bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time cells emerge early in learning and encode stimulus modality past task requirements
Authors: Bhattacharjee Soumya , Nambisan Hrishikesh , Bhalla Upinder S. 
Published: July 2024

SummaryHippocampal neurons represent multiple dimensions of stimulus and behavioural context, including time. It is unclear how soon time-encoding cells emerge during learning, and if they additionally encode context in a manner specific to behavioural paradigm. We investigated simultaneous time and context encoding using 2-photon calcium imaging of mouse hippocampus during a trace eyeblink conditioning (TEC) task with sound and light stimuli. We find that the fraction of time cells is independent of learning and of stimulus modality. Only 13% of cells retain time-encoding on successive days, but persisters remain active within their original stimulus and post-stimulus epochs. Finally, we show that 60% of modality-specific time-encoding cells are active after the stimulus period, but modality-agnostic time cells are rare post-stimulus. Thus, compared to other paradigms, time cells in TEC have distinct learning and turnover properties, and exhibit sustained coding of stimulus modality and time which may subserve associations with subsequent events.
Multivariate, Multi-omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits
Authors: Davis Christal N. , Toikumo Sylvanus , Hatoum Alexander S. , Khan Yousef , Pham Benjamin K. , Pakala Shreya R. , Feuer Kyra L. , Gelernter Joel , Sanchez-Roige Sandra , Kember Rachel L. , Kranzler Henry R. 
Published: July 2024

AbstractSomatoform traits, which manifest as persistent physical symptoms without a clear medical cause, are prevalent and pose challenges to clinical practice. Understanding the genetic basis of these disorders could improve diagnostic and therapeutic approaches. With publicly available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits—fatigue, irritable bowel syndrome, pain intensity, and health satisfaction—in 799,429 individuals genetically similar to Europeans. Using genomic structural equation modeling, GWAS identified 134 loci significantly associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched gene expression in 12 brain tissues. Six genes, including members of the CD300 family, had putatively causal effects mediated by protein abundance. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated most strongly with obesity, Type 2 diabetes, tobacco use disorder, and mood/anxiety disorders in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors. Mendelian randomization indicated potentially protective effects of gut microbiota, includingRuminococcus bromii. These biological insights provide promising avenues for treatment development.
Plasma Proteomic Signature of Mucolipidosis Type IV
Authors: Tobin Brendan , Misko Albert , Miller-Browne Victoria , Sangster Madison , Grishchuk Yulia , Wood Levi B. 
Published: July 2024

AbstractMucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by the loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, lysosomal abnormalities, and increased cytokine expression. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. In the current study, we analyzed 7,322 proteins in the plasma proteome and compare protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). To do so, we used aptamer-based protein profiling on plasma isolated from 18 MLIV patients and 37 aged-matched controls from a biorepository. We identified a total of 1,961 differentially expressed proteins between MLIV and control subjects, with functions spanning many major hallmarks of MLIV. Our analysis revealed a decrease in the abundance of neuronal proteins and an increase in muscle proteins, consistent with the neuronal dysfunction and muscle pathology observed in patients. In particular, lower levels of synaptic proteins (e.g., GABARAP) best correlated with disease severity. Next, we compared the plasma proteome of patients to the brain proteome from the mouse model of MLIV and identified shared alterations in 45 proteins. The up-regulated overlapping proteins were largely related to lysosomal function (e.g., ACTN2, GLB1), while the down-regulated proteins were largely related to myelination (e.g. TPPP3, CNTN2). Both signatures are consistent with our understanding of key disease hallmarks: impaired myelination and modified lysosomal function. Collectively, these data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain and suggest candidate markers relevant to MLIV pathology to be validated in future studies.
Dual exposure-by-polygenic score interactions highlight disparities across social groups in the proportion needed to benefit
Authors: Nagpal Sini , Gibson Greg 
Published: July 2024

