bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and characterization of novel proteins from Arizona bark scorpion venom that inhibit Nav1.8, a voltage-gated sodium channel regulator of pain signaling
Authors: Abd El-Aziz Tarek Mohamed , Xiao Yucheng , Kline Jake , Gridley Harold , Heaston Alyse , Linse Klaus D. , Ward Micaiah J. , Rokyta Darin R. , Stockand James D. , Cummins Theodore R. , Fornelli Luca , Rowe Ashlee H. 
Published: June 2021

AbstractThe voltage-gated sodium channel Nav1.8 is linked to neuropathic and inflammatory pain, highlighting the potential to serve as a drug target. However, the biophysical mechanisms that regulate Nav1.8 activation and inactivation gating are not completely understood. Progress has been hindered by a lack of biochemical tools for examining Nav1.8 gating mechanisms. Arizona bark scorpion (Centruroides sculpturatus) venom proteins inhibit Nav1.8 and block pain in grasshopper mice (Onychomys torridus). These proteins provide tools for examining Nav1.8 structure-activity relationships. To identify proteins that inhibit Nav1.8 activity, venom samples were fractioned using liquid chromatography (reversed phase and ion exchange). A recombinant Nav1.8 clone expressed in ND7/23 cells was used to identify subfractions that inhibited Nav1.8 Na+ current. Mass spectrometry-based bottom-up proteomic analyses identified unique peptides from inhibitory subfractions. A search of the peptides against the AZ bark scorpion venom gland transcriptome revealed four novel proteins between 40 and 60% conserved with venom proteins from scorpions in four genera (Centruroides, Parabuthus, Androctonus, and Tityus). Ranging from 63 to 82 amino acids, each primary structure includes 8 cysteines and a “CXCE” motif where X = an aromatic residue (tryptophan, tyrosine or phenylalanine). Electrophysiology data demonstrated that the inhibitory effects of bioactive subfractions can be removed by hyperpolarizing the channels, suggesting that proteins may function as gating modifiers as opposed to pore blockers.
WMW-A: Rank-based two-sample independent test for smallsample sizes through an auxiliary sample
Authors: Guo Yin , Li Limin 
Published: June 2021

AbstractTwo-sample independent test methods are widely used in case-control studies to identify significant changes or differences, for example, to identify key pathogenic genes by comparing the gene expression levels in normal and disease cells. However, due to the high cost of data collection or labelling, many studies face the small sample problem, for which the traditional two-sample test methods often lose power. We propose a novel rank-based nonparametric test method WMW-A for small sample problem by introducing a three-sample statistic through another auxiliary sample. By combining the case, control and auxiliary samples together, we construct a three-sample WMW-A statistic based on the gap between the average ranks of the case and control samples in the combined samples. By assuming that the auxiliary sample follows a mixed distribution of the case and control populations, we analyze the theoretical properties of the WMW-A statistic and approximate the theoretical power. The extensive simulation experiments and real applications on microarray gene expression data sets show the WMW-A test could significantly improve the test power for two-sample problem with small sample sizes, by either available unlabelled auxiliary data or generated auxiliary data.
Photoinactivation of Catalase Sensitizes Wide-Ranging Bacteria to ROS-Producing Agents and Immune Cells
Authors: Dong Pu-Ting , Jusuf Sebastian , Hui Jie , Zhan Yuewei , Zhu Yifan , Liu George Y. , Cheng Ji-Xin 
Published: June 2021

