bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dietary methionine restriction impairs anti-tumor immunity through gut microbiota
Authors: Ji Ming , Xu Xiaojiang , Xu Qing , Xu Xin , Azcarate-Peril M. Andrea , Wu Xiaoyue , Liu Juan , Locasale Jason W. , Li Jian-Liang , Shats Igor , Li Xiaoling 
Published: August 2021

AbstractDietary methionine restriction has been reported to repress cancer growth and improve therapeutic responses in several pre-clinical settings. However, how this dietary intervention impacts cancer progression in the context of the intact immune system is unknown. Here we report that methionine restriction exacerbates cancer growth and influences the outcomes of anti-tumor immunotherapy through gut microbiota and immune suppression in immunocompetent settings. Methionine restriction reduces T cell activation, increases tumor growth, and impairs response to anti-tumor immunotherapy. Mechanistically, methionine restriction alters composition of gut microbiota and reduces microbial production of hydrogen sulfide. Fecal transplantation from methionine-restricted tumor-free animals is sufficient to repress T cell activation and enhance tumor growth in tumor-bearing recipient mice. Conversely, dietary supplementation of a hydrogen sulfide donor or methionine stimulates anti-tumor immunity and suppresses tumor progression. Our findings reveal a vital role of gut microbiota in mediating methionine restriction-induced suppression of anti-tumor immunity and suggest that any possible anti-cancer benefits of methionine restriction require careful considerations of both the microbiota and the immune system.
Rhes protein transits from neuron to neuron and facilitates mutant huntingtin spreading in the brain
Authors: Ramírez-Jarquín Uri Nimrod , Sharma Manish , Shahani Neelam , Li Yuqing , Boregowda Siddaraju , Subramaniam Srinivasa 
Published: August 2021

ABSTRACTRhes (RASD2) is a thyroid hormone-induced gene that regulates striatal motor activity and promotes neurodegeneration in Huntington disease (HD) and tauopathy. Previously, we showed that Rhes moves between cultured striatal neurons and transports the HD protein, polyglutamine-expanded huntingtin (mHTT) via tunneling nanotube (TNT)-like membranous protrusions. However, similar intercellular Rhes transport has not yet been demonstrated in the intact brain. Here, we report that Rhes induces TNT-like protrusions in the striatal medium spiny neurons (MSNs) and transported between dopamine-1 receptor (D1R)-MSNs and D2R-MSNs of intact striatum and organotypic brain slices. Notably, mHTT is robustly transported within the striatum and from the striatum to the cortical areas in the brain, and Rhes deletion diminishes such transport. Moreover, we also found transport of Rhes to the cortical regions following restricted expression in the MSNs of the striatum. Thus, Rhes is a first striatum-enriched protein demonstrated to move and transport mHTT between neurons and brain regions, providing new insights on interneuronal protein transport in the brain.
Expression and subcellular localization of USH1C/harmonin in the human retina provide insights into pathomechanisms and therapy
Authors: Nagel-Wolfrum Kerstin , Fadl Benjamin R. , Becker Mirjana M. , Wunderlich Kirsten A. , Schäfer Jessica , Sturm Daniel , Fritze Jacques , Gür Burcu , Kaplan Lew , Andreani Tommaso , Goldmann Tobias , Brooks Matthew , Starostik Margaret R. , Lokhande Anagha , Apel Melissa , Fath Karl R. , Stingl Katarina , Kohl Susanne , DeAngelis Margaret M. , Schlötzer-Schrehardt Ursula , Kim Ivana K. , Owen Leah A. , Vetter Jan M. , Pfeiffer Norbert , Andrade-Navarro Miguel A. , Grosche Antje , Swaroop Anand , Wolfrum Uwe 
Published: August 2021

