bluuebunny/crossref_metadata_2025_split huggingface dataset:
Classical macrophage polarisation is limited by human β-defensin-3 via an autocrine IL-4 dependent process
Authors: Candela Maria E. , Allsop David J.P. , Carter Roderick N. , Semple Fiona , Kilanowski Fiona , Webb Sheila , Taggart David , Mullan Henry J.W , McHugh Brian J. , Dockrell David H. , Davidson Donald J. , Allen Judith E. , Jenkins Stephen J. , Morton Nicholas M. , Dorin Julia R. 
Published: May 2021

AbstractHuman β-defensin 3 (HBD3), is an anti-microbial host-defence peptide, that can rapidly enter macrophages to modulate TLR4 responses to lipopolysaccharide. However, the molecular mechanisms by which HBD3 exerts this anti-inflammatory influence remain unclear. Here, we show mice deleted for the orthologue of HBD3 have an increased acute lipopolysaccharide responsein vivo. Furthermore, we found that HBD3 limited the response of macrophages to classical activation, and contemporaneously drove expression of IL-4. An increase in markers of alternative activation, and a change in metabolic flux was also observed. Consistent with these results, HBD3 enhanced the IL-4 mediated polarisation of naïve macrophages. Finally, we demonstrate that the ability of HBD3 to limit macrophage classical activation requires IL-4Rα. These data reveal a previously unrecognised role for HBD3 in influencing the polarisation state of macrophages to enable a state conducive for repair and resolution.SYNOPSISThe anti-microbial host-defence peptide, Human β-defensin 3 (HBD3), is shown here to modulate the inflammatory response to classical activation by promoting alternative activation through IL-4Rα, to enable a state conducive for repair and resolution.Knockout mice for the orthologous gene for HBD3, demonstrate increased acute lipopolysaccharide inflammatory response.HBD3 limited the classical activation of macrophages polarised with LPS/IFNγ and drove expression of IL-4. Cells also displayed increase in alternative activation markers and promotion of oxidative phosphorylation.HBD3 enhanced the IL-4-mediated activation of naïve macrophages.The ability of HBD3 to limit macrophage classical activation and contemporaneously promote alternative activation required IL-4Rα.
Cortical granularity shapes the organization of afferent paths to the amygdala and its striatal targets in nonhuman primate
Authors: McHale AC , Cho YT , Fudge JL 
Published: May 2021

AbstractThe prefrontal cortex (PFC) and insula, amygdala, and striatum form interconnected networks that drive motivated behaviors. We previously found a connectional trend in which granularity of the ventromedial and orbital PFC/insula predicted connections to the amygdala, and also the breadth of amygdalo-striatal efferents, including projections beyond the ’classic’ ventral striatum. To further interrogate connectional relationships among the cortex, amygdala, and striatum, and to further define the ’limbic (amygdala-recipient) striatum’, we conducted tract tracing studies in two cohorts ofMacaques(Male n = 14, Female n = 1). We focused on the cortico-amygdalo-striatal (indirect) and cortico-‘limbic’ striatal (direct) paths originating in the entire PFC and insula. Larger data sets and a quantitative approach revealed ’cortical rules’ in which cortical granularity predicts the complexity and location of projections toboththe basal nucleus of the amygdala and striatum. Remarkably, projections from ’cortical-like’ basal nucleus to the striatum followed similar patterns. In both ’direct’ and ’indirect’ paths to the ’limbic’ striatum, agranular cortices formed a ’foundational’, broad projection, and were joined by inputs from progressively more differentiated cortices. In amygdalo-striatal paths, the ventral basal nucleus was the ‘foundational’ input, with progressively more dorsal basal nucleus regions gradually adding inputs as the ’limbic striatum’ extended caudally. Together, the ‘indirect’ and ‘direct’ paths followed consistent principles in which cortical granularity dictated the strength and complexity of projections at their targets. Cluster analyses independently confirmed these connectional trends, and also highlighted connectional features that predicted termination in specific subregions of the basal nucleus and ’limbic’ striatum.Significance StatementThe ’limbic system’ broadly refers to brain circuits that coordinate emotional responses. Here, we investigate circuits of the amygdala, which are involved in coding the emotional value of external cues, and their influence on the striatum. Regions of prefrontal cortex and insula form gradients of overlapping inputs to the amygdala’s basal nucleus, which feed forward to the striatum. Direct cortical inputs to these ’amygdala-recipient’ striatal areas are surprisingly organized according to similar principles, but subtly shift from the classic ventral striatum to the caudal ventral striatum. Together, these distinct subsystems—cortico-amygdala-striatal circuits and direct cortico-striatal circuits— provide substantial opportunity for different levels of internal, sensory, and external experiences to be integrated within the striatum, a major motor-behavioral interface.
Capturing the nature of events and event context using Hierarchical Event Descriptors (HED)
Authors: Robbins Kay , Truong Dung , Appelhoff Stefan , Delorme Arnaud , Makeig Scott 
Published: May 2021

