bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function
Authors: Mastwal Surjeet , Li Xinjian , Stowell Rianne , Manion Matthew , Zhang Wenyu , Kim Nam-Shik , Yoon Ki-jun , Song Hongjun , Ming Guo-li , Wang Kuan Hong 
Published: February 2023

ABSTRACTDopamine system dysfunction is commonly implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive to such pharmacological treatments and novel research paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in theArcorDISC1genes to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but notArcmutant mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits inDISC1mutant mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders.
SIN3 gene regulatory activity is linked to RNA polymerase II pausing
Authors: Soukar Imad , Mitra Anindita , Pile Lori 
Published: February 2023

ABSTRACTThe chromatin environment has a significant impact on gene expression. Chromatin structure is highly regulated by histone modifications and RNA polymerase II binding dynamics. The SIN3 histone modifying complex regulates the chromatin environment leading to changes in gene expression. InDrosophila melanogaster, theSin3Agene is alternatively spliced to produce different protein isoforms, two of which include SIN3 220 and SIN3 187. Both SIN3 isoforms are scaffolding proteins that interact with several other factors to regulate the chromatin landscape. The mechanism through which the SIN3 isoforms regulate chromatin is not well understood. Here, we analyze publicly available data sets to allow us to ask specific questions on how SIN3 isoforms regulate chromatin and gene activity. We determined that genes repressed by the SIN3 isoforms exhibited enrichment in histone H3K4me2 and H3K4me3 near the transcription start site. We observed an increase in the amount of paused RNA polymerase II on the promoter of genes repressed by the isoforms as compared to genes that require SIN3 for maximum activation. Furthermore, we analyzed a subset of genes regulated by SIN3 187 that suggest a mechanism in which SIN3 187 might exhibit hard regulation as well as soft regulation. Data presented here expand our knowledge of how the SIN3 isoforms regulate the chromatin environment and RNA polymerase II binding dynamics.Summary statementSIN3 cofactors can activate or repress genes. Using bioinformatic analysis, we find that histone methylation and RNA polymerase II binding profiles differ at SIN3-regulated genes with distinct transcriptional outcomes.
Development of a Robust Consensus Modeling Approach for Identifying Cellular and Media Metabolites Predictive of Mesenchymal Stromal Cell Potency
Authors: Van Grouw Alexandria , Colonna Maxwell B. , Maughon Ty S. , Shen Xunan , Larey Andrew M. , Moore Samuel G. , Yeago Carolyn , Fernández Facundo M. , Edison Arthur S. , Stice Steven L. , Bowles-Welch Annie C. , Marklein Ross A. 
Published: February 2023

AbstractMesenchymal stromal cells (MSCs) have shown promise in regenerative medicine applications due in part to their ability to modulate immune cells. However, MSCs demonstrate significant functional heterogeneity in terms of their immunomodulatory function because of differences in MSC donor/tissue source, as well as non-standardized manufacturing approaches. As MSC metabolism plays a critical role in their ability to expand to therapeutic numbersex vivo, we comprehensively profiled intracellular and extracellular metabolites throughout the expansion process to identify predictors of immunomodulatory function (T cell modulation and indoleamine-2,3-dehydrogenase (IDO) activity). Here, we profiled media metabolites in a non-destructive manner through daily sampling and nuclear magnetic resonance (NMR), as well as MSC intracellular metabolites at the end of expansion using mass spectrometry (MS). Using a robust consensus machine learning approach, we were able to identify panels of metabolites predictive of MSC immunomodulatory function for 10 independent MSC lines. This approach consisted of identifying metabolites in 2 or more machine learning models and then building consensus models based on these consensus metabolite panels. Consensus intracellular metabolites with high predictive value included multiple lipid classes (such as phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins) while consensus media metabolites included proline, phenylalanine, and pyruvate. Pathway enrichment identified metabolic pathways significantly associated with MSC function such as sphingolipid signaling and metabolism, arginine and proline metabolism, and autophagy. Overall, this work establishes a generalizable framework for identifying consensus predictive metabolites that predict MSC function, as well as guiding future MSC manufacturing efforts through identification of high potency MSC lines and metabolic engineering.
eXclusionarY: Ten years later, where are the sex chromosomes in GWAS?
Authors: Sun Lei , Wang Zhong , Lu Tianyuan , Manolio Teri A. , Paterson Andrew D. 
Published: February 2023

