bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma
Authors: Starrett Gabriel J. , Thakuria Manisha , Chen Tianqi , Marcelus Christina , Cheng Jingwei , Nomburg Jason , Thorner Aaron R. , Slevin Michael K. , Powers Winslow , Burns Robert T. , Perry Caitlin , Piris Adriano , Kuo Frank C. , Rabinowits Guilherme , Giobbie-Hurder Anita , MacConaill Laura E. , DeCaprio James A. 
Published: March 2019

AbstractMerkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin mediated by the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome. The viral baitset identified integration junctions in the tumor genome and generated assemblies that strongly support a model of a hybrid, virus-host, circular DNA intermediate during integration that promotes focal amplification of host DNA. Using the clear delineation between virus-positive and virus-negative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival. These results demonstrate the value of high-confidence virus detection for identifying clinically important features in MCC that impact patient outcome.
5-HT2Bserotonin receptor agonist BW723C86 shapes the macrophage gene profile via AhR and impairs monocyte-to-osteoclast differentiation
Authors: Nieto Concha , Rayo Ignacio , de las Casas-Engel Mateo , Izquierdo Elena , Alonso Bárbara , Vega Miguel A. , Corbí Ángel L. 
Published: March 2019

ABSTRACTPeripheral serotonin (5-HT) exacerbates or limits inflammatory pathologies through interaction with seven types of 5-HT receptors (5-HT1-7). As central regulators of inflammation, macrophages are critical targets of 5-HT, which promotes their anti-inflammatory and pro-fibrotic polarization primarily via the 5-HT7-Protein Kinase A (PKA) axis. However, anti-inflammatory human macrophages are also characterized by the expression of 5-HT2B, an off-target of anesthetics, anti-parkinsonian drugs and Selective Serotonin Reuptake Inhibitors (SSRI) that contributes to 5-HT-mediated pathologies. Since 5-HT2Bprevents mononuclear phagocyte degeneration in amyotrophic lateral sclerosis and modulates motility of murine microglial processes, we sought to determine the functional and transcriptional consequences of 5-HT2Bactivation in human macrophages. Ligation of 5-HT2Bby the 5-HT2B-specific agonist BW723C86, which exhibits antidepressant- and anxiolytic-like effects in animal models, significantly modified the cytokine profile and the transcriptional signature in macrophages. Importantly, 5-HT2Bagonist-induced transcriptional changes were partly mediated through activation of the Aryl hydrocarbon Receptor (AhR), a ligand-dependent transcription factor that regulates immune responses and the biological responses to xenobiotics. Besides, BW723C86 triggered transcriptional effects that could not be abrogated by 5-HT2Bantagonists and impaired monocyte-to-osteoclast differentiation by affecting the expression of negative (IRF8) and positive (PRDM1) regulators of osteoclastogenesis. Therefore, our results demonstrate the existence of a functional 5-HT2B-AhR axis in human macrophages and indicate that the commonly used 5-HT2Bagonist BW723C86 exhibits 5-HT2B-independent effects. The 5-HT2B-AhR link extends the range of signaling pathways initiated upon 5-HT receptor engagement and identifies a point of convergence for endogenous and exogenous agents with ability to modulate inflammatory responses.KEY POINTS-The serotonin receptor 5-HT2Bmodifies the human macrophage transcriptome through activation of the Aryl Hydrocarbon Receptor.-BW723C86, an agonist used for 5-HT2Bactivationin vivo, exerts 5-HT2B-independent effects and limits monocyte osteoclastogenic potential.
Adult Drosophila Muscle Morphometry through MicroCT reveals dynamics during aging
Authors: Chaturvedi Dhananjay , Prabhakar Sunil , Aggarwal Aman , VijayRaghavan K 
Published: March 2019