AbstractEvent-related data analysis plays a central role in EEG and MEG (MEEG) and other neuroimaging modalities such as fMRI. Choices about which events to report and how to annotate their full natures significantly influence the value, reliability, and reproducibility of neuroimaging datasets for further analysis and meta- ormega-analysis. A powerful annotation strategy using the new third-generation formulation of the Hierarchical Event Descriptors (HED) framework and tools (hedtags.org) combines robust event description with details of experiment design and metadata in a human-readable as well as machine-actionable form, making event annotation relevant to the full range of neuroimaging and other time series data. This paper considers the event design and annotation process using as a case study the well-known multi-subject, multimodal dataset of Wakeman and Henson made available by its authors as a Brain Imaging Data Structure (BIDS) dataset (bids.neuroimaging.io). We propose a set of best practices and guidelines for event annotation integrated in a natural way into the BIDS metadata file architecture, examine the impact of event design decisions, and provide a working example of organizing events in MEEG and other neuroimaging data. We demonstrate how annotations using HED can document events occurring during neuroimaging experiments as well as their interrelationships, providing machine-actionable annotation enabling automated within- and across-experiment analysis and comparisons. We discuss the evolution of HED software tools and have made an accompanying HED-annotated BIDS-formatted edition of the MEEG data of the Wakeman and Henson dataset (openneuro.org, ds003645).
An intramolecular scrambling path controlled by a gatekeeper in Xkr8 phospholipid scramblase
Authors: Sakuragi Takaharu , Kanai Ryuta , Tsutsumi Akihisa , Narita Hirotaka , Onishi Eriko , Miyazaki Takuya , Baba Takeshi , Nakagawa Atsushi , Kikkawa Masahide , Toyoshima Chikashi , Nagata Shigekazu 
Published: May 2021

AbstractXkr8-Basigin is a phospholipid scramblase at plasma membranes that is activated by kinase or caspase. We investigated its structure at a resolution of 3.8Å. Its membrane-spanning region had a cuboid-like structure stabilized by salt bridges between hydrophilic residues in helices in the lipid layer. The molecule carried phosphatidylcholine in a cleft on the surface that may function as an entry site for phospholipids. Five charged residues placed from top to bottom inside the molecule were essential for providing a path for scrambling phospholipids. A tryptophan residue was present at the extracellular end of the pathway and its mutation made the Xkr8-Basigin complex constitutively active, indicating its function as a gatekeeper. The structure of Xkr8-Basigin provides novel insights into the molecular mechanisms underlying phospholipid scrambling.
Ser/Thr phospho-regulation by PknB and Stp mediates bacterial quiescence and antibiotic persistence inStaphylococcus aureus
Authors: Huemer Markus , Shambat Srikanth Mairpady , Pereira Sandro , Van Gestel Lies , Bergada-Pijuan Judith , Gómez-Mejia Alejandro , Chang Chun-Chi , Vulin Clement , Bär Julian , Dworkin Jonathan , Zinkernagel Annelies S. 
Published: May 2021

