bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discrete TrkB-expressing neurons of the dorsomedial hypothalamus regulate feeding and thermogenesis
Authors: Houtz Jessica , Liao Guey-Ying , Xu Baoji 
Published: September 2020

AbstractMutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-expressing neurons in the DMH (DMHTrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of DMHTrkBneurons on energy homeostasis has not been explored. In this study, we show that activation of DMHTrkBneurons leads to a robust increase in adaptive thermogenesis and energy expenditure without altering heart rate or blood pressure, while silencing DMHTrkBneurons impairs thermogenesis. Furthermore, we reveal neuroanatomically and functionally distinct populations of DMHTrkBneurons that regulate food intake or thermogenesis. Activation of DMHTrkBneurons projecting to the raphe pallidus stimulates thermogenesis and increased energy expenditure, whereas DMHTrkBneurons that send collaterals to the paraventricular hypothalamus and preoptic area inhibit feeding. Together, our findings provide evidence that DMHTrkBneuronal activity plays an important role in regulating energy expenditure and delineate distinct neurocircuits that underly the separate effects of DMHTrkBneuronal activity on food intake and thermogenesis.Brief summaryThis study shows that TrkB-expressing DMH neurons stimulate thermogenesis through projection to raphe pallidus, while inhibiting feeding through collaterals to paraventricular hypothalamus and preoptic area.
Mutation in position of 32 (G>U) of S2M differentiate human SARS-CoV2 from Bat Coronavirus
Authors: Vahed Majid , Vahed Mohammad , Sweeney Aaron , Shirazi Farshad H , Mirsaeidi Mehdi 
Published: September 2020

ABSTRACTThe new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a zoonotic pathogen that has rapidly mutated and become transmissible to humans. There is little existing data on the mutations in SARS-CoV-2 and the impact of these polymorphisms on its transmission and viral load. In this study, the SARS-CoV-2 genomic sequence was analyzed to identify variants within the 3’UTR region of its cis-regulatory RNA elements. A 43-nucleotide genetic element with a highly conserved stem-loop II-like motif (S2M), was discovered. The research revealed 32 G>U and 16 G>U/A mutations located within the S2M sequence in human SARS-CoV-2 models. These polymorphisms appear to make the S2M secondary and tertiary structures in human SARS-CoV-2 models less stable when compared to the S2M structures of bat/pangolin models. This grants the RNA structures more flexibility, which could be one of its escape mechanisms from host defenses or facilitate its entry into host proteins and enzymes. While this S2M sequence may not be omnipresent across all human SARS-CoV-2 models, when present, its sequence is always highly conserved. It may be used as a potential target for the development of vaccines and therapeutic agents.
Effect of Renin-Angiotensin-Aldosterone System inhibitors on outcomes of COVID-19 patients with hypertension: Systematic review and Meta-analysis
Authors: Beressa Tamirat Bekele , Sahilu Tamiru , Deyno Serawit 
Published: September 2020

AbstractObjectiveThis research aimed to systematically review and summarize the influence of Renin-Angiotensin-Aldosterone System(RAAS) inhibitors on the outcome of COVID_19 patients with hypertension.MethodsElectronic databases; PubMed/Medline, CINAHL, the Cochrane Central Register of Controlled Trials, clinical trial.gov, and Google Scholar were searched from 2019 to June 1, 2020. Additionally, the references of identified articles were also searched.ResultsA total of 9 articles comprising 3,823 patients were incorporated; 1416 patients on RAAS inhibitors and 3469 on non-RAAS inhibitors. The study demonstrated that the taking of RAAS inhibitors in COVID_19 patients with hypertension significantly reduced mortality where patients on RAAS inhibitors had a 27% decrease of mortality (RR = 0.73 [95% CI: 0.63- 0.85, p< 0.0001, I2= 0%, random-effects model]) compared to those not taking ACEI/ARB. No significant association were observed in disease severity (RR = 0.92 (95% CI: 0.74- 1.14) and hospitalization (WMD = –2.33[95% CI: –5.60, 0.75]), random-effects model.ConclusionThis study supports RAAS inhibitors’ safe use among COVID_19 patients with hypertension.
Is tumor mutational burden predictive of response to immunotherapy?
Authors: Gurjao Carino , Tsukrov Dina , Imakaev Maxim , Luquette Lovelace J. , Mirny Leonid A. 
Published: September 2020

