bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine
Authors: Pekarskaya Elizabeth A , Holt Emma S , Gingrich Jay A , Ansorge Mark S , Javitch Jonathan A , Canetta Sarah E 
Published: January 2021

ABSTRACTDepression and anxiety are two of the most common mental health disorders, often sharing symptoms and administrations. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. Therefore, to better understand how disease etiology may predict treatment response, we studied mice exposeddevelopmentallyto the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through the mu-opioid receptor (MOR) instead of directly targeting monoaminergic systems, would be more effective in this model.We injected C57BL/6J (C57) pups with either FLX (10 mg/kg, i.p) or vehicle from postnatal (PN) day 2 to 11, a period in which mouse brain development parallels that of the third trimester of a human pregnancy. Prior work established that adult 129SvEv (129) mice exposed to FLX in this time period (PN-FLX) showed increased avoidant and decreased hedonic behaviors, which correspond to anxiety- and depressive-like symptoms in humans, respectively. We performed baseline testing in adulthood in C57 PN-FLX animals and confirmed a similar avoidant phenotype to that reported in 129 PN-FLX mice. We then treated these animals with chronic FLX (18 mg/kg in the drinking water) and evaluated effects on two tasks that measure avoidant behavior – the open field and novelty suppressed feeding (NSF) tasks. This administration failed to improve, and even exacerbated, avoidance symptoms in PN-FLX mice. The same animals then underwent chronic administration with TIA (30 mg/kg, 2x/day, i.p.) as an alternative treatment strategy. TIA administration decreased avoidance behavior as measured in the open field and NSF. Overall, this demonstrates that TIA may be a promising alternative treatment to typical antidepressants, especially in patients whose serotonergic system has been altered.
A tool for assessing alignment of biomedical data repositories with open, FAIR, citation and trustworthy principles
Authors: Murphy Fiona , Bar-Sinai Michael , Martone Maryann E. 
Published: January 2021

AbstractIncreasing attention is being paid to the operation of biomedical data repositories in light of efforts to improve how scientific data is handled and made available for the long term. Multiple groups have produced recommendations for functions that biomedical repositories should support, with many using requirements of the FAIR data principles as guidelines. However, FAIR is but one set of principles that has arisen out of the open science community. They are joined by principles governing open science, data citation and trustworthiness, all of which are important aspects for biomedical data repositories to support. Together, these define a framework for data repositories that we call OFCT: Open, FAIR, Citable and Trustworthy. Here we developed an instrument using the open source PolicyModels toolkit that attempts to operationalize key aspects of OFCT principles and piloted the instrument by evaluating eight biomedical community repositories listed by the NIDDK Information Network (dkNET.org). Repositories included both specialist repositories that focused on a particular data type or domain, in this case diabetes and metabolomics, and generalist repositories that accept all data types and domains. The goal of this work was both to obtain a sense of how much the design of current biomedical data repositories align with these principles and to augment the dkNET listing with additional information that may be important to investigators trying to choose a repository, e.g., does the repository fully support data citation? The evaluation was performed from March to November 2020 through inspection of documentation and interaction with the sites by the authors. Overall, although there was little explicit acknowledgement of any of the OFCT principles in our sample, the majority of repositories provided at least some support for their tenets.
TheabaI/abaRquorum sensing system effects pathogenicity inAcinetobacter baumannii
Authors: Sun Xiaoyu , Ni Zhaohui , Tang Jie , Ding Yue , Wang Xinlei , Li Fan 
Published: January 2021

