bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mucosal host–microbe interactions associate with clinical phenotypes in inflammatory bowel disease
Authors: Hu Shixian , Bourgonje Arno R. , Gacesa Ranko , Jansen Bernadien H. , Björk Johannes R. , Bangma Amber , Hidding Iwan J. , van Dullemen Hendrik M. , Visschedijk Marijn C. , Faber Klaas Nico , Dijkstra Gerard , Harmsen Hermie J. M. , Festen Eleonora A. M. , Vila Arnau Vich , Spekhorst Lieke M. , Weersma Rinse K. 
Published: June 2022

AbstractDysregulation of gut mucosal host–microbe interactions is a central feature of inflammatory bowel disease (IBD). To study tissue-specific interactions, we performed transcriptomic (RNA-seq) and microbial (16S-rRNA-seq) profiling of 696 intestinal biopsies derived from 353 patients with IBD and controls. Analysis of transcript-bacteria interactions identified six distinct groups of inflammation-related pathways that were associated with intestinal microbiota, findings we could partially validate in an independent cohort. An increased abundance of Bifidobacterium was associated with higher expression of genes involved in fatty acid metabolism, while Bacteroides was associated with increased metallothionein signaling. In fibrostenotic Crohn’s disease, a transcriptional network dominated by immunoregulatory genes associated with Lachnoclostridium bacteria in non-stenotic tissue. In patients using TNF-α-antagonists, a transcriptional network dominated by fatty acid metabolism genes associated with Ruminococcaceae. Mucosal microbiota composition was associated with enrichment of specific intestinal cell types. Overall, we identify multiple host–microbe interactions that may guide microbiota-directed precision medicine.
UNC-45 has a crucial role in maintaining muscle sarcomeres during aging in Caenorhabditis elegans
Authors: Matheny Courtney J. , Qadota Hiroshi , Kimelman Marion , Bailey Aaron O. , Oberhauser Andres F. , Benian Guy M. 
Published: June 2022

Summary/AbstractAs people live longer, age-related diseases, like sarcopenia, will become a greater public health concern. We use the model organism C. elegans to better understand the molecular mechanisms behind muscle maintenance. Muscle function is dependent on having properly organized and functioning thick filaments, which are primarily composed of myosin. The myosin head requires the chaperone UNC-45 to initially fold it after translation and is likely used to re-fold back to functionality after thermal or chemical stress induced unfolding. We observe an early onset of sarcopeania when UNC-45 is perturbed during adulthood. We observe that during adult aging, there is a sequential decline of HSP-90, UNC-45, and then myosin. Myosin and UNC-45 protein decline are independent of steady state mRNA levels. Loss of UNC-45 is correlated with an increase in phosphorylation of the protein. By mass spectrometry, S111 was identified as being phosphorylated and this modification may affect binding to HSP-90. A longevity mutant with delayed onset of sarcopenia also shows a delay in the loss of HSP-90, UNC-45, and myosin. We also see a decrease in UNC-45 protein, but not transcript, in an hsp-90 loss of function mutant, suggesting a role for HSP-90 in stabilizing UNC-45. This leads us to propose the model that during aging, a loss of HSP-90 leads to UNC-45 being post translationally modified, such as phosphorylation, and degraded, which then leads to a loss of myosin, and thus muscle mass and function. A better understanding of how myosin and its chaperone proteins are regulated and affected by aging will lead to better preventative care and treatment of sarcopenia and, possibly, the age-related decline of heart muscle function.Graphical AbstractIn young adults, under normal conditions the UCS domain of UNC-45 (shown in green) is bound to the myosin head (in red) and the TPR domain (in yellow) is bound to HSP-90 (in purple). Under stress conditions, HSP-90 detaches from the TPR domain, causing a conformational change in UNC-45 that allows the Central domain (in blue) to bind to the myosin neck (in red) resulting in inhibition of the myosin power stroke while the UCS domain protects/re-folds the myosin head. HSP-90 can then rebind the TPR domain, causing the Central domain to release the myosin neck, allowing movement of the myosin motor. However, aged adults experience a loss of HSP-90 and UNC-45 (which has increased post translational modification with aging). The loss of the Myosin chaperones leads to increased aggregation and degradation of Myosin with age.This loss of Myosin at the thick filament results in decline in muscle mass and function, also known as sarcopenia. Note that only the myosin head and neck are shown for simplicity of illustration.
ASAR lncRNAs control DNA replication timing through interactions with multiple hnRNP/RNA binding proteins
Authors: Thayer Mathew J. , Heskett Michael B. , Smith Leslie G. , Spellman Paul T. , Yates Phillip A. 
Published: June 2022