Cancer immunotherapy by checkpoint blockade (ICB) is effective for various cancer types, yet its clinical use is encumbered by a high variability of patient response. Several studies have reported that the number of non-synonymous mutations (Tumor Mutational Burden, TMB), can predict patient response to ICB. This belief has become widespread and led to the FDA approval of immunotherapy patient prioritization based on TMB levels. The notion that TMB is predictive of response to immunotherapy is rooted in the neoantigen theory. It stipulates that cancer-specific mutations can form neoantigens recognized by the immune system; the more mutations a tumor has, the more likely the immune response is triggered. Here we revisit the data underlying the reported association of TMB with response, and the neoantigen theory. First we assembled the largest pan-cancer dataset of immunotherapy patients with sequencing and clinical data. Surprisingly, we find little evidence that TMB is predictive of response to ICB. We demonstrate that associations similar to the ones reported previously can be observed in shuffled data, suggesting that previous studies suffered from a lack of correction for multiple hypotheses testing and confounding disease subtypes.Second, we develop a model that expands the neoantigen theory and can be consistent with both immunogenicity of neoantigens and the lack of association between TMB and response. Our analysis shows that the use of TMB in clinical practice is not supported by available data and can deprive patients of treatment to which they are likely to respond.
Role of ERK activation inH. pylori-induced disruption of cell-cell tight junctions
Authors: Sekar Amita , Ho Bow 
Published: September 2020

AbstractBackgroundTight junctions, a network of claudins and other proteins, play an important role in maintaining barrier function and para-cellular permeability.H. pylori, the major etiological agent of various gastroduodenal diseases, is known to cause tight junction disruption. However, the molecular events that triggered cell-cell tight junction disruption inH. pylori-infected cells, remain largely elusive.Materials and MethodsTrans-epithelial electrical resistance (TEER) and FITC-Dextran permeability measurement were performed to determine the barrier function inH. pylori88-3887-infected polarized MKN28 cells. For visualization of tight junction protein localization, immunofluorescence and immunoblotting techniques were used. To examine the role of ERK activation in tight junction disruption, U0126, a MEK inhibitor, was employed. To further support the study, computational analyses ofH. pylori-infected primary gastric cells were carried out to decipher the transcriptomic changes.ResultsThe epithelial barrier of polarized MKN28 cells when infected withH. pyloridisplayed disruption of cell-cell junctions as shown by TEER & FITC-dextran permeability tests. Claudin-4 was shown to delocalize from host cytoplasm to nucleus inH. pylori-infected cells. In contrast, delocalization of claudin-4 was minimized when ERK activation was inhibited. Interestingly, transcriptomic analyses revealed the upregulation of genes associated with cell-junction assembly and ERK pathway forming a dense interacting network of proteins.ConclusionTaken together, evidence from this study indicates thatH. pyloriregulates ERK pathway triggering cell-cell junction disruption, contributing to host pathogenesis. It indicates the vital role of ERK in regulating key events associated with the development ofH. pylori-induced gastroduodenal diseases.
Neuronal perception of the social environment intergenerationally controls germline development and generation time inC. elegans
Authors: Perez Marcos Francisco , Shamalnasab Mehrnaz , Mata-Cabana Alejandro , Valle Simona Della , Olmedo María , Francesconi Mirko , Lehner Ben 
Published: September 2020

