

Most of the current literature on macroeconomic policies focus on cyclical phenomena such as politically induced business cycles, and how short-sighted policies can be overcome through proper institutional design. This paper instead focuses on the lasting effects of macroeconomic policies on such “real” economic variables as unemployment and distribution, and we argue that traditional distributive politics is important for understanding the choice over policies and institutions. We derive our hypotheses from a rational expectations model of the choice over macroeconomic policies, wage bargaining institutions, and union wage strategies, and we present evidence from Europe that corroborates these hypotheses. The model helps us understand not only cross-national differences in macroeconomic policies, institutions and performance, but also the effects on these variables of international monetary integration.
Assessment of Statistical Methodologies and Pitfalls of Dissertations Carried Out at National Cancer Institute, Cairo University

Purpose: To identify statistical errors and pitfalls in dissertations performed as part of the requirements for the Medical Doctorate (MD) degree at the National Cancer Institute (NCI), Cairo University (CU) to improve the quality of medical research. Methods: A critical assessment of 62 MD dissertations conducted in 3 departments at NCI, CU, between 2009 and 2013 was carried out regarding statistical methodology and presentation of the results. To detect differences in study characteristics over time, grouping was into two periods; 2009-2010 and 2011-2013. Results: Statistical methods were appropriate in only 13 studies (24.5%). The most common statistical tests applied were chi-square, log-rank, and Mann-Whitney tests. Four studies estimated sample size and/or power. Only 37.1% and 38.7% of dissertation results supported aims and answered the research questions, respectively. Most of results were misinterpreted (82.3%) with misuse of statistical terminology (77.4%). Tabular and graphical data display was independently informative in only 36 dissertations (58.1%) with accurate titles and labels in only 17 (27.4%). Statistical tests fulfilled the assumptions only in 29 studies; with evident misuse in 33. Ten dissertations reported non-significance regarding their primary outcome measure; the median power of the test was 35.5% (range: 6-60%). There was no significant change in the characteristics between the time periods. Conclusion: MD dissertations at NCI have many epidemiological and statistical defects that may compromise the external validity of the results. It is recommended to involve a biostatistician from the very start to improve study design, sample size calculation, end points estimation and measures.
Personalized Saliency and Its Prediction

Nearly all existing visual saliency models by far have focused on predicting a universal saliency map across all observers. Yet psychology studies suggest that visual attention of different observers can vary significantly under specific circumstances, especially a scene is composed of multiple salient objects. To study such heterogenous visual attention pattern across observers, we first construct a personalized saliency dataset and explore correlations between visual attention, personal preferences, and image contents. Specifically, we propose to decompose a personalized saliency map (referred to as PSM) into a universal saliency map (referred to as USM) predictable by existing saliency detection models and a new discrepancy map across users that characterizes personalized saliency. We then present two solutions towards predicting such discrepancy maps, i.e., a multi-task convolutional neural network (CNN) framework and an extended CNN with Person-specific Information Encoded Filters (CNN-PIEF). Extensive experimental results demonstrate the effectiveness of our models for PSM prediction as well their generalization capability for unseen observers.
Efficacy and safety of duloxetine 60 mg and 120 mg daily in patients hospitalized for severe depression: a double-blind randomized trial.

OBJECTIVE To assess whether hospitalized patients with severe depression and potential suicidal ideation/behavior have earlier and better response to duloxetine 120 mg daily than 60 mg daily. METHOD Adults from 34 sites in 4 countries with severe major depressive disorder, defined by DSM-IV criteria, who were demonstrating Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥ 30, 6-item Hamilton Depression Rating Scale (HDRS-6) scores ≥ 12, and Clinical Global Impressions-Severity of Illness scale (CGI-S) ≥ 4 and hospitalized ≥ 2 weeks underwent double-blind treatment with either duloxetine 60 mg (n = 167) or 120 mg (n = 171) daily for 8 weeks. Patients treated with 60 mg/d who did not respond had their doses titrated up to 120 mg/d. Primary outcome was the difference in baseline to week 4 change in MADRS scores between the groups. Secondary outcomes were baseline to week 8 changes in MADRS and HDRS-6 scores, response and remission, CGI-S scores, CGI-Improvement scores, Patient Global Impressions-Improvement, Hamilton Anxiety Rating Scale scores, and Reasons For Living inventory results. Safety was also assessed. The study was conducted between February 9, 2007, and August 26, 2008. RESULTS There was no significant difference in mean baseline to week 4 MADRS score change between the 60-mg (-20.1) and 120-mg (-19.9) groups (P = .88). At week 4, 96/166 (60 mg) and 106/170 (120 mg) patients responded and maintained responses at week 8 by further decreasing mean MADRS scores to 5.8 (60 mg) and 5.6 (120 mg). At week 8, 226/336 (67.3%) patients achieved remission, with no difference demonstrated between groups. Most secondary efficacy measures were significantly reduced from baseline to week 8 within each group and did not differ between groups. Treatment-emergent adverse events observed with > 10% frequency in both groups were headache and nausea. CONCLUSIONS Duloxetine 60-mg and 120-mg doses were equally effective and demonstrated no significant differences in treating severe depressive symptoms in hospitalized patients. The safety and tolerability profile of duloxetine in both dosages did not differ and was similar to those reported in previous duloxetine studies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00422162.
Unsupervised learning techniques for an intrusion detection system