AbstractThe transferability of polygenic scores across population groups is a major concern with respect to the equitable clinical implementation of genomic medicine. Since genetic associations are identified relative to the population mean, inevitably differences in disease or trait prevalence among social strata influence the relationship between PGS and risk. Here we quantify the magnitude of PGS-by-Exposure (PGSxE) interactions for seven human diseases (coronary artery disease, type 2 diabetes, obesity thresholded to body mass index and to waist-to-hip ratio, inflammatory bowel disease, chronic kidney disease, and asthma) and pairs of 75 exposures in the White-British subset of the UK Biobank study (n=408,801). Across 24,198 PGSxE models, 746 (3.1%) were significant by two criteria, at least three-fold more than expected by chance under each criterion. Predictive accuracy is significantly improved in the high-risk exposures and by including interaction terms with effects as large as those documented for low transferability of PGS across ancestries. The predominant mechanism for PGS×E interactions is shown to be amplification of genetic effects in the presence of adverse exposures such as low polyunsaturated fatty acids, mediators of obesity, and social determinants of ill health. We introduce the notion of the proportion needed to benefit (PNB) which is the cumulative number needed to treat across the range of the PGS and show that typically this is halved in the 70thto 80thpercentile. These findings emphasize how individuals experiencing adverse exposures stand to preferentially benefit from interventions that may reduce risk, and highlight the need for more comprehensive sampling across socioeconomic groups in the performance of genome-wide association studies.
Genetic Overlap Between Inflammatory Bowel Disease and Neurological Disorders: Insights from GWAS and Gene Expression Analysis
Authors: Tripathi Utkarsh , Stern Yam , Dagan Inbal , Nayak Ritu , Romanovsky Eva , Zittan Eran , Stern Shani 
Published: July 2024

AbstractInflammatory Bowel Disease (IBD), which includes Crohn’s disease (CD) and Ulcerative Colitis (UC), is a complex and multifactorial condition marked by chronic inflammation of the gastrointestinal tract. This study leverages genome-wide association studies (GWAS) and gene expression data from the Genotype-Tissue Expression (GTEx) project to investigate IBD’s genetic and expression profiles and subtypes. We examined 207 studies related to IBD, 71 specific to CD, and 66 focused on UC, identifying both shared and unique genetic factors among these conditions. GWAS meta-analysis revealed the top IBD-associated genes, which include IL23R, NOD2, ATG16L1, HLA-DRB9, and more. Pathway enrichment analyses identified consistently enriched pathways such as the NF-kappa B signaling pathway, JAK-STAT signaling pathway, and cytokine-cytokine receptor interaction, all of which play critical roles in immune responses and inflammation. Gene Ontology (GO) term analysis highlighted processes like cytokine production, cell activation, and leukocyte activation, reinforcing their involvement in the pathogenesis of IBD. Gene expression analysis showed that genes associated with IBD are expressed not only in the gastrointestinal tract but also in various regions of the brain, suggesting potential links between IBD and neurological functions. Our study further explored the genetic overlap between IBD and several neurological disorders, including schizophrenia, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder, uncovering a shared genetic architecture. These findings emphasize the systemic nature of IBD and its potential neurological implications, paving the way for targeted therapeutic strategies that address both gastrointestinal and neurological aspects of the disease.
Baseline correlation between pain, range of motion, disability, and health-related quality of life variables in subjects with frozen shoulder: A cross-sectional study
Authors: Poser A , Brindisino F , Feller D , Venturin D 
Published: July 2024