AbstractASARs are a family of very-long noncoding RNAs that control replication timing on individual human autosomes, and are essential for chromosome stability. The eight known ASAR lncRNAs remain closely associated with their parent chromosomes. Analysis of RNA-protein interaction data (from ENCODE) revealed numerous RBPs with significant interactions with multiple ASAR lncRNAs, with several hnRNPs as abundant interactors. An ∼7kb domain within the ASAR6-141 lncRNA shows a striking density of RBP interaction sites. Genetic deletion and ectopic integration assays indicate that this ∼7kb RNA binding protein domain contains functional sequences for controlling replication timing of entire chromosomes incis. shRNA-mediated depletion of 10 different RNA binding proteins, including HNRNPA1, HNRNPC, HNRNPL, HNRNPM, HNRNPU, or HNRNPUL1, results in dissociation of ASAR lncRNAs from their chromosome territories, and disrupts the synchronous replication that occurs on all autosome pairs, recapitulating the effect of individual ASAR knockouts on a genome-wide scale. Our results further demonstrate the role that ASARs play during the temporal order of genome-wide replication, and we propose that ASARs function as essential RNA scaffolds for the assembly of hnRNP complexes that help maintain the structural integrity of each mammalian chromosome.
Anaerobic single particle cryoEM of nitrogenase
Authors: Warmack Rebeccah A. , Rees Douglas C. 
Published: June 2022

AbstractThe enzyme nitrogenase catalyzes the reduction of dinitrogen to ammonia during biological nitrogen fixation through a mechanism involving the ATP dependent interaction of two component proteins adopting multiple conformational states. To date, high resolution structural information has been provided by X-ray crystallography, which restricts the states that can be accessed to those that can be crystallized. Cryo-electron microscopy (cryoEM) presents a new opportunity for structural characterization of nitrogenase solution structures, and may yield new information on the mechanism of nitrogenase by revealing structures of transient or heterogeneous states. In this study, we present single particle cryoEM structures of the MoFe-nitrogenase endogenously isolated from Azotobacter vinelandii. To maintain the fully reduced cluster states of this oxygen sensitive protein, we prepared samples within an anaerobic chamber and employed specialized conditions to minimize partial disordering of the α-subunit at the air-water interface during freezing. Under these conditions, cryoEM structures of the as-isolated MoFe-protein and stabilized MoFe-protein-Fe-protein ADP-AlF4-complex were generally found to closely resemble their corresponding X-ray crystallographic structures. The cryoEM structures did reveal disordering in regions of the MoFe-protein α-subunit reminiscent of that observed previously for the ΔnifB MoFe-protein lacking the FeMo-cofactor, suggesting that this disorder may reflect functionally relevant dynamics, as well as the possibility of asymmetric binding of the Fe-protein to the MoFe-protein in solution. The methods presented here pave the way toward the capture and interrogation of turnover-relevant nitrogenase states by cryoEM.
Autoregulation of a trimeric transporter involves the cytoplasmic domains of both adjacent subunits
Authors: Leone Vanessa , Bradshaw Richard T. , Koshy Caroline , Lee Paul Suhwan , Fenollar-Ferrer Cristina , Heinz Veronika , Ziegler Christine , Forrest Lucy R. 
Published: June 2022