AbstractStaphylococcus aureuscolonizes 30 to 50% of healthy adults and can cause a variety of diseases, ranging from superficial to life-threatening invasive infections such as bacteraemia and endocarditis. Often, these infections are chronic and difficult-to-treat despite adequate antibiotic therapy. Most antibiotics act on metabolically active bacteria in order to eradicate them. Thus, bacteria with minimized energy consumption resulting in metabolic quiescence, have increased tolerance to antibiotics. The most energy intensive process in cells – protein synthesis – is attenuated in bacteria entering into quiescence. Eukaryote-like serine/threonine kinases (STKs) and phosphatases (STPs) can fine-tune essential cellular processes, thereby enabling bacteria to quickly respond to environmental changes and to modulate quiescence. Here, we show that deletion of the only annotated functional STP, named Stp, inS. aureusleads to increased bacterial lag-phase and phenotypic heterogeneity under different stress challenges, including acidic pH, intracellular milieu andin vivoabscess environment. This growth delay was associated with reduced intracellular ATP levels and increased antibiotic persistence. Using phosphopeptide enrichment and mass spectrometry-based proteomics, we identified possible targets of Ser/Thr phosphorylation that regulate cellular processes and bacterial growth, such as ribosomal proteins including the essential translation elongation factor EF-G. Finally, we show that acid stress leads to a reduced translational activity in thestpdeletion mutant indicating metabolic quiescence correlating with increased antibiotic persistence.One-sentence summaryPhospho-regulation mediates quiescence and antibiotic persistence inStaphylococcus aureus.
Heat Shock Factor 1 (HSF1) as a new tethering factor for ESR1 supporting its action in breast cancer
Authors: Vydra Natalia , Janus Patryk , Kuś Paweł , Stokowy Tomasz , Mrowiec Katarzyna , Toma-Jonik Agnieszka , Krzywon Aleksandra , Cortez Alexander Jorge , Wojtaś Bartosz , Gielniewski Bartłomiej , Jaksik Roman , Kimmel Marek , Widłak Wiesława 
Published: May 2021

AbstractHeat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was recently linked to estrogen (E2) signaling through ESR1. We found that an HSF1 deficiency could lead to the inhibition of the mitogenic action of E2 in breast cancer cells. The stimulatory effect of E2 on the transcriptome is weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ESR1 to chromatin. HSF1 and ESR1 can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ESR1 through a mechanism involving chromatin reorganization. Analyses of data from the TCGA database indicate that HSF1 increases the transcriptome diversity in ER-positive breast cancer and can enhance the genomic action of ESR1. Moreover,ESR1andHSF1are only prognostic when analyzed together (the worst prognosis for ER−/HSF1highcancers).
A phylogeny-based metric for estimating changes in transmissibility from recurrent mutations in SARS-CoV-2
Authors: Richard Damien , Shaw Liam P , Lanfear Rob , Corbett-Detig Russell , Hinrichs Angie , McBroome Jakob , Turakhia Yatish , Acman Mislav , Owen Christopher J , Tan Cedric CS , van Dorp Lucy , Balloux François 
Published: May 2021

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally to cause the COVID-19 pandemic. Despite the constant accumulation of genetic variation in the SARS-CoV-2 population, there was little evidence for the emergence of significantly more transmissible lineages in the first half of 2020. Starting around November 2020, several more contagious and possibly more virulent ‘Variants of Concern’ (VoCs) were reported in various regions of the world. These VoCs share some mutations and deletions that haven arisen recurrently in distinct genetic backgrounds. Here, we build on our previous work modelling the association of mutations to SARS-CoV-2 transmissibility and characterise the contribution of individual recurrent mutations and deletions to estimated viral transmissibility. We then assess how patterns of estimated transmissibility in all SARS-CoV-2 clades have varied over the course of the COVID-19 pandemic by summing transmissibility estimates for all individual mutations carried by any sequenced genome analysed. Such an approach recovers the Delta variant (21A) as the most transmissible clade currently in circulation, followed by the Alpha variant (20I). By assessing transmissibility over the time of sampling, we observe a tendency for estimated transmissibility within clades to slightly decrease over time in most clades. Although subtle, this pattern is consistent with the expectation of a decay in transmissibility in mainly non-recombining lineages caused by the accumulation of weakly deleterious mutations. SARS-CoV-2 remains a highly transmissible pathogen, though such a trend could conceivably play a role in the turnover of different global viral clades observed over the pandemic so far.CaveatsThis work is not about the severity of disease. We do not analyse the severity of disease. We do not present any evidence that SARS-CoV-2 has decreased in severity.Lineage replacement dynamics are affected by many factors. The trend we recover for a decrease in inferred transmissibility of a clade over time is a small effect. We caution against over-interpretation. This result would not affect the management of the SARS-CoV-2 pandemic: for example, we make no claims about any impact on the efficacy of particular non-pharmaceutical interventions (NPIs).Our phylogeny-based method to infer changes in estimated transmissibility due to recurrent mutations and deletions makes a number of simplifying assumptions. These may not all be valid. The consistent trend for the slight decrease we report might be due to an as-yet-unidentified systematic bias.
Discovery of the fastest myosin, its amino acid sequence, and structural features
Authors: Haraguchi Takeshi , Tamanaha Masanori , Suzuki Kano , Yoshimura Kohei , Imi Takuma , Tominaga Motoki , Sakayama Hidetoshi , Nishiyama Tomoaki , Murata Takeshi , Ito Kohji 
Published: May 2021