AbstractIndirect Flight Muscles (IFMs) in adult Drosophila have served as a valuable model for studying muscle development. In terms of function, they provide the key power stroke in adult insect flight. Variability in their architecture including of fiber numbers, shape and arrangement may provide insightful clues into adult muscle function. Conventional histological preparations in imaging techniques severely limit exact morphometric analysis of flight muscles, thereby impeding causal or correlative studies between muscle morphology and function. In this study we employ MicroCT scanning on a tissue preparation that retains muscle morphology under homeostatic conditions. We use this method to deliver precise measurements of a subset of IFMs, the Direct Longitudinal Muscles’ (DLMs) size and shape, in male and female Drosophila and changes therein, with age. Our findings reveal several unexpected characteristics of muscle fibers. We also demonstrate application to other insect species making it a valuable tool for histological analysis of insect biodiversity.Significance StatementAdult Drosophila muscles serve as models of homeostatic muscles. Accurate analysis of their form and function is key to understanding affects of genetic and physiological states on them. Recording adult muscle shape and volume has so far depended on protocols that inevitably distort tissue. Here, we use a MicroCT scanning based method that delivers changes in shape, size and organization between males and females, with time. This method is a significant step forward in recording muscle structure in situ with applications across species.
Population divergence time estimation using individual lineage label switching
Authors: Beerli Peter , Ashki Haleh , Mashayekhi Somayeh , Palczewski Michal 
Published: March 2019

AbstractDivergence time estimation from multilocus genetic data has become common in population genetics and phylogenetics. We present a new Bayes inference method that treats the divergence time as a random variable. The divergence time is calculated from an assembly of splitting events on individual lineages in a genealogy. The waiting time for such a splitting event is drawn from a hazard function of the truncated normal distribution. This allows easy integration into the standard coalescence framework used in programs such as MIGRATE. We explore the accuracy of the new inference method with simulated population splittings over a wide range of divergence time values and with a dataset of the Zika virus; the geographic analyses of the expansion of the pathogen follows a trajectory from Africa to Asia to America, corroborating analyses based only on the dates of incidences. Evaluations of simple divergence models show high accuracy, whereas the accuracy of the results of isolation with migration (IM) models depend on the magnitude of the immigration rate and potentially on the number of samples. High immigration rates lead to a time of the most recent common ancestor of the sample that predates the divergence time, thus loses any potential signal of the divergence event in the sample data. This reduced accuracy with high immigration rates is problematic for all IM methods, including ours.
Interleukin-1 receptor antagonist treatment in acute ischaemic stroke does not alter systemic markers of anti-microbial defence
Authors: McCulloch Laura , Allan Stuart M. , Smith Craig J. , McColl Barry W. 
Published: March 2019

ABSTRACTAimBlockade of the cytokine interleukin-1 (IL-1) with IL-1 receptor antagonist (IL-1Ra) is a candidate treatment for stroke entering phase II/III trials, which acts by inhibiting harmful inflammatory responses. Infection is a common complication after stroke that significantly worsens outcome and is related to stroke-induced deficits in systemic immune function thought to be mediated by the sympathetic nervous system. Therefore, immunomodulatory treatments for stroke, such as IL-1Ra, carry a risk of aggravating stroke-associated infection. Our primary objective was to determine if factors associated with antibody-mediated antibacterial defences were further compromised in patients treated with IL-1Ra after stroke.MethodsWe assessed plasma concentrations of immunoglobulin isotypes and complement components in stroke patients treated with IL-1Ra or placebo and untreated non-stroke controls using multiplex protein assays. Activation of the SNS was determined by measuring noradrenaline, a major SNS mediator.ResultsThere were significantly lower plasma concentrations of IgM, IgA, IgG1 and IgG4 in stroke-patients compared to non-stroke controls, however there were no differences between stroke patients treated with placebo or IL-1Ra. Concentrations of complement components associated with the classical pathway were increased and those associated with the alternative pathways decreased in stroke patients, neither being affected by treatment with IL-1Ra. Noradrenaline concentrations were increased after stroke in both placebo and IL-1Ra-treated stroke patients compared to non-stroke controls.ConclusionThese data show treatment with IL-1Ra after stroke does not alter circulating immunoglobulin and complement concentrations, and is therefore unlikely to further aggravate stroke-associated infection susceptibility through reduced availability of these key anti-microbial mediators.
Ubiquinone biosynthesis over the entire O2range: characterization of a conserved, O2-independent pathway
Authors: Pelosi Ludovic , Vo Chau-Duy-Tam , Abby Sophie Saphia , Loiseau Laurent , Rascalou Bérengère , Chehade Mahmoud Hajj , Faivre Bruno , Goussé Mathieu , Chenal Clothilde , Touati Nadia , Binet Laurent , Cornu David , Fyfe Cameron David , Fontecave Marc , Barras Frédéric , Lombard Murielle , Pierrel Fabien 
Published: March 2019

