Miracle-dz/UniFAR-FTUs huggingface dataset:
Gender Bias in Human Systemic Lupus Erythematosus: A Problem of Steroid Receptor Action?

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease resulting from abnormal interactions between T and B cells. The acquisition of SLE is linked to genetic susceptibility, and diverse environmental agents can trigger disease onset in genetically susceptible individuals. However, the strongest risk factor for developing SLE is being female (9:1 female to male ratio). The female sex steroid, estradiol, working through its receptors, contributes to the gender bias in SLE although the mechanisms remain enigmatic. In a small clinical trial, monthly administration of the estrogen receptor (ERα) antagonist, ICI182,780 (fulvestrant), significantly reduced disease indicators in SLE patients. In order to identify changes that could account for improved disease status, the present study utilized fulvestrant (Faslodex) to block ERα action in cultured SLE T cells that were purified from blood samples collected from SLE patients (n = 18, median age 42 years) and healthy control females (n = 25, median age 46 years). The effects of ERα antagonism on estradiol-dependent gene expression and canonical signaling pathways were analyzed. Pathways that were significantly altered by addition of Faslodex included T helper (Th) cell differentiation, steroid receptor signaling [glucocorticoid receptor (GR), ESR1 (ERα)], ubiquitination, and sumoylation pathways. ERα protein expression was significantly lower (p < 0.018) in freshly isolated, resting SLE T cells suggesting ERα turnover is inherently faster in SLE T cells. In contrast, ERα/ERβ mRNA and ERβ protein levels were not significantly different between SLE and normal control T cell samples. Plasma estradiol levels did not differ (p > 0.05) between SLE patients and controls. A previously undetected interaction between GR and ERα signaling pathways suggests posttranslational modification of steroid receptors in SLE T cells may alter ERα/GR actions and contribute to the strong gender bias of this autoimmune disorder.
Profiles of referrals to a psychiatric service: a descriptive study of survivors of the Nairobi US Embassy terrorist bomb blast.

OBJECTIVE To document the socio-demographic characteristics and psychiatric profiles of the survivors of the Nairobi United States Embassy terrorist bomb blast referred to a psychiatric and psychotherapy (counselling) service. METHOD This was a descriptive cross-sectional study. Clinical interviews and structured questionnaires for post-traumatic stress disorder (PTSD) and stress were administered. Survivors of the bomb blast referred to a psychiatric and psychotherapy service one year or more after the bombing were included in the study. These survivors had been treated using psychopharmacotherapy and individualised (not group) therapy/counselling. RESULTS Eighty-three consecutive referrals to a psychiatric service participated in this study. There were more males and the sample was generally well educated. The referrals made contact with the referring agency for a number of reasons including seeking psychological, financial and medical assistance. All the patients reported varying degrees of psychiatric symptoms and functional impairment on various aspects of social occupational functioning. High scores for PTSD and other related stress were recorded one or more years after the bombing. CONCLUSION Although the survivors indicated that initial counselling following the blast had helped them, they still scored high on PTSD suggesting that clinically, the initial counselling had little, if any impact on the development of PTSD. There is need for a holistic approach to the management of psychotrauma in individuals.
A security configuration assessment for android devices

The wide spreading of mobile devices, such as smartphones and tablets, and their always-advancing capabilities makes them an attractive target for attackers. This, together with the fact that users frequently store critical personal information in such devices and that many organizations currently allow employees to use their personal devices to access the enterprise information infrastructure and applications, makes the assessment of the security of mobile devices a key issue. This paper proposes an approach supported by a tool that allows assessing the security of Android devices based on the user-defined settings, which are known to be a key source of security vulnerabilities. The tool automatically extracts 41 settings from the mobile devices under testing, 14 of which defined and proposed in this work and the remaining adapted from the well-known CIS benchmarks. The paper discusses the settings that are analyzed, describes the overall architecture of the tool, and presents a preliminary evaluation that demonstrates the importance of this type of tools as a foundation towards the assessment of the security of mobile devices.
Effect of Temperature Thresholds on Modeled Aedes aegypti (Diptera: Culicidae) Population Dynamics

Abstract Dynamic simulation models provide vector abundance estimates using only meteorological data. However, model outcomes may heavily depend on the assumptions used to parameterize them. We conducted a sensitivity analysis for a model of Aedes aegypti (L.) abundance using weather data from two locations where this vector is established, La Margarita, Puerto Rico and Tucson, Arizona. We tested the effect of simplifying temperature-dependent development and mortality rates and of changing development and mortality thresholds as compared with baselines estimated using biophysical models. The simplified development and mortality rates had limited effect on abundance estimates in either location. However, in Tucson, where the vector is established but has not transmitted viruses, a difference of 5 °C resulted in populations either surviving or collapsing in the hot Arizona mid-summer, depending on the temperature thresholds. We find three important implications of the observed sensitivity to temperature thresholds. First, this analysis indicates the need for better estimates of the temperature tolerance thresholds to refine entomologic risk mapping for disease vectors. Second, our results highlight the importance of extreme temperatures on vector survival at the marginal areas of this vector's distribution. Finally, the model suggests that adaptation to warmer temperatures may shift regions of pathogen transmission.
Patients with Early Rheumatoid Arthritis in the 2000s Have Equal Disability and Pain Despite Less Disease Activity Compared with the 1990s: Data from the BARFOT Study over 8 Years