AbstractUsher syndrome (USH) is the most common form of hereditary deafness-blindness in humans. USH is a complex genetic disorder, assigned to three clinical subtypes differing in onset, course, and severity, with USH1 being the most severe. Rodent USH1 models do not reflect the ocular phenotype observed in human patients to date; hence, little is known about the pathophysiology of USH1 in the human eye. One of the USH1 genes, USH1C, exhibits extensive alternative splicing and encodes numerous harmonin protein isoforms that function as scaffolds for organizing the USH interactome. RNA-seq analysis of human retinas uncovered harmonin_a1 as the most abundant transcript of USH1C. Bulk RNA-seq analysis and immunoblotting showed abundant expression of harmonin in Müller glia cells (MGCs) and retinal neurons. Furthermore, harmonin was localized in the terminal endfeet and apical microvilli of MGCs, presynaptic region (pedicle) of cones, and outer segments of rods as well as at adhesive junctions of MGCs and photoreceptors in the outer limiting membrane (OLM). Our data provide evidence for the interactions of harmonin with OLM molecules in photoreceptors (PRCs) and MGCs and rhodopsin in PRCs. Subcellular expression and colocalization of harmonin correlate with the clinical phenotype observed in USH1C patients. In addition, primary cilia defects in USH1C patient-derived fibroblasts could be reverted by the delivery of harmonin_a1 transcript isoform. Our data provide novel insights into PRC cell biology, USH1C pathophysiology, and for developing gene therapy treatment.
Structural dynamics of SARS-CoV-2 nucleocapsid protein induced by RNA binding
Authors: Filho Helder Veras Ribeiro , Jara Gabriel Ernesto , Batista Fernanda Aparecida Heleno , Schleder Gabriel Ravanhani , Tonoli Celisa Caldana , Soprano Adriana Santos , Guimarães Samuel Leite , Borges Antonio Carlos , Cassago Alexandre , Bajgelman Marcio Chaim , Marques Rafael Elias , Trivella Daniela Barreto Barbosa , Franchini Kleber Gomes , Figueira Ana Carolina Migliorini , Benedetti Celso Eduardo , de Oliveira Paulo Sergio Lopes 
Published: August 2021

AbstractThe nucleocapsid (N) protein of the SARS-CoV-2 virus, the causal agent of COVID-19, is a multifunction phosphoprotein that plays critical roles in the virus life cycle, including transcription and packaging of the viral RNA. To play such diverse roles, the N protein has two globular RNA-binding modules, the N-(NTD) and C-terminal (CTD) domains, which are connected by an intrinsically disordered region. Despite the wealth of structural data available for the isolated NTD and CTD, how these domains are arranged in the full-length protein and how the oligomerization of N influences its RNA-binding activity remains largely unclear. Herein, using experimental data from electron microscopy and biochemical/biophysical techniques combined with molecular modeling and molecular dynamics simulations, we showed that, in the absence of RNA, the N protein formed structurally dynamic dimers, with the NTD and CTD arranged in extended conformations. However, in the presence of RNA, the N protein assumed a more compact conformation where the NTD and CTD are packed together. We also provided an octameric model for the full-length N bound to RNA that was consistent with electron microscopy images of the N protein in the presence of RNA. Together, our results shed new light on the dynamics and higher-order oligomeric structure of this versatile protein.
Whole-tissue deconvolution and scRNAseq analysis identify altered endometrial cellular compositions and functionality associated with endometriosis
Authors: Bunis Daniel , Wang Wanxin , Vallvé-Juanico Júlia , Houshdaran Sahar , Sen Sushmita , Soltane Isam Ben , Kosti Idit , Vo Kim Chi , Irwin Juan , Giudice Linda C. , Sirota Marina 
Published: August 2021

AbstractThe uterine lining (endometrium) exhibits a pro-inflammatory phenotype in women with endometriosis, resulting in pain, infertility, and poor pregnancy outcomes. The full complement of cell types contributing to this phenotype has yet to be identified, as most studies have focused on bulk tissue or select cell populations. Herein, through integrating whole-tissue deconvolution and single cell RNAseq, we comprehensively characterized immune and nonimmune cell types in endometrium of women with or without disease and their dynamic changes across the menstrual cycle. We designed metrics to evaluate specificity of deconvolution signatures that resulted in single cell identification of 13 novel signatures for immune cell subtypes in healthy endometrium. Guided by statistical metrics, we identified contributions of endometrial epithelial, endothelial, plasmacytoid dendritic cells, classical dendritic cells, monocytes, macrophages, and granulocytes to the endometrial pro-inflammatory phenotype, underscoring roles for nonimmune as well as immune cells to the dysfunctionality of this tissue.Teaser SentenceCell type deconvolution and single cell RNAseq analysis identify altered endometrial cellular compositions in women with endometriosis
LyTS: A Lysosome Localized Complex of TMEM192 and STK11IP
Authors: Angarola B. , Frölich F. , Ferguson S.M. 
Published: August 2021