ABSTRACTAcinetobacter baumanniiis a Gram-negative pathogen that has emerged as one of the most troublesome pathogens for health care institutions globally. Bacterial quorum sensing (QS) is a process of cell-to-cell communication that relies on the production, secretion and detection of autoinducer (AI) signals to share information about cell density and regulate gene expression accordingly. In this study, we performed a comprehensive set of experiments show that deletion of quorum sensing genes showed differences in growth characteristics, morphology, biofilm formation and virulence, and increased susceptibility to some antimicrobials and exhibited motility defects. RNA-seq analysis indicated that genes involved in various aspects of energy production and conversion, Valine, leucine and isoleucine degradation and lipid transport and metabolism showed different expression.IMPORTANCEPrevious studies on bacterial quorum sensing mainly focused on biofilm formation and motility and antibiotic resistance. In this study, we focused on detecting the role of theabaI/abaRQS system in the virulence ofA. baumannii. Our work provides a new insight intoabaI/abaRquorum sensing system effects pathogenicity inA. baumannii. We propose that targeting the AHL synthase enzymeabaIcould provide an effective strategy for attenuating virulence. On the contrary, interdicting the autoinducer synthase–receptorabaRelicits unpredictable consequences, which may lead to enhanced bacterial virulence.
Patterns ofMustelid gammaherpesvirus 1(MusGHV-1) genital reactivation linked to stressors in adult European badgers (Meles meles)
Authors: Tsai Ming-shan , Francois Sarah , Newman Chris , Macdonald David W. , Buesching Christina D. 
Published: January 2021

AbstractHerpesvirus infections are common and mostly asymptomatic in vertebrates, but can result in impaired reproduction. It is therefore important to understand infection patterns and associated risk factors, particularly the effects of different stressors. Here we use Mustelid gammaherpesvirus 1 (MusGHV-1) infection in European badgers (Meles meles) as a host-pathogen wildlife model to study the effects of a variety of demographic, social, physiological and environmental stressors on viral reactivation in the genital tract. We collected 251 genital swabs from 151 free-ranging individuals across 3 trapping seasons (spring, summer and autumn). We screened for MusGHV-1 using PCR and explored possible links between genital MusGHV-1 reactivation and stressors, and their interactions, using logistic regression. In adults, reactivation was more likely in males, especially those in poorer body condition during summer. In females, reactivation was more likely when living in social groups comprising a higher percentage of cubs, but counter to our predictions, recent lactation appeared not influential. In relation to age, reactivation was more common in individuals over 8 years old than among prime age adults, and among juveniles (<2 years old), especially females and individuals in better body condition, likely due to early puberty. Environmentally, reactivation was more prevalent in summer when food abundance is typically low. Our results evidence age effects on MusGHV-1 reactivation; in juveniles MusGHV-1 shedding in the genital tract is likely related to primary infection, while in adults, genital MusGHV-1 reactivation from latency was associated with aging, social and/ or environmental stress.ImportanceThe immuno-suppressive effects of elevated stress levels facilitate disease development, and can ultimately cause host extinction at the population level, especially where diseases are transmitted sexually. The impacts of stress on host-pathogen dynamics through disease, however, are still poorly understood outside the laboratory or captive environments. Our study provides rare evidence from a free-ranging wild mammal population that the infection dynamics of a common and sexually transmittable gammaherpesvirus are linked to demographic, social, physiological and environmental stress. We propose that the effects of stressors on STIs and viral reactivation are an important factor to be taken into account in conservation efforts when working with vulnerable wildlife populations.
In silicoanalysis and cluster validation of potential breast cancer nsSNPs of serological tumor marker CA27.29
Authors: Lakhani Jyoti , Harwani Dharmesh 
Published: January 2021

