Miracle-dz/UniFAR-FTUs huggingface dataset:
Gene expression‐based in vivo and in vitro prediction of liver toxicity allows compound selection at an early stage of drug development

We have analyzed gene expression and histopathology of rat liver treated with a histamine‐3 receptor inverse agonist under development for the treatment of obesity 24 h after a single acute administration. While histopathology did not identify a clear liver toxicity, analysis of gene changes strongly suggested the development of toxicity. This prediction was confirmed in a 2‐week repeat‐dose rat study where prominent liver pathology occurred, while gene changes that lead to the prediction persisted. A subset of these genes was analyzed in vitro in both rat and human hepatocytes to reveal the potential relevancy of the findings for the situation in humans. This comprehensive analysis of the development compound at the gene expression level allowed interpretation of findings of the follow‐up compound in a frontloaded 24‐h single‐dose acute study that was initiated before regular 2‐week repeat‐dose studies started. The high similarity of the follow‐up compound to the lead compound based on gene expression lead to the immediate termination of the development program for this compound series. Our data demonstrate the value of genomics‐based early toxicity prediction in short‐term in vivo studies for the characterization of compounds to allow prioritization and selection of suited candidates before compound‐, animal‐, and cost‐intensive longer term studies are undertaken. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 25:183–194, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.20375
Target organ damage in primary hypertensive patients: role of the morning heart rate surge

ABSTRACT Background: The morning heart rate surge (MHRS) and morning blood pressure surge (MBPS) may be responsible for the high prevalence of cardiovascular events during the morning period. The clinical significance of the MBPS has been well established, but that of the MHRS remains unclear. Thus, we evaluated the association between the MHRS and target organ damage (TOD). Methods: A cross-sectional study of 580 hypertensive patients was performed. MHRS and heart rate variability (HRV) were analyzed by 24 h electrocardiogram. TOD was assessed by estimated glomerular filtration rate, carotid intima-media thickness (IMT), and left ventricular mass index. Results: The prevalence of TOD tended to decrease with sleep-trough MHRS (first to fourth quartiles: 71%, 70.3%, 58.6%, and 52.7%, respectively) or prewaking MHRS quartiles (first to fourth quartiles: 65.3%, 73.6%, 61.4%, and 54.2%, respectively), whereas the opposite trend was observed for standard deviation of all normal NN intervals (SDNN). Moreover, sleep-trough MHRS, prewaking MHRS, SDNN, and SDNN index were significantly lower in patients with TOD than in those without TOD. According to four logistic regression models, the associations of prewaking MHRS, SDNN, and SDNN index with TOD were lost after adjustment for age and BP. Patients in the first (≤11.125 bpm) and second sleep-trough MHRS quartiles (11.125–15.75 bpm) had a 1.95–2.06-fold increased risk of TOD compared with those in the fourth quartile (p < 0.05). Conclusion: A blunted sleep-trough MHRS, which may serve as a surrogate marker for autonomic imbalance, was independently associated with TOD in primary hypertensive patients.
Serum adiponectin is a predictor of coronary heart disease: a population-based 10-year follow-up study in elderly men.

CONTEXT Cross-sectional and nested case-control studies indicate a relationship between adiponectin, obesity, and coronary heart disease (CHD). OBJECTIVE Our objective was to investigate whether adiponectin could predict CHD in a population-based cohort of elderly men. DESIGN AND SETTING From 1991-1995 a baseline investigation was carried out in 832 healthy men aged 70 yr in the Uppsala Longitudinal Study of Adult Men (ULSAM study). They were followed up to 10.4 yr using Swedish national registry data. The baseline investigation included anthropometry, blood pressure, smoking, serum lipids, a euglycemic insulin clamp, and fasting serum adiponectin. MAIN OUTCOME MEASURES Main outcome measures were defined as death or first-time hospitalization for CHD (n = 116), recorded in the Cause of Death Registry or in the Hospital-Discharge Registry of the National Board of Health and Welfare, Sweden. Associations were analyzed using Cox's proportional hazards regression, presented as hazard ratios (HR) with 95% confidence intervals (CI) for 1 sd increase in the predictor variable. RESULTS In a multivariable analysis including total cholesterol (HR, 1.24; CI, 1.02-1.50), high-density lipoprotein cholesterol (HR, 0.72; CI, 0.58-0.89), smoking (HR, 1.39; CI, 0.91-2.14), and systolic blood pressure (HR, 1.26; CI, 1.05-1.52), serum adiponectin was associated with lower risk for CHD (HR, 0.81; CI, 0.66-0.99). The association was independent of BMI and remained significant after adjustment for insulin sensitivity index. CONCLUSIONS In this population-based cohort of healthy men, elevated serum levels of adiponectin were associated with a lower risk for CHD. Importantly, the association between adiponectin and CHD was independent of other well-known risk factors.
CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth

Hypoxia-inducible factor 1 (HIF-1) is a major mediator of tumor physiology, and its activation is correlated with tumor progression, metastasis, and therapeutic resistance. HIF-1 is activated in a broad range of solid tumors due to intratumoral hypoxia or genetic alterations that enhance its expression or inhibit its degradation. As a result, decreasing HIF-1α expression represents an attractive strategy to sensitize hypoxic tumors to anticancer therapies. Here, we show that cyclin-dependent kinase 1 (CDK1) regulates the expression of HIF-1α, independent of its known regulators. Overexpression of CDK1 and/or cyclin B1 is sufficient to stabilize HIF-1α under normoxic conditions, whereas inhibition of CDK1 enhances the proteasomal degradation of HIF-1α, reducing its half-life and steady-state levels. In vitro kinase assays reveal that CDK1 directly phosphorylates HIF-1α at a previously unidentified regulatory site, Ser668. HIF-1α is stabilized under normoxic conditions during G2/M phase via CDK1-mediated phosphorylation of Ser668. A phospho-mimetic construct of HIF-1α at Ser668 (S668E) is significantly more stable under both normoxic and hypoxic conditions, resulting in enhanced transcription of HIF-1 target genes and increased tumor cell invasion and migration. Importantly, HIF-1α (S668E) displays increased tumor angiogenesis, proliferation, and tumor growth in vivo compared with wild-type HIF-1α. Thus, we have identified a novel link between CDK1 and HIF-1α that provides a potential molecular explanation for the elevated HIF-1 activity observed in primary and metastatic tumors, independent of hypoxia, and offers a molecular rationale for the clinical translation of CDK inhibitors for use in tumors with constitutively active HIF-1.
Niche conservatism above the species level

Traits that enable species to persist in ecological environments are often maintained over time, a phenomenon known as niche conservatism. Here we argue that ecological niches function at levels above species, notably at the level of genus for mammals, and that niche conservatism is also evident above the species level. Using the proxy of geographic range size, we explore changes in the realized niche of North American mammalian genera and families across the major climatic transition represented by the last glacial–interglacial transition. We calculate the mean and variance of range size for extant mammalian genera and families, rank them by range size, and estimate the change in range size and rank during the late Pleistocene and late Holocene. We demonstrate that range size at the genus and family levels was surprisingly constant over this period despite range shifts and extinctions of species within the clades. We suggest that underlying controls on niche conservatism may be different at these higher taxonomic levels than at the species level. Niche conservatism at higher levels seems primarily controlled by intrinsic life history traits, whereas niche conservatism at the species level may reflect underlying environmental controls. These results highlight the critical importance of conserving the biodiversity of mammals at the genus level and of maintaining an adequate species pool within genera.
GPU-Accelerated Parallel Hierarchical Extreme Learning Machine on Flink for Big Data