SummaryTen years ago, a detailed analysis of genome-wide association studies showed that only 33% of the studies included the X chromosome. Multiple recommendations were made to combat eXclusion. Here we re-surveyed the research landscape to determine if these earlier recommendations had been translated. Unfortunately, among the summary statistics reported in 2021 in the NHGRI-EBI GWAS catalog, only 25% provided results for the X chromosome and 3% for the Y chromosome, suggesting that the eXclusion phenomenon documented earlier not only persists but has also expanded into an eXclusionarY problem. Normalizing by physical length of the chromosome, the average number of studies published until 11/29/22 with genome-wide significant findings on the X chromosome is ~1 study/Mb. In contrast, it ranges from ~6 to ~16 studies/Mb for chromosomes 4 and 19, respectively. Compared with the autosomal growth rate of ~0.086 studies/Mb/year over the last decade, studies of the X chromosome grew at less than one-seventh that rate, only ~0.012 studies/Mb/year. Among the studies that reported significant association on the X chromosome, there were extreme heterogeneities in how they analyzed the data and documented the results, suggesting the need for guidelines. Not surprisingly, among the 430 scores sampled from the PolyGenic Score catalog, 0% contained weights for sex chromosomal SNPs. To overcome the dearth of sex chromosome analyses, we provide five sets of recommendations and future directions. Finally, until the sex chromosomes are included in a whole-genome study, instead of GWAS, we propose they be more properly referred to as “AWAS” for “autosome-wide scan”.
Naïve T lymphocytes chemotax to CCL21 but not to S1P-rich serum
Authors: Garcia-Seyda Nicolas , Song Solene , David-Broglio Luc , Matti Christoph , Artinger Marc , Biarnes-Pelicot Martine , Valignat Marie-Pierre , Legler Daniel F. , Bajénoff Marc , Theodoly Olivier 
Published: February 2023

SummaryNaïve T lymphocytes traffic through the organism in their search for antigen, alternating between blood and secondary lymphoid organs. Lymphocyte homing to lymph nodes relies on the chemokine CCL21, while exit into efferent lymphatics relies on the sphingolipid S1P. Surprisingly, while both molecules are claimed chemotactic, a quantitative analysis of naïve T lymphocyte migration along defined gradients is missing. Here, we used a reductionistin vitroapproach to study the real-time, single-cell response of naïve T lymphocytes to CCL21 and S1P-rich serum. Using high-throughput microfluidic and optical micropatterning ad hoc tools, we show that CCL21 triggers long-range chemotaxis whereas S1P-rich serum does not. Instead, S1P-rich serum triggers a transient polarization that may represent a brief transmigration step through exit portals. Our data thus validate naïve T lymphocyte chemotaxis towards CCL21 but not S1P, which complementsin vivoobservations and is of interest for a better tailoring of immunosuppressive drugs.
Commensal bacteria can inhibit the growth ofP. aeruginosain cystic fibrosis airway infections through a released metabolite
Authors: Tony-Odigie Andrew , Dalpke Alexander H. , Boutin Sébastien , Yi Buqing 
Published: February 2023

AbstractIn cystic fibrosis (CF), infections withPseudomonas aeruginosaor other typical pathogens play a critical role in eliciting disease progression, leading to tissue damage and finally loss of lung function. Previous observations showed that the presence of various commensal bacteria and a higher airway microbiome diversity were associated with better lung function and less severe disease burden. Thus, the hypothesis was raised that commensal bacteria might be able to interfere with pathogenic bacteria. In this study, we aimed to identify airway commensal bacteria that inhibit the growth ofP. aeruginosa.Through a screening experiment of co-culture withP. aeruginosaPAO1, we could identify more than 30 CF commensal strains from various species that inhibited the growth ofP. aeruginosa. With multiple selected strains, we further verified the results withP. aeruginosaCF isolates and several other pathogens isolated from CF patients, and most of the identified commensal strains showed consistent results strongly inhibiting the growth of diverse CF pathogens.The underlying mechanisms of the growth-inhibition effects were first investigated through genomic analysis by comparing strains with and without growth-inhibition effects, which revealed that genes responsible for carbohydrate transport and metabolism were highly enriched in the inhibitory commensals. Metabolite analysis and functional analysis showed that commensals with inhibitory effects produce large amounts of acetate. Exogenous addition of acetate under a low pH inhibited the growth ofP. aeruginosa, indicating acetate produced and released by commensals may affect the growth ofP. aeruginosaliving in the same microenvironment.In summary, through co-culture ofP. aeruginosawith commensals, we could identify that a variety of airway commensal strains can inhibit the growth ofP. aeruginosaby producing acetate. The data provide insights into possible novel strategies for controlling infections in people with CF and also emphasize the importance of preserving airway commensals when designing infection treatment strategies.
Assembly and operation of a cooling stage to immobilizeC. eleganson their culture plates
Authors: Wang Yao L. , Grooms Noa William Franklin , Ma Claire , Chung Samuel H. 
Published: February 2023

