Miracle-dz/UniFAR-FTUs huggingface dataset:
HJURP antagonizes CENP-A mislocalization driven by the H3.3 chaperones HIRA and DAXX

The centromere specific histone H3 variant CENP-A/CENH3 specifies where the kinetochore is formed in most eukaryotes. Despite tight regulation of CENP-A levels in normal cells, overexpression of CENP-A is a feature shared by various types of solid tumors and results in its mislocalization to non-centromeric DNA. How CENP-A is assembled ectopically and the consequences of this mislocalization remain topics of high interest. Here, we report that in human colon cancer cells, the H3.3 chaperones HIRA and DAXX promote ectopic CENP-A deposition. Moreover, the correct balance between levels of the centromeric chaperone HJURP and CENP-A is essential to preclude ectopic assembly by H3.3 chaperones. In addition, we find that ectopic localization can recruit kinetochore components, and correlates with mitotic defects and DNA damage in G1 phase. Finally, CENP-A occupancy at the 8q24 locus is also correlated with amplification and overexpression of the MYC gene within that locus. Overall, these data provide insights into the causes and consequences of histone variant mislocalization in human cancer cells.
A Brain–Computer Interface-Based Action Observation Game That Enhances Mu Suppression

Action observation training based on the theory of activation of the mirror-neuron system has been used for the rehabilitation of patients with stroke. In this paper, we sought to assess whether a brain–computer interface (BCI)-based action observation rehabilitation game, using a flickering action video, could preferentially activate the mirror-neuron system. Feedback of stimulus observation, evoked by the flickering action video, was provided using steady state visually evoked potential and event-related desynchronization. Fifteen healthy subjects have experienced the game with BCI interaction (game and interaction), without BCI interaction (game without interaction), observed non-flickering stimuli, and flickering stimuli without the game background (stimuli only) in a counter-balanced order. The game and interface condition was resulted in significantly stronger activation of the mirror-neuron system than did the other three conditions. In addition, the amount of mirror-neuron system activation is gradually decreased in the game without interface, non-flickering stimuli, and stimuli only conditions in a time-dependent manner; however, in the game and interface condition, the amount of mirror-neuron system activation was maintained until the end of the training. Taken together, these data suggest that the proposed game paradigm, which integrates the action observation paradigm with BCI technology, could provide interactive responses for whether watching video clips can engage patients and enhance rehabilitation.
Single-molecule force spectroscopy reveals folding steps associated with hormone binding and activation of the glucocorticoid receptor

Significance The glucocorticoid receptor (GR) is an important signaling protein and a prominent drug target. Cortisone, one of the drugs directed against the GR, is among the most prescribed drugs worldwide. Hormone binding leads to activation of the receptor, which is then transported into the nucleus, affecting gene transcription. Despite its importance, little is known about the structural prerequisites of hormone binding and the associated conformational changes. We used a mechanical single-molecule method that allowed us to observe in detail the steps of folding and hormone binding of GR. We identify a structural element that opens and closes upon hormone binding. Our results form the basis for understanding GR activation and its regulation by chaperone proteins. The glucocorticoid receptor (GR) is a prominent nuclear receptor linked to a variety of diseases and an important drug target. Binding of hormone to its ligand binding domain (GR-LBD) is the key activation step to induce signaling. This process is tightly regulated by the molecular chaperones Hsp70 and Hsp90 in vivo. Despite its importance, little is known about GR-LBD folding, the ligand binding pathway, or the requirement for chaperone regulation. In this study, we have used single-molecule force spectroscopy by optical tweezers to unravel the dynamics of the complete pathway of folding and hormone binding of GR-LBD. We identified a “lid” structure whose opening and closing is tightly coupled to hormone binding. This lid is located at the N terminus without direct contacts to the hormone. Under mechanical load, apo-GR-LBD folds stably and readily without the need of chaperones with a folding free energy of 41 kBT (24 kcal/mol). The folding pathway is largely independent of the presence of hormone. Hormone binds only in the last step and lid closure adds an additional 12 kBT of free energy, drastically increasing the affinity. However, mechanical double-jump experiments reveal that, at zero force, GR-LBD folding is severely hampered by misfolding, slowing it to less than 1·s−1. From the force dependence of the folding rates, we conclude that the misfolding occurs late in the folding pathway. These features are important cornerstones for understanding GR activation and its tight regulation by chaperones.
Long-Term Effects of Intensive Glycemic and Blood Pressure Control and Fenofibrate Use on Kidney Outcomes.

