Miracle-dz/UniFAR-FTUs huggingface dataset:
Diverse Vectors and Mechanisms Spread New Delhi Metallo-β-Lactamases among Carbapenem-Resistant Enterobacteriaceae in the Greater Boston Area

New Delhi metallo-beta-lactamases (NDMs) are an uncommon but emerging cause of carbapenem resistance in the United States. Genomic factors promoting their domestic spread remain poorly characterized. ABSTRACT New Delhi metallo-beta-lactamases (NDMs) are an uncommon but emerging cause of carbapenem resistance in the United States. Genomic factors promoting their domestic spread remain poorly characterized. A prospective genomic surveillance program among Boston-area hospitals identified multiple new occurrences of NDM-carrying strains of Escherichia coli and Enterobacter cloacae complex in inpatient and outpatient settings, representing the first occurrences of NDM-mediated resistance since initiating genomic surveillance in 2011. Cases included domestic patients with no international exposures. PacBio sequencing of isolates identified strain characteristics, resistance genes, and the complement of mobile vectors mediating spread. Analyses revealed a common 3,114-bp region containing the blaNDM gene, with carriage of this conserved region among unique strains by diverse transposon and plasmid backbones. Functional studies revealed a broad capacity for blaNDM transmission by conjugation, transposition, and complex interplasmid recombination events. NDMs represent a rapidly spreading form of drug resistance that can occur in inpatient and outpatient settings and in patients without international exposures. In contrast to Tn4401-based spread of Klebsiella pneumoniae carbapenemases (KPCs), diverse transposable elements mobilize NDM enzymes, commonly with other resistance genes, enabling naive strains to acquire multi- and extensively drug-resistant profiles with single transposition or plasmid conjugation events. Genomic surveillance provides effective means to rapidly identify these gene-level drivers of resistance and mobilization in order to inform clinical decisions to prevent further spread.
Toward the Development of SMART Communication Technology: Automating the Analysis of Communicative Trouble and Repair in Dementia

Abstract Background and Objectives Communication difficulties have been reported as one of the most stress-inducing aspects of caring for people with dementia. Notably, with disease progression comes an increase in the frequency of communication difficulty and a reduction in the effectiveness of attempts to remedy breakdowns in communication. The aim of the current research was to evaluate the utility of an automated discourse analysis tool (i.e., Discursis) in distinguishing between different types of trouble and repair signaling behaviors, demonstrated within conversations between people with dementia and their professional care staff. Research Design and Methods Twenty conversations between people with dementia and their professional care staff were human-coded for instances of interactive/noninteractive trouble and typical/facilitative repair behaviors. Associations were then examined between these behaviors and recurrence metrics generated by Discursis. Results Significant associations were identified between Discursis metrics, trouble-indicating, and repair behaviors. Discussion and Implications These results suggest that discourse analysis software is capable of discriminating between different types of trouble and repair signaling behavior, on the basis of term recurrence calculated across speaker turns. The subsequent recurrence metrics generated by Discursis offer a means of automating the analysis of episodes of conversational trouble and repair. This achievement represents the first step toward the future development of an intelligent assistant that can analyze conversations in real time and offers support to people with dementia and their carers during periods of communicative trouble.
Insulin function in obese children within the low and high ranges of impaired fasting glycemia

Impaired fasting glycemia (IFG) reflects an intermediate hyperglycemia in the fasting state. Which fasting glucose level that actually is associated with impaired insulin‐glucose homeostasis in children and adolescents with obesity is unknown. The aim of this study was to investigate how insulin and glucose homeostasis in children and adolescents with obesity in Sweden varies within different fasting glucose levels in the non‐diabetic range.
Gossypin inhibits gastric cancer growth by direct targeting of AURKA and RSK2