AbstractBacteria have evolved to cope with the detrimental effects of reactive oxygen species (ROS) using their essential molecular components. Catalase, a heme-containing tetramer protein expressed universally in most of the aerobic bacteria, plays an indispensable role in scavenging excess hydrogen peroxide (H2O2). Here, through utilization of wild-type and catalase-deficient mutants, we identified catalase as an endogenous therapeutic target of 400-420 nm blue light. Catalase residing in bacteria could be effectively inactivated by blue light, subsequently rendering the pathogens extremely vulnerable to H2O2and H2O2-producing agents. As a result, photoinactivation of catalase and H2O2synergistically eliminate a wide range of catalase-positive planktonic bacteria andP. aeruginosainside biofilms. In addition, photoinactivation of catalase is shown to facilitate macrophages to defend against intracellular pathogens. The antimicrobial efficacy of catalase photoinactivation is further validated using aPseudomonas aeruginosa-induced mice abrasion model. Taken together, our findings offer a catalase-targeting phototherapy against multidrug-resistant bacterial infections.
Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state
Authors: Daniel Bence , Belk Julia A. , Meier Stefanie L. , Chen Andy Y. , Sandor Katalin , Qi Yanyan , Kitano Hugo , Wheeler Joshua R. , Foster Deshka S. , Januszyk Michael , Longaker Michael T. , Chang Howard Y. , Satpathy Ansuman T. 
Published: June 2021

SummaryCell cycle (CC) is a fundamental biological process with robust, cyclical gene expression programs to facilitate cell division. In the immune system, a productive immune response requires the expansion of pathogen-responsive cell types, but whether CC also confers unique gene expression programs that inform the subsequent immunological response remains unclear. Here we demonstrate that single macrophages adopt different plasticity states in CC, which is a major source of heterogeneity in response to polarizing cytokines. Specifically, macrophage plasticity to interferon gamma (IFNG) is substantially reduced, while interleukin 4 (IL-4) can induce S-G2/M-biased gene expression. Additionally, IL-4 polarization shifts the CC-phase distribution of the population towards G2/M phase, providing a mechanism for reduced IFNG-induced repolarization. Finally, we show that macrophages express tissue remodeling genes in the S-G2/M-phases of CC, that can be also detectedin vivoduring muscle regeneration. Therefore, macrophage inflammatory and regenerative responses are gated by CC in a cyclical phase-dependent manner.HighlightsSingle-cell chromatin maps reveal heterogeneous macrophage polarization statesCell cycle coincides with heterogeneity and alters macrophage plasticity to polarizing cytokinesMacrophage polarization is a cell cycle phase-dependent immunological processS-G2/M-biased gene expression is linked to tissue remodeling and detected in proliferating macrophages during muscle regeneration
Pre-existing anxiety, depression, and neurological disability is associated with long COVID: A prospective and longitudinal cohort of the United Kingdom Multiple Sclerosis Register
Authors: Garjani Afagh , Middleton Rodden M , Nicholas Richard , Evangelou Nikos 
Published: June 2021

ABSTRACTObjectivesTo assess the prevalence of long COVID among people with multiple sclerosis (MS) and its predictors, including their pre-COVID-19 functional status.DesignCommunity-based prospective and longitudinal cohort studySettingThe United Kingdom (UK) MS Register (UKMSR) COVID-19 studyParticipantsA national cohort of people with MS and COVID-19Main outcome measuresParticipants used the online questionnaire-based platform of the UKMSR to update their COVID-19 symptoms, recovery status, and duration of symptoms for those who had fully recovered. Questionnaires were date-stamped for estimation of COVID-19 symptom duration for those who had not recovered at their last follow-up. The UKMSR holds demographic and up-to-date clinical data on participants as well as their web-based Expanded Disability Status Scale (a measure of physical disability in MS) and Hospital Anxiety and Depression Scale scores. The association between these factors and recovery from COVID-19 was assessed using multivariable Cox regression analysis.ResultsOut of 7,977 people with MS who participated in the UKMSR COVID-19 study, 599 had COVID-19 and updated their recovery status prospectively. At least 181 participants (31.1%) had long-standing COVID-19 symptoms for ≥4 weeks and 76 (13.1 %) for ≥12 weeks. Participants with higher levels of pre-COVID-19 physical disability, participants with anxiety and/or depression prior to COVID-19 onset, and women were less likely to report recovery from COVID-19.ConclusionsLong COVID appears to disproportionately affect people with pre-existing mental health problems or physical disabilities. As post-COVID-19 rehabilitation services are being developed, individualised pathways should be considered to accommodate the needs of these vulnerable populations.Trial RegistrationClinicalTrials.gov: NCT04354519
mOTUpan: a robust Bayesian approach to leverage metagenome assembled genomes for core-genome estimation
Authors: Buck Moritz , Mehrshad Maliheh , Bertilsson Stefan 
Published: June 2021

