bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection
Authors: Sasaki Yo , Zhu Jian , Shi Yun , Gu Weixi , Kobe Bostjan , Ve Thomas , DiAntonio Aaron , Milbrandt Jeffrey 
Published: July 2021

AbstractSARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase. Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD+ related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD+ precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD+ precursor nicotinic acid mononucleotide (NaMN). We show that NaMN inhibits SARM1 activation, and demonstrate that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Analysis of the NaMN-ARM domain co-crystal structure shows that NaMN competes with NMN for binding to the SARM1 allosteric site and promotes the open, autoinhibited configuration of SARM1 ARM domain. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD+, and NaMN to monitor cellular NAD+ homeostasis and regulate SARM1 NAD+ hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders.HighlightsNaMN binds to SARM1 N-terminal allosteric site and inhibits SARM1 NAD+ hydrolaseNaMN inhibits SARM1 activation by stabilizing its open, inactive structureNMN deamidase promotes strong axonal protection by reducing NMN and increasing NaMN
BET protein inhibition regulates macrophage chromatin accessibility and microbiota-dependent colitis
Authors: O’Connor Michelle Hoffner , Berglind Ana , Kennedy Meaghan M. , Keith Benjamin P. , Lynch Zachary J. , Schaner Matthew R. , Steinbach Erin C. , Herzog Jeremy , Trad Omar K. , Jeck William R. , Arthur Janelle C. , Sartor R. Balfour , Furey Terrence S. , Sheikh Shehzad Z. 
Published: July 2021

AbstractIntroductionIn colitis, macrophage functionality is altered compared to homeostatic conditions. Loss of IL-10 signaling results in an inappropriate and chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice.MethodsWe performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence or absence of lipopolysaccharide (LPS) and with or without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization.ResultsTreatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in the attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo reduced severity of colitis as compared with vehicle-treated mice.ConclusionWe identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.FundingThis work was funded in part through Helmsley Charitable Trust (SHARE Project 2), NIDDK P01DK094779, NIDDK 1R01DK104828, NIDDK P30-DK034987, NIDDK 1R01DK124617, NIH Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship (1F31DK122704), NIH T32 Genetics NIGMS Training Grant (T32-GM007092-43), NIH T32 Translational Medicine Training Grant (T32-GM122741), NIH T32 Gastroenterology Research Training Grant (T32-DK007737), and Crohn’s and Colitis Foundation Student Research Fellowship Award, and Gnotobiotic Animal Facility.
BAI-Net: Individualized Anatomical Cerebral Cartography using Graph Neural Network
Authors: Ma Liang , Zhang Yu , Zhang Hantian , Cheng Luqi , Zhuo Junjie , Shi Weiyang , Lu Yuheng , Li Wen , Yang Zhengyi , Wang Jiaojian , Fan Lingzhong , Jiang Tianzi 
Published: July 2021

AbstractBrain atlas is an important tool in the diagnosis and treatment of neurological disorders. However, due to large variations in the organizational principles of individual brains, many challenges remain in clinical applications. Brain atlas individualization network (BAI-Net) is an algorithm that subdivides individual cerebral cortex into segregated areas using brain morphology and connectomes. BAI-Net integrates topological priors derived from a group atlas, adjusts the areal probability using the connectivity context derived from diffusion tractography, and provides reliable and explainable individualized brain parcels across multiple sessions and scanners. We demonstrate that BAI-Net outperforms the conventional iterative clustering approach by capturing significantly heritable topographic variations in individualized cartographies. The topographic variability of BAI-Net cartographies shows strong associations with individual variability in brain morphology, connectivity fingerprints and cognitive behaviors. This study provides a new framework for individualized brain cartography and paves the way of atlas-based precision medicine in clinical practice.
The molecular architecture of vimentin filaments
Authors: Eibauer Matthias , Weber Miriam S. , Turgay Yagmur , Sivagurunathan Suganya , Goldman Robert D. , Medalia Ohad 
Published: July 2021