ABSTRACTBackground & ObjectivesCA27.29 is a breast cancer-associated glycoprotein. Many genetic variations caused by non-synonymous nucleotide polymorphisms (nsSNPs) are known to affect the functionality of the CA27.29 protein.MethodsIn the present manuscript, anin silicoanalysis of the genetic variations in CA27.29 was done to observe functional nsSNPs that possibly alter its stability. Among 2205 SNPs identified from the publically available SNP database (dbSNP), 213 (9.66%) synonymous SNPs, 24 (1.09%) non-synonymous SNPs, and 1351 (61.27%) noncoding intronic SNPs were observed. The function predictability tools SIFT, Provean and Polyphen2 were used to uncover variations in the analyzed nsSNPs and their functionality.ResultsA total of 16, 20 and 10 non-synonymous SNPs (nsSNPs) were predicted to be damaging or deleterious by SIFT, Polyphen, and Provean tools respectively. Intriguingly, 9 nsSNPs were predicted to be damaging by all the three tools used while 4 nsSNPs were predicted to be damaging by SIFT and Polyphen tools. The substitutions C/G->T and G->A/T were observed to be dominant in the analyzed nsSNPs that probably have damaging role to CA27.29 glycoprotein. Moreover, the validation of results using ClinVar tool revealed that all the analyzed possibly, probably and highly damaging nsSNPs are yet to be reported and studied. Besides this, we found Global minor allele frequency (Global MAF) for only 11 nsSNPs, the values of which were observed to be <0.1% that further confirmed the novelty of the analyzed variants.Interpretation & ConclusionsAmong the analyzed nsSNPs, 3 nsSNPs rs145691584, rs148332231 and rs191544901 were found to be located in 3’UTR region of CA27.29 gene that were assumed to have the possible functional roles in altering the protein stability. The present study is useful to gain useful insights into the genetic variations in nsSNPs that may playing a critical role in determining the susceptibility to breast cancer.
Heart Rate Variability in Patients with Cirrhosis: A Systematic Review and Meta-analysis
Authors: Oyelade Tope , Canciani Gabriele , Carbone Gabriele , Alqahtani Jaber , Moore Kevin , Mani Ali R. 
Published: January 2021

AbstractBackgroundCirrhosis is associated with abnormal autonomic function and regulation of cardiac rhythm. Measurement of heart rate variability (HRV) provides an accurate and non-invasive measurement of autonomic function as well as liver disease severity currently calculated using the MELD, UKELD, or ChildPugh scores. This review assesses the methods employed for the measurement of HRV, and evaluates the alteration of HRV indices in cirrhosis, as well as their value in prognosis.MethodWe undertook a systematic review using Medline, Embase and Pubmed databases in July 2020. Data were extracted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias of included studies was assessed by a modified version of the Newcastle Ottawa Scale. The studies descriptive were analysed and the standardized mean differences of HRV indices were pooled.ResultsOf the 247 studies generated from our search, 14 studies were included. One of the 14 studies was excluded from meta-analysis because it reported only median of HRV indices. The studies included have a low risk of bias, and include 583 patients with cirrhosis and 349 healthy controls. The HRV time and frequency domains were significantly lower in cirrhotic patients. Between-studies heterogeneity was high in most of the pooled studies (P<0.05). Further, HRV indices predict survival independent of the severity of liver disease as assessed by MELD.ConclusionHRV is decreased in patients with cirrhosis compared with healthy matched controls. HRV correlated with severity of liver disease and independently predicted survival. There was considerable variation in the methods used for HRV analysis, and this impedes interpretation and clinical applicability. Based on the data analysed, SDNN (standard deviation of inter-beat intervals) and cSDNN (i.e. SDNN corrected for basal heart rate) are the most suitable indices for prognosis in patients with cirrhosis.
Histone dynamics mediate DNA unwrapping and sliding in nucleosomes: insights from multi-microsecond molecular dynamics simulations
Authors: Armeev Grigoriy A. , Kniazeva Anastasia S. , Komarova Galina A. , Kirpichnikov Mikhail P. , Shaytan Alexey K. 
Published: January 2021

AbstractNucleosomes are elementary building blocks of chromatin in eukaryotes. They tightly wrap ~147 DNA base pairs around an octamer of histone proteins. How nucleosome structural dynamics affect genome functioning is not completely clear. Here we report all-atom molecular dynamics simulations of nucleosome core particles at a timescale of 15 microseconds. At this timescale, functional modes of nucleosome dynamics such as spontaneous nucleosomal DNA breathing, unwrapping, twisting, and sliding were observed. We identified atomistic mechanisms of these processes by analyzing the accompanying structural rearrangements of the histone octamer and histone-DNA contacts. Octamer dynamics and plasticity were found to enable DNA unwrapping and sliding. Through multi-scale modeling, we showed that nucle-osomal DNA dynamics contribute to significant conformational variability of the chromatin fiber at the supranucleosomal level. Our study further supports mechanistic coupling between fine details of histone dynamics and chromatin functioning, provides a framework for understanding the effects of various chromatin modifications.We developed a web site for an interactive preview of molecular dynamics trajectories athttps://intbio.github.io/Armeev_et_al_2021.
γδ intraepithelial lymphocytes facilitate pathological epithelial cell shedding via CD103-mediated granzyme release
Authors: Hu Madeleine D. , Golovchenko Natasha B. , Kelly Thomas J. , Agos Jonathan , Zeglinski Matthew R. , Bonder Edward M. , Sandrock Inga , Prinz Immo , Granville David J. , Watson Alastair J.M. , Edelblum Karen L. 
Published: January 2021