AbstractThe degradative and signaling functions of lysosomes are dependent on numerous peripherally associated proteins. Targeting of lysosomes to sites of need is controlled by adaptors that link lysosomes to both dynein and kinesin motors. SKIP is one such adaptor that promotes microtubule plus-end-directed movement through its interaction with Arl8 on the lysosome surface and kinesin-1. Sequence homology between SKIP and STK11IP (also known as LIP1) led us to investigate a potential role for STK11IP at lysosomes. After first establishing that STK11IP localizes to lysosomes, we identified TMEM192, an abundant lysosomal integral membrane protein, as the major binding partner of STK11IP and demonstrated that STK11IP depends on TMEM192 for both its lysosome localization as well as its stability. Depletion studies furthermore support a role for these proteins in the control of lysosome homeostasis. Collectively, these new results define a lysosome localized complex of TMEM192 and STK11IP that we have named LyTS (“lights”).
Rapid depletion of CTCF and cohesin proteins reveals dynamic features of chromosome architecture
Authors: Liu Ning Qing , Magnitov Mikhail , Schijns Marijne , van Schaik Tom , van der Weide Robin H. , Teunissen Hans , van Steensel Bas , de Wit Elzo 
Published: August 2021

SUMMARYThe interphase genome is mainly shaped by cohesin-mediated loop extrusion and cohesin-independent compartmentalization. Extrusion is a dynamic process of cohesin loading, loop extension and release. Cohesin release is mediated by WAPL. Loss of WAPL leads to the formation of longer loops and counters compartmentalization. The dynamics of these changes in chromosome organization have been unclear. We have used acute depletion of WAPL to show that within six hours cohesin accumulates at CTCF-bound loop anchors and extended loops are formed. When we deplete WAPL and CTCF simultaneously, new loops are formed between active genes. Surprisingly, active gene clustering is independent of cohesin. Stabilization of cohesin on chromatin leads to a decrease in compartmentalization, which is rapidly restored by depletion of cohesin. Our analyses show that loop extrusion counters compartmentalization and plays a central role in many aspects of chromosome organization.HIGHLIGHTSCohesin accumulates at CTCF-mediated chromatin loop anchors following WAPL depletion.Actively transcribed genes form long-range gene clusters independent of the cohesin complex.Plumes are a novel architectural feature of juxtaposed DNA formed by cohesin at open chromatin islands.Chromosome compartmentalization can be uncoupled from nuclear lamina interactions.
Ankylosis homologue mediates cellular efflux of ATP, not pyrophosphate
Authors: Szeri Flora , Niaziorimi Fatemeh , Donnelly Sylvia , Fariha Nishat , Tertyshnaia Mariia , Patel Drithi , Lundkvist Stefan , van de Wetering Koen 
Published: August 2021

AbstractThe plasma membrane protein Ankylosis Homologue (ANKH, mouse ortholog: Ank) prevents pathological mineralization of joints by controlling extracellular levels of the mineralization inhibitor pyrophosphate (PPi). It was long thought that ANKH acts by transporting PPi into the joints, but we recently showed that ANKH releases large amounts of nucleoside triphosphates (NTPs), predominantly ATP, into the culture medium. This ATP is converted extracellularly into PPi and AMP by the ectoenzyme Ectonucleotide Pyrophosphatase Phosphodiesterase 1 (ENPP1). We could not rule out, however, that cells also release PPi directly via ANK. We now addressed this question by determining the effect of a complete absence of ENPP1 on ANKH-dependent extracellular PPi concentrations. Introduction of ANKH in ENPP1-deficient HEK293 cells resulted in robust cellular ATP release without the concomitant increase in extracellular PPi seen in ENPP1-proficient cells.Ank-activity was previously shown to be responsible for about 75% of the PPi found in mouse bones. However, bones of Enpp1-/- mice contained < 2.5% of the PPi found in bones of wild type mice, showing that Enpp1-activity is also a prerequisite for Ank-dependent PPi incorporation into the mineralized bone matrix in vivo. Hence, ATP release precedes ENPP1-mediated PPi formation. We find that ANKH also provides about 25% of plasma PPi, whereas we have previously shown that 60-70 % of plasma PPi is derived from the NTPs extruded by the ABC transporter, ABCC6. Both transporters that keep plasma PPi at sufficient levels to prevent pathological calcification, therefore do so by extruding NTPs rather than PPi itself.
DENR/MCTS1 knockdown modulates repeat-associated non-AUG translation
Authors: Green Katelyn M. , Miller Shannon L. , Malik Indranil , Todd Peter K. 
Published: August 2021

