bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allele frequency differences of causal variants have a major impact on low cross-ancestry portability of PRS
Authors: Saitou Marie , Dahl Andy , Wang Qingbo , Liu Xuanyao 
Published: October 2022

AbstractGenome-wide association studies (GWAS) are overwhelmingly biased toward European ancestries. Nearly all existing studies agree that transferring genetic predictions from European ancestries to other populations results in a substantial loss of accuracy. This is commonly referred to as low portability of polygenic risk scores (PRS) and is one of the most important barriers to the ethical clinical deployment of PRS. Yet, it remains unclear how much various genetic factors, such as linkage disequilibrium (LD) differences, allele frequency differences or causal effect differences, contribute to low PRS portability. In this study, we used gene expression levels in lymphoblastoid cell lines (LCLs) as a simplified model of complex traits with minimal environmental variation, in order to understand how much each genetic factor contributes to PRS portability from European to African populations. We found thatcis-genetic effects on gene expression are highly similar between European and African individuals (). This stands in stark contrast to the very low estimates ofcis-genetic correlation between Europeans and Africans in previous studies, which we demonstrate are artifacts of statistical bias. We showed that portability decreases with increasing LD differences in thecis-regions. We also found that allele frequency differences of causal variants have a striking impact on PRS portability. For example, PRS portability is reduced by more than 32% when the causalcis-variant is common (minor allele frequency, MAF > 5%) in European samples (training population) but is rarer (MAF < 5%) in African samples (prediction population). While large allele frequency differences can decrease PRS portability through increasing LD differences, we also show that causal allele frequency can significantly impact portability independently of LD. This observation suggests that improving statistical fine-mapping alone does not overcome the loss of portability caused by causal allele frequency differences. Lastly, we also found that causal allele frequency is the main genetic factor underlying differential gene expression levels across ancestries. We conclude that causal genetic effects are highly similar in Europeans and Africans, and low PRS portability is primarily due to allele frequency differences.
Fish-microbe systems in the hostile but highly biodiverse Amazonian blackwaters
Authors: Sylvain François-Étienne , Leroux Nicolas , Normandeau Eric , Custodio Jaqueline , Mercier Pierre-Luc , Bouslama Sidki , Holland Aleicia , Barroso Danilo , Val Adalberto Luis , Derome Nicolas 
Published: October 2022

AbstractAmazonian blackwaters are extremely biodiverse systems containing some of the most naturally acidic, dissolved organic carbon-rich and ion-poor waters on Earth. Physiological adaptations of fish facing these ionoregulatory challenges are unresolved but could involve microbially-mediated processes. Here, we characterize the physiological response of 964 fish-microbe systems from four blackwater Teleost species along a natural hydrochemical gradient, using dual RNA-Seq and 16S rRNA of gill samples. We find that responses to blackwaters are host-species-specific, but occasionally include the overexpression of Toll-receptors and integrins associated to interkingdom communication. Blackwater gill microbiomes are characterized by a transcriptionally-active betaproteobacterial cluster potentially interfering with epithelial permeability. We explore further blackwater fish-microbe interactions by analyzing transcriptomes of 320 axenic zebrafish larvae exposed to sterile, non-sterile and inverted (non-native bacterioplankton) blackwater. We find that axenic zebrafish do not survive well when exposed to sterile/inverted blackwater, suggesting an essential role of endogenous symbionts in blackwater fish physiology.
A pilot study of exercise training for children and adolescents with inflammatory bowel disease: an evaluation of feasibility, safety, satisfaction, and efficacy
Authors: Bjelica Mila , Walker Rachel G. , Obeid Joyce , Issenman Robert M. , Timmons Brian W. 
Published: October 2022

AbstractBackgroundChildren with inflammatory bowel disease (IBD) experience extra-intestinal side effects including altered body composition, impaired muscle strength and aerobic capacity. Exercise training may remedy these issues.PurposeTo assess the feasibility, safety, participant satisfaction and efficacy of a training program for youth with IBD.MethodsChildren with IBD completed 16 weeks of training (2 supervised+1 home sessions per week). Feasibility was assessed by tracking recruitment, adherence, and compliance rates. Safety was assessed by tracking symptoms and adverse events. Post-training interviews gauged satisfaction. Circulating inflammatory markers, body composition, muscle strength, aerobic fitness, and habitual physical activity, were measured at baseline, mid-training (8 weeks), and post-training.ResultsEleven youth were recruited and 10 completed the study. Participants adhered to 28±1 of 32 prescribed supervised sessions and 8±4 of 16 prescribed home sessions. There were no adverse events, and overall feedback on training was positive. Post-training, we observed an increase in lean mass (+2.4±1.1 kg), bone density (+0.0124±0.015 g•cm-2), aerobic fitness (+2.8±5.7 mL•kgLM-1•min-1), and vigorous physical activity levels (+13.09± 8.95 min•hr-1) but no change in inflammation or muscle strength.ConclusionSupervised exercise training is feasible, safe, and effective for youth with IBD and should be encouraged.
Comparison of common respiratory pathogen detection in nasopharyngeal swabs, saline gargle specimens, pleural effusion and lower respiratory tract samples
Authors: Anastasiou Olympia E. 
Published: October 2022

