Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of antibacterial compounds that constrain evolutionary pathways to resistance

Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here, we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC50 50–75 µM against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3-resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which constrain evolutionary escape routes in pathogens.
Orchestration of Dopamine Neuron Population Activity in the Ventral Tegmental Area by Caffeine: Comparison With Amphetamine

Abstract Background Among psychostimulants, the dopamine transporter ligands amphetamine and cocaine display the highest addictive potential; the adenosine receptor antagonist caffeine is most widely consumed but less addictive. Psychostimulant actions of amphetamine were correlated with its ability to orchestrate ventral tegmental dopamine neuron activity with contrasting shifts in firing after single vs repeated administration. Whether caffeine might impinge on dopamine neuron activity has remained elusive. Methods Population activity of ventral tegmental area dopamine neurons was determined by single-unit extracellular recordings and set in relation to mouse behavior in locomotion and conditioned place preference experiments, respectively. Results A single dose of caffeine reduced population activity as did amphetamine and the selective adenosine A2A antagonist KW-6002, but not the A1 antagonist DPCPX. Repeated administration of KW-6002 or amphetamine led to drug-conditioned place preference and to unaltered or even enhanced population activity. Recurrent injection of caffeine or DPCPX, in contrast, failed to cause conditioned place preference and persistently reduced population activity. Subsequent to repetitive drug administration, re-exposure to amphetamine or KW-6002, but not to caffeine or DPCPX, was able to reduce population activity. Conclusions Behavioral sensitization to amphetamine is attributed to persistent activation of ventral tegmental area dopamine neurons via the ventral hippocampus. Accordingly, a switch from acute A2A receptor-mediated reduction of dopamine neuron population activity to enduring A1 receptor-mediated suppression is correlated with tolerance rather than sensitization in response to repeated caffeine intake.
Genomic and pleiotropic analyses of resting QT interval identifies novel loci and overlap with atrial electrical disorders

Abstract The resting QT interval, an electrocardiographic (ECG) measure of ventricular myocardial repolarization, is a heritable risk marker of cardiovascular mortality, but the mechanisms remain incompletely understood. Previously reported candidate genes have provided insights into the regulatory mechanisms of the QT interval. However, there are still important knowledge gaps. We aimed to gain new insights by (i) providing new candidate genes, (ii) identifying pleiotropic associations with other cardiovascular traits, and (iii) scanning for sexually dimorphic genetic effects. We conducted a genome-wide association analysis for resting QT interval with ~9.8 million variants in 52 107 individuals of European ancestry without known cardiovascular disease from the UK Biobank. We identified 40 loci, 13 of which were novel, including 2 potential sex-specific loci, explaining ~11% of the trait variance. Candidate genes at novel loci were involved in myocardial structure and arrhythmogenic cardiomyopathy. Investigation of pleiotropic effects of QT interval variants using phenome-wide association analyses in 302 000 unrelated individuals from the UK Biobank and pairwise genome-wide comparisons with other ECG and cardiac imaging traits revealed genetic overlap with atrial electrical pathology. These findings provide novel insights into how abnormal myocardial repolarization and increased cardiovascular mortality may be linked.
Shoulder electromyography-based indicators to assess manifestation of muscle fatigue during laboratory-simulated manual handling task

Abstract Muscle fatigue is a risk factor for developing shoulder musculoskeletal disorders. The aim of this study was to identify shoulder electromyographic indicators that are most indicative of muscle fatigue during a laboratory simulated manual handling task. Thirty-two participants were equipped with electromyographic electrodes on 10 shoulder muscles and moved boxes for 45-minutes. The modified rate of perceived exertion (mRPE) was assessed every 5-minutes and multivariate linear regressions were performed between myoelectric manifestation of fatigue (MMF) and the mRPE scores. During a manual handling task representative of industry working conditions, spectral entropy, median frequency, and mobility were the electromyographic indicators that explained the largest percentage of the mRPE. Overall, the deltoids, biceps and upper trapezius were the muscles that most often showed significant changes over time in their electromyographic indicators. The combination of these three indicators may improve the accuracy for the assessment of MMF during manual handling. Practitioner Summary: To date, muscle fatigue has primarily been assessed during tasks done to exhaustion, which are not representative of typical working conditions. During a manual handling task representative of industry working conditions, EMG-derived spectral entropy, and median frequency, both extracted from time-frequency analysis, and mobility extracted from time domain, were the best indicators of the manifestation of muscle fatigue.
Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness

The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing of point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance.
Correlation of SOD and MDA Expression in the Organ of Corti and Changes in the Function of Outer Hair Cells Measured by DPOAE Examination in Noise-Exposed Rat Cochlea.

