Miracle-dz/UniFAR-FTUs huggingface dataset:
nextflu: real-time tracking of seasonal influenza virus evolution in humans

Summary: Seasonal influenza viruses evolve rapidly, allowing them to evade immunity in their human hosts and reinfect previously infected individuals. Similarly, vaccines against seasonal influenza need to be updated frequently to protect against an evolving virus population. We have thus developed a processing pipeline and browser-based visualization that allows convenient exploration and analysis of the most recent influenza virus sequence data. This web-application displays a phylogenetic tree that can be decorated with additional information such as the viral genotype at specific sites, sampling location and derived statistics that have been shown to be predictive of future virus dynamics. In addition, mutation, genotype and clade frequency trajectories are calculated and displayed. Availability and implementation: Python and Javascript source code is freely available from https://github.com/blab/nextflu, while the web-application is live at http://nextflu.org. Contact: tbedford@fredhutch.org
Serotonin Signaling Through the 5-HT1B Receptor and NADPH Oxidase 1 in Pulmonary Arterial Hypertension

Objective— Serotonin can induce human pulmonary artery smooth muscle cell (hPASMC) proliferation through reactive oxygen species (ROS), influencing the development of pulmonary arterial hypertension (PAH). We hypothesize that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase–derived ROS generation and reduced Nrf-2 (nuclear factor [erythroid-derived 2]-like 2) antioxidant systems, promoting vascular injury. Approach and Results— HPASMCs from controls and PAH patients, and PASMCs from Nox1−/− mice, were stimulated with serotonin in the absence/presence of inhibitors of Src kinase, the 5-HT1B receptor, and NADPH oxidase 1 (Nox1). Markers of fibrosis were also determined. The pathophysiological significance of our findings was examined in vivo in serotonin transporter overexpressing female mice, a model of pulmonary hypertension. We confirmed thatserotonin increased superoxide and hydrogen peroxide production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and hyperoxidized peroxiredoxin and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated and dependent on cellular Src-related kinase, 5-HT1B receptor, and the serotonin transporter in human pulmonary artery smooth muscle cells from PAH subjects. Proliferation and extracellular matrix remodeling were exaggerated in human pulmonary artery smooth muscle cells from PAH subjects and dependent on 5-HT1B receptor signaling and Nox1, confirmed in PASMCs from Nox1−/− mice. In serotonin transporter overexpressing mice, SB216641, a 5-HT1B receptor antagonist, prevented development of pulmonary hypertension in a ROS-dependent manner. Conclusions— Serotonin can induce cellular Src-related kinase–regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, associated with mitogenic responses. 5-HT1B receptors contribute to experimental pulmonary hypertension by inducing lung ROS production. Our results suggest that 5-HT1B receptor–dependent cellular Src-related kinase-Nox1-pathways contribute to vascular remodeling in PAH.
Reduction of Glucose Uptake through Inhibition of Hexose Transporters and Enhancement of Their Endocytosis by Methylglyoxal in Saccharomyces cerevisiae*