ABSTRACTIntermediate filaments are integral components of the cytoskeleton in metazoan cells. Due to their specific viscoelastic properties they are principal contributors to flexibility and tear strength of cells and tissues. Vimentin, an intermediate filament protein expressed in fibroblasts and endothelial cells, assembles into ~11 nm thick biopolymers, that are involved in a wide variety of cellular functions in health and disease. Here, we reveal the structure of in-situ polymerized vimentin filaments to a subnanometer resolution by applying cryo-electron tomography to mouse embryonic fibroblasts grown on electron microscopy grids. We show that vimentin filaments are tube-like assemblies with a well-defined helical symmetry. Their structure is comprised of five octameric, spring-like protofibrils harboring 40 vimentin polypeptide chains in cross-section. The protofibrils are connected by the intrinsically disordered head and helix 1A domains of vimentin. Individual filaments display two polymerization states characterized by either the presence or absence of a luminal density along the helical axis. The structure of vimentin filaments unveils the generic building plan of the intermediate filament superfamily in molecular details.
Comprehensive taxon sampling and vetted fossils help clarify the time tree of shorebirds (Aves, Charadriiformes)
Authors: Černý David , Natale Rossy 
Published: July 2021

AbstractShorebirds (Charadriiformes) are a globally distributed clade of modern birds and, due to their ecological and morphological disparity, a frequent subject of comparative studies. While molecular phylogenies have been instrumental to resolving the suprafamilial backbone of the charadriiform tree, several higher-level relationships, including the monophyly of plovers (Charadriidae) and the phylogenetic positions of several monotypic families, have remained unclear. The timescale of shorebird evolution also remains uncertain as a result of extensive disagreements among the published divergence dating studies, stemming largely from different choices of fossil calibrations. Here, we present the most comprehensive non-supertree phylogeny of shorebirds to date, based on a total-evidence dataset comprising 336 ingroup taxa (89% of all extant species), 24 loci (15 mitochondrial and 9 nuclear), and 69 morphological characters. Using this phylogeny, we clarify the charadriiform evolutionary timeline by conducting a node-dating analysis based on a subset of 8 loci tested to be clock-like and 16 carefully selected, updated, and vetted fossil calibrations. Our concatenated, species-tree, and total-evidence analyses consistently support plover monophyly and are generally congruent with the topologies of previous studies, suggesting that the higher-level relationships among shorebirds are largely settled. However, several localized conflicts highlight areas of persistent uncertainty within the gulls (Laridae), true auks (Alcinae), and sandpipers (Scolopacidae). At shallower levels, our phylogenies reveal instances of genus-level nonmonophyly that suggest changes to currently accepted taxonomies. Our node-dating analyses consistently support a mid-Paleocene origin for the Charadriiformes and an early diversification for most major subclades. However, age estimates for more recent divergences vary between different relaxed clock models, and we demonstrate that this variation can affect phylogeny-based macroevolutionary studies. Our findings demonstrate the impact of fossil calibration choice on the resulting divergence time estimates, and the sensitivity of diversification rate analyses to the modeling assumptions made in time tree inference.
Exploring the tymovirids landscape through metatranscriptomics data
Authors: Bejerman Nicolás , Debat Humberto 
Published: July 2021

AbstractTymovirales is an order of viruses with positive-sense, single-stranded RNA genomes that mostly infect plants, but also fungi and insects. The number of tymovirid sequences has been growing in the last few years with the extensive use of high-throughput sequencing platforms. Here we report the discovery of 31 novel tymovirid genomes associated with 27 different host plant species, which were hidden in public databases. These viral sequences were identified through a homology searches in more than 3,000 plant transcriptomes from the NCBI Sequence Read Archive (SRA) using known tymovirids sequences as query. Identification, assembly and curation of raw SRA reads resulted in 29 viral genome sequences with full-length coding regions, and two partial genomes. Highlights of the obtained sequences include viruses with unique and novel genome organizations among known tymovirids. Phylogenetic analysis showed that six of the novel viruses were related to alphaflexiviruses, seventeen to betaflexiviruses, two to deltaflexiviruses and six to tymoviruses. These findings resulted in the most complete phylogeny of tymovirids to date and shed new light on the phylogenetic relationships and evolutionary landscape of this group of viruses. Furthermore, this study illustrates the complexity and diversity of tymovirids genomes and demonstrates that analyzing SRA public data provides an invaluable tool to accelerate virus discovery and refine virus taxonomy.
The tetrameric assembly of 2-aminomuconic acid dehydrogenase is a functional requirement of cofactor NAD+ binding
Authors: Shi Qiuli , Chen Yanjuan , Li Xinxin , Dong Hui , Chen Cheng , Zhong Zhihui , Yang Cheng , Liu Guangfeng , Su Dan 
Published: July 2021