AbstractMultiplex PCR panels have been used for the diagnosis of viral respiratory infections in the last years. While the types of manufacturer validated and thus officially approved materials are usually limited, the tested materials in the clinical routine or studies often vary, which presents a challenge in light of the new EU-IVDR guideline. Aim of our present study was to evaluate if testing of lower respiratory tract (LRT) or saline gargle specimens (SGS) provided an advantage compared to the testing of nasopharyngeal swabs (NPS) and if the testing of pleural effusions (PE) provided any advantage compared to the testing of LRT samples.We included 367 NPS vs LRT cases, of which 202 (55%) were negative in both samples, 108 (29%) were positive in both samples, 28 (8%) had a positive NPS and a negative LRT and 29 (8%) had a negative NPS but a positive LRT, with no significant differences between immunocompetent and immunosuppressed cases. We included 46 NPS vs SGS cases, of which 18 (39%) were negative in both samples, 18 (39%) were positive in both samples, 4 (9%) had a positive NPS and a negative SGS and 6 (13%) had a negative NPS but a positive SGS. Out of the 82 tested PE samples, only one (1%) was positive for Influenza B RNA (detected in the PE but not LTR), while for 5 positive LTR samples no viral genome could be detected in the PE. The samples were tested with the FTD respiratory viral panel for common respiratory viruses.Testing of a lower respiratory tract sample after a negative upper respiratory tract sample may have an incremental diagnostic value. Gargle and nasopharyngeal swab samples seem to have a comparable diagnostic performance, while pleural effusion is a substandard material for the diagnosis of common respiratory virus infections.
Morpho-electric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex
Authors: Chartrand Thomas , Dalley Rachel , Close Jennie , Goriounova Natalia A. , Lee Brian R. , Mann Rusty , Miller Jeremy A. , Molnar Gabor , Mukora Alice , Alfiler Lauren , Baker Katherine , Bakken Trygve E. , Berg Jim , Bertagnolli Darren , Braun Thomas , Brouner Krissy , Casper Tamara , Csajbok Eva Adrienn , Dee Nick , Egdorf Tom , Enstrom Rachel , Galakhova Anna A. , Gary Amanda , Gelfand Emily , Goldy Jeff , Hadley Kristen , Heistek Tim S. , Hill DiJon , Jorstad Nik , Kim Lisa , Kocsis Agnes Katalin , Kruse Lauren , Kunst Michael , Leon Gabriela , Long Brian , Mallory Matthew , McGraw Medea , McMillen Delissa , Melief Erica J. , Mihut Norbert , Ng Lindsay , Nyhus Julie , Omstead Victoria , Peterfi Zoltan , Pom Alice , Potekhina Lydia , Rajanbabu Ramkumar , Rozsa Marton , Ruiz Augustin , Sandle Joanna , Sunkin Susan M. , Szots Ildiko , Tieu Michael , Toth Martin , Trinh Jessica , Vargas Sara , Vumbaco David , Williams Grace , Wilson Julia , Yao Zizhen , Barzo Pal , Cobbs Charles , Ellenbogen Richard G. , Esposito Luke , Ferreira Manuel , Gouwens Nathan W. , Grannan Benjamin , Gwinn Ryder P. , Hauptman Jason S. , Jarsky Tim , Keene C.Dirk , Ko Andrew L. , Koch Christof , Ojemann Jeffrey G. , Patel Anoop , Ruzevick Jacob , Silberberg Daniel L. , Smith Kimberly , Sorensen Staci A. , Tasic Bosiljka , Ting Jonathan T. , Waters Jack , de Kock Christiaan P.J. , Mansvelder Huib D. , Tamas Gabor , Zeng Hongkui , Kalmbach Brian , Lein Ed S. 
Published: October 2022

