bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of candidate biomarkers and signaling pathways associated with Alzheimer’s disease using bioinformatics analysis of next generation sequencing data
Authors: Vastrad Basavaraj , Vastrad Chanabasayya 
Published: December 2024

AbstractAlzheimer’s disease (AD) is the most common cause of dementia, and one of the most common health problems all over the world. However, the specific molecular mechanisms of AD have not been fully investigated. The current investigation aimed to elucidate potential key candidate genes and signaling pathways in AD. Next generation sequencing (NGS) dataset GSE203206 was downloaded from the Gene Expression Omnibus (GEO) database, which included data from 39 AD samples and 8 normal control samples. Differentially expressed genes (DEGs) were identified using t-tests in the limma R bioconductor package. These DEGs were subsequently investigated by Gene ontology (GO) and pathway enrichment analysis, and a protein-protein interaction (PPI) network and modules were constructed and analyzed. The miRNA-hub gene regulatory network and TF-hub gene regulatory network analysis were performed to identify key miRNAs and TFs. The receiver operating characteristic (ROC) curve analysis was performed to estimate the clinical diagnostic value of the hub genes. A total of 958 DEGs, including 479 up regulated genes and 479 down regulated genes, were screened between AD and normal control samples. GO and pathway enrichment analysis results revealed that the up regulated genes were mainly enriched in response to stimulus, cytoplasm, small molecule binding and signal transduction, whereas down regulated genes were mainly enriched in multicellular organism development, cell junction, ion binding and cardiac conduction. The PPI network contained 4886 nodes and 10342 edges. HSP90AA1, FN1, KIT, YAP1, LSM2, SKP1, EIF5A2, TAF9, DDX39B and CDK7 were identified as the top hub genes. The regulatory network analysis revealed that microRNA (miRNA) hsa-mir-545-3p and hsa-miR-548f-5p, and transcription factor (TF) PLAG1 and MEF2A might be involved in the development of AD. These findings provide new insights into the pathogenesis of AD. The hub genes, miRNAs and TFs have the potential to be used as diagnostic and therapeutic markers.
Lactococcus lactissubsp.cremorisC60 creates a type I regulatory T cell-dominant anti-inflammatory intestinal environment through functional modification of dendritic cells
Authors: Saito Suguru , Kakizaki Nanae , Okuno Alato , Maekawa Toshio , Tsuji Noriko M. 
Published: December 2024

AbstractLactic acid bacteria (LAB)-mediated probiotics have the capability to modulate intestinal immunity, creating an anti-inflammatory environment. Among the immune-modulatory effects, interleukin (IL)-10-producing CD4+T cells are often discussed for their anti-inflammatory roles. While regulatory T cells (Tregs) are a well-known subset, type I regulatory T (Tr1) cells, which also produce abundant IL-10, receive less attention in LAB-induced anti-inflammatory effects. Here, we report thatLactococcus lactissubsp.cremorisC60, a probiotic LAB strain, increases IL-10-producing Tr1 cells in the intestinal environment, contributing to resistance against inflammatory conditions such as dextran sodium sulfate (DSS)-induced colitis. Intragastric administration of heat-killed (HK)-C60 significantly increased IL-10+CD4+T cells in intestinal tissues compared to control treatment. These populations predominantly consisted of Forkhead box protein P3 (Foxp3)-negative cells, indicating that Tr1 cells were primarily expanded by HK-C60 stimulation. Further analysis revealed that IL-10+Tr1 cells could be classified into two major subpopulations: IL-10 single-positive (SP) and IFN-γ/IL-10 double-positive (DP) cells. Anin vitroco-culture system using CD4+T cells and bone marrow-derived dendritic cells (BMDCs) demonstrated that HK-C60 stimulation modified dendritic cell function, promoting Tr1 cell differentiation. Moreover, pro-inflammatory IFN-γ+CD4+T (Th1) cells differentiated into IL-10+Tr1 cells in the presence of HK-C60-stimulated BMDCs, with the effect being particularly pronounced in DP Tr1 cells. HK-C60-administration attenuated inflammation and reduced pro-inflammatory leukocyte infiltration in the colon of DSS-induced colitis mice, accompanied by the expansion of DP Tr1 cells. The suppressive effect of intestinal CD4+T cells in HK-C60-treated mice was IL-10-dependent, as demonstrated by anin vitroIL-10 neutralizing assay. Thus, C60-based probiotics promote the creation of an anti-inflammatory intestinal environment by increasing IL-10+Tr1 cells rather than Tregs.
Voluntary action sharpens sensory prediction and facilitates neural processing of contingent sensory stimuli
Authors: Ody Edward , Kircher Tilo , Straube Benjamin , He Yifei 
Published: December 2024