ABSTRACTFrozen shoulder (FS) is a debilitating condition affecting the glenohumeral joint. As FS frequently manifests as a chronic condition, it intensifies pain and leads to disability and to a deterioration in overall quality of life, affecting physical, behavioral, mental, and social dimensions.While the impact of pain on disability is widely acknowledged, recent literature highlights a growing body of evidence indicating the correlation between pain and health-related, social, and mental distress and unfavorable outcomes in patients with FS.Up to day, the need for pain to be avoided or alleviated as much as possible has been challenged, with a paradigm shift from traditional biomedical models of pain towards a biopsychosocial model of pain disorders. Research has further shown that psychological factors might affect the function and quality of life in patients with pain and can modulate the individuals’ pain experience and therefore may play a role in the development and/or maintenance of chronic pain states.As the current healthcare pathway for subjects suffering from FS often inadequately addresses these healthcare needs, and professionals tend to predominantly concentrate on biological and clinical symptoms, theaimof this study will be to explore correlations among Patient-Reported Outcome Measures (PROMs) for pain, and disability, health-related domains, and ROM measurements in individuals with FS during their initial physiotherapy consultation
Cost-effectiveness of the Strategies for Surveillance of Antimicrobial-resistant Gonorrhea in the US: a Modelling Study
Authors: Prakhova Sofya 
Published: July 2024

AbstractBackgroundThe Gonococcal Isolate Surveillance Project (GISP) is a sentinel surveillance system to monitor the spread of antimicrobial-resistant (AMR) gonorrhea. Under GISP surveillance strategy, urethral isolates are utilized for monitoring the spread of the resistance and the obtained estimates are used for informing the gonorrhea treatment guidelines. In 2017, the enhanced Gonococcal Isolate Surveillance Project (eGISP) was established which also includes the non-urethral isolates. Using eGISP estimates for informing the gonorrhea treatment guidelines is an alternative surveillance strategy that can be used.MethodsWe utilized our previously developed continuous-time agent-based model of gonorrhea transmission among the US men who have sex with men (MSM) population and calculated the total number of discounted quality-adjusted life years (QALYs) and total discounted costs over 25 years under GISP and eGISP surveillance strategy. We also evaluated cost-effectiveness of both surveillance strategies.ResultsUnder GISP surveillance strategy, $2.9M (95% uncertainty interval: $23,131, $9.4M) were saved and 31.3 (0, 134.9) QALYs were gained in the simulated cohort of 10,000 US MSM over 25 years compared to no surveillance. Performing eGISP surveillance strategy instead would result in additional $57,449 (−$100,914, $221,663) saved and 0.59 (−0.79, 2.5) QALYs gained.ConclusionThe current GISP surveillance strategy significantly reduces the costs and increases the health benefits compared to no surveillance. However, switching from the current strategy to eGISP strategy is cost saving and should be considered in order to improve the population health and reduce the financial burden of gonorrhea.
Hot Spring Residency and Disease Association: a Crossover Gene-Environment Interaction (GxE) Study in Taiwan
Authors: Wu Hsin-Yu , Chang Kao-Jung , Chiu Wei , Wang Ching-Yun , Hsu Yu-Tien , Wen Yuan-Chih , Chiang Pin-Hsuan , Chen Yu-Hsiang , Dai He-Jhen , Lu Chia-Hsin , Chen Yi-Cheng , Tsai Han-Ying , Chen Yu-Chun , Hsu Chih-Hung , Hsieh Ai-Ru , Chiou Shih-Hwa , Yang Yi-Ping , Hsu Chih-Chien 
Published: July 2024