AbstractNeocortical layer 1 (L1) is a site of convergence between pyramidal neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion of human neocortex is marked by distinctive pyramidal neuron types with extensive branching in L1, but whether L1 interneurons are similarly diverse is underexplored. Using patch-seq recordings from human neurosurgically resected tissues, we identified four transcriptomically defined subclasses, unique subtypes within those subclasses and additional types with no mouse L1 homologue. Compared with mouse, human subclasses were more strongly distinct from each other across all modalities. Accompanied by higher neuron density and more variable cell sizes compared with mouse, these findings suggest L1 is an evolutionary hotspot, reflecting the increasing demands of regulating the expanding human neocortical circuit.One Sentence SummaryUsing transcriptomics and morpho-electric analyses, we describe innovations in human neocortical layer 1 interneurons.
Sex-specific effects of voluntary wheel running on behavior and the gut microbiota-immune-brain axis in mice
Authors: Williams Zoë AP , Szyszkowicz Joanna Kasia , Osborne Natasha , Allehyany Bshaier , Nadon Christophe , Udechukwu Maryann Chinonye , Santos Ana , Audet Marie-Claude 
Published: October 2022

AbstractPhysical exercise has been positioned as a promising strategy to prevent and/or alleviate anxiety and depression, but the mechanisms underlying its effects on mental health have yet to be entirely determined. Although the prevalence of depression and anxiety in women is about twice that of men, very few studies have examined whether physical exercise could affect mental health differently according to sex. This study examined, in mice, the sex-specific effects of voluntary exercise on body weight, depressive- and anxiety-like behaviors, as well as different markers along the gut microbiota-immune-brain axis. Male and female C57BL/6N mice had voluntary access to running wheels in their home-cages for 24 days or were left undisturbed in identical home-cages without running wheels. Behaviors were then examined in the open field, Splash, elevated plus maze, and tail suspension tests. Gene expression of pro-inflammatory cytokines, microglia activation-related genes, and tight junction proteins was determined in the jejunum and the hippocampus, while microbiota composition and predicted function were verified in cecum contents. Voluntary exercise limited weight gains, reduced anxiety-like behaviors, and altered grooming patterns in males exclusively. Although the exercise intervention resulted in changes to brain inflammatory activity and to cecal microbiota composition and inferred function in both sexes, reductions in the jejunal expression of pro-inflammatory markers were observed in females only. These findings support the view that voluntary exercise, even when performed during a short period, is beneficial for mental and intestinal health and that its sex-specific effects on behavior could be, at least in part, mediated by the gut microbiota-immune-brain axis.
Skeletal muscle nuclei in mice are not post-mitotic
Authors: Borowik Agnieszka K , Davidyan Arik , Peelor Frederick F , Voloviceva Evelina , Doidge Stephen , Bubak Matthew P , Mobley Christopher B , McCarthy John J , Dupont-Versteegden Esther E , Miller Benjamin F 
Published: October 2022

AbstractThe skeletal muscle research field generally accepts that nuclei in skeletal muscle fibers (i.e., myonuclei) are post-mitotic and unable to proliferate. Because our deuterium oxide (D2O) labeling studies showed DNA synthesis in skeletal muscle tissue, we hypothesized that resident myonuclei can replicatein vivo. To test this hypothesis, we used a mouse model that temporally labeled myonuclei with GFP followed by D2O labeling during normal cage activity, functional overload, and with satellite cell ablation. During normal cage activity, we observed deuterium enrichment into myonuclear DNA in 7 out of 7 plantaris (PLA), 6 out of 6 tibialis anterior (TA), 5 out of 7 gastrocnemius (GAST) and 7 out of 7 quadriceps (QUAD). The average fractional synthesis rates (FSR) of DNA in myonuclei were: 0.0202 ± 0.0093 in PLA, 0.0239 ± 0.0040 in TA, 0.0076 ± 0. 0058 in GAST, and 0.0138 ± 0.0039 in QUAD, while there was no replication in myonuclei from EDL. These FSR values were largely reproduced in the overload and satellite cell ablation conditions although there were higher synthesis rates in the overloaded PLA muscle. We further provided evidence that myonuclear replication is through endoreplication that results in polyploidy. These novel findings contradict the dogma that skeletal muscle nuclei are post-mitotic and open potential avenues to harness the intrinsic replicative ability of myonuclei for muscle maintenance and growth.Graphical Abstract
Machine learning unveils latent architecture of superiority illusion that predicts visual illusion perception and metacognitive performance
Authors: Matsuyoshi Daisuke , Isato Ayako , Yamada Makiko 
Published: October 2022