Objective. To compare outcomes over the first 8 years in patients with early rheumatoid arthritis (RA) recruited in the 1990s and the 2000s, with a special focus on functional disability and its possible predictors. Methods. Data were acquired from 1938 patients with early RA (American College of Rheumatology 1987 criteria) included in the BARFOT study, who had completed the 8-year followup. The patients were divided into 2 cohorts: cohort 1 (n = 928, 68% women) included from 1992 to 1999 and cohort 2 (n = 1010, 70% women) included from 2000 to 2006. Health Assessment Questionnaire (HAQ), 28-joint Disease Activity Score (DAS28), visual analog scale pain, and radiographs of hands and feet scored by the van der Heijde modified Sharp method were assessed during the 8 years. Longitudinal data analyses were performed using a generalized linear model. Results. Despite more active medical treatment during the 2000s, the courses of HAQ and pain showed no difference between the cohorts during followup, in either women or in men, with significantly higher levels in women compared with men. However, as expected, disease activity decreased more over time in cohort 2 compared with cohort 1, for both sexes, and women in cohort 2 had less radiographic progression compared with cohort 1. HAQ was associated with DAS28, pain, radiological scores, and sex in both cohorts, and in cohort 2 also with age and smoking. Conclusion. Patients included in the 2000s had lower disease activity, but not less activity limitation and pain over 8 years of followup despite more active treatment. Pain, aging, and smoking might explain why patients included in the 2000s still had the same disability levels as those included in the 1990s.
Molecular Characterization of a Novel N-Acetylneuraminate Lyase from a Deep-Sea Symbiotic Mycoplasma

N-acetylneuraminic acid (Neu5Ac) based novel pharmaceutical agents and diagnostic reagents are highly required in medical fields. However, N-acetylneuraminate lyase（NAL）for Neu5Ac synthesis is not applicable for industry due to its low catalytic efficiency. In this study, we biochemically characterized a deep-sea NAL enzyme (abbreviated form: MyNal) from a symbiotic Mycoplasma inhabiting the stomach of a deep-sea isopod, Bathynomus jamesi. Enzyme kinetic studies of MyNal showed that it exhibited a very low Km for both cleavage and synthesis activities compared to previously described NALs. Though it favors the cleavage process, MyNal out-competes the known NALs with respect to the efficiency of Neu5Ac synthesis and exhibits the highest kcat/Km values. High expression levels of recombinant MyNal could be achieved (9.56 mol L−1 culture) with a stable activity in a wide pH (5.0–9.0) and temperature (40–60 °C) range. All these features indicated that the deep-sea NAL has potential in the industrial production of Neu5Ac. Furthermore, we found that the amino acid 189 of MyNal (equivalent to Phe190 in Escherichia coli NAL), located in the sugar-binding domain, GX189DE, was also involved in conferring its enzymatic features. Therefore, the results of this study improved our understanding of the NALs from different environments and provided a model for protein engineering of NAL for biosynthesis of Neu5Ac.
CHANGE-POINT DETECTION AS MODEL SELECTION

We present a new method for solving the change-point detection problem for ARMA systems which are assumed to have a slow and non-decaying drift after the change occurs. The proposed technique is inspired by the stochastic complexity theory, which gives a basis of comparison of different models with different change-point . imes. Some partial results on the analysis of the estimator are stated. A simulation is included which shows that the approach exhibits surprisingly good detection capabilities.
Suicides Among American Indian/Alaska Natives — National Violent Death Reporting System, 18 States, 2003–2014

Suicide disproportionately affects American Indians/Alaska Natives (AI/AN). The suicide rate among AI/AN has been increasing since 2003 (1), and in 2015, AI/AN suicide rates in the 18 states participating in the National Violent Death Reporting System (NVDRS) were 21.5 per 100,000, more than 3.5 times higher than those among racial/ethnic groups with the lowest rates. * To study completed suicides across all ages of AI/AN, NVDRS data collected from 2003 to 2014 were analyzed by comparing differences in suicide characteristics and circumstances between AI/AN and white decedents. Group differences were assessed using chi-squared tests and logistic regression. Across multiple demographics, incident characteristics, and circumstances, AI/AN decedents were significantly different from white decedents. More than one third (35.7%) of AI/AN decedents were aged 10-24 years (versus 11.1% of whites). Compared with whites, AI/AN decedents had 6.6 times the odds of living in a nonmetropolitan area, 2.1 times the odds of a positive alcohol toxicology result, and 2.4 times the odds of a suicide of a friend or family member affecting their death. Suicide prevention efforts should incorporate evidence-based, culturally relevant strategies at individual, interpersonal, and community levels (2) and need to account for the heterogeneity among AI/AN communities (3,4).
Superresolution Imaging of Human Cytomegalovirus vMIA Localization in Sub-Mitochondrial Compartments