AbstractRecent advances in sequencing and bioinformatics have expanded the tree of life by providing genomes for uncultured environmentally relevant clades, either through metagenome assembled genomes (MAGs) or single-cell assembled genomes (SAGs). While this expanded diversity can provide novel insights about microbial population structure, most tools available for core-genome estimation are overly sensitive to genome completeness. Consequently a major portion of the huge phylogenetic diversity uncovered by environmental genomics approaches remain excluded from such analyses. We present mOTUpan, a novel iterative Bayesian method for computing the core-genome for sets of genomes of highly diverse completeness range. The likelihood for each gene-cluster to belong to core- or accessory-genome is estimated by computing the probability of its presence/absence pattern in the target set of genomes. The core-genome prediction is computationally efficient and can be scaled up to thousands of genomes. It has shown comparable estimates as state-of-the-art tools Roary and PPanGGoLiN for high-quality genomes and outperforms them at lower completeness thresholds. mOTUpan wraps a bootstrapping procedure to estimate the quality of a specific core-genome prediction, as the accuracy of each run will depend on the specific completeness distribution and the number of genomes in the dataset under scrutiny. mOTUpan is implemented in the mOTUlizer software package, and available at github.com/moritzbuck/mOTUlizer, under GPL 3.0 license.
Coupling of pupil- and neuronal population dynamics reveals diverse influences of arousal on cortical processing
Authors: Pfeffer Thomas , Keitel Christian , Kluger Daniel S. , Keitel Anne , Russmann Alena , Thut Gregor , Donner Tobias H. , Gross Joachim 
Published: June 2021

AbstractFluctuations in arousal, controlled by subcortical neuromodulatory systems, continuously shape cortical state, with profound consequences for information processing. Yet, how arousal signals influence cortical population activity in detail has so far only been characterized for a few selected brain regions. Traditional accounts conceptualize arousal as a homogeneous modulator of neural population activity across the cerebral cortex. Recent insights, however, point to a higher specificity of arousal effects on different components of neural activity and across cortical regions. Here, we provide a comprehensive account of the relationships between fluctuations in arousal and neuronal population activity across the human brain. Exploiting the established link between pupil size and central arousal systems, we performed concurrent magnetoencephalographic (MEG) and pupillographic recordings in a large number of participants, pooled across three laboratories. We found a cascade of effects relative to the peak timing of spontaneous pupil dilations: Decreases in low-frequency (2-8 Hz) activity in temporal and lateral frontal cortex, followed by increased high-frequency (>64 Hz) activity in mid-frontal regions, followed by monotonic and inverted-U relationships with intermediate frequency-range activity (8-32 Hz) in occipito-parietal regions. Pupil-linked arousal also coincided with widespread changes in the structure of the aperiodic component of cortical population activity, indicative of changes in the excitation-inhibition balance in underlying microcircuits. Our results provide a novel basis for studying the arousal modulation of cognitive computations in cortical circuits.
Flexible encoding of objects and space in single cells of the dentate gyrus
Authors: GoodSmith Douglas , Kim Sang Hoon , Puliyadi Vyash , Ming Guo-li , Song Hongjun , Knierim James J. , Christian Kimberly M. 
Published: June 2021