AbstractSelf- and externally generated sensations differ in sensory responses and motor preparation. However, mechanistic evidence linking the two is scarce. Here, participants made active (self-initiated) or passive (finger moved by electromagnet) movements that triggered a bimodal auditory/visual stimulus. These were followed, in a block-wise manner, by a unimodal auditory/visual comparison stimulus, and participants judged which stimulus was brighter or louder. Motor preparation ERPs encoded task modality and movement, while sensory ERPs showed reduced task differences for active, demonstrating sensory suppression. Next, we decoded task modality within active and passive. During motor preparation, the active condition showed higher accuracy, reflecting enhanced predictive processes. In the sensory perception period, accuracy was higher in the passive condition, mirroring previous reports of reduced sensory responses to self-generated stimuli. Temporal generalisation showed pattern similarities in the alpha band amplitude between the motor preparation and the stimulus perception windows. This suggests that alpha oscillations may encode sensory predictions generated during motor preparation. Our findings provide mechanistic evidence of action-effect prediction during voluntary actions.
Simulations provide a mechanistic interpretation of Bateman gradients
Authors: Sanghvi Krish , Henshaw Jonathan M. , Kacelnik Alex , Janicke Tim , Sepil Irem 
Published: December 2024

AbstractThe Bateman gradient (BG or 𝛽𝑠𝑠) is a fundamental metric of sexual selection, and is often interpreted as the fitness advantage individuals can gain by increasing their number of mates. However, researchers commonly misconceive the relationship between mating success (MS) and reproductive success (RS) as always being causal, leading to a misinterpretation of the BG. The BG is phenomenological and therefore uninformative about the mechanisms leading to correlations between MS and RS. Here, we simulate sequential matings in males from biological systems with varying levels of anisogamy and sperm competition, to better understand the underlying processes that modulate male BGs. We show that the BG does not solely reflect the causal influence of MS on RS as is typically interpreted, but is also a consequence of covariances between male MS and male ejaculate traits, female fecundity, or female post-mating decisions. For example, we show that the BG is substantially shallower when the ejaculate size of males negatively co-varies with their MS, such as in species with alternative male reproductive tactics. Such covariances can lead to a misinterpretation of the measured BG, because here, it does not merely represent the strength of selection on intra-sexual competition for mates. We suggest how such covariances can be visually assessed, and accounted for using partial Bateman gradients, to better interpret the influence of MS on RS, thus the strength of pre-copulatory sexual selection. Among other simplifications, our simulations have a male-only focus, but they provide insights into the mechanisms driving inter- and intra-specific variation in the BG, clarify its meaning, and improve our understand of sexual selection.
Mechanism of small heat shock protein client sequestration and induced polydispersity
Authors: Miller Adam P. , Reichow Steve L. 
Published: December 2024

ABSTRACTSmall heat shock proteins (sHSPs) act as first responders during cellular stress by recognizing and sequestering destabilized proteins (clients), preventing their aggregation and facilitating downstream refolding or degradation1–3. This chaperone function is critically important to proteostasis, conserved across all kingdoms of life, and associated with various protein misfolding diseases in humans4,5. Mechanistic insights into how sHSPs sequester destabilized clients have been limited due to the extreme molecular plasticity and client-induced polydispersity of sHSP/client complexes6–8. Here, we present high-resolution cryo-EM structures of the sHSP fromMethanocaldococcus jannaschii(mjHSP16.5) in both the apo-state and in an ensemble of client-bound states. The ensemble not only reveals key molecular mechanisms by which sHSPs respond to and sequester client proteins, but also provides insights into the cooperative nature of chaperone-client interactions. Engagement with destabilized client induces a polarization of stability across themjHSP16.5 scaffold, proposed to facilitate higher-order assembly and enhance client sequestration capacity. Some higher-order sHSP oligomers appear to form through simple insertion of dimeric subunits into new geometrical features, while other higher-order states suggest multiple sHSP/client assembly pathways. Together, these results provide long-sought insights into the chaperone function of sHSPs and highlight the relationship between polydispersity and client sequestration under stress conditions.
Isolation and Characterization of Antibodies Against VCAM-1 Reveals Putative Role for Ig-like Domains 2 and 3 in Cell-to-Cell Interaction
Authors: Perera Binura , Wu Yuao , Pickett Jessica R. , Panagides Nadya , Barretto Francisca M. , Fercher Christian , Sester David P. , Jones Martina L. , Ta Hang T. , Zacchi Lucía F. 
Published: December 2024

