Miracle-dz/UniFAR-FTUs huggingface dataset:
IS26-Mediated Transfer of blaNDM–1 as the Main Route of Resistance Transmission During a Polyclonal, Multispecies Outbreak in a German Hospital

One of the most demanding challenges in infection control is the worldwide dissemination of multidrug-resistant (MDR) bacteria in clinical settings. Especially the increasing prevalence of carbapenemase producing Gram-negative pathogens poses an urgent threat to public health, as these enzymes confer resistance to almost all β-lactam antibiotics including carbapenems. In this study, we report a prolonged nosocomial outbreak of various NDM-1-producing Enterobacterales species due to clonal spread and cross-species exchange of plasmids and possibly transposons. Between July 2015 and September 2017, a total of 51 carbapenemase-positive isolates were collected from 38 patients and three environmental sources in a single German hospital. Combining molecular typing methods and whole genome sequencing, the metallo-β-lactamase gene blaNDM–1 was found to be present in 35 isolates of which seven additionally carried the carbapenemase gene blaKPC–2. Core genome MLST (cgMLST) revealed different clusters of closely related isolates of Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Morganella morganii or Enterobacter cloacae indicating clonal spread. The detailed reconstruction of the plasmid sequences revealed that in all outbreak-associated isolates blaNDM–1 was located on similar composite transposons, which were also very similar to Tn125 previously described for Acinetobacter baumannii. In contrast to Tn125, these structures were flanked by IS26 elements, which could facilitate horizontal gene transfer. Moreover, the identical plasmid was found to be shared by E. coli and M. morganii isolates. Our results highlight the importance of detailed genome-based analyses for complex nosocomial outbreaks, allowing the identification of causal genetic determinants and providing insights into potential mechanisms involved in the dissemination of antibiotic resistances between different bacterial species.
Conformation Transition of Intracellular Part of Glucagon Receptor in Complex With Agonist Glucagon by Conventional and Accelerated Molecular Dynamics Simulations

The inactive conformations of glucagon receptor (GCGR) are widely reported by crystal structures that support the precision structure for drug discovery of type 2 diabetes. The previous study shows that the intracellular part is open in the glucagon-bound GCGR (glu-GCGR) and closed in the apo-GCGR by accelerated molecular dynamics (aMD) simulations. However, the crystal structure of GCGR in complex with partial agonist shows that the intracellular part is closed in the inactive conformation. To understand the differences between the studies of aMD simulations and crystal structure, the 2,500 ns conventional molecular dynamics (cMD) simulations are performed on the simulated model of glu-GCGR. The result shows that the transmembrane helices (TMH) 6 of glu-GCGR is outward ~4 Å to drive the intracellular part of glu-GCGR open until ~390 ns cMD simulations. The (TMH) 6 of glu-GCGR becomes closed after ~490 ns cMD simulations, which are consistent with the crystal structure of GCGR in complex with the partial agonist. To further elucidate the activation mechanism of GCGR deeply, the simulated models of glu-GCGR, apo-GCGR, and antagonist-bound GCGR (ant-GCGR) are constructed to perform 10 of parallel 300 ns aMD simulations, respectively. The results show that both of glu-GCGR and apo-GCGR can generate the open conformations of the intracellular part. But the glu-GCGR has the higher percentage of open conformations than apo-GCGR. The ant-GCGR is restricted to generate the open conformations of the intracellular part by antagonist MK-0893. It indicates that the glu-GCGR, apo-GCGR, and ant-GCGR can be distinguished by the aMD simulated method. Free energy landscape shows that the open conformations of the intracellular part of GCGR are in intermediate state. Our results show that aMD simulations enhance the space samplings of open conformations of GCGR via adding extra boost potential. It indicates that the aMD simulations are an effective way for drug discovery of GCGR.
Heat Adaptation in Military Personnel: Mitigating Risk, Maximizing Performance

The study of heat adaptation in military personnel offers generalizable insights into a variety of sporting, recreational and occupational populations. Conversely, certain characteristics of military employment have few parallels in civilian life, such as the imperative to achieve mission objectives during deployed operations, the opportunity to undergo training and selection for elite units or the requirement to fulfill essential duties under prolonged thermal stress. In such settings, achieving peak individual performance can be critical to organizational success. Short-notice deployment to a hot operational or training environment, exposure to high intensity exercise and undertaking ceremonial duties during extreme weather may challenge the ability to protect personnel from excessive thermal strain, especially where heat adaptation is incomplete. Graded and progressive acclimatization can reduce morbidity substantially and impact on mortality rates, yet individual variation in adaptation has the potential to undermine empirical approaches. Incapacity under heat stress can present the military with medical, occupational and logistic challenges requiring dynamic risk stratification during initial and subsequent heat stress. Using data from large studies of military personnel observing traditional and more contemporary acclimatization practices, this review article (1) characterizes the physical challenges that military training and deployed operations present (2) considers how heat adaptation has been used to augment military performance under thermal stress and (3) identifies potential solutions to optimize the risk-performance paradigm, including those with broader relevance to other populations exposed to heat stress.
Clinical Usefulness of Computational Modeling-Guided Persistent Atrial Fibrillation Ablation: Updated Outcome of Multicenter Randomized Study