The extreme learning machine (ELM) has become one of the most important and popular algorithms of machine learning, because of its extremely fast training speed, good generalization, and universal approximation/classification capability. The proposal of hierarchical ELM (H-ELM) extends ELM from single hidden layer feedforward networks to multilayer perceptron, greatly strengthening the applicability of ELM. Generally speaking, during training H-ELM, large-scale datasets (DSTs) are needed. Therefore, how to make use of H-ELM framework in processing big data is worth further exploration. This paper proposes a parallel H-ELM algorithm based on Flink, which is one of the in-memory cluster computing platforms, and graphics processing units (GPUs). Several optimizations are adopted to improve the performance, such as cache-based scheme, reasonable partitioning strategy, memory mapping scheme for mapping specific Java virtual machine objects to buffers. Most importantly, our proposed framework for utilizing GPUs to accelerate Flink for big data is general. This framework can be utilized to accelerate many other variants of ELM and other machine learning algorithms. To the best of our knowledge, it is the first kind of library, which combines in-memory cluster computing with GPUs to parallelize H-ELM. The experimental results have demonstrated that our proposed GPU-accelerated parallel H-ELM named as GPH-ELM can efficiently process large-scale DSTs with good performance of speedup and scalability, leveraging the computing power of both CPUs and GPUs in the cluster.
Male mate choice relies on major histocompatibility complex class I in a sex‐role‐reversed pipefish

Mate choice for compatible genes is often based on genes of the major histocompatibility complex (MHC). Although MHC‐based mate choice is commonly observed in female choice, male mate choice remains elusive. In particular, if males have intense paternal care and are thus the choosing sex, male choice for females with dissimilar MHC can be expected. Here, we investigated whether male mate choice relies on MHC class I genes in the sex‐role reversed pipefish Syngnathus typhle. In a mate choice experiment, we determined the relative importance of visual and olfactory cues by manipulating visibility and olfaction. We found that pipefish males chose females that maximize sequence‐based amino acid distance between MHC class I genotypes in the offspring when olfactory cues were present. Under visual cues, large females were chosen, but in the absence of visual cues, the choice pattern was reversed. The use of sex‐role reversed species thus revealed that sexual selection can lead to the evolution of male mate choice for MHC class I genes.
Mathematical Modeling and Analysis in Biochemical Engineering: Past Accomplishments and Future Opportunities

This is a personal commentary on the history and future prospects of mathematical modeling and analysis in biochemical engineering. Major transitions in these fields were driven by the appearance of the Aiba, Humphrey, and Millis text, Fredrickson's guidance on conceptualizing mathematical representations of cell populations, and Ramkrishna's development of the cybernetic modeling approach. The value of mathematical models to organize data, to consider interactions in complex systems in a rational way, to correct the conventional wisdom, and to understand essential qualitative features of biological systems has been clearly documented in prior research. The impact of this research in biotechnology discovery has so far been limited, but this will change in the future if we are adept in recognizing emerging opportunities and in integrating new concepts and tools into our research. Mathematical structures and methods, allied with extraordinary contemporary computing power, are essential to the emerging field of functional genomics. Important in this quest is a hierarchy of powerful modeling, analysis, and computational tools which can capture essential quantitative features of available experimental data and use these effectively for analysis and design of metabolism.
Sex Composition of Staff, Authority and Collegality in Secondary Schools

A research project, supported by the Social Science Research Council, involved a survey of a sample of forty-five English secondary schools, representative of the national distribution of schools by status: grammar, 11 per cent, modern, 24 per cent and comprehensive, 65 per cent, The main purpose was to investigate the organisation of pupil learning and behaviour, and some of the results have already been reported (King, 1981a, 1981b, 1982). However, the opportunity was taken to gather data concerned with two aspects of the organisation of relationships between teachers: staff meetings and the distribution of posts of responsibility. The sources
Differential Susceptibility of Male and Female Mice to Encephalomyocarditis Virus: Effects of Castration, Adrenalectomy, and the Administration of Sex Hormones

Male mice have been noted to be more susceptible to encephalomyocarditis (EMC) virus than female animals. Castration of male mice abolished this difference and resulted in enhanced resistance similar to that of female mice. This increase in resistance in castrated males could be eliminated by adrenalectomy. Adrenalectomy alone increased susceptibility in male mice but not in female mice. The administration of a long-acting preparation of testosterone markedly increased susceptibility both in castrated male and female mice, as well as in intact females. Testosterone also had a similar effect in immature mice of both sexes. On the other hand, estradiol, but not progesterone, increased susceptibility to EMC virus in castrated mice of both sexes. These data indicate that testicular, ovarian, and adrenal hormones may influence resistance to EMC virus in the mouse and may be critical determinants of the clinical outcome of infection with this virus.
Cancer stage at diagnosis in patients infected with the human immunodeficiency virus and transplant recipients