Background Hearing loss due to noise can cause the disturbances toward the quality of life and cause mechanical damage and metabolic decompensation. Distortion Product Otoacoustic Emission (DPOAE) is an examination to assess the sensory function of outer hair cells. Superoxide Dismutase (SOD) and Malondialdehyde (MDA) are markers of oxidative stress. The aim of this study was to identify the correlation between DPOAE examination and SOD and MDA expression in rats exposed to noise. Methods This research was conducted on 27 rats which were divided into 3 groups, group 1 (control), group 2, and group 3 were groups with 100 dB and 110 dB noise exposure respectively. Results Our findings show a decrease in SOD expression and DPOAE values as well as an increase in MDA expression in rats exposed to noise and there is a positive correlation between Signal to Noise Ratio (SNR) value with SOD expression (r= 0.733, p= 0.025) and a negative correlation between SNR value with MDA expression (r= -0.678, p= 0.045). Conclusion our study find the correlation of oxidant and antioxidant status values in the organ of corti and changes in the function of outer hair cells in noise-exposed rat models.
Quercetin Impairs HuR-Driven Progression and Migration of Triple Negative Breast Cancer (TNBC) Cells

Abstract In the present study, we have explored the prognostic value of HuR gene as well as protein in breast cancers. Furthermore, we have also investigated the HuR therapeutic relevance in TNBCs, which is an aggressive breast cancer subtype. Using an online meta-analysis tool, we found that HuR protein overexpression positively correlates with reduced overall survival of TNBC patients (p = 0.028). Furthermore, we demonstrated that the TNBC breast cancer cell lines i.e., MDA-MB-231 and MDA-MB-468 are good model systems to study HuR protein, as they both exhibit a significant amount of cytoplasmic HuR (active form). Quercetin treatment significantly inhibited the cytoplasmic HuR in both TNBC cell lines. By using specific HuR siRNA, we established that quercetin-mediated inhibition of adhesion and migration of TNBC cells is dependent on HuR. Upon analyzing adhesion proteins i.e., β-catenin and CD44, we found that quercetin mediated effect on TNBC adhesion and migration was through the HuR-β-catenin axis and CD44, independently. Overall, the present results demonstrate that elevated HuR levels are associated with TNBC progression and relapse, and the ability of quercetin to inhibit cytoplasmic HuR protein provides a rationale for using it as an anticancer agent for the treatment of aggressive TNBCs. Supplemental data for this article is available online at at 10.1080/01635581.2021. 1952628.
Design, Development, and Evaluation of a Telemedicine Platform for Patients With Sleep Apnea (Ognomy): Design Science Research Approach

Background With an aging population and the escalating cost of care, telemedicine has become a societal imperative. Telemedicine alternatives are especially relevant to patients seeking care for sleep apnea, with its prevalence approaching one billion cases worldwide. Increasing awareness has led to a surge in demand for sleep apnea care; however, there is a shortage of the resources and expertise necessary to cater to the rising demand. Objective The aim of this study is to design, develop, and evaluate a telemedicine platform, called Ognomy, for the consultation, diagnosis, and treatment of patients with sleep apnea. Methods Using the design science research methodology, we developed a telemedicine platform for patients with sleep apnea. To explore the problem, in the analysis phase, we conducted two brainstorming workshops and structured interviews with 6 subject matter experts to gather requirements. Following that, we conducted three design and architectural review sessions to define and evaluate the system architecture. Subsequently, we conducted 14 formative usability assessments to improve the user interface of the system. In addition, 3 trained test engineers performed end-to-end system testing to comprehensively evaluate the platform. Results Patient registration and data collection, physician appointments, video consultation, and patient progress tracking have emerged as critical functional requirements. A telemedicine platform comprising four artifacts—a mobile app for patients, a web app for providers, a dashboard for reporting, and an artificial intelligence–based chatbot for customer onboarding and support—was developed to meet these requirements. Design reviews emphasized the need for a highly cohesive but loosely coupled interaction among the platform’s components, which was achieved through a layered modular architecture using third-party application programming interfaces. In contrast, critical findings from formative usability assessments focused on the need for a more straightforward onboarding process for patients, better status indicators during patient registration, and reorganization of the appointment calendar. Feedback from the design reviews and usability assessments was translated into technical improvements and design enhancements that were implemented in subsequent iterations. Conclusions Sleep apnea is an underdiagnosed and undertreated condition. However, with increasing awareness, the demand for quality sleep apnea care is likely to surge, and creative alternatives are needed. The results of this study demonstrate the successful application of a framework using a design science research paradigm to design, develop, and evaluate a telemedicine platform for patients with sleep apnea and their providers.
Gut bacterial gene changes following pegaspargase treatment in pediatric patients with acute lymphoblastic leukemia