AbstractHumans are typically inept at evaluating their abilities and predispositions, while often disregarding such lack of metacognitive insight into their capacities and even augmenting (albeit illusorily) self-evaluation such that they should have more desirable traits than an average peer. This superiority illusion helps maintain a healthy mental state. However, the scope and range of its influence on broader human behavior, especially perceptual tasks, remain elusive. As belief shapes the way people perceive and recognize, the illusory self-superiority belief potentially regulates our perceptual and metacognitive performance. In this study, we used hierarchical Bayesian estimation and machine learning of signal detection theoretic measures to understand how superiority illusion influences visual perception and metacognition for Ponzo illusion. Our results demonstrated that superiority illusion correlated with visual illusion magnitude and metacognitive performance. Next, we used machine learning with a relaxed elastic net and unveiled the latent architecture that underlies the correlations. We revealed that the “extraversion” superiority dimension tapped into visual illusion magnitude and metacognitive ability. In contrast, the “honesty-humility” and “neuroticism” dimensions were only predictive of visual illusion magnitude and metacognitive ability, respectively. These results suggest common and distinct influences of superiority features on perceptual sensitivity and metacognition. Our findings contribute to the accumulating body of evidence indicating that the superiority illusion leverage is far-reaching, even to visual perception.Significance StatementsPeople have a cognitive bias to overestimate their abilities above the mean (superiority illusion) and thereby help maintain a healthy mental state. In this work, we show that the influences of superiority illusion are more extensive than previously thought. We find that superiority illusion correlated with visual illusion magnitude and metacognitive performance. Furthermore, using hierarchical Bayesian estimation and machine learning, we unveil the latent architecture (i.e., overlapping yet dissociable superiority features) that predicts visual illusion magnitude and metacognitive performance. These findings suggest that superiority illusion is a cardinal cognitive bias that involves a vast assortment of behavior as an illusion is an efficient and adaptive tool for humans to somehow thrive in a world of ambiguity.
Signal Peptide Peptidase-Like 2b affects APP cleavage and exhibits a biphasic Aβ-mediated expression in Alzheimer’s disease
Authors: Maccioni Riccardo , Travisan Caterina , Zerial Stefania , Wagener Annika , Andrade-Talavera Yuniesky , Picciau Federico , Grassi Caterina , Chen Gefei , Lemoine Laetitia , Fisahn André , Jiang Richeng , Fluhrer Regina , Mentrup Torben , Schröder Bernd , Nilsson Per , Tambaro Simone 
Published: October 2022

ABSTRACTAlzheimer’s disease (AD) is a multifactorial disorder driven by abnormal amyloid β-peptide (Aβ) levels. To identify new druggable pathways involved in the Aβ cascade we here investigated the AD pathophysiological role of the presenilin-like intramembrane protease signal peptide peptidase-like 2b (SPPL2b). Aβ42 induced a biphasic modulation of SPPL2b expression in human cell lines and ex vivo mouse brain slices. In addition, SPPL2b was elevated inAppNL-G-Fknock-in AD mice as well as in human AD samples. Early high neuronal expression of SPPL2b was followed by a downregulation in late AD pathology in bothAppNL-G-Fmice and Braak stage V AD brains. Importantly, SPPL2b overexpression or its genetic deletion significantly increased or reduced APP cleavage and Aβ production, respectively. Thus, our results strongly support the involvement of SPPL2b in AD pathology. The early Aβ-induced SPPL2b upregulation may enhance Aβ production in a vicious cycle further aggravating the Aβ pathology suggesting SPPL2b as a potential anti-Aβ drug target.
Needing: an active inference process for physiological motivation
Authors: Bosulu J. , Pezzulo G. , Hétu S. 
Published: October 2022