ABSTRACTAn old and controversial question in biology is whether information perceived by the nervous system of an animal can ‘cross the Weismann barrier’ to alter the phenotypes and fitness of their progeny. Here we show that such intergenerational transmission of sensory information occurs in the model organism,C. elegans, with a major effect on fitness. Specifically, that perception of social pheromones by chemosensory neurons controls the post-embryonic timing of development of one tissue – the germline – relative to others in an animal’s progeny. Neuronal perception of the social environment thus intergenerationally controls the generation time of this animal.
qFit 3: Protein and ligand multiconformer modeling for X-ray crystallographic and single-particle cryo-EM density maps
Authors: Riley Blake T. , Wankowicz Stephanie A. , de Oliveira Saulo H. P. , van Zundert Gydo C. P. , Hogan Daniel , Fraser James S. , Keedy Daniel A. , van den Bedem Henry 
Published: September 2020

AbstractNew X-ray crystallography and cryo-electron microscopy (cryo-EM) approaches yield vast amounts of structural data from dynamic proteins and their complexes. Modeling the full conformational ensemble can provide important biological insights, but identifying and modeling an internally consistent set of alternate conformations remains a formidable challenge. qFit efficiently automates this process by generating a parsimonious multiconformer model. We refactored qFit from a distributed application into software that runs efficiently on a small server, desktop, or laptop. We describe the new qFit 3 software and provide some examples. qFit 3 is open-source under the MIT license, and is available athttps://github.com/ExcitedStates/qfit-3.0.
Development of SARS-CoV-2 Nucleocapsid Specific Monoclonal Antibodies
Authors: Terry James S. , Anderson Loran BR , Scherman Michael S. , McAlister Carley E. , Perera Rushika , Schountz Tony , Geiss Brian J. 
Published: September 2020

AbstractThe global COVID-19 pandemic has caused massive disruptions in every society around the world. To help fight COVID-19, new molecular tools specifically targeting critical components of the causative agent of COVID-19, SARS-Coronavirus-2 (SARS-CoV-2), are desperately needed. The SARS-CoV-2 nucleocapsid protein is a major component of the viral replication processes, integral to viral particle assembly, and is a major diagnostic marker for infection and immune protection. Currently available antibody reagents targeting the nucleocapsid protein were primarily developed against the related SARS-CoV virus and are not specific to SARS-CoV-2 nucleocapsid protein. Therefore, in this work we developed and characterized a series of new mouse monoclonal antibodies against the SARS-CoV-2 nucleocapsid protein. The anti-nucleocapsid monoclonal antibodies were tested in ELISA, western blot, and immunofluorescence analyses. The variable regions from the heavy and light chains from five select clones were cloned and sequenced, and preliminary epitope mapping of the sequenced clones was performed. Overall, the new antibody reagents described here will be of significant value in the fight against COVID-19.
Emergence of stable motifs in consumer-resource communities
Authors: Amarasekare Priyanga , Brose Ulrich , Chase Jonathan , Knight Tiffany , Clark Adam 
Published: September 2020

ABSTRACTUnderstanding how and why complex communities can be stable has preoccupied ecologists for over a century. Data show that real communities tend to exhibit characteristic motifs and topologies. Despite a large body of theory investigating both ecological (niche partitioning) and evolutionary (speciation and extinction) mechanisms, a general explanation for why particular motifs are more common than others remains elusive. Here we develop a mechanistic framework that investigates the set of possible motifs that can emerge under minimal conditions of a nutrient-limited system with no external inputs, and no spatial heterogeneity. Focusing on consumer-resource communities structured by competition and predation, we find that the emergent motifs under these minimal conditions are vertical trophic chains that maximize energy transfer and biomass production. Not only are such motifs stable to perturbations of species’ abundances, but they are also robust to species additions and removals. Our findings provide a mechanistic explanation for why tri-trophic chains are overrepresented in real food webs. They suggest that, because they maximize energy transfer, and can emerge and persist under minimal conditions, vertical trophic chains may constitute the fundamental architecture of consumer-resource communities.
Identification, Localization and Expression of NHE Isoforms in the Alveolar Epithelial Cells
Authors: Kinaneh Safa , Knany Yara , Khoury Emad , Ismael-Badarneh Reem , Hammoud Shadi , Berger Gidon , Abassi Zaid , Azzam Zaher S. 
Published: September 2020