The human cytomegalovirus (HCMV) viral mitochondria-localized inhibitor of apoptosis (vMIA) protein, traffics to mitochondria-associated membranes (MAM), where the endoplasmic reticulum (ER) contacts the outer mitochondrial membrane (OMM). vMIA association with the MAM has not been visualized by imaging. Here, we have visualized this by using a combination of confocal and superresolution imaging. Deconvolution of confocal microscopy images shows vMIA localizes away from mitochondrial matrix at the Mitochondria-ER interface. By gated stimulated emission depletion (GSTED) imaging, we show that along this interface vMIA is distributed in clusters. Through multicolor, multifocal structured illumination microscopy (MSIM), we find vMIA clusters localize away from MitoTracker Red, indicating its OMM localization. GSTED and MSIM imaging show vMIA exists in clusters of ~100–150 nm, which is consistent with the cluster size determined by Photoactivated Localization Microscopy (PALM). With these diverse superresolution approaches, we have imaged the clustered distribution of vMIA at the OMM adjacent to the ER. Our findings directly compare the relative advantages of each of these superresolution imaging modalities for imaging components of the MAM and sub-mitochondrial compartments. These studies establish the ability of superresolution imaging to provide valuable insight into viral protein location, particularly in the sub-mitochondrial compartments, and into their clustered organization.
Diverse Inhibitor Chemotypes Targeting Trypanosoma cruzi CYP51

Background Chagas Disease, a WHO- and NIH-designated neglected tropical disease, is endemic in Latin America and an emerging infection in North America and Europe as a result of population moves. Although a major cause of morbidity and mortality due to heart failure, as well as inflicting a heavy economic burden in affected regions, Chagas Disease elicits scant notice from the pharmaceutical industry because of adverse economic incentives. The discovery and development of new routes to chemotherapy for Chagas Disease is a clear priority. Methodology/Principal Findings The similarity between the membrane sterol requirements of pathogenic fungi and those of the parasitic protozoon Trypanosoma cruzi, the causative agent of Chagas human cardiopathy, has led to repurposing anti-fungal azole inhibitors of sterol 14α-demethylase (CYP51) for the treatment of Chagas Disease. To diversify the therapeutic pipeline of anti-Chagasic drug candidates we exploited an approach that included directly probing the T. cruzi CYP51 active site with a library of synthetic small molecules. Target-based high-throughput screening reduced the library of ∼104,000 small molecules to 185 hits with estimated nanomolar KD values, while cross-validation against T. cruzi-infected skeletal myoblast cells yielded 57 active hits with EC50 <10 µM. Two pools of hits partially overlapped. The top hit inhibited T. cruzi with EC50 of 17 nM and was trypanocidal at 40 nM. Conclusions/Significance The hits are structurally diverse, demonstrating that CYP51 is a rather permissive enzyme target for small molecules. Cheminformatic analysis of the hits suggests that CYP51 pharmacology is similar to that of other cytochromes P450 therapeutic targets, including thromboxane synthase (CYP5), fatty acid ω-hydroxylases (CYP4), 17α-hydroxylase/17,20-lyase (CYP17) and aromatase (CYP19). Surprisingly, strong similarity is suggested to glutaminyl-peptide cyclotransferase, which is unrelated to CYP51 by sequence or structure. Lead compounds developed by pharmaceutical companies against these targets could also be explored for efficacy against T. cruzi.
New strategies to tackle diabetic kidney disease

Purpose of reviewThe purpose of this review is to provide an overview of recent preclinical and clinical studies, which demonstrate new insights for the treatment of diabetic kidney disease (DKD) and to outline future directions with respect to novel therapies. Recent findingsPositive findings with respect to new glucose-lowering agents such as sodium-dependent glucose transporter 2 inhibitors may lead to a change in the way we treat diabetic individuals with or at risk of DKD. Additional positive phase 2 clinical studies with drugs that have hemodynamic actions such as endothelin antagonists and mineralocorticoid receptor antagonists have led to larger phase 3 trials with atrasentan and finerenone, respectively, in order to address if these drugs indeed delay the development of end-stage renal disease. A number of other pathways are currently under active preclinical investigation and hopefully over the next decade will lead to promising drug candidates for subsequent clinical trials. SummaryDKD remains an area of active preclinical and clinical investigation. Positive results with some of the more promising agents should lead to strategies to reverse, attenuate or prevent DKD.
Taxonomy of PMU Data Based Catastrophic Indicators for Power System Stability Assessment