Abstract Treatment of pediatric acute lymphoblastic leukemia (ALL) with pegaspargase exploits ALL cells dependency on asparagine. Pegaspargase depletes asparagine, consequentially affecting aspartate, glutamine and glutamate. The gut as a confounding source of these amino acids (AAs) and the role of gut microbiome metabolism of AAs has not been examined. We examined asparagine, aspartate, glutamine and glutamate in stool samples from patients over pegaspargase treatment. Microbial gene-products, which interact with these AAs were identified. Stool asparagine declined significantly, and 31 microbial genes changed over treatment. Changes were complex, and included genes involved in AA metabolism, nutrient sensing, and pathways increased in cancers. While we identified changes in a gene (iaaA) with limited asparaginase activity, it lacked significance after correction leaving open other mechanisms for asparagine decline, possibly including loss from gut to blood. Understanding pathways that change AA availability, including by microbes in the gut, could be useful in optimizing pegaspargase therapy.
First Life Table of Synthesiomyia nudiseta (Diptera: Muscidae) From Palearctic Region for Analyzing the Effect on Its Dispersal Ability

Abstract To better understand the population dynamics and dispersal ability of insect species, it is often helpful to derive a life table containing fundamental demographic data. The aim of this study was to determine a life table for the predatory necrophagous species Synthesiomyia nudiseta (van der Wulp, 1883) on a pig liver diet and under controlled laboratory conditions (29.5 ± 2. 5°C, RH 50 ± 15%, and a photoperiod of 12:12). This species has medical and veterinary importance and its distribution extends in tropical and subtropical areas and now it has been established in the southwestern of Europe. The mean adult longevity was 36. 18 ± 2. 06 d and the net reproduction rate, R, was 27.65 offspring/female, the mean generation time, T, was 22. 09 d, the finite rate of increase, λ, was 1. 16 d–1, and the intrinsic rate of increase, r, was 0. 15 d–1. These results indicate that S. nudiseta cannot be considered an r-strategist as the most common synanthropic necrophagous blowflies due to its predatory behavior; however, its invasive and colonist abilities are discussed. This is the first life table study of this species from Palearctic region to analyze the effect of its dispersal ability.
Bone, Biomarker, Body Composition, and Performance Responses to 8 Weeks of ROTC Training.

CONTEXT Military personnel engage in vigorous exercise, often resulting in higher bone mineral density; however, lower leg bone injuries are common in this population. Predictors of change in tibial bone quality and strength need to be characterized in this high-risk population. OBJECTIVE This study aimed to examine the effects of an eight-week military training intervention on total body and site-specific bone density and tibial bone quality, serum biomarkers (parathyroid hormone and sclerostin), body composition, and physical performance. Additionally, we sought to investigate what outcome variables (biomarkers, body composition, physical performance) would be predictive of estimated tibial bone strength in college-aged Reserve Officers' Training Corps (ROTC) members. DESIGN Prospective Cohort Study. SETTING XXX University. Patients of Other Participants: ROTC (n=14 male; n=4 female) were matched for sex, age, and body mass to physically active Controls (n=14 male; n=4 female). ROTC engaged in an eight-week training intervention, while physically active Controls made no changes to their exercise routines. MAIN OUTCOME MEASURES Pre general health questionnaires and pre, mid, and post intervention bone scans (DXA, pQCT), serum blood draws (parathyroid hormone and sclerostin), and physical performance measures (muscle strength and aerobic capacity) were tested. RESULTS ROTC participants exhibited significantly increased hip bone density and content (all p≤0.03) after the eight-week intervention. Sclerostin, not PTH, was a significant positive correlate and predictor in all ROTC models for estimated bone strength at the fracture prone 38% tibial site. Both groups decreased total body and regional fat mass and ROTC increased aerobic capacity (all p≤0.05). CONCLUSIONS All bone, body composition, and performance measures either improved or were maintained in response to ROTC training and sclerostin should be further investigated as a potential early indicator of changes in estimated tibial bone strength in military cohorts.
Upregulation of PAIP1 promotes the gallbladder tumorigenesis through regulating PLK1 level