Objective Catheter ablation of persistent atrial fibrillation (AF) is still challenging, no optimal extra-pulmonary vein lesion set is known. We previously reported the clinical feasibility of computational modeling-guided AF catheter ablation. Methods We randomly assigned 118 patients with persistent AF (77.8% men, age 60.8 ± 9.9 years) to the computational modeling-guided ablation group (53 patients) and the empirical ablation group (55 patients) based on the operators’ experience. For virtual ablation, four virtual linear and one electrogram-guided lesion sets were tested on patient heart computed tomogram-based models, and the lesion set with the fastest termination time was reported to the operator in the modeling-guided ablation group. The primary outcome was freedom from atrial tachyarrhythmias lasting longer than 30 s after a single procedure. Results During 31.5 ± 9.4 months, virtual ablation procedures were available in 95.2% of the patients (108/118). Clinical recurrence rate was significantly lower after a modeling-guided ablation than after an empirical ablation (20.8 vs. 40.0%, log-rank p = 0.042). Modeling-guided ablation was independently associated with a better long-term rhythm outcome of persistent AF ablation (HR = 0.29 [0.12–0.69], p = 0.005). The rhythm outcome of the modeling-guided ablation showed better trends in males, non-obese patients with a less remodeled atrium (left atrial dimension < 50 mm), ejection fraction ≥ 50%, and those without hypertension or diabetes (p < 0.01). There were no significant differences between the groups for the total procedure time (p = 0.403), ablation time (p = 0.510), and major complication rate (p = 0.900). Conclusion Among patients with persistent AF, the computational modeling-guided ablation was superior to the empirical catheter ablation regarding the rhythm outcome. Clinical Trial Registration This study was registered with the ClinicalTrials.gov, number NCT02171364.
The Contrasting Role of Extracellular Vesicles in Vascular Inflammation and Tissue Repair

Extracellular vesicles are a heterogeneous family of vesicles, generated from different subcellular compartments and released into the extracellular space. Composed of a lipid bilayer encompassing both soluble cytosolic material and nuclear components, these organelles have been recently described as novel regulators of intercellular communication between adjacent and remote cells. Due to their diversified composition and biological content, they portray specific signatures of cellular activation and pathological processes, their potential as diagnostic and prognostic biomarkers has raised significant interest in cardiovascular diseases. Circulating vesicles, especially those released from platelets, leukocytes, and endothelial cells are found to play a critical role in activating several fundamental cells within the vasculature, including endothelial cells and vascular smooth muscle cells. Their intrinsic activity and immunomodulatory properties lends them to not only promote vascular inflammation, but also enhance tissue regeneration, vascular repair, and indeed resolution. In this review we aim to recapitulate the recent findings concerning the roles played by EVs that originate from different circulating cells, with particular reference to their action on the endothelium. We focus herein, on the interaction of platelet and leukocyte EVs with the endothelium. In addition, their potential biological function in promoting tissue resolution and vascular repair will also be discussed.
Public Health Messages and Weight-Related Beliefs: Implications for Well-Being and Stigma

Across two studies, we examined the double-edged sword hypothesis, which outlines effects of weight-related beliefs and public health messages on physical and mental health. The double-edged sword hypothesis proposes that growth mindsets and messages (weight is changeable) predict reduced well-being and stigma via an increase in blame, but also predict greater well-being via an increase in efficacy and less stigma via a reduction in essentialist thinking. We tested this model in a correlational study (N = 311) and in an experimental study, randomly assigning participants (N = 392) to different weight-based public health messages. In Study 1, growth mindsets predicted greater onset blame and more offset efficacy. Blame did not predict any of the outcomes. However, offset efficacy predicted reduced risk for eating disorders, fewer unhealthy weight control behaviors, and less psychological distress. And, growth mindsets had a negative indirect effect on outcomes. In Study 2, we experimentally demonstrated that a changeable message about the nature of weight, designed to also reduce blame, indirectly decreased eating disorder risk, unhealthy weight control behaviors, body shame, and prejudice through increased offset efficacy and decreased social essentialism. This work contributes to our theoretical understanding of the psychological consequences of weight beliefs and messages on well-being and stigma.
Editorial: Gendered Paths into STEM. Disparities Between Females and Males in STEM Over the Life-Span