SummaryThe hippocampus is involved in the formation of memories that require associations among stimuli to construct representations of space and the items and events within that space. Neurons in the dentate gyrus (DG), an initial input region of the hippocampus, have robust spatial tuning, but it is unclear how nonspatial information may be integrated with spatially modulated firing at this stage. We recorded from the DG of 21 adult mice as they foraged for food in an environment that contained discrete objects. By classifying recorded DG cells into putative granule cells and mossy cells, we examined how the addition or displacement of objects affected the spatial firing of these DG cell types. We found DG cells with multiple firing fields at a fixed distance and direction from objects (landmark vector cells) as well as cells that exhibited localized changes in spatial firing when objects in the environment were manipulated. When mice were exposed to a second environment with the same objects, DG spatial maps were completely reorganized, suggesting standard global remapping, and a largely different subset of cells responded to object manipulations. Together, these data reveal the capacity of DG cells to detect small changes in the environment, while preserving a stable spatial representation of the overall context.
The NLRP3/eIF2 axis drives cell cycle progression in acute myeloid leukemia
Authors: Luciano Michela , Blöchl Constantin , Vetter Julia , Urwanisch Laura , Neuper Theresa , Elmer Dominik P. , Bauer Renate , Dang Hieu-Hoa , Strandt Helen , Neureiter Daniel , Krenn Peter , Tesanovic Suzana , Rieser Sebastian , Bergsleitner Olivia , Zell Lukas , Binder Stephanie , Schaller Susanne , Strunk Dirk , Pleyer Lisa , Greil Richard , Winkler Stephan , Hartmann Tanja N. , Huber Christian G. , Aberger Fritz , Horejs-Hoeck Jutta 
Published: June 2021

AbstractAberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediates numerous inflammatory diseases. Oncogenes can activate the NLRP3 inflammasome and thereby promote myeloproliferative neoplasia, suggesting a crucial role of NLRP3 in the malignant transformation of hematopoietic cells. Here, we show that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, IL-1β and IL-18 and that high-level expression of NLRP3 is linked to poor survival of AML patients. Pharmacological and genetic inhibition of NLRP3 inflammasome activation attenuated cell proliferation of MOLM-13 AML cells in vitro. In vivo, genetic inhibition of NLRP3 in MOLM-13 AML cells resulted in reduced engraftment potential in xenografts, along with reduced splenomegaly and organ infiltration. Differential proteomic analysis revealed the eIF2 pathway as potential target of NLRP3 in AML, with a significant increase of eIF2α phosphorylation upon NLRP3 inhibition. NLRP3 inhibition also caused a strong decrease in cyclin – dependent kinases CDK4 and CDK6, accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A) and a marked arrest of cell cycle progression in the G0/G1 phase, consistent with the role of eIF2α phosphorylation as negative cell cycle regulator.Taken together, we show that inhibition of the NLRP3 inflammasome reduces AML cell proliferation by promoting eIF2α phosphorylation, which in turn enhances the expression of cell cycle arrest genes such as p21. Thus, the study uncovers the NLRP3/eIF2 axis as new driver of AML proliferation and proposes a novel therapeutic treatment of AML by targeted inhibition of NLRP3 activation.
The contribution of the European LIFE program to mitigate damages caused by large carnivores in Europe
Authors: Oliveira Teresa , Treves Adrian , López-Bao José Vicente , Krofel Miha 
Published: June 2021

AbstractGovernments around the world invest considerable resources to reduce damages caused by large carnivores on human property. To use these investments more efficiently and effectively, we need to understand which interventions successfully prevent such damages and which do not. In the European Union, the LIFE program represents by far the largest financial instrument to help EU Member States with the implementation of conservation activities, including mitigation of damages caused by large carnivores. However, we currently lack information about the effectiveness of this funding program in reducing carnivore damages. We reviewed 135 LIFE projects dealing with large carnivores between 1992 and 2019 to provide an overview of the use of damage prevention methods and evaluate their functional and perceived effectiveness. Methods evaluated ranged from non-lethal and lethal interventions, to information dissemination and compensation schemes. The largest number of the projects was focused on grey wolf (Canis lupus) and brown bears (Ursus arctos) in the Mediterranean countries and in Romania. Electric fences were reported as the most successful method for reducing damages by large carnivores, and most of the non-lethal methods used showed at least moderate effectiveness. However, standards of measuring and reporting effectiveness were in general relatively low, which limits our ability to measure actual impact. Therefore we urge project managers and evaluators to improve these standards, as well as the dissemination of the project results. We provide a list of recommendations for improving measuring and reporting success of implemented interventions for the benefit of future projects aimed to reduce damages caused by wildlife.Article impact statementElectric fences were reported as the most effective method to prevent large-carnivore damages and are recommended for future use.
Disrupted social memory ensembles in the ventral hippocampus underlie social amnesia in autism-associated Shank3 mutant mice
Authors: Tao Kentaro , Chung Myung , Watarai Akiyuki , Huang Ziyan , Wang Mu-Yun , Okuyama Teruhiro 
Published: June 2021