SUMMARYMost bacteria can generate ATP by respiratory metabolism, in which electrons are shuttled from reduced substrates to terminal electron acceptors, via quinone molecules likeubiquinone. Dioxygen (O2) is the terminal electron acceptor of aerobic respiration and serves as a co-substrate in the biosynthesis ofubiquinone. Here, we characterize a novel, O2-independent pathway for the biosynthesis ofubiquinone. This pathway relies on three proteins UbiT (YhbT), UbiU (YhbU) and UbiV (YhbV). UbiT contains an SCP2 lipid-binding domain and is likely an accessory factor of the biosynthetic pathway, while UbiU-UbiV are involved in hydroxylation reactions and represent a novel class of O2-independent hydroxylases. We demonstrate that UbiU-UbiV form a heterodimer, wherein each protein binds a 4Fe-4S cluster via conserved cysteines that are essential for activity. The UbiT, -U, -V proteins are found in α-, β-, γ-proteobacterial clades including several human pathogens, supporting the widespread distribution of a previously-unrecognized capacity to synthesizeubiquinone in the absence of O2. Together, the O2-dependent and O2-independentubiquinone biosynthesis pathways contribute to optimize bacterial metabolism over the entire O2range.IMPORTANCEIn order to colonize environments with large O2gradients or fluctuating O2levels, bacteria have developed metabolic responses that remain incompletely understood. Such adaptations have been recently linked to antibiotic resistance, virulence and the capacity to develop in complex ecosystems like the microbiota. Here, we identify a novel pathway for the biosynthesis ofubiquinone, a molecule with a key role in cellular bioenergetics. We link three uncharacterized genes ofEscherichia colito this pathway and show that the pathway functions independently from O2. In contrast, the long-described pathway forubiquinone biosynthesis requires O2as substrate. In fact, we find that many proteobacteria are equipped with the O2-dependent and O2-independent pathways, supporting that they are able to synthesizeubiquinone over the entire O2range. Overall, we propose that the novel O2-independent pathway is part of the metabolic plasticity developed by proteobacteria to face varying environmental O2levels.
The effects of cerebellar transcranial direct current stimulation on the cognitive stage of sequence learning
Authors: Ballard Hannah K. , Goen James R. M. , Maldonado Ted , Bernard Jessica A. 
Published: March 2019