It is unknown whether immunosuppression results in more aggressive, advanced stage cancers. Because cancer stage is influenced both by tumor biology and medical surveillance, the authors assessed cancer stage in individuals infected with the human immunodeficiency virus (HIV) and solid organ transplant recipients, 2 immunosuppressed groups with differences in their health care use.
Marchés avec coûts de transaction : approximations de leland et arbitrage

Cette these aborde plusieurs problemes qui se posent pour les marches financiers soumis a des couts de transaction. Nous revisitons d'abord la methode d'approximation des portefeuilles de couverture des options Europeennes suggerees par Leland pour le calI Europeen. On met en evidence la convergence en probabilite des portefeuilles discretises vers le pay-off lorsque ce dernier est bien plus general. Dans le meme esprit, on mesure la vitesse de convergence en estimant la moyenne de l'erreur quadratique. Cela nous conduit a formuler un theoreme de convergence en loi de l'erreur d'approximation du type central-limite. Toutefois, le modele de Black et Scholes utilise est critiquable dans la pratique puisque la volatilite est supposee constante. C'est pourquoi, nous proposons d'etablir un theoreme de convergence en probabilite analogue au precedent lorsque la volatilite ne depend pas seulement du temps mais aussi de l'actif risque sous-jacent. Enfin, on s'interesse a d'es marches continus plus abstraits decrits par des cones generes par les couts de transactions. Nous formulons quelques notions d'arbitrage mais surtout on propose une description duale des prix de couverture des options americaines comme cela a deja ete fait pour les marches discretises.
Pythium insidiosum Keratitis in Contact Lens Wear: A Case Report

Purpose: The purpose of this study was to report a case of contact lens-related Pythium insidiosum corneal ulcer. Methods: The authors conducted an interventional case report. We report the clinical presentations, histopathologic findings, and treatments of a patient with P. insidiosum keratitis associated with contact lens wear. Results: A 22-year-old Thai woman presented to our clinic with a nonresponsive, progressive corneal ulcer of the left eye. Slit lamp examination showed a large central ulcer measuring 5.4 × 5.2 mm with underlying dense stromal infiltrates surrounded by subepithelial and superficial stromal opacity in a reticular pattern along with radial perineural-like infiltrates. Histopathologic examination revealed broad, branched, thin-walled nonparallel hyaline hyphae with rare septates consistent with P. insidiosum. The corneal culture confirmed the diagnosis. The infection recurred after multiple therapeutic penetrating keratoplasties. Enucleation was eventually performed to eradicate the infection. No definite report of contact lens-related P. insidiosum keratitis existed in the literature. Conclusion: Pythium keratitis may present with central ulcer and radial keratoneuritis similar to acanthamoeba keratitis. Contact lens wear can be a risk factor for this infection. Increasing awareness, early diagnosis, and intervention may improve the prognosis.
Homeownership, saving and financial wealth: a comparative and longitudinal analysis

Abstract The finding that homeowners own more non-housing wealth than tenants is well known. We examine whether the higher financial wealth of owners can be partly explained with increases in saving when becoming a homeowner in two distinct institutional contexts. Using longitudinal data for the UK (British Household Panel Survey) and Germany (Socio-Economic Panel Study), we find that homeowners save more and are financially wealthier than tenants. However, when controlling for time-constant selection into homeownership, upon entering homeownership households reduce their probability to save in Germany and reduce their average saving rate in Germany and the UK. For Germany, there is some evidence that processes of homemaking (family formation and home improvement) lead to less saving. For the UK, we find no evidence that increasing home equity over time discourages saving. Finally, tenants do not compensate for their lack of housing wealth by accumulating more non-housing wealth over time. This disadvantage for tenants seems more pronounced in the UK compared to Germany.
Estimating River Depth From Remote Sensing Swath Interferometry Measurements of River Height, Slope, and Width