AbstractCytoplasmic streaming with extremely high velocity (~70 μm s−1) occurs in cells of the characean algae (Chara). Because cytoplasmic streaming is caused by organelle-associated myosin XI sliding along actin filaments, it has been suggested that a myosin XI, which has a velocity of 70 μm s−1, the fastest myosin measured so far, exists inCharacells. However, the previously clonedChara corallinamyosin XI (CcXI) moved actin filaments at a velocity of around 20 μm s−1, suggesting that an unknown myosin XI with a velocity of 70 μm s−1may be present inChara. Recently, the genome sequence ofChara brauniihas been published, revealing that this alga has four myosin XI genes. In the work reported in this paper, we cloned these four myosin XIs (CbXI-1, 2, 3, and 4) and measured their velocities. While the velocities ofCbXI-3 andCbXI-4 were similar to that ofCcXI, the velocities ofCbXI-1 andCbXI-2 were estimated to be 73 and 66 μm s−1, respectively, suggesting thatCbXI-1 andCbXI-2 are the main contributors to cytoplasmic streaming inCharacells and showing thatCbXI-1 is the fastest myosin yet found. We also report the first atomic structure (2.8 Å resolution) of myosin XI using X-ray crystallography. Based on this crystal structure and the recently published cryo-EM structure of acto-myosin XI at low resolution (4.3 Å), it appears that the actin-binding region contributes to the fast movement ofCharamyosin XI. Mutation experiments of actin-binding surface loop 2 support this hypothesis.Significance statementIt has been suggested for more than 50 years that the fastest myosin in the biological world, with a velocity of 70 μm s−1, exists in the algaCharabecause cytoplasmic streaming with a velocity of 70 μm s−1occurs inCharacells. However, a myosin with that velocity has not yet been identified. In this work, we succeeded in cloning a myosin XI with a velocity of 73 μm s−1, the fastest myosin so far measured. We also successfully crystallized myosin XI for the first time. Structural analyses and mutation experiments suggest that the central regions that define the fast movement ofCharamyosin XI are the actin-binding sites.
A murine model of the human CREBRFR457Qobesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress
Authors: Kanshana Jitendra S. , Mattila Polly E. , Ewing Michael C. , Wood Ashlee N. , Schoiswohl Gabriele , Meyer Anna C. , Kowalski Aneta , Rosenthal Samantha L. , Gingras Sebastien , Kaufman Brett A. , Lu Ray , Weeks Daniel E. , McGarvey Stephen T. , Minster Ryan L. , Hawley Nicola L. , Kershaw Erin E. 
Published: May 2021