AbstractVascular cell adhesion molecule-1 (VCAM-1) plays an important role in inflammation, where it facilitates the recruitment of leukocytes to the inflamed area via leukocytes’ VLA-4 and endothelial cells’ VCAM-1 interaction. VCAM-1 expression is also upregulated in certain cancers. VCAM-1 has 7 Ig-like domains, with domains 1 and 4 shown to be critical for VLA-4 binding. However, the specific functions of individual VCAM-1 Ig-like domains remain poorly understood. In this study, we identified single-chain variable fragment (scFvs) antibodies targeting domains 2, 3, and 5 of VCAM-1, and investigated the ability of these antibodies to block VCAM-1-mediated cell adhesion to macrophages. We show that scFv antibodies against Ig-like domains 2 and 3 significantly interfere with the ability of macrophages to bind endothelial cells, suggesting that these domains also play a role in facilitating this interaction. These results emphasize the need to more carefully study the role of each domain on VCAM-1 function and highlight the potential of targeting these VCAM-1 domains for more tailored therapeutic interventions in inflammatory diseases and cancer.
Dementia Care Specialists Perspectives of Diagnosis and Early Psychosocial Care: A Qualitative Analysis of Focus Groups in Two Large Academic Medical Centers
Authors: Hicks Amelia J. , Brewer Julie , Ahmad Nina , Cornelius Talea , Parker Robert A. , Dams-O’Connor Kristen , Dickerson Bradford , Ritchie Christine , Vranceanu Ana-Maria , Bannon Sarah M. 
Published: December 2024

ABSTRACTBackground and ObjectiveAlzheimer’s disease and related dementias (ADRDs) are progressive conditions that substantially impact individuals and families. Timely diagnosis and early support are critical for long-term adjustment. However, current dementia care models do not meet needs of patients and families. Dementia care specialists treating individuals with dementia offer unique insight into care needs of diverse groups of patients, families, and healthcare systems that can be used to identify opportunities to improve care.To understand dementia care specialists’ impressions of factors impacting ADRD diagnosis and post-diagnosis support. We aimed to identify factors that impact: (1) timely and accurate diagnosis, (2) diagnostic disclosure and provision of post-diagnosis support, and (3) patient and care-partner adjustment after diagnosis.Research Design and MethodsWe recruited dementia care specialists treating persons living with dementia (n=19) from two academic medical centers. Participants completed 60-minute qualitative focus groups or individual interviews. Data were analyzed using a hybrid inductive-deductive approach to thematic analysis.ResultsWe identified subthemes within three overarching a-priori determined themes. Participants highlighted the presence of delays in referrals, time constraints, specialist discomfort, and lack of training as factors impacting the timeliness and accuracy of diagnosis. They also highlighted information needed in disclosure visits, ways of coordinating care, and identifying early support needs. Finally, participants highlighted factors impacting adjustment including families’ insight and acceptance, distress, and available resources.Discussion and ImplicationsOur study highlights the challenges dementia care specialist specialists face in delivering early support for individuals and families impacted by ADRDs and suggests avenues for revising existing care models.
Structural and functional connectivity of the posterior default mode network is associated with sleep disturbance rather than pain in the Twin sub-study of the MAPP Research Network
Authors: Sudhakar Tejaswi , Bogic Marija , Elliott Jonathan E. , Lim Miranda M. , Buchwald Dedra , Strachan Eric , Levendovszky Swati Rane 
Published: December 2024