The Surface Water and Ocean Topography (SWOT) mission is a swath mapping radar interferometer that would provide new measurements of inland water surface elevation (WSE) for rivers, lakes, wetlands, and reservoirs. SWOT WSE estimates would provide a source of information for characterizing streamflow globally and would complement existing in situ gage networks. In this paper, we evaluate the accuracy of river discharge estimates that would be obtained from SWOT measurements over the Ohio river and eleven of its major tributaries within the context of a virtual mission (VM). SWOT VM measurements are obtained by using an instrument measurement model coupled to simulated WSE from the hydrodynamic model LISFLOOD-FP, using USGS streamflow gages as boundary conditions and validation data. Most model pixels were estimated two or three times per 22-day orbit period. These measurements are then input into an algorithm to obtain estimates of river depth and discharge. The algorithm is based on Manning's equation, in which river width and slope are obtained from SWOT, and roughness is estimated a priori. SWOT discharge estimates are compared to the discharge simulated by LISFLOOD-FP. Instantaneous discharge estimates over the one-year evaluation period had median normalized root mean square error of 10.9%, and 86% of all instantaneous errors are less than 25%.
Can shareholder advocacy shape energy governance? The case of the US antifracking movement

Abstract Research on socially responsible investing (SRI) and investor-led governance, especially in the climate sector, suggests that shareholders adopt social movement tactics to influence corporate governance, including building networks, engaging directly with corporations and lobbying regulators. Further, research on corporate transparency and financial disclosure has proliferated, notably in the extractives sector. Our work builds on these existing literatures, with a focus on shareholder resolutions on hydraulic fracturing (HF) in the United States. We analyze US HF-focused shareholder resolutions from 2010 to 2016 to evaluate filing strategies and outcomes. We argue that these resolutions provide space for a range of new actors to shape corporate governance—but their power is constrained. The constraints flow from the same political economy factors that enable shareholders to take collective action: the distance between individual investors and financial decisions; the structure of resolutions and managerial responses; and the complexity of investment vehicles and vote shares. We assess how shareholders respond strategically by altering the focus of resolution demands, liaising with external campaigns and networks, and engaging with government to enhance regulatory interventions. Our work reveals how the upstreaming of power in commodity chains intersects with the power of management boards and the challenges of financialization, with consequences for corporate and energy governance.
Release of angiotensins in paraventricular nucleus of rat in response to physiological and chemical stimuli.

The brain angiotensin (ANG II and III) system is known to play an important role in the central control of cardiovascular function and body water homeostasis. A number of components of the angiotensin system including active peptides, precursors, synthetic enzymes, and receptors have been localized to specific brain nuclei including the paraventricular nucleus (PVN) of the hypothalamus. We and others have hypothesized that the PVN is a major integrative hub of the central angiotensin system receiving angiotensinergic input from central detectors (circumventricular organs) and sending efferents to higher brain and spinal cord centers. Implicit in this idea is that angiotensins, like all neurotransmitters, should be releasable with appropriate chemical and physiological stimuli. Therefore we examined the ability of water deprivation or direct infusion of either 65 mM K+ or 80 microM veratridine to stimulate the release of angiotensins from the PVN of the rat. Using push-pull cannulas to perfuse the PVN and radioimmunoassay (RIA) to analyze the superfusate for immunoreactive angiotensins, we established that 24 h of water deprivation resulted in an approximate 5-fold increase in the angiotensin release rate, whereas 48-h deprivation produced a dramatic 492-fold increase in release. Direct infusion of 65 mM K+ into the PVN was unable to stimulate angiotensin release, but 80 microM veratridine elicited a sevenfold increase in the angiotensin release rate. High-performance liquid chromatographic separation and RIA analysis of veratridine- and water deprivation-stimulated angiotensin release demonstrated that 93.4% of the releasable angiotensin coeluted with ANG III, whereas only 6.8% eluted with authentic ANG II. (ABSTRACT TRUNCATED AT 250 WORDS)