bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hospital outbreak of carbapenem-resistant Enterobacteriales associated with an OXA-48 plasmid carried mostly byEscherichia coliST399
Authors: Ledda Alice , Cummins Martina , Shaw Liam P. , Jauneikaite Elita , Cole Kevin , Lasalle Florent , Barry Deborah , Rosmarin Caryn , Anaraki Sudy , Wareham David , Stoesser Nicole , Paul John , Manuel Rohini , Cherian Benny P , Didelot Xavier 
Published: June 2020

AbstractA hospital outbreak of carbapenem-resistant Enterobacteriales was detected by routine surveillance. Whole genome sequencing and subsequent analysis revealed a conserved promiscuous OXA-48 carrying plasmid as the defining factor within this outbreak. Four different species of Enterobacteriales were involved in the outbreak.Escherichia coliST399 accounted for 20/55 of all the isolates. Comparative genomics with publicly availableE. coliST399 sequence data showed that the outbreak isolates formed a unique clade. The OXA-48 plasmid identified in the outbreak differed from other known plasmids by an estimated five homologous recombination events. We estimated a lower bound to the plasmid conjugation rate to be 0.23 conjugation events per lineage per year. Our analysis suggests co-evolution between the plasmid and its main bacterial host to be a key driver of the outbreak. This is the first study to report carbapenem-resistantE. coliST399 carrying OXA48 as the main cause of a plasmid-borne outbreak within a hospital setting. This study supports complementary roles for both plasmid conjugation and clonal expansion in the emergence of this outbreak.
Selective REM-Sleep Suppression Increases Next-Day Negative Affect and Amygdala Responses to Social Exclusion
Authors: Glosemeyer Robert W , Diekelmann Susanne , Cassel Werner , Kesper Karl , Koehler Ulrich , Westermann Stefan , Steffen Armin , Borgwardt Stefan , Wilhelm Ines , Müller-Pinzler Laura , Paulus Frieder M , Krach Sören , Stolz David S 
Published: June 2020

AbstractHealthy sleep, positive general affect, and the ability to regulate emotional experiences are fundamental for well-being. In contrast, various mental disorders are associated with altered rapid eye movement (REM) sleep, negative affect, and diminished emotion regulation abilities. However, the neural processes mediating the relationship between these different phenomena are still not fully understood. In the present study of 42 healthy volunteers, we investigated the effects of selective REM sleep suppression (REMS) on general affect, as well as on feelings of social exclusion, emotion regulation, and their neural underpinnings. Using functional magnetic resonance imaging we show that REMS increases amygdala responses to experimental social exclusion, as well as negative affect on the morning following sleep deprivation. There was no evidence that emotional responses to experimentally induced social exclusion or their regulation using cognitive reappraisal were impacted by diminished REM sleep. Our findings indicate that general affect and amygdala activity depend on REM sleep, while specific emotional experiences possibly rely on additional psychological processes and neural systems that are less readily influenced by REMS.
In vivo imaging of swimming micromotors using hybrid high-frequency ultrasound and photoacoustic imaging
Authors: Aziz Azaam , Holthof Joost , Meyer Sandra , Schmidt Oliver G. , Medina-Sánchez Mariana 
Published: June 2020

AbstractThe fast evolution of medical micro- and nanorobots in the endeavor to perform non-invasive medical operations in living organisms boosted the use of diverse medical imaging techniques in the last years. Among those techniques, photoacoustic (PA) tomography has shown to be promising for the imaging of microrobots in deep-tissue (ex vivo and in vivo), as it possesses the molecular specificity of optical techniques and the penetration depth of ultrasound imaging. However, the precise maneuvering and function control of microrobots, in particular in living organisms, demand the combination of both anatomical and functional imaging methods. Therefore, herein, we report the use of a hybrid High-Frequency Ultrasound (HFUS) and PA imaging system for the real-time tracking of magnetically driven micromotors (single and swarms) in phantoms, ex vivo, and in vivo (in mice bladder and uterus), envisioning their application for targeted drug-delivery.
Discovery of molecular features underlying morphological landscape by integrating spatial transcriptomic data with deep features of tissue image
Authors: Bae Sungwoo , Choi Hongyoon , Lee Dong Soo 
Published: June 2020

AbstractProfiling molecular features associated with the morphological landscape of tissue is crucial to interrogate structural and spatial patterns that underlie biological function of tissues. Here, we present a new method, SPADE, to identify important genes associated with morphological contexts by combining spatial transcriptomic data with co-registered images. SPADE incorporates deep learning-derived image patterns with spatially resolved gene expression data to extract morphological context markers. Morphological features that correspond to spatial maps of transcriptome were extracted by image patches surrounding each spot, and then, represented by image latent features. The molecular profiles correlated with the image latent features were identified. The extracted genes could be further analyzed to discover functional terms and also exploited to extract clusters maintaining morphological contexts. We apply our approach to spatial transcriptomic data of three different tissues to suggest an unbiased method capable of offering image-integrated gene expression trends.
The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier
Authors: Buzhdygan Tetyana P. , DeOre Brandon J. , Baldwin-Leclair Abigail , McGary Hannah , Razmpour Roshanak , Galie Peter A. , Potula Raghava , Andrews Allison M. , Ramirez Servio H. 
Published: June 2020