ABSTRACTNeed states are internal states that arise from deprivation of crucial biological stimuli. They direct motivation, independently of external learning. Despite their separate origin, they interact with reward processing systems that respond to external stimuli. This paper aims to illuminate the functioning of the needing system through the lens of active inference, a framework for understanding brain and cognition.We propose that need states exert a pervasive influence on the organism, which in active inference terms translates to a “pervasive surprise” - a measure of the distance from the organism’s preferred state. Crucially, we define needing as an active inference process that seeks to reduce this pervasive surprise.Through a series of simulations, we demonstrate that our proposal successfully captures key aspects of the phenomenology and neurobiology of needing. We show that as need states increase, the tendency to occupy preferred states strengthens, independently of external reward prediction. Furthermore, need states increase the precision of states (stimuli and actions) leading to preferred states, suggesting their ability to amplify the value of reward cues and rewards themselves.Collectively, our model and simulations provide valuable insights into the directional and underlying influence of need states, revealing how this influence amplifies the wanting or liking associated with relevant stimuli.
Antagonistic roles of canonical and alternative RPA in tandem CAG repeat diseases
Authors: Gall-Duncan Terence , Luo Jennifer , Jurkovic Carla-Marie , Fischer Laura A. , Fujita Kyota , Leib David E. , Li Vanessa , Harding Rachel J. , Tran Stephanie , Chen Ran , Tanaka Hikari , Deshmukh Amit L. , Mason Amanda G. , Lévesque Dominique , Khan Mahreen , Lanni Stella , Sato Nozomu , Caron Marie-Christine , Masson Jean-Yves , Panigrahi Gagan B. , Prasolava Tanya , Wang Peixiang , Lau Rachel , Tippett Lynette , Turner Clinton , La Spada Albert R. , Campos Eric I. , Curtis Maurice A. , Boisvert François-Michel , Faull Richard L.M. , Davidson Beverly L. , Okazawa Hitoshi , Wold Marc S. , Pearson Christopher E. 
Published: October 2022

ABSTRACTTandem CAG repeat expansion mutations cause >15 neurodegenerative diseases, where ongoing expansions in patients’ brains are thought to drive disease onset and progression. Repeat length mutations will involve single-stranded DNAs prone to form mutagenic DNA structures. However, the involvement of single-stranded DNA binding proteins (SSBs) in the prevention or formation of repeat instability is poorly understood. Here, we assessed the role of two SSBs, canonical RPA (RPA1-RPA2-RPA3) and the related Alternative-RPA (Alt-RPA, RPA1-RPA4-RPA3), where the primate-specific RPA4 replaces RPA2. RPA is essential for all forms of DNA metabolism, while Alt-RPA has undefined functions. RPA and Alt-RPA are upregulated 2- and 10-fold, respectively, in brains of Huntington disease (HD) and spinocerebellar ataxia type 1 (SCA1) patients. Correct repair of slipped-CAG DNA structures, intermediates of expansion mutations, is enhanced by RPA, but blocked by Alt-RPA. Slipped-DNAs are bound and melted more efficiently by RPA than by Alt-RPA. Removal of excess slipped-DNAs by FAN1 nuclease is enhanced by RPA, but blocked by Alt-RPA. Protein-protein interactomes (BioID) reveal unique and shared partners of RPA and Alt-RPA, including proteins involved in CAG instability and known modifiers of HD and SCA1 disease. RPA overexpression inhibits rampant CAG expansions in SCA1 mouse brains, coinciding with improved neuron morphology and rescued motor phenotypes. Thus, SSBs are involved in repeat length mutations, where Alt-RPA antagonistically blocks RPA from suppressing CAG expansions and hence pathogenesis. The processing of repeat length mutations is one example by which an Alt-RPA↔RPA antagonistic interaction can affect outcomes, illuminating questions as to which of the many processes mediated by canonical RPA may also be modulated by Alt-RPA.
Sign-epistatic centromere drive in panmictic populations
Authors: Brud Evgeny 
Published: October 2022

AbstractComparative work has revealed a highly non-random elevation of karyotypic homogeneitywithinmammalian species for either telocentric chromosomes or centric fusions, and a karyotypic bimodalityamongspecies for these binary chromosome morphologies. A verbal theory developed by Pardo-Manuel de Villena and Sapienza argues that morphology-biased segregation in female meiosis explains the corresponding directional evolution in favor of one or the other chromosome form within species, and moreover, periodic reversals of meiotic spindle asymmetry explain the pattern of bimodality observed among species. Here I investigate a population genetic model in which I assume that the direction of the spindle asymmetry is under the control of a modifier gene, either linked or unlinked to a focal karyotypic mutant (linkage being to a centric fusion, say), and I derive the corresponding invasion conditions for the modifier-centric-fusion gene complex. I demonstrate that the scenario put forth in the verbal theory can be explained by a two-step process in which (1) a centric-fusion invades to fixation while the linked modifier winds up at an intermediate frequency by hitchhiking, and then (2) subsequent fixations of unlinked centric fusions occur. Via numerical iteration of the model, I demonstrate that the typical post-hitchhiking frequency of the linked modifier (from step 1) is broadly sufficient for subsequent unlinked invasions (step 2). Sign-reversing modifier evolution is therefore concluded to be a plausible mechanism instantiating the principles of a female drive theory of karyotype evolution.