AbstractRepeat associated non-AUG (RAN) translation of mRNAs containing repeat-expansion mutations produces toxic peptides in neurons of patients suffering from neurodegenerative diseases. Recent findings indicate that RAN translation in diverse model systems is not inhibited by cellular stressors that impair global translation through phosphorylation of the alpha subunit of eIF2, the essential eukaryotic translation initiation factor that brings the initiator tRNA to the 40S ribosome. Usingin vitro, cell-based, andDrosophilamodels, we examined the role of alternative ternary complex factors that may function in place of eIF2, including eIF2A, eIF2D, and DENR/MCTS1. Among these factors, DENR knockdown had the greatest inhibitory effect on RAN translation of expanded GGGGCC and CGG repeat reporters, and its reduction improved survival ofDrosophilaexpressing expanded GGGGCC repeats. Taken together, these data support a role for alternative initiation factors in RAN translation and suggest they may serve as novel therapeutic targets in neurodegenerative disease.
Discriminating predation attempt outcomes during natural foraging using the post-buzz pause in Japanese large-footed bat Myotis macrodactylus
Authors: Mizuguchi Yuuka , Fujioka Emyo , Heim Olga , Fukui Dai , Hiryu Shizuko 
Published: August 2021

AbstractBats emit a series of echolocation calls with an increasing repetition rate (the terminal buzz), when attempting to capture prey. This is often used as an acoustic indicator of prey-capture attempts. However, because it is directly linked to foraging efficiency, predation success is a more useful measure than predation attempts in ecological research. The characteristics of echolocation calls that consistently signify predation success across different situations have not been identified. Due to additional influencing factors, identification of these characteristics is particularly challenging for wild bats foraging in their natural environment compared to those in flight chambers. This study documented the natural foraging behavior of wild Japanese large-footed bat Myotis macrodactylus using synchronized acoustic and video recordings. From the video recordings, we could assign 137 attacks to three outcome categories: prey captured (51.8%), prey dropped (29.2%), and failed attempt (19%). Based on previous indications from laboratory studies that the length of the silent interval following the terminal buzz (post-buzz pause) might reflect the prey capture outcome, we compared post-buzz pause durations among categories of attack outcomes. The post-buzz pause was longest in the case of successful capture, suggesting that the length of the post-buzz pause is a useful acoustic indicator of predation success during natural foraging in M. macrodactylus. Our finding will advance the study of bat foraging behavior using acoustic data, including estimations of foraging efficiency and analyses of feeding habitat quality.Summary statementWe investigated the natural foraging behavior of wild Myotis macrodactylus and found that the length of the post-buzz pause is a useful acoustic indicator of predation success.
Highly sensitive genetically-encoded sensors for population and subcellular imaging of cAMP in vivo
Authors: Massengill Crystian I , Bayless-Edwards Landon , Ceballos Cesar C , Cebul Elizabeth R , Qin Maozhen , Whorton Matthew R , Ye Bing , Mao Tianyi , Zhong Haining 
Published: August 2021

AbstractCyclic adenosine monophosphate (cAMP) integrates information from diverse G protein-coupled receptors, such as neuromodulator receptors, to regulate pivotal biological processes in a cellular- and subcellular-specific manner. However, in vivo cellular-resolution imaging of cAMP dynamics in neurons has not been demonstrated. Here, we screen existing genetically-encoded cAMP sensors, and further develop the best performer to derive three improved variants, called cAMPFIREs. These sensors exhibit up to ten-fold increased sensitivity to cAMP and a corrected, cytosolic distribution. cAMPFIREs are compatible with both ratiometric and fluorescence lifetime imaging, and can detect cAMP dynamics elicited by norepinephrine at physiologically-relevant, nanomolar concentrations. Imaging of cAMPFIREs in awake mice reveals tonic levels of cAMP in cortical neurons that are associated with wakefulness, and are differentially regulated in different subcellular compartments. Furthermore, enforced locomotion elicits neuron-specific, bidirectional cAMP dynamics, in part, mediated by norepinephrine. Finally, cAMPFIREs also function in Drosophila, suggesting that they have broad applicability for studying intracellular signaling in vivo.
Context-Dependent Flux Coupling via Conserved Small-Molecule Regulatory Structures
Authors: Euler Christian , Mahadevan Radhakrishnan 
Published: August 2021