Gossypin is a flavone extracted from Hibiscus vitifolius, which has been reported to exhibit anti‐inflammatory, antioxidant, and anticancer activities. However, the anticancer properties of gossypin and its molecular mechanism of action against gastric cancer have not been fully investigated. In the present study, we report that gossypin is an Aurora kinase A (AURKA) and RSK2 inhibitor that suppresses gastric cancer growth. Gossypin attenuated anchorage‐dependent and anchorage‐independent gastric cancer cell growth as well as cell migration. Based on the results of in vitro screening and cell‐based assays, gossypin directly binds to and inhibits AURKA and RSK2 activities and their downstream signaling proteins. Gossypin decreased S phase and increased G2/M phase cell cycle arrest by reducing the expression of cyclin A2 and cyclin B1 and the phosphorylation of the CDC protein. Additionally, gossypin also induced intrinsic apoptosis by activating caspases and PARP and increasing the expression of cytochrome c. Our results demonstrate that gossypin is an AURKA and RSK2 inhibitor that could be useful for treating gastric cancer.
Ca2+‐dependent and Ca2+‐independent somatic release from trigeminal neurons

Besides the nerve endings, the soma of trigeminal neurons also respond to membrane depolarizations with the release of neurotransmitters and neuromodulators in the extracellular space within the ganglion, a process potentially important for the cross‐communication between neighboring sensory neurons. In this study, we addressed the dependence of somatic release on Ca2+ influx in trigeminal neurons and the involvement of the different types of voltage‐gated Ca2+ (Cav) channels in the process. Similar to the closely related dorsal root ganglion neurons, we found two kinetically distinct components of somatic release, a faster component stimulated by voltage but independent of the Ca2+ influx, and a slower component triggered by Ca2+ influx. The Ca2+‐dependent component was inhibited 80% by ω‐conotoxin‐MVIIC, an inhibitor of both N‐ and P/Q‐type Cav channels, and 55% by the P/Q‐type selective inhibitor ω‐agatoxin‐IVA. The selective L‐type Ca2+ channel inhibitor nimodipine was instead without effect. These results suggest a major involvement of N‐ and P/Q‐, but not L‐type Cav channels in the somatic release of trigeminal neurons. Thus antinociceptive Cav channel antagonists acting on the N‐ and P/Q‐type channels may exert their function by also modulating the somatic release and cross‐communication between sensory neurons.
Yes-Associated Protein 1 as a Novel Prognostic Biomarker for Gastrointestinal Cancer: A Meta-Analysis

Background Yes-associated protein 1 (YAP1) is an effector of Hippo pathway, which plays a significant role in cell proliferation and tumor progression. The relationship between YAP1 and gastrointestinal cancer has been explored in many previous studies. We conducted a meta-analysis to explore the prognostic effect of YAP1 in patients with gastrointestinal cancer. Methods A systematic search was performed through the PubMed, Web of Science, Embase, and Cochrane library databases to collect eligible studies. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate the relationship between YAP1 expression and gastrointestinal cancer clinical outcomes. Results A total of 2941 patients from 18 studies were enrolled. The results showed that elevated YAP1 expression predicted a poor prognosis in gastrointestinal cancer (HR = 1.56; 95% CI: 1.29-1.89; P < 0.001). Subgroup analyses indicated significant association between YAP1 overexpression and shorter OS of patients with esophageal squamous cell carcinoma (HR = 1.85; 95% CI: 1.25-2.73; P = 0.002), gastric cancer (HR = 1.41,95% CI: 1.02-1.95; P = 0.037), and colorectal cancer (pooled HR = 1.75; 95% CI: 1.42-2.15; P < 0.001). However, YAP1 expression did not affect DFS of patients with gastrointestinal cancer (pooled HR = 1.33; 95% CI: 0.95-1.88; P = 0.101). Conclusion Elevated YAP1 expression in patients with gastrointestinal cancer might be related to shorter OS. YAP1 protein could serve as a potential predictor of poor prognosis in gastrointestinal cancer.
Impact of chemotherapy in the prognosis of non-small-cell lung cancer patients with severe to very severe COPD