AbstractObesity and diabetes have strong heritable components, yet the genetic contributions to these diseases remain largely unexplained. In humans, a missense variant in Creb3 regulatory factor (CREBRF) [rs373863828 (p.Arg457Gln); CREBRFR457Q] is strongly associated with increased odds of obesity but decreased odds of diabetes. Although virtually nothing is known about CREBRF’s mechanism of action, emerging evidence implicates it in the adaptive transcriptional response to nutritional stress downstream of TORC1. The objectives of this study were to generate a murine model with knockin of the orthologous variant in mice (CREBRFR458Q) and to test the hypothesis that this CREBRF variant promotes obesity and protects against diabetes by regulating energy and glucose homeostasis downstream of TORC1. To test this hypothesis, we performed extensive phenotypic analysis of CREBRFR458Qknockin mice at baseline and in response to acute (fasting/refeeding), chronic (low- and high-fat diet feeding), and extreme (prolonged fasting) nutritional stress as well as with pharmacological TORC1 inhibition. The results demonstrate that the murine CREBRFR458Qmodel of the human CREBRFR457Qvariant does not influence energy/glucose homeostasis in response to these interventions. Alternative preclinical models and/or studies in humans will be required to decipher the mechanisms linking this variant to human health and disease.
Development of Potent and Effective Synthetic SARS-CoV-2 Neutralizing Nanobodies
Authors: Stefan Maxwell A. , Light Yooli K. , Schwedler Jennifer L. , McIlroy Peter R. , Courtney Colleen M. , Saada Edwin A. , Thatcher Christine E. , Phillips Ashlee M. , Bourguet Feliza A. , Mageeney Catherine M. , McCloy Summer A. , Collette Nicole M. , Negrete Oscar A. , Schoeniger Joseph S. , Weilhammer Dina R. , Harmon Brooke 
Published: May 2021

AbstractThe respiratory virus responsible for Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-2), has impacted nearly every aspect of life worldwide, claiming the lives of over 2.5 million people globally, at the time of this publication. Neutralizing nanobodies (VHH) represent a promising therapeutic intervention strategy to address the current SARS-2 pandemic and provide a powerful toolkit to address future virus outbreaks. Using a synthetic, high-diversity VHH bacteriophage library, several potent neutralizing VHH antibodies were identified and evaluated for their capacity to tightly bind to the SARS-2 receptor-binding domain (RBD), to prevent binding of SARS-2 spike (S) to the cellular receptor Angiotensin-converting enzyme 2 (ACE2), and to neutralize viral infection. Preliminary preclinical evaluation of multiple nanobody candidates demonstrate that they are prophylactically and therapeutically effectivein vivoagainstwildtypeSARS-2. The identified and characterized nanobodies described herein represent viable candidates for further preclinical evaluation and another tool to add to our therapeutic arsenal to address the COVID-19 pandemic.Author SummaryTo fully address the on-going pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-2), it will be important to have both vaccines and therapeutic strategies to prevent and mitigate the effects of SARS-2. In this study, we describe the identification and characterization of potently neutralizing humanized single domain heavy chain (VHH) antibodies that have binding affinity for both the original Wuhan strain and widely circulating B.1.1.7/UK strain. VHH antibodies have the same therapeutic potential as conventional antibodies in half the size and with greater stability and solubility. Using a synthetic humanized high-diversity VHH phage library we identified several candidates with strong affinity for the SARS-2 spike that block the interaction of SARS-2 spike with the cellular receptor ACE2, and effectively neutralize infection with SARS-2in vitro. By sequencing viral escape mutants generated in the presence of each VHH we mapped the binding sites of the VHH antibodies and assessed their affinity against newly emerging SARS-2 variants. Finally, we demonstrate that two of these VHH antibodies show prophylactic and therapeutic efficacyin vivoagainst challenge with SARS-2. This study establishes that screening highly diverse VHH phage libraries against viral threats can yield highly effective therapeutic agents in real time.
Identification of DAXX As A Restriction Factor Of SARS-CoV-2 Through A CRISPR/Cas9 Screen
Authors: Mac Kain Alice , Maarifi Ghizlane , Aicher Sophie-Marie , Arhel Nathalie , Baidaliuk Artem , Munier Sandie , Donati Flora , Vallet Thomas , Tran Quang Dinh , Hardy Alexandra , Chazal Maxime , Porrot Françoise , OhAinle Molly , Carlson-Stevermer Jared , Oki Jennifer , Holden Kevin , Simon-Lorière Etienne , Bruel Timothée , Schwartz Olivier , van der Werf Sylvie , Jouvenet Nolwenn , Nisole Sébastien , Vignuzzi Marco , Roesch Ferdinand 
Published: May 2021

AbstractInterferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identified DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX was sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricted infection. In contrast with most of its previously described antiviral activities, DAXX-mediated restriction of SARS-CoV-2 was independent of the SUMOylation pathway. SARS-CoV-2 infection triggered the re-localization of DAXX to cytoplasmic sites and promoted its degradation. Mechanistically, this process was mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.