AbstractMembrane transporters mediate the passage of molecules across membranes and are essential for cellular function. While the transmembrane region of these proteins is responsible for substrate transport, often the cytoplasmic regions are required for modulating their activity. However, it can be difficult to obtain atomic-resolution descriptions of these autoregulatory domains by classical structural biology techniques if they lack a single, defined structure, as they may not be resolved or may be truncated or modified to facilitate crystallization. The betaine permease, BetP, a homotrimer, is a prominent and well-studied example of a membrane protein whose autoregulation depends on cytoplasmic N- and C-terminal segments. These domains sense and transduce changes in K+ concentration and in lipid bilayer properties caused by osmotic stress. However, structural data for these terminal domains is incomplete, which hinders a clear description of the molecular mechanism of autoregulation. Here we used µs-scale molecular simulations of the BetP trimer to compare reported conformations of the 45 amino-acid long C-terminal tails. The simulations provide support for the idea that the conformation derived from EM data represents a stable global orientation of the C-terminal segment under downregulating conditions. The simulations also allow a detailed molecular description of the C-terminal tail dynamics as well as its interactions with lipids, potassium ions, and the cytoplasmic surface of neighboring transporter subunits. Nevertheless, they do not provide information on the N-terminal segment, whose structure was not resolved by the structural studies. We therefore examined the possible interactions of the N-terminal tail by generating de novo models of its structure in the context of the EM-derived structure. The resultant full-length models of the BetP trimer provide a molecular framework for the arrangement of the terminal domains in the downregulated protein. In this framework, each C-terminal tail contacts the neighboring protomer in the clockwise direction (viewed from the cytoplasm), while the N-terminal tails only contact the protomer in the counterclockwise direction. This framework indicates an intricate interplay between the three protomers of BetP and, specifically, a multi-directionality that may facilitate autoregulation of betaine transport.
Human ERG Oncoprotein Represses Chip/LDB1 LIM-Domain Binding Gene in Drosophila
Authors: Bharti Mahima , Bajpai Anjali , Rautela Umanshi , Manzar Nishat , Ateeq Bushra , Sinha Pradip 
Published: June 2022

AbstractERG oncoprotein, a master transcription factor, targets diverse arrays of genes in different cancers. Identifying oncogenically relevant ones from these ERG targets, however, is challenging. Here we show that heterologous ERG disrupts a LIM-homeodomain (LIM-HD) complex, Chip-Tailup, in Drosophila. In the posterior thorax (notum) primordium, ERG-induced upregulation of E(z)/EZH2 trimethylates histones in Chip promoter. A consequent loss of the Chip-Tailup complex releases repression of N-Wg signaling in the notum, inducing de novo wings and, alternatively, carcinogenesis of ERG-expressing notal cells displaying loss of Lgl tumor suppressor. ERG-induced developmental or oncogenic fallouts are abrogated upon gain of Chip, N, or E(z) loss, besides Wg ligand sequestration. ERG-positive prostate cancer (PCa) cells, too, display suppression of mammalian homolog of Drosophila Chip, LIM Domain Binding1, LDB1. Deep homology in gene regulatory networks, like that of Chip-Tup complex, thus help prioritize identification of functionally relevant targets of human oncoproteins in Drosophila.HighlightsHuman ERG suppresses Chip, a LIM-domain binding, LDB gene in Drosophila via E(z)ERG-mediated Chip loss induces ectopic Wg morphogen signaling in the notum primordiumChip gain suppresses ERG-induced Wg morphogen and tumor progression in lgl clonesERG-positive human PCa cell lines show downregulation of a Chip homolog, LDB1In briefMammalian ERG oncoprotein displays a diverse and perplexing range of targets in different cancers. By driving ERG in Drosophila developing appendages, Bharti et al. reveal its repression of a LIM-domain coding gene, Chip/LDB1. ERG-positive prostate cancer cells, too, display Chip/LDB1 repression. Deep homology across phylogeny thus helps uncover oncoprotein targets.
Modeling suicide mortality in US counties using population socioeconomic indicators
Authors: Kandula Sasikiran , Martinez-Alés Gonzalo , Rutherford Caroline , Gimbrone Catherine , Olfson Mark , Gould Madelyn S. , Keyes Katherine M. , Shaman Jeffrey 
Published: June 2022