SummaryExcessive shedding of enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. However, the mechanisms underlying this phenomenon remain unclear. Intraepithelial lymphocytes (IEL) expressing the γδ T-cell receptor (TCR) provide surveillance of the intestinal mucosa at steady-state, which is regulated, in part, by CD103. Intravital microscopy of lipopolysaccharide (LPS)-treated mice revealed that γδ IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, as CD103 blockade significantly reduces LPS-induced shedding. Furthermore, we find that granzymes A and B, but not perforin, are required for cell shedding, and that these granzymes are released by γδ IELs both constitutively and following CD103/E-cadherin ligation. These findings indicate that extracellular granzyme facilitates shedding, likely through cleavage of extracellular matrix proteins. Our results uncover a previously unrecognized role for γδ IELs in facilitating pathological cell shedding in a CD103- and granzyme-dependent manner.
A two-year study on the phenology, host and habitat associations, and pathogens ofHaemaphysalis longicornisin Virginia, U.S.A.
Authors: Thompson Alec T. , White Seth A. , Shaw David , Garrett Kayla B. , Wyckoff Seth T. , Doub Emily E. , Ruder Mark G. , Yabsley Michael J. 
Published: January 2021

AbstractUnderstanding the abiotic and biotic variables affecting tick populations is essential for studying the biology and health risks associated with vector species. We conducted a study on the phenology of exoticHaemaphysalis longicornis(Asian longhorned tick) at a site in Albemarle County, Virginia. We assessed the importance of available wildlife hosts, habitats, and microclimate variables such as temperature, relative humidity, and wind speed on this exotic tick’s presence and abundance. In addition, we determined the prevalence of selected tick-borne pathogens potentially transmitted byH. longicornis. We determined that the seasonal activity ofH. longicorniswas slightly different from previous studies in the northeastern United States. We observed nymphal ticks persist year-round but were most active in the spring, followed by a peak in adult activity in the summer and larval activity in the fall seasons. We also observed a lower probability of detectingH. longicornisin field habitats and the summer months. In addition, we detectedH. longicornison several wildlife hosts, including coyote (Canis latrans), eastern cottontail (Sylvilagus floridanus), raccoon (Procyon lotor), Virginia opossum (Didelphis virginiana), white-tailed deer(Odocoileus virginianus), woodchuck (Marmota monax), and aPeromyscussp. This is the first detection of this tick on a rodent host important to the epidemiology of tick-borne pathogens of humans and animals. Finally, we continued to detect the exotic piroplasm parasite,Theileria orientalisIkeda, inH. longicornisas well as other pathogens, includingRickettsia felis, Anaplasma phagocytophilum(AP-1), and aHepatozoonsp. previously characterized inAmblyomma americanum. These represent some of the first detections of arthropod-borne pathogens native to the United States in host-seekingH. longicornis. These data increase our understanding ofH. longicornisbiology in the United States and provide valuable information into the future health risks associated with this tick and pathogens.
RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signalling
Authors: Chen Kaiwen W. , Demarco Benjamin , Heilig Rosalie , Ramos Saray P , Grayczyk James P , Assenmacher Charles-Antoine , Radaelli Enrico , Joannas Leonel D. , Henao-Mejia Jorge , Brodsky Igor E , Broz Petr 
Published: January 2021