Background: Methylglyoxal is a typical 2-oxoaldehyde derived from glycolysis. Results: Methylglyoxal inhibited the activity of yeast hexose transporters as well as mammalian glucose transporters (GLUT1 and GLUT4) and enhanced the endocytosis of hexose transporters in yeast. Conclusion: Methylglyoxal inhibited glucose uptake in yeast cells. Significance: Phospholipase C and protein kinase C were involved in endocytosis of hexose transporters. Diabetes mellitus is characterized by an impairment of glucose uptake even though blood glucose levels are increased. Methylglyoxal is derived from glycolysis and has been implicated in the development of diabetes mellitus, because methylglyoxal levels in blood and tissues are higher in diabetic patients than in healthy individuals. However, it remains to be elucidated whether such factors are a cause, or consequence, of diabetes. Here, we show that methylglyoxal inhibits the activity of mammalian glucose transporters using recombinant Saccharomyces cerevisiae cells genetically lacking all hexose transporters but carrying cDNA for human GLUT1 or rat GLUT4. We found that methylglyoxal inhibits yeast hexose transporters also. Glucose uptake was reduced in a stepwise manner following treatment with methylglyoxal, i.e. a rapid reduction within 5 min, followed by a slow and gradual reduction. The rapid reduction was due to the inhibitory effect of methylglyoxal on hexose transporters, whereas the slow and gradual reduction seemed due to endocytosis, which leads to a decrease in the amount of hexose transporters on the plasma membrane. We found that Rsp5, a HECT-type ubiquitin ligase, is responsible for the ubiquitination of hexose transporters. Intriguingly, Plc1 (phospholipase C) negatively regulated the endocytosis of hexose transporters in an Rsp5-dependent manner, although the methylglyoxal-induced endocytosis of hexose transporters occurred irrespective of Plc1. Meanwhile, the internalization of hexose transporters following treatment with methylglyoxal was delayed in a mutant defective in protein kinase C.
Invariant-based automatic testing of AJAX user interfaces

AJAX-based Web 2.0 applications rely on stateful asynchronous client/server communication, and client-side runtime manipulation of the DOM tree. This not only makes them fundamentally different from traditional web applications, but also more error-prone and harder to test. We propose a method for testing AJAX applications automatically, based on a crawler to infer a flow graph for all (client-side) user interface states. We identify AJAX-specific faults that can occur in such states (related to DOM validity, error messages, discoverability, back-button compatibility, etc.) as well as DOM-tree invariants that can serve as oracle to detect such faults. We implemented our approach in ATUSA, a tool offering generic invariant checking components, a plugin-mechanism to add application-specific state validators, and generation of a test suite covering the paths obtained during crawling. We describe two case studies evaluating the fault revealing capabilities, scalability, required manual effort and level of automation of our approach.
Polycystic ovary syndrome: Is obesity a sine qua non? A clinical, hormonal, and metabolic assessment in relation to body mass index

Objective: To determine the proportion of polycystic ovarian syndrome (PCOS) patients who have normal body mass index (BMI) and to compare the clinical, hormonal, and metabolic profile between lean and overweight patients of PCOS. Materials and Methods: One hundred consecutive infertile women with PCOS were studied and divided into lean (BMI between 18.5 and 23) and overweight (BMI ≥ 23). Metabolic and hormonal profile (serum FSH, LH, testosterone, prolactin, TSH on days 2–3 of menstrual cycle; serum progesterone premenstrually; serum insulin—fasting and 2 hours postglucose, glucose tolerance test, and fasting serum lipid profile) was performed along with pelvic sonogropahy; and clinical features, viz. waist hip ratio, hirsutism, acne, acanthosis nigricans, and clitoromegaly were recorded. Results: 42% of the PCOS subjects had normal BMI. Average age, hirsutism (80.9% vs. 89.7%), irregular cycles (92.8% vs. 96.6%), acne (9.5% vs. 15.5%), clitoromegaly (2.3% vs. 3.4%), endometrial thickness >4 mm (9.5% vs. 15.5%), and hormonal profile were similar in the lean and overweight PCOS groups. Family history of diabetes (9.5% vs. 24.1%), abnormal glucose tolerance test (GTT) (4.7% vs. 10.3%), deranged lipid profile (14.2% vs. 31%), and 2-hour postprandial insulin levels were higher in the overweight PCOS (P < 0.05). Insulin resistance was observed in 83.3% of lean PCOS but was still lower than 93.1% seen in overweight PCOS (P < 0.05). Conclusion: 42% of the PCOS had normal BMI, but clinical and hormonal profile was similar to PCOS patients with elevated BMI (overweight/obese). However, insulin resistance is observed in 83.3% of lean PCOS. Family history of diabetes, impaired GTT, deranged lipid profile, and insulin resistance were more prevalent in overweight PCOS.
Bayesian approach of pollen-based palaeoclimate reconstructions: Toward the modelling of ecological processes