1 Institute of Education, Universität der Bundeswehr München, Neubiberg, Germany, 2 Institute for Early Childhood and Primary Teacher Education, University College of Teacher Education Styria, Graz, Austria, Department of Education, University of Potsdam, Potsdam, Germany, Department of STEM Education, North Carolina State University, Raleigh, NC, United States, Department of Psychology, University of Graz, Graz, Austria
Formulation of a Highly Effective Inoculant for Common Bean Based on an Autochthonous Elite Strain of Rhizobium leguminosarum bv. phaseoli, and Genomic-Based Insights Into Its Agronomic Performance

Common bean is a poor symbiotic N-fixer, with a low response to inoculation owing to its promiscuous nodulation with competitive but inefficient resident rhizobia. Consequently, farmers prefer to fertilize them rather than rely on their capacity for Biological Nitrogen Fixation (BNF). However, when rhizobial inoculants are based on autochthonous strains, they often have superior BNF performance in the field due to their genetic adaptations to the local environment. Nevertheless, there is scant information at the genomic level explaining their superiority or on how their genomes may influence the inoculant performance. This information is especially important in technologically advanced agri-systems like Europe, where environmental concerns and increasingly stringent fertilizer regulations are encouraging a return to the use of rhizobial inoculants, but based upon strains that have been thoroughly characterized in terms of their symbiotic performance and their genetics. The aim of this study was to design an inoculant formulation based on a superior autochthonous strain, Rhizobium leguminosarum bv. phaseoli LCS0306, to assess its performance in the field, and to determine the genomic features contributing to the high effectiveness of its symbiosis with common bean. Plants inoculated with the autochthonous strain LCS0306 fixed significantly more nitrogen than those with the allochthonous strains R. phaseoli ATCC 14482T and R. etli CFN42T, and had grain yield similar to the nitrogen-fertilized controls. Inoculation with LCS0306 was particularly efficacious when formulated with a carrier based upon a mixture of perlite and biochar. Whole genome comparisons revealed no differences in the classical symbiotic genes of strain LCS0306 within the symbiovar phaseoli. However, its symbiotic superior performance might be due to its genomic versatility, as it harbors a large assortment of genes contributing to fitness and competitiveness. It is concluded that inoculation with elite rhizobia formulated with perlite-biochar carriers might constitute a step-change in the sustainable cultivation of common bean in Spanish soils.
The Cellular Transcriptome in the Maternal Circulation During Normal Pregnancy: A Longitudinal Study

Pregnancy represents a unique immunological state in which the mother adapts to tolerate the semi-allogenic conceptus; yet, the cellular dynamics in the maternal circulation are poorly understood. Using exon-level expression profiling of up to six longitudinal whole blood samples from 49 pregnant women, we undertook a systems biology analysis of the cellular transcriptome dynamics and its correlation with the plasma proteome. We found that: (1) chromosome 14 was the most enriched in transcripts differentially expressed throughout normal pregnancy; (2) the strongest expression changes followed three distinct longitudinal patterns, with genes related to host immune response (e.g., MMP8, DEFA1B, DEFA4, and LTF) showing a steady increase in expression from 10 to 40 weeks of gestation; (3) multiple biological processes and pathways related to immunity and inflammation were modulated during gestation; (4) genes changing with gestation were among those specific to T cells, B cells, CD71+ erythroid cells, natural killer cells, and endothelial cells, as defined based on the GNF Gene Expression Atlas; (5) the average expression of mRNA signatures of T cells, B cells, and erythroid cells followed unique patterns during gestation; (6) the correlation between mRNA and protein abundance was higher for mRNAs that were differentially expressed throughout gestation than for those that were not, and significant mRNA-protein correlations were observed for genes part of the T-cell signature. In summary, unique changes in immune-related genes were discovered by longitudinally assessing the cellular transcriptome in the maternal circulation throughout normal pregnancy, and positive correlations were noted between the cellular transcriptome and plasma proteome for specific genes/proteins. These findings provide insights into the immunobiology of normal pregnancy.
Cell Phone Use Habits Among the Spanish Population: Contribution of Applications to Problematic Use