With the continuous evolution of the types of attacks against computer networks, traditional intrusion detection systems, based on pattern matching and static signatures, are increasingly limited by their need of an up-to-date and comprehensive knowledge base. Data mining techniques have been successfully applied in host-based intrusion detection. Applying data mining techniques on raw network data, however, is made difficult by the sheer size of the input; this is usually avoided by discarding the network packet contents.In this paper, we introduce a two-tier architecture to overcome this problem: the first tier is an unsupervised clustering algorithm which reduces the network packets payload to a tractable size. The second tier is a traditional anomaly detection algorithm, whose efficiency is improved by the availability of data on the packet payload content.
Infection-Enhancing and -Neutralizing Activities of Mouse Monoclonal Antibodies against Dengue Type 2 and 4 Viruses Are Controlled by Complement Levels

ABSTRACT Dengue viruses are distributed widely in the tropical and subtropical areas of the world and cause dengue fever and its severer form, dengue hemorrhagic fever. While neutralizing antibodies are considered to play a major role in protection from these diseases, antibody-dependent enhancement (ADE) of infection is an important mechanism involved in disease severity, in addition to the involvement of T lymphocytes. Here, we analyzed relationships between neutralizing and enhancing activities at a clonal level using models of dengue type 2 virus (DENV2) and dengue type 4 virus (DENV4). Totals of 33 monoclonal antibodies (MAbs) against DENV2 and 43 against DENV4 were generated, all directed to the envelope protein. In these MAbs, enhancing activities were shown at subneutralizing doses under normal ADE assay conditions where test samples were heat inactivated. However, the inclusion of commercial rabbit complement or fresh sera from healthy humans in the ADE assay system abolished the enhancing activities of all these MAbs. The reductive effect of fresh sera on enhancing activities was significantly reduced by their heat inactivation or the use of C1q- or C3-depleted sera. In some fresh sera, enhancing activities were shown within a range of 20 to 80% of normal complement levels in a dose-dependent fashion. These results indicate that a single antibody species possesses two distinct activities (neutralizing/enhancing), which are controlled by the level of complement, suggesting the involvement of complement in dengue disease severity. Fresh human sera also tended to reduce enhancing activities more effectively in homologous than heterologous combinations of viruses (DENV2/DENV4) and MAbs (against DENV2/DENV4).
Prevalence of newcastle disease virus in broiler chickens (Gallus gallus) in Brazil

This study was carried out during 2002/2003, aiming to determine the prevalence of virulent Newcastle disease virus strains (NDV) in Brazilian commercial poultry farms. Clinical samples were obtained from the Southeastern, Southern and Central-Western regions, which comprise the main area of the Brazilian poultry production. Serum samples and tracheal and cloacal swabs of 23,745 broiler chickens from 1,583 flocks, including both vaccinated chickens and those with no vaccination information, were tested for NDV using a diagnostic ELISA kit. The seropositivity was 39.1%, and the isolation percentage by flock varied from 1.0 to 7.6%, and by region from 6.5 to 58.4%. Higher isolation rates (74.3-83.3%) were obtained after three passages in embryonated chicken eggs. All isolates preliminarily identified as NDV were characterized as nonpathogenic strains, as their Intracerebral Pathogenicity Index (ICPI) was below 0.7. Based on results of this study, Brazil can claim a virulent NDV-free status for commercial flocks.
The effects of perceived and received support on self-confidence

Abstract A sample of 222 university athletes (mean age 19.8 years, s = 2.0), ranging in standard from university second team to international competitor, completed a measure of perceived support 2 weeks before an important competition or match. On the day before the competition or match, the athletes completed measures of stressors, stress, received support, and self-confidence. Moderated hierarchical regression analyses revealed the following key findings: (i) main effects for both perceived (ΔR 2 = 0.11) and received support (ΔR 2 = 0.14) upon self-confidence; (ii) stress-buffering effects for both perceived (ΔR 2 = 0.02) and received (ΔR 2 = 0.07) support upon self-confidence; (iii) when both aspects of support were considered simultaneously, stress-buffering effects were primarily attributable to the influence of received support. These results demonstrate the beneficial impact of social support on self-confidence, both directly and by reducing the negative effect of stress on self-confidence. Our findings emphasize the need to recognize the distinction between perceived and received support, both in terms of theory and the design of social support interventions with athletes.
Antileishmanial Activity of the Antiulcer Agent Omeprazole