Pollen preserved in lacustrine sediments form a crucial archive for reconstructing past climate and terrestrial vegetation change. Currently, climate reconstructions are based on statistical models describing the link between climate and pollen. These models raise methodological problems because they are all based on the hypothesis that climate-pollen relationships are constant over times; implying that non-climatic parameters driving the relation have weak influence. This is not in agreement with recent developments in ecology and ecophysiology. That is why, in this work, we develop an approach integrating a dynamical vegetation model and major processes linking vegetation and pollen trapped in lakes. The Bayesian framework provides us with a theoretical basis and tools for the inference of model parameters and past climate. We use these new models for reconstructing Holocene climate in various European sites. This approach, which may allow spatio-temporal reconstructions still requires developments around statistical inference for semi-mechanistic models.
Modeling the 2013 Zika Outbreak in French Polynesia: Intervention Strategies

The ongoing Zika virus (ZIKV) in the Americas has been a serious public health emergency since 2015. Since Zika is a vector-borne disease, the size of the vector population in the affected area plays a key role in controlling the scale of the outbreak. The primary vectors for Zika, the Aedes Agypti and Aedes Albopictus species of mosquitoes, are highly sensitive to climatic conditions for survival and reproduction. Additionally, increased international travel over the years has caused the disease outbreak to turn into a pandemic affecting five continents. The mosquito population and the human travel patterns are the two main driving forces affecting the persistence and resurgence of Zika and other vector-borne diseases. This paper presents an enhanced dynamic model that simulates the 2013–2014 French Polynesia Zika outbreak incorporating the temperature dependent mosquito ecology and the local transit network (flights and ferries). The study highlights the importance of human travel patterns and mosquito population dynamics in a disease outbreak. The results predict that more than 85% of the population was infected by the end of the outbreak and it lasted for more than five months across the islands. The basic reproduction number ( R 0 ) for the outbreak is also calculated using the next-generation-matrix for validation purposes. Additionally, this study is focused on measuring the impact of intervention strategies like reducing the mosquito population, preventing mosquito bites and imposing travel bans. French Polynesia was chosen as the region of interest for the study because of available demographic, climate and transit data. Additionally, results from similar studies for the region are available for validation and comparison. However, the proposed system can be used to study the transmission dynamics of any vector-borne disease in any geographic region by altering the climatic and demographic data, and the transit network.
Base methylations in the double-stranded RNA by a fused methyltransferase bearing unwinding activity

Modifications of rRNAs are clustered in functional regions of the ribosome. In Helix 74 of Escherichia coli 23S rRNA, guanosines at positions 2069 and 2445 are modified to 7-methylguanosine(m7G) and N2-methylguanosine(m2G), respectively. We searched for the gene responsible for m7G2069 formation, and identified rlmL, which encodes the methyltransferase for m2G2445, as responsible for the biogenesis of m7G2069. In vitro methylation of rRNA revealed that rlmL encodes a fused methyltransferase responsible for forming both m7G2069 and m2G2445. We renamed the gene rlmKL. The N-terminal RlmL activity for m2G2445 formation was significantly enhanced by the C-terminal RlmK. Moreover, RlmKL had an unwinding activity of Helix 74, facilitating cooperative methylations of m7G2069 and m2G2445 during biogenesis of 50S subunit. In fact, we observed that RlmKL was involved in the efficient assembly of 50S subunit in a mutant strain lacking an RNA helicase deaD.
LSD alters eyes‐closed functional connectivity within the early visual cortex in a retinotopic fashion