Background The aim of the study was to investigate if first-line chemotherapy improves total survival time in non-small-cell lung cancer (NSCLC) patients complicated with severe to very severe COPD. Materials and methods This retrospective observational clinical study included 267 consecutive NSCLC patients with COPD complications at the Department of Respiratory and Critical Care Medicine of Tianjin Chest Hospital between January 2009 and January 2018. Sixty-nine evaluable patients were included. The clinical characteristics, toxicity profile, objective response rate, and prognosis were analyzed and compared between patients receiving and those not receiving chemotherapy. Results Forty-five and 24 patients received first-line chemotherapy plus supportive care and supportive care alone, respectively. Kaplan–Meier curves showed that patients receiving chemotherapy had a statistically significant 6-month longer median overall survival (OS) than that of patients receiving supportive care alone (14.0, 95% CI: 8.5–19.5 vs 8.0, 95% CI: 6.4–9.6, respectively) (chi2=8.857, P=0.003). In the multivariate Cox proportional hazard model adjusted for the most relevant variables, the adjusted hazard ratio (HRadj) differed significantly for the receipt of chemotherapy (HRadj=0.4464, 95% CI: 0.2495–0.7988; P=0.0066) but not for gender (HRadj=0.8527, 95% CI: 0.4461–1.6298; P=0.6297), age (HRadj=1.0021, 95% CI: 0.9609–1.0451; P=0.9214), histology (HRadj=1.4422, 95% CI: 0.6959–2.9889; P=0.3247), cancer stage (HRadj=1.9098, 95% CI: 0.8607–4.2375; P=0.1116), performance status score (HRadj=1.5155, 95% CI: 0.7523–3.0529; P=0.2446), lung function (HRadj=1.3856, 95% CI: 0.7149–2.6857; P=0.3341), or respiratory symptoms (HRadj=1.0518, 95% CI: 0.6032–1.8342; P=0.8586). Patients with grade 3/4 adverse reactions accounted for 29% (13/45) of the chemotherapy group. Conclusion The results indicated that chemotherapy may improve the OS of NSCLC patients with severe to very severe COPD.
Use of Multimodal Magnetic Resonance Imaging Techniques to Explore Cognitive Impairment in Leukoaraiosis

Leukoaraiosis, also referred to as white-matter hyperintensities (WMHs) or age-related white matter changes, is the most frequently seen lesion on brain magnetic resonance images (MRI) in the elderly. LA is a subject of intense research interest, and is correlated with stroke, cognitive impairment or dementia, disturbances, affective disorders, and poor prognoses. Rapid advances in neuroimaging have enabled greater understanding of LA associated with aging-related cognitive decline or dementia. Recently, the techniques of multimodal MRI, such as structural MRI (sMRI), resting-state functional MRI (rs-MRI), cerebrovascular reactivity (CVR), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and dynamic contrast-enhanced MRI (DCE-MRI), have been used to explore the underlying mechanism of cognitive impairment in patients with LA. These multimodal MRI techniques may provide further insights into the structural and functional changes of LA with cognitive dysfunction.
Understanding the importance of low‐molecular weight (ethylene oxide‐ and propylene oxide‐induced) DNA adducts and mutations in risk assessment: Insights from 15 years of research and collaborative discussions