AbstractBackgroundSuicide is one of the leading causes of death in the United States and population risk prediction models can inform the type, location, and timing of public health interventions. Here, we report the development of a prediction model of suicide risk using population characteristics.MethodsAll suicide deaths reported to the Nation Vital Statistics System between 2005-2019 were identified, and age, sex, race, and county-of-residence of the decedents were extracted to calculate baseline risk. County-wise annual measures of socioeconomic predictors of suicide risk — unemployment, weekly wage, poverty prevalence, median household income, and population density — along with two state-wise measures of prevalence of major depressive disorder and firearm ownership were compiled from public sources. Conditional autoregressive (CAR) models, which account for spatiotemporal autocorrelation in response and predictors, were used to estimate county-level risk.ResultsEstimates derived from CAR models were more accurate than from models not adjusted for spatiotemporal autocorrelation. Inclusion of suicide risk/protective covariates further reduced errors. Suicide risk was estimated to increase with each standard deviation increase in firearm ownership (2.8%), prevalence of major depressive episode (1%) and unemployment (2.8%). Conversely, risk was estimated to decrease by 4.3% for each standard deviation increase in both median household income and population density. Increased heterogeneity of risk across counties was also noted.ConclusionsArea-level characteristics and the CAR model structure can estimate population-level suicide risk and thus inform decisions on resource allocation and focused interventions during outbreaks.
Proteome-wide microarray-based screening of PAR-binding proteins
Authors: Kang Bong Gu , Kang Sung-Ung , Kim Jae Jin , Kwon Ji-Sun , Gagné Jean-Philippe , Lee Seo Yun , Kim Soyeon , Sangwon Karl L. , Ha Shinwon , Jeong Jun Seop , Lee Yun-Il , Zhu Heng , Kim Dongsan , Poirier Guy G. , Kang Ho Chul , Dawson Valina L. , Dawson Ted M. 
Published: June 2022

SUMMARYPoly(ADP-ribose) (PAR) plays a crucial role in intracellular signaling and scaffolding through covalent modification or non-covalent binding to target proteins. The non- covalent binding PARylome has not been extensively characterized. Here we performed a PAR-binding screen using a human protein microarray that covers most of the human proteome to characterize the non-covalent binding PARylome. A total of 356 PAR- binding proteins were identified. The PAR-binding PARylome suggests that PAR- binding regulates a variety of biological processes beyond well-characterized DNA damage signaling and DNA repair. Proteins that may be reprogrammed by PAR-binding include signaling molecules, transcription factors, nucleic acid binding proteins, calcium binding proteins, ligases, oxidoreductases, enzymes, transferases, hydrolases, and receptors. The global database of PAR-binding proteins that we established will be a valuable tool for further in-depth analysis of the role of PARylation in a wide range of biological contexts.
Artificial neural network modelling of the neural population code underlying mathematical operations
Authors: Nakai Tomoya , Nishimoto Shinji 
Published: June 2022

AbstractMathematical operations have long been regarded as a sparse, symbolic process in neuroimaging studies. In contrast, advances in artificial neural networks (ANN) have enabled extracting distributed representations of mathematical operations. Recent neuroimaging studies have compared distributed representations of the visual, auditory and language domains in ANNs and biological neural networks (BNNs). However, such a relationship has not yet been examined in mathematics. Here we used the fMRI data of a series of mathematical problems with nine different combinations of operators to construct voxel-wise encoding models using both sparse operator and latent ANN features. Representational similarity analysis demonstrated shared representations between ANN and BNN, an effect particularly evident in the intraparietal sulcus. Feature-brain similarity analysis served to reconstruct a sparse representation of mathematical operations based on distributed ANN features. Such reconstruction was more efficient when using features from deeper ANN layers. Moreover, latent ANN features allowed the decoding of novel operators not used during model training from brain activity. The current study provides novel insights into the neural code underlying mathematical thought.
The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm
Authors: Hamdorf Matthias , Imhof Thomas , Bailey-Elkin Ben , Betz Janina , Theobald Sebastian J , Simonis Alexander , Cristanziano Veronica Di , Gieselmann Lutz , Dewald Felix , Lehmann Clara , Augustin Max , Klein Florian , Alcazar Miguel A Alejandre , Rongisch Robert , Fabri Mario , Rybniker Jan , Goebel Heike , Stetefeld Jörg , Brachvogel Bent , Cursiefen Claus , Koch Manuel , Bock Felix 
Published: June 2022