The question of how spatially organized activity in the visual cortex behaves during eyes‐closed, lysergic acid diethylamide (LSD)‐induced “psychedelic imagery” (e.g., visions of geometric patterns and more complex phenomena) has never been empirically addressed, although it has been proposed that under psychedelics, with eyes‐closed, the brain may function “as if” there is visual input when there is none. In this work, resting‐state functional connectivity (RSFC) data was analyzed from 10 healthy subjects under the influence of LSD and, separately, placebo. It was suspected that eyes‐closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesized that, under LSD, patches of the visual cortex with congruent retinotopic representations would show greater RSFC than incongruent patches. Using a retinotopic localizer performed during a nondrug baseline condition, nonadjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches. Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal–horizontal and vertical–vertical) and those with incongruent specificity (horizontal–vertical and vertical–horizontal) increased significantly under LSD relative to placebo, suggesting that activity within the visual cortex becomes more dependent on its intrinsic retinotopic organization in the drug condition. This result may indicate that under LSD, with eyes‐closed, the early visual system behaves as if it were seeing spatially localized visual inputs. Hum Brain Mapp 37:3031–3040, 2016. © 2016 Wiley Periodicals, Inc.
A TEST OF THE CHITTY HYPOTHESIS: INHERITANCE OF LIFE‐HISTORY TRAITS IN MEADOW VOLES MICROTUS PENNSYLVANICUS

The Chitty hypothesis proposes that the demographic changes occurring in microtine cycles are mediated by natural selection operating on the genetic composition of the population. Implicit in this hypothesis is the assumption that a suite of life‐history traits is simultaneously undergoing selection and that these traits are strongly heritable. We tested this in two ways: first, by determining whether the year‐to‐year differences in phenotypes in fluctuating meadow vole populations in the field are maintained in samples of young animals raised in the laboratory, and second, whether the variation seen in the field has a heritable basis as determined by half‐sib analysis. Parents were obtained in the springs of successive years from a fluctuating meadow vole population. These animals were bred in small field enclosures, and their progeny were raised in the laboratory. Animals raised in the laboratory differed significantly from those in the natural field population. In the field, young from the year when population size was increasing grew more rapidly than those from the peak year; in the laboratory, the opposite occurred. The ages at sexual maturity showed similar differences. Heritability analysis was performed on body weight, growth rate, and age and weight at sexual maturity. Virtually all these traits showed significant dam effects, but small or nonexistant sire effects. Thus, most of the variation was nongenetic in origin; maternal and other environmental effects were of overriding importance. We conclude that the heritabilities of these traits in nature are usually lower than necessary for natural selection to operate in the time frames characteristic of microtine cycles.
Low Serum Fetuin-A as a Biomarker to Predict Pneumococcal Necrotizing Pneumonia and Hemolytic Uremic Syndrome in Children

AbstractStreptococcus pneumoniae, a neuraminidase-producing pathogen, can cause invasive pneumococcal disease (IPD) with or without hemolytic uremic syndrome (HUS) in humans.We aimed to identify serum sialoglycoproteins that are targeted by neuraminidases in severe pneumococcal infection. We hypothesized that serum sialoglycoprotein such as fetuin-A can serve as a biomarker to predict IPD or HUS.We constructed serum sialoglycoprotein profiles before and after pneumococcal neuraminidase treatment using liquid chromatography-tandem mass spectrometry (LC-MS/MS), a proteomic approach. An observational study was conducted using clinical data and serum samples from pediatric patients with pneumococcal infection to verify the predictive role of fetuin-A in IPD. Serum fetuin-A levels were determined by enzyme-linked immunosorbent assay.The most abundant serum sialoglycoproteins identified by LC-MS/MS after neuraminidase treatment and peanut lectin capture were immunoglobulins, apolipoproteins, fibrinogens, keratins, complement system proteins, and fetuin-A. Serum fetuin-A levels in the HUS patients were significantly lower (207 ± 80 mg/L, P < 0.001) than in patients with lobar pneumonia (610 ± 190 mg/L) as well as the healthy controls (630 ± 250 mg/L). In comparing HUS with necrotizing pneumonia and lobar pneumonia, the ROC area under the curve was 0.842; a cutoff value of 298 mg/L yielded sensitivity of 92.9% (95% CI: 68.5–98.7%) and specificity of 71.9% (95% CI: 54.6–84.4%). This observational study with validation cohorts of patients with HUS, complicated pneumonia, and lobar pneumonia demonstrates the high performance of low serum fetuin-A levels as a biomarker to predict severe IPD and HUS in children.
Motivations for socio-collaborative learning practices: examining how community and interactions support learning among registered users on OpenLearn