AbstractHigh-resolutionin vivomicroscopy approaches can reveal subtle information and fine details inside the model animalCaenorhabditis elegans(C. elegans) but requires strong animal immobilization. Unfortunately, most current immobilization techniques require substantial manual effort, rendering high-resolution imaging low-throughput. We greatly simplify theC. elegansimmobilization procedure by using a cooling approach that can easily immobilize entire populations ofC. elegansdirectly on their cultivation plates. The cooling stage can establish and maintain a wide range of temperatures on the cultivation plate and ensures even temperature distribution across the agarose surface. In this article, we document the whole process of building the cooling stage from scratch. We envision that a typical researcher can build an operational cooling stage in their lab following our protocol without difficulty. We show how to utilize the cooling stage under three protocols, which have advantages for different experiments. We also show an example cooling profile of the stage as it approaches its final temperature and include some helpful tips in using cooling immobilization.
Correspondence between functional scores from deep mutational scans and predicted effects on protein stability
Authors: Gerasimavicius Lukas , Livesey Benjamin J , Marsh Joseph A. 
Published: February 2023

AbstractMany methodologically diverse computational methods have been applied to the growing challenge of predicting and interpreting the effects of protein variants. As many pathogenic mutations have a perturbing effect on protein stability or intermolecular interactions, one highly interpretable approach is to use protein structural information to model the physical impacts of variants and predict their likely effects on protein stability and interactions. Previous efforts have assessed the accuracy of stability predictors in reproducing thermodynamically accurate values and evaluated their ability to distinguish between known pathogenic and benign mutations. Here, we take an alternate approach, and explore how well stability predictor scores correlate with functional impacts derived from deep mutational scanning (DMS) experiments. In this work, we compare the predictions of 9 protein stability-based tools against mutant protein fitness values from 45 independent DMS datasets, covering 161,441 unique single amino acid variants. We find that FoldX and Rosetta show the strongest correlations with DMS-based functional scores, similar to their previous top performance in distinguishing between pathogenic and benign variants. For both methods, performance is considerably improved when considering intermolecular interactions from protein complex structures, when available. Finally, we also highlight that predicted stability effects show consistently higher correlations with certain DMS experimental phenotypes, particularly those based upon protein abundance, and, in certain cases, can be competitive with other sequence-based variant effect prediction methodologies for predicting functional scores from DMS experiments.
Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue
Authors: Many Gina M. , Sanford James A. , Sagendorf Tyler J. , Hou Zhenxin , Nigro Pasquale , Whytock Katie , Amar David , Caputo Tiziana , Gay Nicole R. , Gaul David A. , Hirshman Michael , Jimenez-Morales David , Lindholm Malene E. , Muehlbauer Michael J. , Vamvini Maria , Bergman Bryan , Fernández Facundo M. , Goodyear Laurie J. , Ortlund Eric A. , Sparks Lauren M. , Xia Ashley , Adkins Joshua N. , Bodine Sue C. , Newgard Christopher B. , Schenk Simon ,   The MoTrPAC Study Group
Published: February 2023

AbstractSubcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training and sex on its molecular landscape has not been fully established. Utilizing an integrative multi-omics approach with data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we identified profound sexual dimorphism in the dynamic response of rat scWAT to endurance exercise training. Despite similar cardiorespiratory improvements, only male rats reduced whole-body adiposity, scWAT adipocyte size, and total scWAT triglyceride abundance with training. Multi-omic analyses of adipose tissue integrated with phenotypic measures identified sex-specific training responses including enrichment of mTOR signaling in females, while males displayed enhanced mitochondrial ribosome biogenesis and oxidative metabolism. Overall, this study reinforces our understanding that sex impacts scWAT biology and provides a rich resource to interrogate responses of scWAT to endurance training.
Recognizing the opponent: the consolidation of long-term social memory in zebrafish males
Authors: Cavallino Luciano , Scaia María Florencia , Pozzi Andrea Gabriela , Pedreira María Eugenia 
Published: February 2023