Mobile phone abuse may be associated with health problems as well as with interferences in daily life. However, beyond the mobile as a device, the contributions of specific utilities and applications to the problematic mobile phone use remains to be analyzed. To address this important question we conducted 1,126 online interviews in Spain with participants aged 16 to 65 who are representative of the general population. The aim of the study was to analyze the patterns and differences of cell phone use based on habitual use, abuse, and problematic use, considering the most frequently used utilities and applications. Additional variables used were personal perception of cell phones, intensity of use, and participant’s lifestyle with regard to entertainment and the maintenance of healthy habits. Further, we aimed to analyze difference between problematic and non-problematic mobile phone users in the utilization of applications, controlling for additional variables such as age, gender, educational level, consumption of tobacco and alcohol and illegal drugs. Results show that problematic use is consistent with the self-perception of abuse and is related to internet browsing, social media, music, and mobile games; particular applications of interest include Facebook, music applications, and Twitter. Furthermore, among problematic users, a pattern of interference with other activities or inappropriate use in certain contexts is observed, with a differential pattern of entertainment and abandonment of healthy habits. Finally, two binary logistic regression analyses demonstrated that beyond the cell phones themselves, specific utilities and applications such as browsing, chatting, or downloading and listening to music contribute to the differences between problematic and non-problematic users. Specifically, the use of Facebook, Twitter, and music applications have the greatest power to discriminate between the two types of users.
Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies

The white matter disease spectrum is associated with many genetic diseases, including AARS2, CADASIL, ALD, and others. In this study, to determine the novel alanyl-tRNA synthetase 2 mutation implicated in white matter disease, several families with an autosomal recessive inheritance pattern of white matter disease were analyzed by whole-exome sequencing. Variants were prioritized according to their rarity and pathogenic variants in genes already known to be associated with leukodystrophies and were confirmed by Sanger sequencing using standard protocols. We identified 5 rare variants (c.452T>C chr6:44279256 p.M151T, c.1871G>A chr6:44272054 p.W624X, c.802A>G chr6:44278128 p.M268V, c.1703-1704del chr6:-44272430-44272431 p.Q568fs, and c.179C>A chr6-44280882 p.P60H) with varying expression in 4 independent Chinese families with leukodystrophy. These single nucleotide variants (SNVs), or deletion mutations, each induced a frameshift, causing a missense mutation in alanyl-tRNA synthetase 2. These findings suggested that all mutations might contribute to the development of leukodystrophy in the examined family members. Combined with previous findings, our data confirmed that the novel mutations are located in leukodystrophy-related risk genes. We also summarized all the alanyl-tRNA synthetase 2 mutations related to the onset of leukodystrophies in adults.
Discrete Graphical Models - An Optimization Perspective

This monograph is about discrete energy minimization for discrete graphical models. It considers graphical models, or, more precisely, maximum a posteriori inference for graphical models, purely as a combinatorial optimization problem. Modeling, applications, probabilistic interpretations and many other aspects are either ignored here or find their place in examples and remarks only. It covers the integer linear programming formulation of the problem as well as its linear programming, Lagrange and Lagrange decomposition-based relaxations. In particular, it provides a detailed analysis of the polynomially solvable acyclic and submodular problems, along with the corresponding exact optimization methods. Major approximate methods, such as message passing and graph cut techniques are also described and analyzed comprehensively. The monograph can be useful for undergraduate and graduate students studying optimization or graphical models, as well as for experts in optimization who want to have a look into graphical models. To make the monograph suitable for both categories of readers we explicitly separate the mathematical optimization background chapters from those specific to graphical models.
Software Change Prediction: A Systematic Review and Future Guidelines

Background: The importance of Software Change Prediction (SCP) has been emphasized by several studies. Numerous prediction models in literature claim to eﬀectively predict change-prone classes in software products. These models help software managers in optimizing resource usage and in developing good quality, easily maintainable products. Aim: There is an urgent need to compare and assess these numerous SCP models in order to evaluate their eﬀectiveness. Moreover, one also needs to assess the advancements and pitfalls in the domain of SCP to guide researchers and practitioners. Method: In order to fulﬁll the above stated aims, we conduct an extensive literature review of 38 primary SCP studies from January 2000 to June 2019. Results: The review analyzes the diﬀerent set of predictors, experimental settings, data analysis techniques, statistical tests and the threats involved in the studies, which develop SCP models. Conclusion: Besides, the review also provides future guidelines to researchers in the SCP domain, some of which include exploring methods for dealing with imbalanced training data, evaluation of search-based algorithms and ensemble of algorithms for SCP amongst others.
Extracellular vesicles isolated from Trypanosoma cruzi affect early parasite migration in the gut of Rhodnius prolixus but not in Triatoma infestans

The protozoan Trypanosoma cruzi has the ability to spontaneously secrete extracellular vesicles (EVs). In this paper, T. cruzi EVs derived from epimastigote forms were evaluated during interaction with triatomine bugs Rhodnius prolixus and Triatoma infestans. T. cruzi EVs were purified and artificially offered to the insects prior to infection with epimastigote forms. No effect of EVs was detected in the parasite counts in the guts of both vectors after 49-50 days. On the other hand, pre-feeding with EVs delayed parasite migration to rectum only in the gut in R. prolixus after 21-22 days. Those data suggest a possible role of T. cruzi EVs during the earlier events of infection in the invertebrate host.