The interpretation and significance of DNA adduct data, their causal relationship to mutations, and their role in risk assessment have been debated for many years. An extended effort to identify key questions and collect relevant data to address them was focused on the ubiquitous low MW N7‐alkyl/hydroxyalkylguanine adducts. Several academic, governmental, and industrial laboratories collaborated to gather new data aimed at better understanding the role and potential impact of these adducts in quantifiable genotoxic events (gene mutations/micronucleus). This review summarizes and evaluates the status of dose–response data for DNA adducts and mutations from recent experimental work with standard mutagenic agents and ethylene oxide and propylene oxide, and the importance for risk assessment. This body of evidence demonstrates that small N7‐alkyl/hydroxyalkylguanine adducts are not pro‐mutagenic and, therefore, adduct formation alone is not adequate evidence to support a mutagenic mode of action. Quantitative methods for dose–response analysis and derivation of thresholds, benchmark dose (BMD), or other points‐of‐departure (POD) for genotoxic events are now available. Integration of such analyses of genetox data is necessary to properly assess any role for DNA adducts in risk assessment. Regulatory acceptance and application of these insights remain key challenges that only the regulatory community can address by applying the many learnings from recent research. The necessary tools, such as BMDs and PODs, and the example datasets, are now available and sufficiently mature for use by the regulatory community. Environ. Mol. Mutagen. 60: 100–121, 2019. © 2018 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.
Questionnaire Breakoff and Item Nonresponse in Web-Based Questionnaires: Multilevel Analysis of Person-Level and Item Design Factors in a Birth Cohort

Background Web-based questionnaires are increasingly used in epidemiologic studies, as traditional methods are facing a decrease in response rates and an increase in costs. However, few studies have investigated factors related to the level of completion of internet-based epidemiologic questionnaires. Objective Our objective was to identify person-level characteristics and item design factors associated with breakoff (not finishing the questionnaire) and item nonresponse in a Web-based questionnaire. Methods This study was a cross-sectional analysis of the baseline questionnaire, applied from 2005 to 2016, of the Italian NINFEA (Nascita e Infanzia: gli Effetti dell’Ambiente) birth cohort. The baseline questionnaire was administered to enrolled women, who could register at any time during pregnancy. We used logistic regression to analyze the influence of person-level factors on questionnaire breakoff, and a logistic multilevel model (first level: items of the questionnaire; second level: sections of the questionnaire; third level: study participants) to analyze the influence of person-level and item design factors on item nonresponse. Since the number of applicable items depended on the respondent’s characteristics and breakoff, we used inverse probability weighting to deal with missing by design. Results Of 5970 women, 519 (8.69%) did not finish the questionnaire. Older age (adjusted odds ratio 1.40, 95% CI 1.05-1.88), lower educational level (adjusted odds ratio [OR] 1.53, 95% CI 1.23-1.90), and earlier stage of pregnancy (adjusted OR 3.01, 95% CI 2.31-3.92) were positively associated with questionnaire breakoff. Of the 1,062,519 applicable items displayed for the participants, 22,831 were not responded to (overall prevalence of item nonresponse 2.15%). Item nonresponse was positively associated with older age (adjusted OR 1.25, 95% CI 1.14-1.38), being in the first trimester of pregnancy (adjusted OR 1.18, 95% CI 1.06-1.31), and lower educational level (adjusted OR 1.23, 95% CI 1.14-1.33). Dropdown menu items (adjusted OR 1.77, 95% CI 1.56-2.00) and items organized in grids (adjusted OR 1.69, 95% CI 1.49-1.91) were positively associated with item nonresponse. Conclusions It is important to use targeted strategies to keep participants motivated to respond. Item nonresponse in internet-based questionnaires is affected by person-level and item design factors. Some item types should be limited to reduce item nonresponse.
microRNAs: Key players in virus‐associated hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR‐222, miR‐25, miR‐92a, miR‐1, let‐7f, and miR‐21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV‐ and HBV‐related miRNAs which led to HCC progression.
Cytotoxin- and Chemotaxis-Genes Cooperate to Promote Adhesion of Photobacterium damselae subsp. damselae