AbstractBackgroundThe advent of genetic biobanking has powered gene-environment interaction (GxE) studies in various disease contexts. Therefore, we aimed to discover novel GxE effects that address hot spring residency as a risk to inconspicuous disease association.MethodsA complete genetic and demographic registry comprising 129,451 individuals was obtained from Taiwan Biobank (TWB). Geographical disease prevalence was analyzed to identify putative disease association with hot-spring residency, multivariable regression and logistic regression were rechecked to exclude socioeconomic confounders in geographical-disease association. Genome-wide association study (GWAS), gene ontology (GO), and protein-protein interaction (PPI) analysis identified predisposing genetic factors among hotspring-associated diseases. Lastly, a polygenic risk score (PRS) model was formulated to stratify environmental susceptibility in accord to their genetic predisposition.ResultsAfter socioeconomic covariate adjustment, prevalence of dry eye disease (DED) and valvular heart disease (VHD) was significantly associated with hot spring distribution. Through single nucleotide polymorphisms (SNPs) discovery and subsequent PPI pathway aggregation, CDKL2 and BMPR2 kinase pathways were significantly enriched in hot-spring specific DED and VHD functional SNPs. Notably, PRS predicted disease well in hot spring regions (PRSDED: AUC=0.9168; PRSVHDAUC=0.8163). Hot spring and discovered SNPs contributed to crossover GxE effect on both DED (relative risk (RR)G+E-=0.99; RRG+E+=0.35; RRG+E+=2.04) and VHD (RRG+E-=0.99; RRG+E+=0.49; RRG+E+=2.01).ConclusionWe identified hot-spring exposure as a modifiable risk in the PRS predicted GxE context of DED and VHD.Abstract Figure
Orbitofrontal thickness and network associations as transdiagnostic signature of negative symptoms along the bipolar-schizophrenia spectrum
Authors: Franz Marlene , Kebets Valeria , Berg Xaver , Georgiadis Foivos , Burrer Achim , Brakowski Janis , Kaiser Stefan , Seifritz Erich , Homan Philipp , Walton Esther , van Erp Theo G. M. , Turner Jessica A. , Misic Bratislav , Valk Sofie L. , Yeo B.T. Thomas , Bernhardt Boris C. , Kirschner Matthias 
Published: July 2024

AbstractNegative symptoms are core features of schizophrenia (SCZ) and also prevalent in bipolar disorder (BD). While orbitofrontal cortex (OFC) alterations have been implicated in the development of negative symptoms, their contributions across disorders remain to be established. Here, we tested how OFC thickness and related network associations relate to severity of negative symptom dimensions across the BD-SCZ spectrum. We included 50 individuals with SCZ, 49 with BD, alongside 122 controls. We assessed amotivation and diminished expression and estimated thickness in the medial and lateral OFC as regions-of-interest as well as 64 other cortical regions. Across BD and SCZ, reduced right lateral and bilateral medial OFC thickness were specifically associated with amotivation, but not diminished expression or other clinical factors. We then generated OFC structural co-variation networks to evaluate how the system-level embedding of the OFC would link to brain-wide cortical maps of negative symptoms. We found that medial OFC co-variation networks spatially correlated with the cortical maps of both negative symptom dimensions. Confirmatory analyses in independent SCZ data from the ENIGMA consortium (n=4,474) revealed similar associations with lateral OFC co-variation networks. Finally, the brain-wide cortical alteration pattern of amotivation was significantly correlated with normative functional and structural white-matter connectivity profiles of the right medial and left lateral OFC as well as adjacent prefrontal and limbic regions. Our work identifies OFC alterations as a possible transdiagnostic signature of amotivation and provide insights into network associations underlying the system-wide cortical alterations of negative symptoms across SCZ and BD.
Methods for joint modelling of longitudinal omics data and time-to-event outcomes: Applications to lysophosphatidylcholines in connection to aging and mortality in the Long Life Family Study
Authors: Arbeev Konstantin G. , Bagley Olivia , Ukraintseva Svetlana V. , Kulminski Alexander , Stallard Eric , Schwaiger-Haber Michaela , Patti Gary J. , Gu Yian , Yashin Anatoliy I. , Province Michael A. 
Published: July 2024

AbstractStudying relationships between longitudinal changes in omics variables and risks of events requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study focusing on understudied associations of longitudinal changes in lysophosphatidylcholines (LPC) with mortality and aging-related outcomes (23 LPC species, 5,790 measurements of each in 4,011 participants, 1,431 of whom died during follow-up). JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the largest effect size observed for LPC 15:0/0:0 (hazard ratio: 0.715, 95% CI (0.649, 0.788)). SPM applications to LPC 15:0/0:0 revealed how the association found in JM reflects underlying aging-related processes: decline in robustness to deviations from optimal LPC levels, better ability of males’ organisms to return to equilibrium LPC levels (which are higher in females), and increasing gaps between the optimum and equilibrium levels leading to increased mortality risks with age. Our results support LPC as a biomarker of aging and related decline in robustness/resilience, and call for further exploration of factors underlying age-dynamics of LPC in relation to mortality and diseases.
The Contribution of the membrane-bound complement regulatory proteins CD46 and CD55 in phases of acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML)
Authors: Saeed Lobna Onsi , Ammar Perihan Ashraf , AbdElaziz Hisham , Abou-Aisha Khaled , Farag Noha Samir , El-Azizi Mohamed 
Published: July 2024