AbstractRecognizing and remembering another individual in a social context could be beneficial for individual fitness. Especially in agonistic encounters, remembering an opponent and the previous fight could allow avoiding new conflicts. Considering this, we hypothesized that this type of social interaction forms a long-term recognition memory lasting several days. It has been shown that a second encounter 24 hours later between the same pair of zebrafish males is resolved with lower levels of aggression. Here, we evaluated if this behavioral change could last for longer intervals and a putative mechanism associated with memory storage: the recruitment of NMDA receptors. We found that if a pair of zebrafish males fight and 48 or 72 hours later fight again, they resolved the second encounter with lower levels of aggression. However, if immediately after the first encounter opponents were exposed to MK-801 (NMDA receptor antagonist), they resolve the second one with the same levels of aggression, that is, no reduction in aggressive behaviors was observed. These results suggest the formation of a long-term social memory related to recognizing a particular opponent and/or the outcome and features of a previous fight.
Visualizing and exploring patterns of large mutational events with SigProfilerMatrixGenerator
Authors: Khandekar Azhar , Vangara Raviteja , Barnes Mark , Díaz-Gay Marcos , Abbasi Ammal , Bergstrom Erik N. , Steele Christopher D. , Pillay Nischalan , Alexandrov Ludmil B. 
Published: February 2023

ABSTRACTBackgroundAll cancers harbor somatic mutations in their genomes. In principle, mutations affecting between one and fifty base pairs are generally classified as small mutational events. Conversely, large mutational events affect more than fifty base pairs, and, in most cases, they encompass copy-number and structural variants affecting many thousands of base pairs. Prior studies have demonstrated that examining patterns of somatic mutations can be leveraged to provide both biological and clinical insights, thus, resulting in an extensive repertoire of tools for evaluating small mutational events. Recently, classification schemas for examining large-scale mutational events have emerged and shown their utility across the spectrum of human cancers. However, there has been no standard bioinformatics tool that allows visualizing and exploring these large-scale mutational eventsResultsHere, we present a new version of SigProfilerMatrixGenerator that now delivers integrated capabilities for examining large mutational events. The tool provides support for examining copy-number variants and structural variants under two previously developed classification schemas and it supports data from numerous algorithms and data modalities. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment.ConclusionsThe new version of SigProfilerMatrixGenerator provides the first standardized bioinformatics tool for optimized exploration and visualization of two previously developed classification schemas for copy number and structural variants. The tool is freely available athttps://github.com/AlexandrovLab/SigProfilerMatrixGeneratorwith an extensive documentation athttps://osf.io/s93d5/wiki/home/.
Conflict during learning reconfigures the neural representation of positive valence and approach behaviour
Authors: Molina-García Laura , Colinas-Fischer Susana , Benavides-Laconcha Sergio , Lin Lucy , Clark Emma , Treloar Neythen J. , García-Minaur-Ortíz Blanca , Barnes Chris P. , Barrios Arantza 
Published: February 2023

AbstractPunishing and rewarding experiences can change the valence of sensory stimuli and guide animal behaviour in opposite directions, resulting in avoidance or approach. Often, however, a stimulus is encountered with both positive and negative experiences. How is such conflicting information represented in the brain and resolved into a behavioural decision? We address this question by dissecting a circuit for sexual conditioning inC. elegans. In this learning paradigm, an odour is conditioned with both a punishment (starvation) and a reward (mates) resulting in odour approach. We find that negative and positive experiences are both encoded by the neuropeptide PDF-1 being released from and acting on different neurons. Each experience creates a separate, parallel memory in the circuit for odour processing. This results in the sensorimotor representation of odour being different in naïve and sexually conditioned animals despite both displaying approach. Our results reveal that the positive valence of a stimulus is not represented in the activity of any single neuron class but flexibly represented within the circuit according to the experiences and predictions associated with the stimulus.
A systematic review of the diversity and virulence correlates of metastrongyle lungworms in marine mammals
Authors: Fischbach Jared R. , Seguel Mauricio 
Published: February 2023

AbstractMetastrongyle lungworms could be particularly detrimental for diving animals such as marine mammals, however little is known of the drivers of pathogenic host-parasite relationships in this group. This systematic review analyzed the diversity of metastrongyles in marine mammals and the host and parasite traits associated with virulence. There have been at least 40 species of metastrongyles described in 66 species of marine mammals. After penalization for study biases,Halocercus hyperoodoni,Otostrongylus circumlitus,Parafilaroides gymnurus,Halocercus brasiliensis, andStenurus minorwere the metastrongyles with the widest host range. Most studies (80.12%, n=133/166) reported that metastrongyles caused bronchopneumonia, while in the cardiovascular system metastrongyles caused vasculitis in nearly half of the studies (45.45%, n=5/11) that assessed these tissues. Metastrongyles were associated with otitis in 23.08% (n=6/26) of the studies. Metastrongyle infection was considered a potential contributory to mortality in 44.78% (n=90/201) of the studies while 10.45% (n=21/201) of these studies considered metastrongyles the main cause of death. Metastrongyle species with a wider host range were more likely to induce pathogenic effects. Metastrongyles can cause significant tissue damage and mortality in marine mammals although virulent host-parasite relationships are dominated by a few metastrongyle species with wider host ranges.