AbstractThe bacterium Pseudomonas sp. AP–3 is able to use the environmental pollutant 2-aminophenol as its sole source of carbon, nitrogen, and energy. Eight genes (amnA, B, C, D, E, F, G, and H) encoding 2-aminophenol metabolizing enzymes are clustered into a single operon. 2-aminomuconic 6-semialdehyde dehydrogenase (AmnC), a member of the aldehyde dehydrogenase (ALDH) superfamily, is responsible for oxidizing 2-aminomuconic 6-semialdehyde to 2-aminomuconate. In contrast to many other members of the ALDH superfamily, the structural basis of the catalytic activity of AmnC remains elusive. Here, we present the crystal structure of AmnC, which displays a homotetrameric quaternary assembly that is directly involved in its enzymatic activity. The tetrameric state of AmnC in solution was also presented using small-angle X-ray scattering. The tetramerization of AmnC is mediated by the assembly of a protruding hydrophobic beta-strand motif and residues V121 and S123 located in the NAD+-binding domain of each subunit. Dimeric mutants of AmnC dramatically lose NAD+ binding affinity and enzyme activity, indicating that tetrameric assembly of AmnC is required for oxidizing the unstable metabolic intermediate 2-aminomuconic 6-semialdehyde to 2-aminomuconic acid in the 2-aminophenol metabolism pathway.
Quantifying and correcting slide-to-slide variation in multiplexed immunofluorescence images
Authors: Harris C.R. , McKinley E.T. , Roland J.T. , Liu Q. , Shrubsole M.J. , Lau K.S. , Coffey R.J. , Wrobel J. , Vandekar S.N. 
Published: July 2021

AbstractMotivationThe multiplexed imaging domain is a nascent single-cell analysis field with a complex data structure susceptible to technical variability that disrupts inference. These in situ methods are valuable in understanding cell-cell interactions, but few standardized processing steps or normalization techniques of multiplexed imaging data are available.ResultsWe implement and compare data transformations and normalization algorithms in multiplexed imaging data. Our methods adapt the ComBat and functional data registration methods to remove slide effects in this domain, and we present an evaluation framework to compare the proposed approaches. We present clear slide-to-slide variation in the raw, unadjusted data, and show that many of the proposed normalization methods reduce this variation while preserving and improving the biological signal. Further, we find that dividing this data by its slide mean, and the functional data registration methods, perform the best under our proposed evaluation framework. In summary, this approach provides a foundation for better data quality and evaluation criteria in the multiplexed domain.Availability and ImplementationSource code is provided at https://github.com/statimagcoll/MultiplexedNormalization.Contactcoleman.r.harris@vanderbilt.eduSupplementary informationSupplementary information is available online.
The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin
Authors: Krastev Dragomir B. , Li Shudong , Sun Yilun , Wicks Andrew , Weekes Daniel , Badder Luned M. , Knight Eleanor G. , Marlow Rebecca , Calvo Mercedes Pardo , Yu Lu , Talele Tanaji T. , Bartek Jiri , Choudhary Jyoti , Pommier Yves , Pettitt Stephen J. , Tutt Andrew , Ramadan Kristijan , Lord Christopher J. 
Published: July 2021

Summary paragraphPoly-(ADP-ribose) polymerase inhibitors (PARPi) elicit anti-tumour activity in homologous recombination defective cancers by promoting cytotoxic, chromatin-bound, “trapped” PARP1. How cells process trapped PARP1 remains unclear. By exploiting wild-type or trapping-resistant PARP1 transgenes combined with either a rapid immunoprecipitation mass-spectrometry of endogenous proteins (RIME)-based approach, or PARP1 Apex2-proximity labelling linked to mass-spectrometry, we generated proteomic profiles of trapped and non-trapped PARP1 complexes. This combined approach identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase (aka VCP). Subsequent experiments demonstrated that upon trapping, PARP1 is SUMOylated by the SUMO-ligase PIAS4 and subsequently ubiquitinated by the SUMO-targeted E3-ubiquitin ligase, RNF4, events that promote p97 recruitment and p97 ATPase-mediated removal of trapped-PARP1 from chromatin. Consistent with this, small molecule p97 complex inhibitors, including a metabolite of the clinically-used drug disulfiram (CuET) that acts as a p97 sequestration agent, prolong PARP1 trapping and thus enhance PARPi-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Taken together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 from chromatin and the response of homologous recombination defective tumour cells to PARPi.
Multiple parasitoid species enhance top-down control, but parasitoid performance is context-dependent
Authors: Thierry Mélanie , Pardikes Nicholas A. , Ximénez-Embún Miguel G. , Proudhom Grégoire , Hrček Jan 
Published: July 2021