BACKGROUND AND OBJECTIVES In people with type 2 diabetes, aggressive control of glycemia, BP, and lipids have resulted in conflicting short-term (<5 years) kidney outcomes. We aimed to determine the long-term kidney effects of these interventions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Action to Control Cardiovascular Risk in Diabetes (ACCORD) was a multifactorial intervention study in people with type 2 diabetes at high risk for cardiovascular disease (n=10,251), to examine the effects of intensive glycemic control (hemoglobin A1c <6.0% versus 7%-7.9%), BP control (systolic BP <120 mm Hg versus <140 mm Hg) or fenofibrate versus placebo added to simvastatin on cardiovascular events and death. The glycemia trial lasted 3.7 years and participants were followed for another 6.5 years in ACCORDION, the ACCORD Follow-On Study. The post hoc primary composite kidney outcome was defined as incident macroalbuminuria, creatinine doubling, need for dialysis, or death by any cause. Cox proportional hazards regression estimated the effect of each intervention on the composite outcome and individual components. In secondary outcome analyses, competing risk regression was used to account for the risk of death in incident kidney outcomes. Analyses were adjusted for sociodemographics, randomization groups, and clinical factors. RESULTS There were 988 cases of incident macroalbuminuria, 954 with doubling of creatinine, 351 requiring dialysis, and 1905 deaths. Hazard ratios (HRs) for the composite outcome with intensive glycemic, BP control, and fenofibrate use compared with standard therapy were 0.92 (95% confidence interval [95% CI], 0.86 to 0.98), 1.16 (95% CI, 1.05 to 1.28), and 1.16 (95% CI, 1.06 to 1.27). Multivariable, secondary outcome analyses showed that in the glycemia trial, only macroalbuminuria was significantly decreased (HR, 0.68; 95% CI, 0.59 to 0.77). In the BP and lipid trials, only creatinine doubling was affected (HR, 1.64; 95% CI, 1.30 to 2.06 and HR, 2.00; 95% CI, 1.61 to 2.49, respectively). CONCLUSIONS In people with type 2 diabetes at high risk for cardiovascular disease, intensive glycemic control may result in a long-term reduction in macroalbuminuria; however, intensive BP control and fenofibrates may increase the risk for adverse kidney events.
Genetic Polymorphisms and In Silico Mutagenesis Analyses of CYP2C9, CYP2D6, and CYPOR Genes in the Pakistani Population

Diverse distributions of pharmacogenetically relevant variants of highly polymorphic CYP2C9, CYP2D6 and CYPOR genes are responsible for some varied drug responses observed across human populations. There is limited data available regarding the pharmacogenetic polymorphisms and frequency distributions of major allele variants in the Pakistani population. The present in silico mutagenesis study conducted on genotype pharmacogenetic variants and comparative analysis with a global population aims to extend the currently limited pharmacogenetic available evidence for the indigenous Pakistani population. Extracted genomic DNA from 244 healthy individuals’ venous blood samples were amplified for distinct variant loci in the CYP2C9, CYP2D6 and CYPOR genes. Two-way sequencing results were compared with standard PubMed data and sequence variant loci confirmed by Chromas. This study revealed significant variations in CYP2C9 (rs1799853, rs1057910 and rs72558189), CYP2D6 (rs16947 and rs1135840), and CYPOR (rs1057868, rs781919285 and rs562750402) variants in intraethnic and interethnic frequency distributions. In silico mutagenesis and three-dimensional protein structural alignment analysis approaches clearly exposed the possible varied impact of rare CYPOR (rs781919285 and rs562750402) single nucleotide polymorphisms (SNPs) and confirmed that the influences of CYP2C9 and CYP2D6 variants are consistent with what was found in earlier studies. This investigation highlighted the need to study pharmacogenetic relevance loci and documentation since evidence could be utilized to elucidate genetic backgrounds of drug metabolism, and provide a basis for future pharmacogenomic studies and adequate dose adjustments in Pakistani and global populations.
Association of Anemia and Iron Parameters With Mortality Among Patients Undergoing Prevalent Hemodialysis in Taiwan: The AIM‐HD Study