Photobacterium damselae subsp. damselae (Pdd) is an emerging pathogen of marine animals that sometimes causes serious infections in humans. Two related pore forming toxins, phobalysins P and C, and damselysin, a phospholipase D, confer strong virulence of Pdd in mice. Because infections by Pdd are typically caused following exposure of wounds to sea water we investigated how salinity impacts toxin activity, swimming, and association of Pdd with epithelial cells. These activities were low when bacteria were pre-cultured in media with 3.5% NaCl, the global average salinity of sea water. In contrast, lower salinity increased swimming of wild type Pdd peaking at 2% NaCl, hemolysis, and association with epithelial cells peaking at 1–1.5%. Previously, we have found that hemolysin genes enhance the association of Pdd with epithelial cells, but the underlying mechanisms have remained ill-defined. We here searched for potential links between hemolysin-production, chemotaxis and association of Pdd with target cells at varying salt concentrations. Unexpectedly, disruption of chemotaxis regulator cheA not only affected bacterial swimming and association with epithelial cells at intermediate to low salinity, but also reduced the production of plasmid-encoded phobalysin (PhlyP). The results thus reveal unforeseen links between chemotaxis regulators, a pore forming toxin and the association of a marine bacterium with target cells.
Intranasal erythropoietin ameliorates neurological function impairments and neural pathology in mice with chronic alcoholism by regulating autophagy-related Nrf2 degradation

The neurological disorders and neural pathology brought about by chronic alcoholism are difficult to be reversed. Increasing evidence highlights the protective roles of erythropoietin (EPO) in neurodegenerative diseases and injuries of the central nervous system. In the present study, we investigated the therapeutic effects of EPO on the neurological function deficits and neural pathology caused by chronic alcoholism and the regulatory mechanisms. Using the canonical mouse model of chronic alcohol exposure designed to mimic the repeated cycles of heavy abuse typical of chronic alcoholism, it was found that EPO delivered via intranasal route effectively restored the alcohol-impaired motor cooperation in rotarod and beam walk tests, reversed alcoholic cognitive and emotional alterations in the novel location recognition task and open-filed test, and rescued alcohol-disrupted nervous conduction in the somatosensory-evoked potential (SSEP) test. Consistently, the intranasally administered EPO promoted the remyelination and synapse formation in chronic alcohol-affected neocortex and hippocampus as evidenced by immunofluorescence staining and transmission electron microscopy. Additionally, we discovered that the exogenous rhEPO, which entered the cerebrum through intranasal route, activated the erythropoietin receptor (EPOR) and the downstream ERKs and PI3K/AKT signaling, and suppressed autophagy-related degradation of nuclear factor, erythroid 2-like 2 (Nrf2). Furthermore, the intranasal EPO-exerted neuroprotection was almost abolished when the specific Nrf2 antagonist ATRA was administered intraperitoneally prior to intranasal EPO treatment. Collectively, our data demonstrated the repairing potential of EPO for the neurological disorders and neural pathology caused by chronic alcoholism, and identified the Nrf2 activity as the key mechanism mediating the protective effects of EPO.
Cryptic selection forces and dynamic heritability in generalized phenotypic evolution

Individuals with different phenotypes can have widely-varying responses to natural selection, yet many classical approaches to evolutionary dynamics emphasize how a population’s average phenotype increases in fitness over time. However, recent experimental results have produced examples of populations that have multiple fitness peaks, or that experience frequency-dependence that affects the direction and strength of selection on certain individuals. Here, we extend classical fitness gradient formulations of natural selection in order to describe the dynamics of a phenotype distribution in terms of its moments—such as the mean, variance, skewness, etc. The number of governing equations in our model can be adjusted in order to capture different degrees of detail about the population. We compare our simplified model to direct Wright-Fisher simulations of evolution in several canonical fitness landscapes, we find that our model provides a low-dimensional description of complex dynamics not typically explained by classical theory, such as cryptic selection forces due to selection on trait ranges, time-variation of the heritability, and nonlinear responses to stabilizing or disruptive selection due to asymmetric trait distributions. In addition to providing a framework for extending general understanding of common qualitative concepts in phenotypic evolution—such as fitness gradients, selection pressures, and heritability—our approach has practical importance for studying evolution in contexts in which genetic analysis is infeasible.