AbstractEcological communities are composed of many species, forming complex networks of interactions. Current environmental changes are altering community composition. We thus need to identify which aspects of species interactions are primarily driven by community structure and which by species identity to predict changes in the functioning of communities. Yet, this partitioning of effects is challenging and thus rarely explored.Here we disentangled the influence of community structure and the identity of co-occurring species on the outcome of consumer-resource interactions using a host-parasitoid system.We used four community modules that are common in host-parasitoid communities to represent community structure (i.e., host-parasitoid, exploitative competition, alternative host, and a combination of both exploitative competition and alternative host). We assembled nine different species combinations per community module in a laboratory experiment using a pool of threeDrosophilahosts and three larval parasitoid species. To investigate the potential mechanisms at play, we compared host suppression and parasitoid performance across community modules and species assemblages.We found that multiple parasitoid species enhanced host suppression due to sampling effect, weaker interspecific than intraspecific competition between parasitoids, and synergism. However, the effects of community structure on parasitoid performance were species-specific and dependent on the identity of co-occurring species. Consequently, multiple parasitoid species generally strengthen top down-control, but the performance of the parasitoids depends on the identity of either the co-occurring parasitoid species, the alternative host species, or both.Our results highlight the importance of preserving predator diversity for ecosystem functioning, but also show that other effects depend on community composition, and will therefore be likely altered by current environmental changes.
Structural connectivity-based segmentation of the human entorhinal cortex
Authors: Syversen Ingrid Framås , Witter Menno P. , Kobro-Flatmoen Asgeir , Goa Pål Erik , Schröder Tobias Navarro , Doeller Christian F. 
Published: July 2021

AbstractThe medial (MEC) and lateral entorhinal cortex (LEC), widely studied in rodents, are well defined and characterized. In humans, however, the exact locations of their homologues remain uncertain. Previous functional magnetic resonance imaging (fMRI) studies have subdivided the human EC into posterior-medial (pmEC) and anterior-lateral (alEC) parts, but uncertainty remains about the choice of imaging modality and seed regions, in particular in light of a substantial revision of the classical model of EC connectivity based on novel insights from rodent anatomy. Here, we used structural, not functional imaging, namely diffusion tensor imaging (DTI) and probabilistic tractography to segment the human EC based on differential connectivity to other brain regions known to project selectively to MEC or LEC. We defined MEC as more strongly connected to presubiculum and retrosplenial cortex (RSC), and LEC as more strongly connected to distal CA1 and proximal subiculum (dCA1pSub) and orbitofrontal cortex (OFC). Although our DTI segmentation had a larger medial-lateral component than in previous fMRI studies, our results show that the human MEC and LEC homologues have a border oriented both towards the posterior-anterior and medial-lateral axes, supporting the differentiation between pmEC and alEC.
Phylogenetic profiling suggests early origin of the core subunits of Polycomb Repressive Complex 2 (PRC2)
Authors: Sharaf Abdoallah , Vijayanathan Mallika , Oborník Miroslav , Mozgová Iva 
Published: July 2021

AbstractPolycomb Repressive Complex 2 (PRC2) is involved in establishing transcriptionally silent chromatin states through its ability to methylate lysine 27 of histone H3 by the catalytic subunit Enhancer of zeste [E(z)]. Polycomb group (PcG) proteins play a crucial role in the maintenance of cell identity and in developmental regulation. Previously, the diversity of PRC2 subunits within some eukaryotic lineages has been reported and its presence in early eukaryotic evolution has been hypothesized. So far however, systematic survey of the presence of PRC2 subunits in species of all eukaryotic lineages is missing. Here, we report the diversity of PRC2 core subunit proteins in different eukaryotic supergroups with emphasis on the early-diverged lineages and explore the molecular evolution of PRC2 subunits by phylogenetics. In detail, we investigate the SET-domain protein sequences and their evolution across the four domains of life and particularly focus on the structural diversity of the SET-domain subfamily containing E(z), the catalytic subunit of PRC2. We show that PRC2 subunits are already present in early eukaryotic lineages, strengthening the support for PRC2 emergence prior to diversification of eukaryotes. We identify a common presence of E(z) and ESC, suggesting that Su(z)12 may have emerged later and/or may be dispensable from the evolutionarily conserved functional core of PRC2. Furthermore, our results broaden our understanding of the E(z) evolution within the SET-domain protein family, suggesting possibilities of function evolution. Through this, we shed light on a possible emerging point of the PRC2 and the evolution of its function in eukaryotes.