ABSTRACTAs researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system includes neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-COV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is expressed throughout various caliber vessels in the frontal cortex. Additionally, ACE2 was also detectable in primary human brain microvascular endothelial (hBMVEC) maintained under cell culture conditions. Analysis for cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48hr exposure window. However, when the viral spike proteins were introduced into model systems that recapitulate the essential features of the Blood-Brain Barrier (BBB), breach to the barrier was evident in various degrees depending on the spike protein subunit tested. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluid model of the human BBB, a platform that most closely resembles the human physiological conditions at this CNS interface. Subsequent analysis also showed the ability for SARS-CoV-2 spike proteins to trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.
Lack of mucosal cholinergic innervation is associated with increased risk of enterocolitis in Hirschsprung’s disease
Authors: Keck Simone , Galati-Fournier Virginie , Kym Urs , Moesch Michèle , Usemann Jakob , Subotic Ulrike , Tharakan Sasha J. , Krebs Thomas , Stathopoulos Eleuthere , Schmittenbecher Peter , Cholewa Dietmar , Romero Philipp , Reingruber Bertram , Bruder Elisabeth ,   NIG study Group, Holland-Cunz Stefan 
Published: June 2020

Background & AimsHirschsprung’s disease (HSCR) is a congenital intestinal motility disorder defined by the absence of enteric nervous cells (ganglia). The development of HSCR-associated enterocolitis remains a life-threatening complication. Absence of enteric ganglia implicates extramural innervation of acetylcholine-secreting (cholinergic) nerve fibers. Cholinergic signals have been reported to control excessive inflammation, but the impact on HSCR-associated enterocolitis is unknown.MethodsWe enrolled 44 HSCR patients in a prospective multicenter study and grouped them according to their degree of colonic mucosal cholinergic innervation using immunohistochemistry. The fiber phenotype was correlated with the tissue cytokine profile as well as immune cell frequencies using quantitative reverse-transcribed real-time polymerase chain reaction (qRT-PCR) of whole colonic tissue and fluorescence-activated cell sorting (FACS) analysis of isolated colonic immune cells. Fiber-associated immune cells were identified using confocal immunofluorescence microscopy and characterized by RNA-seq analysis. Microbial dysbiosis was analyzed in colonic patient tissue using 16S rDNA gene sequencing. Finally, the fiber phenotype was correlated with postoperative enterocolitis manifestation.ResultsWe provided evidence that extrinsic mucosal innervation correlated with reduced interleukin (IL)-17 cytokine levels and T-helper-17 (Th17) cell frequencies. Bipolar CD14highmacrophages colocalized with neurons and expressed significantly less interleukin-23, a Th17-promoting cytokine. HSCR patients lacking mucosal cholinergic nerve fibers showed microbial dysbiosis and had a higher incidence of postoperative enterocolitis.ConclusionThe mucosal fiber phenotype might serve as a new prognostic marker for enterocolitis development in HSCR patients and may offer an approach to personalized patient care and new future therapeutic options. (www.clinicaltrials.govaccessing numberNCT03617640)
Naturally mutated spike proteins of SARS-CoV-2 variants show differential levels of cell entry
Authors: Ozono Seiya , Zhang Yanzhao , Ode Hirotaka , Tan Toong Seng , Imai Kazuo , Miyoshi Kazuyasu , Kishigami Satoshi , Ueno Takamasa , Iwatani Yasumasa , Suzuki Tadaki , Tokunaga Kenzo 
Published: June 2020

AbstractThe causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is steadily mutating during continuous transmission among humans. Such mutations can occur in the spike (S) protein that binds to the angiotensin-converting enzyme-2 (ACE2) receptor and is cleaved by transmembrane protease serine 2 (TMPRSS2). However, whether S mutations affect SARS-CoV-2 infectivity remains unknown. Here, we show that naturally occurring S mutations can reduce or enhance cell entry via ACE2 and TMPRSS2. A SARS-CoV-2 S-pseudotyped lentivirus exhibits substantially lower entry than SARS-CoV S. Among S variants, the D614G mutant shows the highest cell entry, as supported by structural observations. Nevertheless, the D614G mutant remains susceptible to neutralization by antisera against prototypic viruses. Taken together, these data indicate that the D614G mutation enhances viral infectivity while maintaining neutralization susceptibility.
CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+CD8+T cells in mice
Authors: Yamauchi Takayoshi , Hoki Toshifumi , Oba Takaaki , Attwood Kristopher , Cao Xuefang , Ito Fumito 
Published: June 2020