ABSTRACT The benzimidazole compound omeprazole, used widely for the treatment of peptic ulcer disease, inhibits the growth of Leishmania donovani, the causative agent of visceral leishmaniasis. Promastigotes cultured at acidic pH and amastigotes within infected macrophages are reduced 90% or more with 150 μM omeprazole. Antiparasitic action of the drug is due to its inhibition of the P-type K+,H+-ATPase on the surface membrane. This enzyme is important for pH homeostasis and the maintenance of proton motive force across the membrane in Leishmania. The drug is effective only at acidic pH, a condition that mimics the in vivo environment within the phagolysosomal vesicles where the amastigote form of the parasite resides. Omeprazole deserves consideration as an alternative to currently available chemotherapeutics, which have severe toxic side effects.
Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6- and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7- and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6- to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b−/−), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1- to 18.4-fold; P < 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.
Protein ubiquitination is modulated by O‐GlcNAc glycosylation

During the past two decades, O‐GlcNAc modification of cytosolic and nuclear proteins has been intensively studied. Nevertheless, the function of this post‐translational modification remains unclear. It has been recently speculated that O‐GlcNAc could act as a protective signal against proteasomal degradation, both by modifying target substrates and/or by inhibiting the proteasome itself. In this work, we have investigated the putative relation between O‐GlcNAc and the ubiquitin pathway. First, we showed that the level of both modifications increased rapidly after thermal stress but, unlike ubiquitinated proteins, O‐GlcNAc‐modified proteins failed to be stabilized by inhibiting proteasome function. Increasing O‐GlcNAc levels, using glucosamine or PUGNAc, enhanced ubiquitination. Inversely, when O‐GlcNAc levels were reduced, using forskolin or glucose deprivation, ubiquitination decreased. Targeted‐RNA interference of O‐GlcNAc transferase also reduced ubiquitination and moreover halved cell thermotolerance. Finally, we demonstrated that the ubiquitin‐activating enzyme E1 was O‐GlcNAc modified and that its glycosylation and its interaction with Hsp70 varied according to the conditions of cell culture. Altogether, these results show that O‐GlcNAc and ubiquitin are not strictly antagonistic post‐translational modifications, but rather that the former might regulate the latter, and also suggest that E1 could be one of the common links between the two pathways. —Guinez, C. , Mir, A. ‐M. , Dehennaut, V. , Cacan, R. , Harduin‐Lepers, A. , Michalski, J.‐C. , Lefebvre, T. Protein ubiquitination is modulated by O‐GlcNAc glycosylation. FASEB J. 22, 2901–2911 (2008)
Growth of Mouse Yolk Sac Cells Cultured in Vivo

The proliferation and differentiation of yolk sac cells from 10 1/2‐day‐old mouse embryos were studied in diffusion chambers implanted into syngeneic and allogeneic hosts. The most striking observation was the appearance, proliferation and predominance of immature and mature plasma cells. The data suggested that the differentiation into plasma cells and the rate of growth of yolk sac cells cultured in vivo may be dependent on the genetics of the strain of mouse and host.
Enhanced Rule-Based Phonetic Transcription for the Romanian Language

This paper presents a rule-based approach for the phonetic transcription of the Romanian language. We integrate this phonetic analysis in the text processing component of a text-to-speech system for Romanian. Grapheme-to-phoneme rules are constructed based on expert information from DOOMII dictionary. In the cases when rules are useless, we employed decision trees constructed on engineered training sets to help the classifiers to learn the language exceptions.
Gastroretentive Gabapentin (G-GR) Formulation Reduces Intensity of Pain Associated With Postherpetic Neuralgia (PHN)

Objective:To evaluate the safety and efficacy of a once-daily gastroretentive formulation of gabapentin (G-GR; 1800 mg). Methods:This was an 11-week, double-blind, randomized, placebo-controlled Phase 3 clinical trial in patients with postherpetic neuralgia. Patients underwent a 2-week dose titration, 8 weeks of stable dosing, and 1 week of dose tapering. The primary endpoint was the change in average daily pain intensity score from Baseline to Week 10 using Baseline Observation Carried Forward (BOCF) imputation. Results:Four-hundred and fifty-two patients (mean age 65.6 y, BMI 29 Kg/m2) were randomized. Baseline average daily pain intensity score during the week prior to randomization was 6.6 and 6.5 for the G-GR and placebo treatment groups, respectively. Three hundred and seventy-seven patients completed the study (84% G-GR, 83% placebo). G-GR significantly reduced BOCF change in average daily pain intensity compared with placebo (−2.1 vs. −1.6; G-GR vs. placebo, P=0.013). Compared with placebo, more G-GR-treated patients reported “much” or “very much” improvement (patient global impression of change, 43% vs. 34%; P<0.0434), and G-GR reduced sleep interference (−2.3 vs. −1.59; P<0.0001), although neither endpoint was considered statistically significant based on a stringent hierarchical statistical paradigm. Other secondary endpoints showed similar trends. The most common adverse events were dizziness (G-GR, 11.3% vs. placebo, 1.7 %) and somnolence (G-GR, 5.4% vs. placebo, 3.0%). Conclusion:Once-daily G-GR 1800 mg was effective and well tolerated for the relief of pain in patients with postherpetic neuralgia.