Though extensive work is reported on various catastrophic indicators for the assessment of power system stability, the comparative assessment has not received much attention by the researchers. With the advent of WAMS technology and near real-time tools available, these indicators can play an important role in operation and control of the system. The choice of the indicator(s) has to be based on the performance measures (accuracy, reliability, security, mis-detection, false-alarm, and correctness), which use a common platform for evaluation. This companion paper presents a critical review of the catastrophic indicators and computes the performance measures to assess the indicators, which is illustrated by an implementation architecture. The approach starts by generating a contingency dataset of a network, followed by obtaining the network measurements to the contingency dataset. These measurements are used as an input to the indicators for detecting stability/instability cases. The performance measures are computed to each indicator for their assessment. In addition to the above performance measures, robustness and sensitivity are obtained to each indicator. The IEEE 39 and IEEE 118 test networks are considered for comparing the performance measures. Additionally, 50-machine 145-bus system is used to demonstrate the applicability of indicators on practical systems. This work provides systematic taxonomy and insight into various indicators bringing out salient features on a comparative note to help decision makers to make suitable choice of indicator(s) for their system.
Fusion of hyperspectral images and height models using edge probability

We propose a method for data fusion of hyperspectral images (HSI) and digital surface models (DSM) basing on the edge probabilities from both datasets. A height discontinuity in DEM and change in material in HSI represent the high probability of an edge. Edge probabilities are computed in scale-space and combined according to the Gaussian mixture model. The reliability of the datasets can be included into this model as a prior knowledge. The method is tested on an urban area, where building boundaries represent the high probabilities of an edge in both datasets. Our results show, that the probabilistic fusion technique is advantageous where boundary detected from only one dataset are unreliable.
Osteopontin b and c Splice isoforms in Leukemias and Solid Tumors: Angiogenesis Alongside Chemoresistance

Osteopontin (OPN) is a glycoprotein involved in regulation of various influences on tumor progression, such as cellular proliferation, apoptosis, angiogenesis, and metastasis. Vascular endothelial growth factor (VEGF) is a secreted molecule supporting angiogenesis in various cancers through activation of the PI3K/AKT/ERK1/2 pathway. OPN and VEGF have a number of isoforms with various activities. In spite of the well-defined association between OPN and VEGF isoform expression and cure rate for solid tumors, there is a scarcity of information as to any association in leukemia. Based on the critical role of OPN in cell survival, it seems reasonable to hypothesize that OPN and VEGF isoform expression levels may impact on chemoresistance and relapse in leukemia the same as in solid tumors. Hence, the aim of our review was to explain relationships between OPN and VEGF isoforms and angiogenesis and related pathways in chemoresistance of leukemia and solid tumors. Our findings demonstrated that OPNb and OPNc alongside with VEGF isoforms and other gene pathways are involved in angiogenesis and also might promote chemoresistance and even recurrence in leukemia and solid tumors. To sum up, targeting OPN isoforms, particularly b and c, might be a novel therapeutic strategy for the treatment of leukemia as well as solid tumors.
Evaluation of sFLT1 protein levels in human eyes with the FLT1 rs9943922 polymorphism

ABSTRACT Purpose: Age-related macular degeneration (AMD) is a devastating disease characterized by central vision impairment in individuals with advanced age. Neovascular AMD is a form of end-stage disease in which choroidal vessel outgrowth occurs beneath the retina. While many hypotheses have been raised as to what triggers the formation of pathological choroidal neovascular membranes, the exact mechanism for their initiation remains unresolved. Polymorphisms in the FLT1 gene have previously been associated with neovascular AMD risk, including the rs9943922 single nucleotide polymorphism (SNP). Here, we aimed to determine the association between the high-risk FLT1 genotype and FLT1 protein levels in human retina or retinal pigment epithelium (RPE)/choroid tissue. Methods: Retina and RPE/choroid tissue from 10 human donor eyes was selected from a collection of eyes genotyped for the rs9943922 SNP. Differences in soluble and membrane bound FLT1 protein levels were assessed for retina versus RPE/choroid donor tissue using ELISA and Western blotting analyses. Genotype-associated changes in FLT1 protein levels were also evaluated. Results: We found soluble FLT1 levels in the RPE/choroid tissue to be approximately three times higher than that of the retina (p < 0.001), while both samples have similar levels of the membrane bound form. When tissue with the rs9943922 SNP was compared with controls, no significant genotypic differences in FLT1 protein levels were observed. Conclusions: Based on these data, we conclude that the rs9943922 SNP in the FLT1 gene does not result in a large difference in FLT1 protein levels, regardless of whether it is the soluble or the membrane bound form.