AbstractThe use of tumor mutation-derived neoantigen represents a promising approach for cancer vaccines. Preclinical and early-phase human clinical studies have shown the successful induction of tumor neoepitope-directed responses; however, overall clinical efficacy of neoantigen vaccines has been limited. One major obstacle of this strategy is the prevailing lack of sufficient understanding of the mechanism underlying the generation of neoantigen-specific CD8+T cells. Here, we report a correlation between antitumor efficacy of neoantigen/toll-like receptor 3 (TLR3)/CD40 vaccination and the generation of antigen-specific CD8+T cells expressing CX3C chemokine receptor 1 (CX3CR1) in a preclinical model. Mechanistic studies using mixed bone marrow chimeras identified that CD40 and CD80/86, but not CD70 signaling in Batf3-dependent conventional type 1 dendritic cells (cDC1s) is required for antitumor efficacy of neoantigen vaccine and generation of neoantigen-specific CX3CR1+CD8+T cells. Although CX3CR1+CD8+T cells exhibited robustin vitroeffector function, depletion of this subset did not alter the antitumor efficacy of neoantigen/TLR3/CD40 agonists vaccination, suggesting that the expanded CX3CR1+CD8+T cell subset represents the post-differentiatedin vivoeffective CX3CR1-negative CD8+T cell subset. Taken together, our results reveal a critical role of CD40 and CD80/86 signaling in cDC1s in antitumor efficacy of neoantigen-based therapeutic vaccines, and implicate the potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine therapy.
Multi Locus View : An Extensible Web Based Tool for the Analysis of Genomic Data
Authors: Sergeant Martin J , Hughes Jim R , Hentges Lance , Lunter Gerton , Downes Damien J , Taylor Stephen 
Published: June 2020

AbstractMotivationTracking and understanding data quality, analysis and reproducibility are critical concerns in the biological sciences. This is especially true in genomics where Next Generation Sequencing (NGS) based technologies such as ChIP-seq, RNA-seq and ATAC-seq are generating a flood of genome-scale data. These data-types are extremely high level and complex with single experiments capable of mapping ten to hundreds of thousands of biologically meaningful events across the genome. However, such data are usually processed with automated tools and pipelines, generating tabular outputs and static visualizations. These are difficult to interact with and require substantial bioinformatic skills to manipulate and query. Similarly, interpretation is normally made at a high level without the ability to visualise the underlying data in detail and so the complexity and quality of the real underlying biological signal is lost. Also genomics datasets require integration with other genomics datasets to be properly interpreted and this integration with multiple tracks again requires substantial bioinformatics skills and is difficult to visualise across multiple pertinent datasets. Conventional genome browsers do allow for the detailed visualisation of multiple tracks but are limited to browsing single locations and do not allow for interactions with the dataset as a whole. MLV has been developed to allow users to fluidly interact with genomics datasets at multiple scales, from complete metadata labelled and clustered populations to detailed representations of individual elements. It has inbuilt tools to integrate signals across multiple datasets and to perform dimensionality reduction and clustering analysis based on the extracted signal, allowing for the high-level analysis of complex datasets while maintaining visualisation of the fine grain structure of the data. MLV’s ability to visualise clustering within the data combined with efficient tools for large-scale tagging of individual elements makes it a unique tool for the generation of annotated datasets for modern machine learning approaches.ResultsMulti Locus View (MLV) is a web based tool for the visualisation, analysis and annotation of Next Generation Sequencing data sets. The user is able to browse the raw data, cluster, and combine the data with other analysis. Intuitive filtering and visualisation then enables the user to quickly locate and annotate regions of interest. User datasets can then be shared with other users or made public for quick assessment from the academic community. MLV is publically available athttps://mlv.molbiol.ox.ac.ukand the source code is available athttps://github.com/Hughes-Genome-Group/mlv
Linear-time cluster ensembles of large-scale single-cell RNA-seq and multimodal data
Authors: Do Van Hoan , Ringeling Francisca Rojas , Canzar Stefan 
Published: June 2020