AbstractInjection of effector proteins to block host innate immune signalling is a common strategy used by many pathogenic organisms to establish an infection. PathogenicYersiniaspecies for example inject the acetyltransferase YopJ into target cells to inhibit NF-κB and MAPK signalling. To counteract this, detection of YopJ activity in myeloid cells promotes the assembly of a RIPK1-caspase-8 death-inducing platform that confers antibacterial defence. While recent studies revealed that caspase-8 cleaves the pore-forming protein, gasdermin D (GSDMD) to trigger pyroptosis in macrophages, whether RIPK1 activates additional substrates downstream of caspase-8 to promote host defence is unclear. Here, we report that the related gasdermin family member gasdermin E (GSDME) is activated upon detection of YopJ activity in a RIPK1 kinase-dependent manner. Specifically, GSDME promotes neutrophil pyroptosis and IL-1β release, which is critical for anti-Yersiniadefence. Duringin vivoinfection, IL-1β neutralisation increases bacterial burden in wild type but notGsdme-deficient mice. Thus, our study establishes GSDME as an important mediator that counteracts pathogen blockade of innate immune signalling.
Inhibition of microglial GBA hampers the microglia-mediated anti-oxidant and protective response in neurons
Authors: Brunialti Electra , Villa Alessandro , Mekhaeil Marianna , Mornata Federica , Vegeto Elisabetta , Maggi Adriana , Di Monte Donato A. , Ciana Paolo 
Published: January 2021

AbstractHomozygotic mutations in the GBA gene cause Gaucher’s disease, moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson’s disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher’s disease. In the brain, most of the pathological effects caused by GBA mutations have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. Here, we applied the bioluminescence imaging technology, immunohistochemical and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia co-cultures and in cell lines. Our data demonstrate the existence of a novel mechanism by which microglia sustain the antioxidant/detoxifying response mediated by the nuclear factor erythroid 2-related factor 2 in neurons. The central role played by microglia in this neuronal responsein vivowas proven by pharmacological depletion of the lineage in the brain, while co-cultures experiments provided insight on the nature of this cell-to-cell communication showing that this mechanism requires a direct microglia-to-neuron contact supported by functional actin structures. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, turn on an anti-inflammatory/repairing pathway and hinder the microglia ability to activate the anti-oxidant/detoxifying response, thus increasing the neuronal susceptibility to neurotoxins.Altogether, our data suggest that microglial β-glucocerebrosidase inhibition impairs microglia-to-neuron communication increasing the sensitivity of neurons to oxidative or toxic insults, thus providing a possible mechanism for the increased risk of neurodegeneration observed in carriers of GBA mutations.Graphical AbstractIn BriefMicroglia, through actin-dependent structures, contact neurons and induce a detoxification response by increasing the NFE2L2 signalling pathway. Inhibition of GCase activity by CBE treatment produces a morpho-functional change in microglia cells hampering the neuroprotective microglia-neuron communication thus inducing a phenotype in dopaminergic neurons characterized by increased susceptibility to oxidative stress or toxic insults.
Unraveling the origin of Glucose mediated disparate proliferation dynamics of Cancer stem cells
Authors: Samanta Tagari , Kar Sandip 
Published: January 2021

AbstractCancer stem cells (CSCs) often switch on their self-renewal programming aggressively to cause a relapse of cancer. Intriguingly, glucose differentially triggers the proliferation propensities in CSCs in an origin-dependent manner by controlling the expression of the key transcription factor like Nanog. However, the factors that critically govern this glucose-stimulated proliferation dynamics of CSCs remains elusive. Herein, by proposing a mathematical model of glucose-mediated Nanog regulation in CSCs, we showed that the differential proliferation behavior of CSCs can be explained by considering the experimentally observed varied expression levels of key positive (STAT3) and negative (p53) regulators of Nanog. Our model reconciles various experimental observations and predicts ways to fine-tune the proliferation dynamics of specific CSCs in a context-dependent manner. In future, these modeling insights will be useful in developing improved therapeutic strategies to get rid of harmful CSCs.