Background The Taiwan Health Insurance Bureau has conducted a bundled payment system for hemodialysis reimbursement since 1995. The maximum dose of erythropoiesis‐stimulating agents allowed by insurance is capped at 20 000 U of epoetin or 100 μg of darbepoetin alfa per month. Nephrologists have avoided the use of high dosages of erythropoiesis‐stimulating agents to achieve a hemoglobin level of 10 to 11 g/dL by iron supplementation. The clinical impact of these policies on patients’ outcomes is unknown. The authors aimed to assess the AIM‐HD (Association of Anemia, Iron parameters, and Mortality among the prevalent Hemodialysis patients) Study in Taiwan. Methods and Results The AIM‐HD study was conducted based on the Taiwan Renal Registry Data System. From 2001 to 2008, the authors enrolled 42 230 patients undergoing hemodialysis who were older than 20 years and had received hemodialysis for more than 12 months. Patient follow‐ups occurred until death or December 31, 2008. During a study period of 8 years, 12 653 (30.0%) patients died. After multivariate adjustment, the authors found that a hemoglobin level <10 g/dL was significantly associated with higher risk for all‐cause and cardiovascular deaths. Moreover, a serum ferritin level between 300 and 800 ng/mL and transferrin saturation value between 30% and 50% were associated with the lowest all‐cause mortality. Conclusions The authors recommend avoiding a low hemoglobin level and maintaining serum ferritin between 300 and 800 ng/mL and transferrin saturation between 30% and 50%, which were associated with lower risks of all‐cause mortality among patients undergoing hemodialysis receiving the restricted erythropoiesis‐stimulating agent doses but prompt intravenous iron supplementation in Taiwan.
A Study of the Use and Outcomes From Respiratory Viral Testing at a Mid-Sized Children’s Hospital

This study was a retrospective analysis of inpatient and emergency department (ED) data on respiratory pathogen panel (RPP) testing between December 16, 2013, and December 15, 2015, at a mid-sized children’s hospital. We assessed whether RPP decreases antibiotic days of therapy and length of hospital stay for pediatric patients with acute respiratory infections. In the inpatient population, patients testing positive with RPP were given fewer antibiotic days of therapy (2.99 vs 4.30 days; P = .032) and had shorter hospital stays (2.84 vs 3.80 days; P = .055) than patients testing negative. In the ED population, patients testing positive with RPP received fewer discharge prescriptions for antibiotics than patients not tested (8.8% vs 41.1%; P < .001). RPP use was more prevalent in admitted patients than in ED patients (78.9% vs 7.3%; P < .001). Our results suggest that RPP testing curbs antibiotic use and decreases length of hospital stay.
Change Surfaces for Expressive Multidimensional Changepoints and Counterfactual Prediction

Identifying changes in model parameters is fundamental in machine learning and statistics. However, standard changepoint models are limited in expressiveness, often addressing unidimensional problems and assuming instantaneous changes. We introduce change surfaces as a multidimensional and highly expressive generalization of changepoints. We provide a model-agnostic formalization of change surfaces, illustrating how they can provide variable, heterogeneous, and non-monotonic rates of change across multiple dimensions. Additionally, we show how change surfaces can be used for counterfactual prediction. As a concrete instantiation of the change surface framework, we develop Gaussian Process Change Surfaces (GPCS). We demonstrate counterfactual prediction with Bayesian posterior mean and credible sets, as well as massive scalability by introducing novel methods for additive non-separable kernels. Using two large spatio-temporal datasets we employ GPCS to discover and characterize complex changes that can provide scientific and policy relevant insights. Specifically, we analyze twentieth century measles incidence across the United States and discover previously unknown heterogeneous changes after the introduction of the measles vaccine. Additionally, we apply the model to requests for lead testing kits in New York City, discovering distinct spatial and demographic patterns.
A highly efficient method for isolating urinary exosomes

In the present study, a highly efficient method, referred to as optimized ultrafiltration (OUF), was developed. This method is effective for exosome purification and also facilitates clinical work involving substantial urinary exosome isolation. In the OUF method, 0.22-µm filters along with a dialysis membrane with a molecular weight cut-off of 10,000 kDa were introduced, in order to remove extracellular microvesicles that were >200 nm and concentrate the supernatant up to 1/50 of the initial volume. The existence, purity and production of the exosomes isolated by OUF and conventional ultracentrifugation (UC) were systematically compared by transmission electron microscopy, western blotting and nanoparticle tracking analysis. In addition, colloidal Coomassie-stained gel and reverse transcription-quantitative polymerase chain reaction were used to investigate the stability and integrity of exosomes isolated by these two protocols. The time required and cost of these two methods in the process of isolating urinary exosomes were also estimated. The results indicated that OUF clearly outperforms UC in quantity, quality and biological stability, and this improved method may have extensive applications in the growing fields of clinical biomarker discovery and exosome research.
Impact of the Octagonal Layout Style for MOSFETs using 180nm Bulk CMOS ICs Technology Node