Open Educational Resources (OER) are being produced globally by various educational institutions. Depending on an organisation’s mission, purposes and intent for providing vary, determining what features are made available. In establishing OER the focus has often been on this provider perspective, however how OER will be used also depends on user motivations. This paper presents findings from a study conducted on OpenLearn which focused on motivations for socio-collaborative learning among its registered users. Evidence gathered through interviews with six learners and examinations of fifty-seven user profiles and online output suggests users have intrinsic motivations to interact but are also influenced by various online and offline factors that keep changing, highlighting the dynamic, multidimensional nature of motivation in expertiseand support-linked interactions. Results suggest the value of interactions in self-directed learning and the importance of creating OER that support both content provision and interaction between users, catering for diverse learning needs.
The use of cognitive remediation therapy on a child adolescent eating disorder unit: Patients and therapist perspectives

Cognitive remediation therapy (CRT) is an intervention for anorexia nervosa (AN) that focuses on ameliorating the neuropsychological inefficiencies that underlie the illness. The current literature has reported promising results regarding its efficacy as an intervention for AN. However, there is a scarcity of studies considering the implementation of CRT in a child and adolescent population. This article describes an individual CRT therapy programme for children and adolescents with AN delivered on an inpatient unit for eating disorders. It considers the therapeutic process including the differing viewpoints of the patients and the therapists. The article concludes that CRT can be viewed as an engaging therapeutic intervention that could be useful as an additional treatment for AN.
Household food insufficiency, financial strain, work-family spillover, and depressive symptoms in the working class: the Work, Family, and Health Network study.

OBJECTIVES We evaluated the association of household-level stressors with depressive symptoms among low-wage nursing home employees. METHODS Data were collected in 2006 and 2007 from 452 multiethnic primary and nonprimary wage earners in 4 facilities in Massachusetts. We used logistic regression to estimate the association of depressive symptoms with household financial strain, food insufficiency, and work-family spillover (preoccupation with work-related concerns while at home and vice versa). RESULTS Depressive symptoms were significantly associated with household financial strain (odds ratio [OR] = 1.82; 95% confidence interval [CI] = 1.03, 3.21) and food insufficiency (OR = 2.10; 95% CI = 1.10, 4.18). Among primary earners, stratified analyses showed that food insufficiency was associated with depressive symptoms (OR = 3.60; 95% CI = 1.42, 9.11) but financial strain was not. Among nonprimary wage earners, depressive symptoms correlated with financial strain (OR = 3.65; 95% CI = 1.48, 9.01) and work-family spillover (OR = 3.22; 95% CI = 1.11, 9.35). CONCLUSIONS Household financial strain, food insufficiency, and work-family spillover are pervasive problems for working populations, but associations vary by primary wage earner status. The prevalence of food insufficiency among full-time employees was striking and might have a detrimental influence on depressive symptoms and the health of working-class families.
Additive domain decomposition operator splittings—convergence analyses in a dissipative framework

We analyze temporal approximation schemes based on overlapping domain decompositions. As such schemes enable computations on parallel and distributed hardware, they are commonly used when integrating large-scale parabolic systems. Our analysis is conducted by first casting the domain decomposition procedure into a variational framework based on weighted Sobolev spaces. The time integration of a parabolic system can then be interpreted as an operator splitting scheme applied to an abstract evolution equation governed by a maximal dissipative vector field. By utilizing this abstract setting, we derive an optimal temporal error analysis for the two most common choices of domain decomposition based integrators. Namely, alternating direction implicit schemes and additive splitting schemes of first and second order. For the standard first-order additive splitting scheme we also extend the error analysis to semilinear evolution equations, which may only have mild solutions. The theoretical results are finally illustrated by numerical experiments. (Less)