AbstractThough the cerebellum has been previously implicated in explicit sequence learning, the exact role of this structure in the acquisition of motor skills is not completely clear. The cerebellum contributes to both motor and non-motor behavior. Thus, this structure may contribute not only to the motoric aspects of sequence learning, but may also play a role in the cognitive components of these learning paradigms. Therefore, we investigated the consequence of both disrupting and facilitating cerebellar function using high definition transcranial direct current stimulation (HD-tDCS) prior to the completion of an explicit motor sequence learning paradigm. Using a mixed within- and between-subjects design, we employed cathodal (n=21) and anodal (n=23) tDCS (relative to sham), targeting the lateral posterior cerebellum, to temporarily modulate function and investigate the resulting effects on the acquisition of a sequential pattern of finger movements. Results indicate that cathodal stimulation has a positive influence on learning while anodal stimulation has the opposite effect, relative to sham. Though the cerebellum is presumed to be primarily involved in motor function and movement coordination, our results support a cognitive contribution that may come into play during the initial stages of learning. Using tDCS targeting the right posterior cerebellum, which communicates with the prefrontal cortex via closed-loop circuits, we found polarity-specific effects of cathodal and anodal stimulation on sequence learning. Thus, our results substantiate the role of the cerebellum in the cognitive aspect of motor learning and provide important new insights into the polarity-specific effects of tDCS in this area.New & NoteworthyThe cerebellum contributes to motor and cognitive processes. Investigating the cognitive contributions of the cerebellum in explicit sequence learning stands to provide new insights into this learning domain, and cerebellar function more generally. Using HD-tDCS, we demonstrated polarity-specific effects of stimulation on explicit sequence learning. We speculate that this is due to facilitation of working memory processes. This provides new evidence supporting a role for the cerebellum in the cognitive aspects of sequence learning.
Analyzing dynamic decision-making models using Chapman-Kolmogorov equations
Authors: Barendregt Nicholas W. , Josić Krešimir , Kilpatrick Zachary P. 
Published: March 2019

AbstractDecision-making in dynamic environments typically requires adaptive evidence accumulation that weights new evidence more heavily than old observations. Recent experimental studies of dynamic decision tasks require subjects to make decisions for which the correct choice switches stochastically throughout a single trial. In such cases, an ideal observer’s belief is described by an evolution equation that is doubly stochastic, reflecting stochasticity in the both observations and environmental changes. In these contexts, we show that the probability density of the belief can be represented using differential Chapman-Kolmogorov equations, allowing efficient computation of ensemble statistics. This allows us to reliably compare normative models to near-normative approximations using, as model performance metrics, decision response accuracy and Kullback-Leibler divergence of the belief distributions. Such belief distributions could be obtained empirically from subjects by asking them to report their decision confidence. We also study how response accuracy is affected by additional internal noise, showing optimality requires longer integration timescales as more noise is added. Lastly, we demonstrate that our method can be applied to tasks in which evidence arrives in a discrete, pulsatile fashion, rather than continuously.
Mouse vendor influence on the bacterial and viral gut composition exceeds the effect of diet
Authors: Rasmussen Torben Sølbeck , de Vries Liv , Kot Witold , Hansen Lars Hestbjerg , Castro-Mejía Josué L. , Vogensen Finn Kvist , Hansen Axel Kornerup , Nielsen Dennis Sandris 
Published: March 2019

AbstractOften physiological studiess using mice from one vendor show different outcome when being reproduced using mice from another vendor. These divergent phenotypes between similar mouse strains from different vendors have been assigned to differences in the gut microbiome. During recent years, evidence has mounted that the gut viral community plays a key role in shaping the gut microbiome and may thus also influence mouse phenotype. However, to date inter-vendor variation in the murine gut virome has not been studied. Using a metavirome approach, combined with 16S rRNA gene sequencing, we here compare the composition of the viral and bacterial gut community of C57BL/6N mice from three different vendors exposed to either a chow-based low-fat diet or high-fat diet. Interestingly, both the bacterial and the viral component of the gut community differed significantly between vendors. The different diets also strongly influenced both the viral and bacterial gut community, but surprisingly the effect of vendor exceeded the effect of diet. In conclusion, the vendor effect is substantial on not only the gut bacterial community, but also strongly influences viral community composition. Given the effect of GM on mice phenotype this is essential to consider, for increasing reproducibility of mouse studies.
Predicting Drug Protein Interaction using Quasi-Visual Question Answering System
Authors: Zheng Shuangjia , Li Yongjian , Chen Sheng , Xu Jun , Yang Yuedong 
Published: March 2019