AbstractA fundamental task in single-cell RNA-seq (scRNA-seq) analysis is the identification of transcriptionally distinct groups of cells. Numerous methods have been proposed for this problem, with a recent focus on methods for the cluster analysis of ultra-large scRNA-seq data sets produced by droplet-based sequencing technologies. Most existing methods rely on a sampling step to bridge the gap between algorithm scalability and volume of the data. Ignoring large parts of the data, however, often yields inaccurate groupings of cells and risks overlooking rare cell types. We propose methodSpecterthat adopts and extends recent algorithmic advances in (fast) spectral clustering. In contrast to methods that cluster a (random) subsample of the data, we adopt the idea of landmarks that are used to create a sparse representation of thefulldata from which a spectral embedding can then be computed in linear time. We exploit Specter’s speed in a cluster ensemble scheme that achieves a substantial improvement in accuracy over existing methods and that is sensitive to rare cell types. Its linear time complexity allows Specter to scale to millions of cells and leads to fast computation times in practice. Furthermore, on CITE-seq data that simultaneously measures gene and protein marker expression we demonstrate that Specter is able to utilize multimodal omics measurements to resolve subtle transcriptomic differences between subpopulations of cells. Specter is open source and available athttps://github.com/canzarlab/Specter.
Bacterial flagellins: does only size matter?
Authors: Shchyogolev Sergei Yu. , Burygin Gennady L. , Matora Larisa Yu. 
Published: June 2020

AbstractThe protein sequences of a number ofAzospirillaceaestrains were investigated that contain the pf00669 domain and belong to a variety of bacterial flagellum systems with unusually large flagellin sizes. A set of tools for the homologous and template-based modeling of protein structures was used to reveal the probability of alternative folding, i.e., generation of two protein models with significantly different 3D structures and functions (flagellin or S-layer protein) for a single amino acid sequence.
Beta2 oscillations in the hippocampal-cortical novelty detection circuit
Authors: França Arthur S C , Borgesius Nils Z. , Souza Bryan C. , Cohen Mike X 
Published: June 2020

AbstractNovelty detection is a core feature of behavioral adaptation, and involves cascades of neuronal responses – from initial evaluation of the stimulus to the encoding of new representations – resulting in the behavioral ability to respond to unexpected inputs. In the past decade, a new important novelty detection feature, beta2 (~20 - 30 Hz) oscillations, has been described in the hippocampus. However, the interactions between beta2 and the hippocampal network are unknown, as well as the role – or even the presence – of beta2 in other areas involved with novelty detection. In this work, we used behavioral tasks that modulate novelty in combination with multisite local field potential (LFP) recordings targeting regions involved with novelty detection processing in mice – the CA1 region of the hippocampus, parietal cortex and mid-prefrontal cortex – to describe the oscillatory dynamics associated with novelty. We found that transient beta2 power increases were observed only during interaction with novel contexts and objects, but not with familiar contexts and objects. Also, robust theta-gamma phase-amplitude coupling was observed during the exploration of novel environments. Surprisingly, bursts of beta2 power had strong coupling with the phase of delta-range oscillations. Finally, the parietal and mid-frontal cortices had strong coherence with the hippocampus in both theta and beta2. These results highlight the importance of beta2 oscillations in a larger hippocampal-cortical circuit, suggesting that beta2 is a mechanism for detecting and modulating behavioral adaptation to novelty.
Structural Determinants of Cholesterol Recognition in Helical Integral Membrane Proteins
Authors: Marlow B. , Kuenze G. , Li B. , Sanders C. , Meiler J. 
Published: June 2020

ABSTRACTCholesterol (CLR) is an integral component of mammalian membranes. It has been shown to modulate membrane dynamics and alter integral membrane protein (IMP) function. However, understanding the molecular mechanisms of these processes is complicated by limited and conflicting structural data: Specifically, in co-crystal structures of CLR-IMP complexes it is difficult to distinguish specific and biologically relevant CLR-IMP interactions from a nonspecific association captured by the crystallization process. The only widely recognized search algorithm for CLR-IMP interaction sites is sequence-based, i.e. searching for the so-called ‘CRAC’ or ‘CARC’ motifs. While these motifs are present in numerous IMPs, there is inconclusive evidence to support their necessity or sufficiency for CLR binding. Here we leverage the increasing number of experimental CLR-IMP structures to systematically analyze putative interaction sites based on their spatial arrangement and evolutionary conservation. From this analysis we create three-dimensional representations of general CLR interaction sites that form clusters across multiple IMP classes and classify them as being either specific or nonspecific. Information gleaned from our characterization will eventually enable a structure-based approach for prediction and design of CLR-IMP interaction sites.SIGNIFICANCECLR plays an important role in composition and function of membranes and often surrounds and interacts with IMPs. It is a daunting challenge to disentangle CLRs dual roles as a direct modulator of IMP function through binding or indirect actor as a modulator of membrane plasticity. Only recently studies have delved into characterizing specific CLR-IMP interactions. We build on this previous work by using a combination of structural and evolutionary characteristics to distinguish specific from nonspecific CLR interaction sites. Understanding how CLR interacts with IMPs will underpin future development towards detecting and engineering CLR-IMP interaction sites.