This paper aims to evaluate the impact of the octagonal layout style for MOSFETs regarding the 180nm Bulk CMOS ICs technology node. The main results of this study show that the nMOSFETs with octagonal gate geometries are capable of improving the drain current, Early voltage, intrinsic voltage gain, and on-state drain to source resistance about 150%, 800%, 66% and 50%, respectively, in relation to the standard rectangular MOSFET counterparts, regarding the same bias conditions. Therefore, the LCE and PAMDLE effects continue being actives regarding this 180 nm Bulk CMOS ICs technology node.
Ultra-Thin GaAs Double-Junction Solar Cell With Carbon-Doped Emitter

We address the challenge in depositing ultra-thin GaAs cells (<200 nm) using a more scalable process (metal–organic chemical vapor deposition). We present results for a GaAs/GaAs double-junction solar cell with a 110-nm-thick top cell. Current, voltage, fill factor, and efficiency of this architecture are improved by replacing the zinc doping in the emitter of the top cell with carbon doping. We find that the carbon doping results in a well-defined active junction profile that agrees well with the secondary ion mass spectroscopy measurement. Additionally, we find that the carbon doping coincides with the incorporation of indium in the emitter. We postulate that the incorporation of indium relieves stress in the material, which results in a smoother morphology of the GaAs film. Finally, we show the efficiency achieved with the carbon-doping process is 19.2% for the GaAs/GaAs dual junction cell. The open circuit voltage is 1.087 V for the ultra-thin (110 nm) GaAs top cell and 2.08 V for the dual junction cell.
Ruthenium Incorporated Cobalt Phosphide Nanocubes Derived From a Prussian Blue Analog for Enhanced Hydrogen Evolution

Electrochemical water splitting in alkaline media plays an important role in mass production of hydrogen. Ruthenium (Ru), as the cheapest member of platinum-group metals, has attracted much attention, and the incorporation of trace amount of Ru with cobalt phosphide could significantly improve the hydrogen evolution reaction (HER) catalytic activity. In this work, ruthenium-incorporated cobalt phosphide nanocubes are synthesized via a reaction between Co–Co Prussian blue analog (Co-PBA) and ruthenium chloride (RuCl3) followed by the phosphidation. The sample with a Ru content of ~2.04 wt. % exhibits the best HER catalytic activity with a low overpotential of 51 and 155 mV, to achieve the current densities of −10 and −100 mA cm−2, respectively, and the Tafel slope of 53.8 mV dec−1, which is comparable to the commercial Pt/C. This study provides a new perspective to the design and construction of high performance electrocatalysts for HER and other catalytic applications in a relatively low price.
The ratios of central venous to arterial carbon dioxide content and tension to arteriovenous oxygen content are not associated with overall anaerobic metabolism in postoperative cardiac surgery patients

Background The aim of the present study was to evaluate the ability of the ratios of central venous to arterial carbon dioxide content and tension to arteriovenous oxygen content to predict an increase in oxygen consumption (VO2) upon fluid challenge (FC). Methods and results 110 patients admitted to cardiothoracic ICU and in whom the physician had decided to perform an FC (with 500 ml of Ringer's lactate solution) were included. The arterial pressure, cardiac index (Ci), and arterial and venous blood gas levels were measured before and after FC. VO2 and CO2-O2 derived variables were calculated. VO2 responders were defined as patients showing more than a 15% increase in VO2. Of the 92 FC responders, 43 (46%) were VO2 responders. At baseline, pCO2 gap, C(a-v)O2 were lower in VO2 responders than in VO2 non-responders, and central venous oxygen saturation (ScvO2) was higher in VO2 responders. FC was associated with an increase in MAP, SV, and CI in both groups. With regard to ScvO2, FC was associated with an increase in VO2 non-responders and a decrease in VO2 responders. FC was associated with a decrease in pvCO2 and pCO2 gap in VO2 non-responders only. The pCO2 gap/C(a-v)O2 ratio and C(a-v)CO2 content /C(a-v)O2 content ratio did not change with FC. The CO2 gap content/C(a-v)O2 content ratio and the C(a-v)CO2 content /C(a-v)O2 content ratio did not predict fluid-induced VO2 changes (area under the curve (AUC) [95% confidence interval (CI)] = 0.52 [0.39‒0.64] and 0.53 [0.4–0.65], respectively; p = 0.757 and 0.71, respectively). ScvO2 predicted an increase of more than 15% in the VO2 (AUC [95%CI] = 0.67 [0.55‒0.78]; p<0.0001). Conclusions Our results showed that the ratios of central venous to arterial carbon dioxide content and tension to arteriovenous oxygen content were not predictive of VO2 changes following fluid challenge in postoperative cardiac surgery patients.
Predicting women's persistence in math and science-related college majors