Background Increasing evidence suggests that elevated expression of polyA-binding protein-interacting protein 1 (PAIP1) is associated with cancer development and progression. However, how PAIP1 promotes gallbladder cancer (GBC) is still unclear. Methods Two GBC tissue-derived cell lines, NOZ and GBC-SD cells, were used in this study. Assays of cell proliferation, colony formation, apoptosis, and xenograft tumor model were performed to examine the tumorigenic effects of PAIP1. Immunohistochemical (IHC) staining was used to examine the expression level of PAIP1 in both patient GBC tissues and mouse tumors. Microarray and bioinformatics analysis were used to explore the targets of PAIP1. Quantitative polymerase chain reaction (qPCR) and western blot analysis were used to validate PAIP1-mediated targets. Results We found that upregulated PAIP1 expression was correlated with GBC. Knockdown of PAIP1 in gallbladder cells alleviated cell proliferation, promoted apoptosis, and inhibited xenograft tumor growth. Gene microarray analysis showed that stable silencing of PAIP1 altered various gene expressions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that PAIP1 regulates cell cycle progression. Finally, we found that the PLK1 kinase, a key regulator of cell cycle, was regulated by PAIP1 at the transcriptional and protein levels. PLK1 level was positively correlated with PAIP1 level in both mouse tumors and GBC tissues. PAIP1 interacted with PLK1, and rescue of PAIP1 could recover PLK1 protein level and inhibit apoptosis. Conclusions Our data suggest that PAIP1 contributes to GBC progression likely through regulating PLK1 level. Since upregulated PAIP1 expression is positively associated with GBC, PAIP1 may act as a clinical prognostic biomarker of GBC.
The Impact of Parental Bereavement on Young People: A Thematic Analysis of Using Online Web Forums as a Method of Coping

A qualitative approach was used to explore how online web forums might facilitate recovery and the process of coping. Ten online web forums written by young people who have personally experienced the death of a parent formed the data of this study. Previous research suggests forum users do not receive the supportive reactions from face-to-face interactions that they desire. Thematic analysis found that forums created an environment where young people can process the bereavement of a parent. Forums allowed young people to use their experience of bereavement to positively support others with similar experiences. The findings imply that the process of using forums can positively impact individuals who have experienced the loss of a parent. This supports recommendations by professionals, to consider online forums as a coping strategy. This study presents one of the few analyses of web forums written by young people who have experienced parental bereavement.
The Methodology of Randomized Evaluation

This paper discusses the role that impact evaluations should play in scaling up. Credible impact evaluations are needed to ensure that the most effective programs are scaled up at the national or international levels. Scaling up is possible only if a case can be made that programs that have been successful on a small scale would work in other contexts. Therefore the very objective of scaling up implies that learning from experience is possible. Because programs that have been shown to be successful can be replicated in other countries while unsuccessful programs can be abandoned, impact evaluations are international public goods, thus the international agencies should have a key role in promoting and financing them. In doing this, they would achieve three important objectives: improve the rates of return on the programs they support, improve the rates of return on the programs other policymakers support by providing evidence on the basis of which programs can be selected, and build long-term support for international aid and development by making it possible to credibly signal what programs work and what programs do not work. The paper argues that considerable scope exists for expanding the use of randomized evaluations. For a broad class of development programs, randomized evaluation can be used to overcome the problems often encountered when using current evaluation practices.