AbstractIdentifying novel drug-protein interactions is crucial for drug discovery. For this purpose, many machine learning-based methods have been developed based on drug descriptors and one-dimensional (1D) protein sequences. However, protein sequence can’t accurately reflect the interactions in 3D space. On the other hand, a direct input of 3D structure is of low efficiency due to the sparse 3D matrix, and is also prevented by limited number of co-crystal structures available for training. In this work, we propose an end-to-end deep learning framework to predict the interactions by representing proteins with 2D distance map from monomer structures (Image), and drugs with molecular linear notation (String), following the Visual Question Answering mode. For an efficient training of the system, we introduced a dynamic attentive convolutional neural network to learn fixed-size representations from the variable-length distance maps and a self-attentional sequential model to automatically extract semantic features from the linear notations. Extensive experiments demonstrate that our model obtains competitive performance against state-of-the-art baselines on the DUD-E, Human and BindingDB benchmark datasets. Further attention visualization provides biological interpretation to depict highlighted regions of both protein and drug molecules.
The SSVEP tool as a marker of subjective visibility
Authors: de Heering Adélaïde , Beauny Arnaud , Vuillaume Laurène , Salvesen Leila , Cleeremans Axel 
Published: March 2019

ABSTRACTThis study is part of a larger attempt to explore how the brain produces conscious experience. Our main objective here was to take advantage of a neural signature conveyed by the steady-state visual evoked potentials (SSVEP) technique (1) to explore the extent to which complex visual images can be processed in the absence of consciousness and (2) to determine whether this tool can be used to shed light on participants’ phenomenal experience of these images. To this end, we embedded faces within sequences of non-face stimuli and manipulated their contrast to create a subliminal condition. Our results were threefold. First, we show that a significant brain activation can be delineated with the SSVEP tool even when participants report being unable to see the stimuli. In this subliminal condition, the brain response was confined to the back of the scalp. Second, we observe that the face signal increases in magnitude and propagates bilaterally along a posterior-to-anterior axis as image contrast increases. Third, we suggest that SSVEP could be used as a novel instance of a no-report paradigm because it requires no overt behavioural response, and because at some contrast levels and electrodes, its outputs (signal magnitude and scalp topography) predict people’s self-reported phenomenal experience.
Characterization of pathology-inducing α-synuclein species from human diseased brain tissue
Authors: Graef John D. , Hoque Nina , Polson Craig , Yang Ling , Iben Lawrence , Cao Yang , Devidze Nino , Ahlijanian Michael K. , Meredith Jere E. 
Published: March 2019

AbstractSynucleinopathies are a group of neurodegenerative diseases characterized by the presence of pathological accumulations of misfolded, phosphorylated α-synuclein (αSyn) protein. Multiple lines of evidence indicate that synucleinopathy disease progression is driven by a prion-like process of transmission of a pathologic form of αSyn. One potential therapeutic approach to prevent cell-to-cell propagation is to target this transmissible species with selective antibodies. In this study, a rodent primary neuronal culture reporter system was developed to monitor induction of detergent-insoluble, phosphorylated (pS129) aggregates of αSyn. Induction of pS129 αSyn pathology was observed with both synthetic αSyn fibrils (PFFs) and brain lysates from multiple system atrophy (MSA) patients but not αSyn monomers or human brain lysate controls. The induction-competent species in MSA lysates could be enriched by high-speed centrifugation suggesting that it is present as a high molecular weight aggregate. Furthermore, samples derived from brain lysates from Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) patients also induced pS129 αSyn pathology, but required longer incubation times. Lastly, the potential of αSyn selective antibodies to immunodeplete induction-competent forms of αSyn from both PFF and synucleinopathy brain samples is described. The results demonstrate that antibodies targeting the C-terminal of αSyn are most effective for immunodepletion of pathology-inducing forms of αSyn from samples derived from human synucleinopathy brains. Furthermore, the data support the hypothesis that antibodies that recognize a C-terminal epitope and exhibit selectivity for oligomeric forms over monomeric forms of αSyn represent a desirable target for immunotherapy for synucleinopathy patients.