AbstractThe novel coronavirus pandemic, whose first outbreak was reported in December 2019 in Wuhan, China (COVID-19), is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tissue damage caused by the virus leads to a strong immune response and activation of antigen-presenting cells, which can elicit acute respiratory distress syndrome (ARDS) characterized by the rapid onset of widespread inflammation, the so-called cytokine storm. In many viral infections the recruitment of monocytes into the lung and their differentiation to dendritic cells (DCs) are seen as a response to the viral infection. DCs are critical players in the development of the acute lung inflammation that causes ARDS. Here we focus on the interaction of the ORF8 protein, a specific SARS-CoV-2 open reading frame protein, with dendritic cells (DCs). We show that ORF8 binds to dendritic cells, causes a pre-maturation of differentiating DCs, and induces the secretion of multiple pro-inflammatory cytokines by these cells. In addition, we identified dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) as a possible interaction partner of ORF8 on dendritic cells. Blockade of ORF8 signaling leads to reduced production of IL-1β, IL-6, IL-12p70, TNF-α, MCP-1 (CCL2), and IL-10 by dendritic cells. Analysis of patient sera with high anti-ORF8 antibody titers showed that there was nearly no neutralization of the ORF8 protein and its function. Therefore, a neutralizing antibody that has the capacity of blocking the cytokine and chemokine response mediated by ORF8 protein might be an essential and novel additional step in the therapy of severe SARS-CoV-2 cases.
Extracellular vesicle formation inCryptococcus deuterogattiiimpacts fungal virulence and requires theNOP16gene
Authors: Castelli Rafael F. , Pereira Alana , Honorato Leandro , Valdez Alessandro , de Oliveira Haroldo C. , Bazioli Jaqueline M. , Garcia Ane W. A. , Freitas Klimeck Tabata D’Maiella , Reis Flavia C. G. , Staats Charley C. , Nimrichter Leonardo , Fill Taícia P. , Rodrigues Marcio L. 
Published: June 2022

AbstractSmall molecules are components of fungal extracellular vesicles (EVs), but their biological roles are only superficially known.NOP16is a eukaryotic gene that is required for the activity of benzimidazoles againstCryptococcus deuterogattii. In this study, during the phenotypic characterization ofC. deuterogattiimutants lackingNOP16expression, we observed that this gene was required for EV production. Analysis of the small molecule composition of EVs produced by wild-type cells and two independentnop16Δ mutants revealed that the deletion ofNOP16resulted not only in a reduced number of EVs but also an altered small molecule composition. In aGalleria mellonellamodel of infection, thenop16Δ mutants were hypovirulent. The hypovirulent phenotype was reverted when EVs produced by wild-type cells, but not mutant EVs, were co-injected with thenop16Δ cells inG. mellonella. These results reveal a role forNOP16in EV biogenesis and cargo, and also indicate that the composition of EVs is determinant for cryptococcal virulence.
Fmrp regulates neuronal balance in embryonic motor circuit formation
Authors: Barker Chase M. , Miles Kaleb D. , Doll Caleb A. 
Published: June 2022

AbstractMotor behavior requires the balanced production and integration of a variety of neural cell types. Motor neurons are positioned in discrete locations in the ventral spinal cord, targeting specific muscles to drive locomotive contractions. Specialized spinal interneurons modulate and synchronize motor neuron activity to achieve coordinated motor output. Changes in the ratios of spinal interneurons could drastically alter motor output by tipping the balance of inhibition and excitation onto target motor neurons. Importantly, individuals with Fragile X syndrome (FXS) and associated autism spectrum disorders often have significant motor challenges, including repetitive behaviors and epilepsy. FXS stems from the transcriptional silencing of the gene Fragile X Messenger Ribonucleoprotein 1 (FMR1), which encodes an RNA binding protein that is implicated in a multitude of crucial neurodevelopmental processes, including cell specification. We find that zebrafish fmr1 mutants generate surplus ventral lateral descending (VeLD) interneurons, an early-born cell derived from the pMN domain. These GABAergic interneurons are also associated with changes in synaptogenesis, as fmr1 mutants show increased early expression of the scaffold Gephyrin, but these postsynaptic sites fail to mature. Our work shows that Fmrp regulates the proportionate production of neurons that comprise early embryonic motor circuits. As VeLD interneurons are hypothesized to act as central pattern generators driving the earliest spontaneous movements, this imbalance could profoundly influence the formation and long-term function of motor circuits driving locomotion.