iii ACKNOWLEDGMENTS . iv LIST OF TABLES. viii LIST OF FIGURES. ix CHAPTER ONE: FEWER WOMEN THAN MEN IN MATH/SCIENCE . 1 CHAPTER TWO: REASONS FOR FEWER WOMEN IN MATH/SCIENCE Formation’ of Stereotypes. 9 Vulnerability to Stereotypes . 20 Math/Science Self-Efficacy . 27 Equitable Math/Science Performance . 33 CHAPTER THREE:, JUSTIFICATION FOR CURRENT STUDY AND ' HYPOTHESES. 42 Study Variables. 44 Hypotheses. 44 CHAPTER FOUR: DESCRIPTION OF PARTICIPANTS, MATERIALS, AND PROCEDURE Participants . 47 Materials,. 47 Measurement of Independent Variables . 47 Measurement of Mediator Variable . 50 Measurement of Dependent Variables . 50 Procedure . 53 CHAPTER FIVE: RESULTS OF THE STUDY Data Screening. 54 I ;
DNA mapping and kinetic modeling of the HrdB regulon in Streptomyces coelicolor

Abstract HrdB in streptomycetes is a principal sigma factor whose deletion is lethal. This is also the reason why its regulon has not been investigated so far. To overcome experimental obstacles, for investigating the HrdB regulon, we constructed a strain whose HrdB protein was tagged by an HA epitope. ChIP-seq experiment, done in 3 repeats, identified 2137 protein-coding genes organized in 337 operons, 75 small RNAs, 62 tRNAs, 6 rRNAs and 3 miscellaneous RNAs. Subsequent kinetic modeling of regulation of protein-coding genes with HrdB alone and with a complex of HrdB and a transcriptional cofactor RbpA, using gene expression time series, identified 1694 genes that were under their direct control. When using the HrdB–RbpA complex in the model, an increase of the model fidelity was found for 322 genes. Functional analysis revealed that HrdB controls the majority of gene groups essential for the primary metabolism and the vegetative growth. Particularly, almost all ribosomal protein-coding genes were found in the HrdB regulon. Analysis of promoter binding sites revealed binding motif at the −10 region and suggested the possible role of mono- or di-nucleotides upstream of the −10 element.
Arachidonic Acid Metabolites in Cardiovascular and Metabolic Diseases

Lipid and immune pathways are crucial in the pathophysiology of metabolic and cardiovascular disease. Arachidonic acid (AA) and its derivatives link nutrient metabolism to immunity and inflammation, thus holding a key role in the emergence and progression of frequent diseases such as obesity, diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. We herein present a synopsis of AA metabolism in human health, tissue homeostasis, and immunity, and explore the role of the AA metabolome in diverse pathophysiological conditions and diseases.
Exploiting the laws of order in smart contracts

We investigate a family of bugs in blockchain-based smart contracts, which we dub event-ordering (or EO) bugs. These bugs are intimately related to the dynamic ordering of contract events, i.e. calls of its functions, and enable potential exploits of millions of USD worth of crypto-coins. Previous techniques to detect EO bugs have been restricted to those bugs that involve just one or two event orderings. Our work provides a new formulation of the general class of EO bugs arising in long permutations of such events by using techniques from concurrent program analysis. The technical challenge in detecting EO bugs in blockchain contracts is the inherent combinatorial blowup in path and state space analysis, even for simple contracts. We propose the first use of partial-order reduction techniques, using automatically extracted happens-before relations along with several dynamic symbolic execution optimizations. We build EthRacer, an automatic analysis tool that runs directly on Ethereum bytecode and requires no hints from users. It flags 8% of over 10, 000 contracts analyzed, providing compact event traces (witnesses) that human analysts can examine in only a few minutes per contract. More than half of the flagged contracts are likely to have unintended behaviour.