AbstractNa+/H+ exchangers (NHEs), encoded by Solute Carrier 9A (SLC9A) genes in human, are ubiquitous integral membrane ion transporters that mediate the electroneutral exchange of H+ with Na+ or K+. NHEs, found in the kidney and intestine, play a major role in the process of fluid reabsorption together via Na+,K+-ATPase pump and Na+ channels. Nevertheless, the expression pattern of NHE in the lung and its role in alveolar fluid homeostasis has not been addressed. Therefore, we aimed to examine the expression of NHE specific isoforms in alveolar epithelium cells (AECs), and assess their role in congestive heart failure.Three NHE isoforms were identified in AEC and A549 cell line, at the level of protein and mRNA; NHE1, NHE2 and mainly NHE8, the latter was shown to be localized in the apical membrane of AEC. Treating A549 cells with angiotensin (Ang) II for 1 and 3 hours displayed a significant reduction in NHE8 protein abundance and to lesser extent at 5 hours; however, there was no effect at 24 hours. Moreover, A549 treated overnight with Ang II downregulated NHE8 protein abundance.CHF rats held for 1 week had increased abundance of NHE8 compared to sham operated rats. However, lower abundance of NHE8 was observed in CHF rats held for 4 weeks.Herein we show, for the first time, the expression of a novel NHE isoform by AEC, namely NHE8. Besides being negatively affected by Ang II, NHE8 protein levels were distinctly affected in CHF rats, which may be related to CHF severity.
Detection of native and mirror protein structures based on Ramachandran plot analysis by interpretable machine learning models
Authors: Abel Julia , Kaden Marika , Bohnsack Katrin Sophie , Weber Mirko , Leberecht Christoph , Villmann Thomas 
Published: September 2020

AbstractIn this contribution the discrimination between native and mirror models of proteins according to their chirality is tackled based on the structural protein information. This information is contained in the Ramachandran plots of the protein models. We provide an approach to classify those plots by means of an interpretable machine learning classifier - the Generalized Matrix Learning Vector Quantizer. Applying this tool, we are able to distinguish with high accuracy between mirror and native structures just evaluating the Ramachandran plots. The classifier model provides additional information regarding the importance of regions, e.g.α-helices andβ-strands, to discriminate the structures precisely. This importance weighting differs for several considered protein classes.
Fast and inexpensive whole genome sequencing library preparation from intact yeast cells
Authors: Vonesch Sibylle C , Li Shengdi , Tu Chelsea Szu , Hennig Bianca P , Dobrev Nikolay , Steinmetz Lars M 
Published: September 2020

ABSTRACTThrough the increase in the capacity of sequencing machines massively parallel sequencing of thousands of samples in a single run is now possible. With the improved throughput and resulting drop in the price of sequencing, the cost and time for preparation of sequencing libraries have become the major bottleneck in large-scale experiments. Methods using a hyperactive variant of the Tn5 transposase efficiently generate libraries starting from cDNA or genomic DNA in a few hours and are highly scalable. For genome sequencing, however, the time and effort spent on genomic DNA isolation limits the practicability of sequencing large numbers of samples. Here, we describe a highly scalable method for preparing high quality whole-genome sequencing libraries directly from yeast cultures in less than three hours at 34 cents per sample. We skip the rate-limiting step of genomic DNA extraction by directly tagmenting yeast spheroplasts and add a nucleosome release step prior to enrichment PCR to improve the evenness of genomic coverage. Resulting libraries do not show any GC-bias and are comparable in quality to libraries processed from genomic DNA with a commercially available Tn5-based kit. We use our protocol to investigate CRISPR/Cas9 on- and off-target edits and reliably detect edited variants and shared polymorphisms between strains. Our protocol enables rapid preparation of unbiased and high-quality, sequencing-ready indexed libraries for hundreds of yeast strains in a single day at a low price. By adjusting individual steps of our workflow we expect that our protocol can be adapted to other organisms.
TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin stability
Authors: Balestra Fernando R. , Wolf Benita , Domínguez-Calvo Andrés , Buff Alizée , Averink Tessa , Lipsanen-Nyman Marita , Busso Coralie , Huertas Pablo , Ríos Rosa M. , Gönczy Pierre 
Published: September 2020

ABSTRACTTRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease characterized by impaired growth and increased tumorigenesis, whose cellular etiology is poorly understood. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterized these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We established that an atypicalde novoassembly pathway is notably involved in forming Cenpas, which can nevertheless trigger further centriole assembly and act as MTOCs. We found also that Cenpas are present and act similarly in Mulibrey patient cells. Through correlative light electron microscopy, we uncovered that Cenpas correspond to centriole related structures and elongated electron-dense structures with stripes. Importantly, we established that TRIM37 regulates the stability and solubility of the centriolar protein Centrobin. Our findings suggest that elongated Centrobin assemblies are a major constituent of the striped electron dense structures. Furthermore, we established that Cenpas formation upon TRIM37 depletion requires PLK4 activity, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents the formation of Cenpas that would otherwise threaten genome integrity, including possibly in Mulibrey patients.
Azetidines kill Mycobacterium tuberculosis without detectable resistance by blocking mycolate assembly
Authors: Lanne Alice , Cui Yixin , Browne Edward , Craven Philip G. E. , Cundy Nicholas J. , Coltman Nicholas J. , Dale Katie , Feula Antonio , Frampton Jon , Goff Aaron , Hama Salih Mariwan A. , Lang Xingfen , Li Xingjian , Moon Christopher W. , Morton Michael , Pascoe Jordan , Peng Xudan , Portman Vanessa , Press Cara , Schulz-Utermoehl Timothy , Tortorella Micky , Tu Zhengchao , Underwood Zoe E. , Wang Changwei , Yoshizawa Akina , Zhang Tianyu , Waddell Simon J , Bacon Joanna , Neagoie Cleopatra , Fossey John S. , Alderwick. Luke J. 
Published: September 2020

AbstractTuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10 million new cases and 1.5 million deaths in 2019. This global emergency is exacerbated by the emergence of multi-drug-resistant MDR-TB and extensively-drug-resistant XDR-TB, therefore new drugs and new drug targets are urgently required. From a whole-cell phenotypic screen a series of azetidines derivatives termed BGAz, that elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB were identified. These compounds demonstrate no detectable drug resistance. Mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from existing mycobacterial cell-wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as anti-tubercular chemotherapies.
A single nuclei transcriptomic analysis of the Atlantic salmon gill through smoltification and seawater transfer
Authors: West Alexander C. , Mizoro Yasutaka , Wood Shona H. , Ince Louise M. , Iversen Marianne , Jørgensen Even H. , Nome Torfinn , Sandve Simen Rød , Loudon Andrew S. I. , Hazlerigg David G. 
Published: September 2020

AbstractAnadromous salmonids begin life adapted to the freshwater environments of their natal streams before a developmental transition, known as smoltification, transforms them into marine-adapted fish. In the wild, the extending photoperiods of spring stimulates smoltification, typified by radical reprogramming of the gill from an ion-absorbing organ to ion-excreting organ. Prior work has highlighted the role of specialized “mitochondrion-rich” cells in delivering this phenotype. However, transcriptomic studies identify thousands of smoltification-driven differentially regulated genes, indicating that smoltification causes a multifaceted, multicellular change; but direct evidence of this is lacking.Here, we use single-nuclei RNAseq to characterize the Atlantic salmon gill during smoltification and seawater transfer. We identify 20 distinct clusters of nuclei, including known, but also novel gill cell types. These data allow us to isolate cluster-specific, smoltification-induced changes in gene expression. We also show how cellular make-up of the gill changes through smoltification. As expected, we noted an increase in the proportion of seawater mitochondrion-rich cells, however, we also identify a reduction of several immune-related cells. Overall, our results provide unrivaled detail of the cellular complexity in the gill and suggest that smoltification triggers unexpected immune reprogramming directly preceding seawater entry.