AbstractThe complement system is an essential part of the innate immunity where it is involved in the elimination of pathogens and disposal of apoptotic bodies and immune complexes from the body. Membrane-bound complement regulatory proteins (mCRPs) play key roles in controlling complement activity to avoid any accidental damage of host cells. The role of the complement system during the neoplastic transformation of cells is complicated and has been debated for long. On one hand, the complement system generally acts as a participant in the body’s immune surveillance against cancer. However, recent findings have shown that cancerous cells can use the complement components to assist in certain hallmarks which are fundamental for tumor progression such as angiogenesis, proliferation and metastasis. The aim of the current study is to investigate the differential expression of mCRPs; CD46 and CD55 in of acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). Clinical peripheral blood samples of newly diagnosed AML and ALL patients were used to assess the changes in transcriptional expression levels of CD46 and CD55 compared to age-matched healthy control subjects using quantitative real time PCR (qPCR). Results showed that both CD46 and CD55 were significantly downregulated by 2 to 7 folds in ALL and AML patients compared to healthy controls. The determined downregulation is suggestive of a defense mechanism conducted by leukemic cells to overcome immune defenses. Flow cytometric analysis was conducted for proteomic expression analysis of both proteins on cell surfaces of leukemia patients compared to healthy controls and results showed a reduction in CD46 expression by 1.2 fold and 2.8 fold in CD55 expression in AML patients. Post transcriptional knockdown of both genes was then carried out in HSB-2 leukemic cell model using customized shRNA, followed by flow cytometry analysis to assess the success of CD46 and CD55 silencing step, and ending with cell viability assays. MTT assay results showed a significant reduction in the viability of HSB-2 cells by 3 fold, approximately, following post-transcriptional silencing of CD46 and CD55 suggesting that although the expression of these mCRPs could be normally compromised by cancerous cells to evade complement attack mechanisms, CD46 and CD55 could be vital to the viability and proliferation of cancerous cells at some point in time. Our results suggest the dual role of complement in the tumor microenvironment where a balance between antitumor and tumor-promoting complement activities exists. The multifunctional properties of the complement system could be employed in opposing roles in cancer suggesting that the biological functions of the complement system are much more diverse than a simple elimination of target cells.
Eco-evolutionary dynamics of temperate phages in periodic environments
Authors: Goel Tapan , Beckett Stephen J. , Weitz Joshua S. 
Published: July 2024

AbstractBacteriophage (viruses that exclusively infect bacteria) exhibit a continuum of infection mechanisms, including lysis and lysogeny in interactions with bacterial hosts. Recent work has demonstrated the near-term advantages of lysogeny over lysis in conditions of low host availability. Hence, temperate phage which can switch between lytic and lysogenic strategies — both stochastically and responsively — are hypothesized to have an evolutionary advantage in a broad range of conditions. To examine generalized drivers of viral strategies over the near- and long-term, we explore the eco-evolutionary dynamics of temperate viruses in periodic environments with varying levels of host availability and viral mortality. We use a nonlinear system of ordinary differential equation to simulate periodically-forced dynamics that separate a ‘within-epoch’ phase and a ‘between-epoch’ phase, in which a (potentially unequal) fraction of virus particles and lysogens survive. Using this ecological model and invasion analysis, we show and quantify how conflicts can arise between strategies in the near-term that may favor lysis and strategies in the long-term that may favor lysogeny. In doing so, we identify a wide range of conditions in which temperate strategies can outperform obligately lytic or lysogenic strategies. Finally, we demonstrate that temperate strategies can mitigate against the potential local extinction of viruses in stochastically fluctuating environments, providing further evidence of the eco-evolutionary benefits of being temperate.