ABSTRACTThe ability to remember conspecifics is critical for adaptive cognitive functioning and social communication, and impairments of this ability are hallmarks of autism spectrum disorders (ASDs). Although hippocampal ventral CA1 (vCA1) neurons are known to store social memories, how their activities are coordinated remains unclear. Here we show that vCA1 social memory neurons, characterized by enhanced activity in response to memorized individuals, were preferentially reactivated during sharp-wave ripples (SPW-Rs). Spike sequences of these social replays reflected the temporal orders of neuronal activities within theta cycles during social experiences. In ASD model Shank3 knockout mice, the proportion of social memory neurons was reduced, and neuronal ensemble spike sequences during SPW-Rs were disrupted, which correlated with impaired discriminatory social behavior. These results suggest that SPW-R-mediated sequential reactivation of neuronal ensembles is a canonical mechanism for coordinating hippocampus-dependent social memories and its disruption underlies the pathophysiology of social memory defects associated with ASD.
Chemical mapping exposes the importance of active site interactions in governing the temperature dependence of enzyme turnover
Authors: Winter SD , Jones HBL , Răsădean DM , Crean RM , Danson MJ , Pantoş GD , Katona G , Prentice E , Arcus VL , van der Kamp MW , Pudney CR. 
Published: June 2021

ABSTRACTUncovering the role of global protein dynamics in enzyme turnover is needed to fully understand enzyme catalysis. Recently, we have demonstrated that the heat capacity of catalysis, ΔCP‡, can reveal links between the protein free energy landscape, global protein dynamics and enzyme turnover, suggesting that subtle changes molecular interactions at the active site can affect long range protein dynamics and link to enzyme temperature activity. Here we use a model promiscuous enzyme (Glucose dehydrogenase from Sulfolobus Solfataricus) to chemically map how individual substrate interactions affect the temperature dependence of enzyme activity and the network of motions throughout the protein. Utilizing a combination of kinetics, REES spectroscopy and computational simulation we explore the complex relationship between enzyme-substrate interactions and the global dynamics of the protein. We find that changes in ΔCP‡ and protein dynamics can be mapped to specific substrate-enzyme interactions. Our study reveals how subtle changes in substrate binding affect global changes in motion and flexibility extending throughout the protein.
Efficient prestimulus network integration of FFA biases face perception during binocular rivalry
Authors: Rassi Elie , Wutz Andreas , Peatfield Nicholas , Wiesz Nathan 
Published: June 2021

AbstractOngoing fluctuations in neural excitability and connectivity influence whether or not a stimulus is seen. Do they also influence which stimulus is seen? We recorded magnetoencepahlography data while participants viewed face or house stimuli, either one at a time or under bi-stable conditions induced through binocular rivalry. Multivariate pattern analysis revealed common neural substrates for rivalrous vs. non-rivalrous stimuli with an additional delay of ~36ms for the bi-stable stimulus and poststimulus signals were source-localized to the fusiform face area (FFA). Prior to stimulus onset followed by a face-vs. house-report, FFA showed stronger connectivity to primary visual cortex and to the rest of the cortex in the alpha frequency range (8-13 Hz) but there were no differences in local oscillatory alpha power. The pre-stimulus connectivity metrics predicted the accuracy of post-stimulus decoding and the delay associated with rivalry disambiguation suggesting that perceptual content is shaped by ongoing neural network states.