SummarySmall-molecule regulation modulates enzyme activity and is widespread in metabolic networks. However, the organization of small-molecule regulatory networks and its generalized role is not well understood. We analyze the structure of the genome-wide Escherichia coli small-molecule regulatory network (SMRN) to reveal that it optimizes controllability in the metabolic network. This is achieved by conserved, highly overabundant incoherent feedforward loops. Using multi-omics data, we characterize loop examples in central carbon metabolism. These use signals from hypothesized flux-sensing metabolites phosphoenolpyruvate, α-ketoglutarate, citrate, and malate to distinguish between glycolysis, gluconeogenesis, and glyoxylate shunt activity to differentially couple fluxes across these major modes of metabolism. Our results suggest that coupling of fluxes by direct modulation of enzyme activity is an emergent property of the SMRN that depends heavily on both regulatory structure and metabolic context via the metabolome, and further that flux sensing and coupling may be a global property of the metabolic network.
Excluding loci with substitution saturation improves inferences from phylogenomic data
Authors: Duchêne David A. , Mather Niklas , Van Der Wal Cara , Ho Simon Y.W. 
Published: August 2021

AbstractThe historical signal in nucleotide sequences becomes eroded over time by substitutions occurring repeatedly at the same sites. This phenomenon, known as substitution saturation, is recognized as one of the primary obstacles to deep-time phylogenetic inference using genome-scale data sets. We present a new test of substitution saturation and demonstrate its performance in simulated and empirical data. For some of the 36 empirical phylogenomic data sets that we examined, we detect substitution saturation in around 50% of loci. We found that saturation tends to be flagged as problematic in loci with highly discordant phylogenetic signals across sites. Within each data set, the loci with smaller numbers of informative sites are more likely to be flagged as containing problematic levels of saturation. The entropy saturation test proposed here is sensitive to high evolutionary rates relative to the evolutionary timeframe, while also being sensitive to several factors known to mislead phylogenetic inference, including short internal branches relative to external branches, short nucleotide sequences, and tree imbalance. Our study demonstrates that excluding loci with substitution saturation can be an effective means of mitigating the negative impact of multiple substitutions on phylogenetic inferences.
Comparative kinetic analysis of ascorbate (Vitamin-C) recycling dehydroascorbate reductases from plant and human
Authors: Das Bhaba Krishna , Kumar Amit , Sreekumar Sreeshma Nellootil , Ponraj Kannapiran , Gadave Kaustubh , Kumar Saravanan , Achary V. Mohan Murali , Ray Pratima , Reddy Malireddy K. , Arockiasamy Arulandu 
Published: August 2021

AbstractAscorbate, a primary antioxidant, gets readily oxidized to dehydroascorbate (DHA). Hence, recycling by dehydroascorbate reductase (DHAR) enzymes is vital for protection from cellular oxidative stress in eukaryotes. However, a detailed kinetic analysis of plant DHARs and their human orthologs; chloride intracellular channels (HsCLICs) is lacking. We demonstrate that DHAR from stress adapted pearl milletPennisetum glaucum(PgDHAR) shows the highest turnover rate whereasHsCLIC1, 3, and 4 reduce DHA, albeit at lower rates. We further show that the catalytic cysteine is susceptible to varying levels of oxidation, supported by crystal structures and mass-spectrometry analysis. The differences in kinetic parameters among plant and human DHA reductases corroborate with the levels of reactive oxygen species H2O2encountered in their respective intracellular environment. Our findings may have broader implications in crop improvement using pearl millet DHAR, and anti-cancer therapeutics targeting Vitamin-C recycling capability of human CLICs.
The ascension of executives' tenure, corporate risk-taking and corporate performance: evidence from Malaysia
Authors: Atayah Osama F. , Najaf Khakan , Subramaniam Ravichandran K. , Chin Phaik Nie 
Published: August 2021

PurposeThis study aims to investigate the implication of top executives’ number of years of experience (tenure) on corporate risk-taking behaviour and corporate performance in Malaysian corporations.Design/methodology/approachTo test the hypothesis efficiently, the authors have extracted the data from Bloomberg for 788 listed companies of the Malaysian Stock Exchange. The methodology entails ordinary least squares regressions, quantile regression and dynamic system generalized method of moments model.FindingsFirst, the authors show that executive management tenure has a significant negative relationship with corporate risk-taking. It means that the long-tenured executives tend to undertake less risky strategies and decisions. Second, this study reveals that the longer executive management tenure has a positive relationship with corporate performance. Third, the moderating effect of corporate risk-taking with executive tenure (Tenure dummy*Risk) has a negative relationship with the corporate performance by 1%.Practical implicationsIt implies that the appointment of experienced executive management contributes towards corporate performance directly. However, experienced management trends take less risk, which eventually results in mitigating the corporate performance. On that basis, the findings are significant in highlighting the usefulness of executive leadership term and offers insights to academics, practitioners and policymakers.Originality/valueThis paper is novel since it is unique in evaluating the executive tenure and the preferences to handle risk strategies and how that impact the firm performance.