AbstractThe neurophysiological underpinnings of chronic pain and sleep disturbances, which are commonly comorbid are not well understood. Investigation of common structural and functional brain network alterations of sleep disturbance in the setting of chronic pain may shed light on common mechanisms and improve specificity of treatment for these conditions. Our study examines the association between sleep parameters (including sleep duration, sleep difficulty, and sleep chronotype), pain phenotype, and brain structural and functional connectivity in individuals with chronic pelvic pain by leveraging data from the Twin Studies of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Participants (n= 34 pairs) completed extensive clinical phenotyping and 3T MRI, including resting-state functional MRI (rs-fMRI), diffusion tensor imaging (DTI), and subjective sleep assessments. We observed significant differences in total sleep time (420 ± 58 min vs. 466 ± 61 min) and sleep difficulty (study-specific Likert scale 0-3: 1.35 ± 0.81 vs. 0.95 ± 0.68) among individuals with chronic pelvic pain compared to those without chronic pelvic pain, with sleep difficulty being associated with altered default mode network (DMN) connectivity. No associations were found with the salience network (SN), a network implicated in chronic pain. Additionally, increased total sleep time was associated with decreased posterior callosal white matter integrity. These findings underscore the complex interplay between chronic pain and sleep disturbances and have implications for distinct treatment approaches for patients with comorbid pain and sleep disorders.
Integrated DNA estimation in tissue biopsy and detection in liquid biopsy by HBV-targeted NGS assay
Authors: Liu Hsin-Ni , Lin Selena Y. , Ramirez Ricardo , Chen Shin-En , Heimer Zach , Kubas Roman , Shieh Fwu-Shan , Kim Elena S. , Liu Yuanjie , Lau Daryl T.Y. , Chang Ting-Tsung , Guo Haitao , Wang Zhili , Su Ying-Hsiu 
Published: December 2024

AbstractBackground & AimsIntegrated HBV DNA (iDNA) plays a critical role in HBV pathogenesis, particularly in predicting treatment response and HCC. This study aimed to use an HBV hybridization-capture next-generation sequencing (HBV-NGS) assay to detect HBV-host junction sequences (HBV-JS) in a sensitive nonbiased manner to detect and estimate the iDNA fraction in tissue biopsies and HBV genetics by liquid biopsy.MethodsHBV DNA from plasmid monomers, HBV-HCC cell line (SNU398, Hep3B, and PLC/PRF/5), tissue biopsies of patients with serum HBV DNA <4 log IU/ml, and matched urine and plasma of HBV patients were assessed by HBV-NGS. Junction-specific qPCR (JS-qPCR) assays were developed to quantify abundant HBV-JS.ResultsWe demonstrated high coverage uniformity, reproducibility across all HBV genotypes A-D, and 0.1% sensitivity for detecting iDNA by the HBV-NGS assay. The sequence and structures of iDNA molecules from SNU398 and Hep3B are reported. An iDNA estimation model was developed using six abundant HBV-JS sequences identified from tissue biopsies by HBV-NGS assay and validated using total DNA of SNU398 and Hep3B cells. Furthermore, the utility of the HBV-NGS assay for HBV genetic analysis in liquid biopsies was explored using matched plasma-urine samples from three patients with serum HBV DNA levels ranging from high to undetectable. HBV-JS was detected in all body fluids tested, regardless of viral load.ConclusionThese findings suggest that the iDNA fraction in tissue biopsies from patients with limited or undetectable serum HBV DNA can be estimated using a robust HBV-NGS assay, and a sensitive HBV genetics liquid biopsy can be obtained. This study highlights the potential of NGS-based methods to advance HBV management.Impact and implicationsThis study applied an unbiased, sensitive, and robust HBV-captured NGS method to detect integrated HBV DNA (iDNA) in both tissue and liquid (blood and urine) biopsies and generated a model to estimate the intrahepatic iDNA quantity. The availability of this technology makes possible to not only estimate iDNA fraction in total HBV DNA in tissue biopsies, but also perform HBV genetics in a minimally invasive manner in chronic HBV patients for disease monitoring, HCC risk assessment, and for clinical research.
Exploring clinical characteristics of COVID-19 in children and adolescents using a machine-learning approach
Authors: Fiandrino Stefania , Doná Daniele , Giaquinto Carlo , Poletti Piero , Tira Micheal Davis , Di Chiara Costanza , Paolotti Daniela 
Published: December 2024

AbstractIntroductionThe epidemiology and clinical characteristics of COVID-19 evolved due to new SARS-CoV-2 variants of concern (VOCs). The Omicron VOC’s higher transmissibility increased pediatric COVID-19 cases and hospital admissions. Most research during the Omicron period has focused on hospitalized cases, leaving a gap in understanding the disease’s evolution in community settings. This study targets children with mild to moderate COVID-19 during pre-Omicron and Omicron periods. It aims to identify patterns in COVID-19 morbidity by clustering individuals based on symptom similarities and duration of symptoms and develop a machine-learning tool to classify new cases into risk groups.MethodsWe propose a data-driven approach to explore changes in COVID-19 characteristics analyzing data collected within a pediatric cohort at the University Hospital of Padua. First, we apply an unsupervised machine-learning algorithm to cluster individuals into different groups. Second, we classify new patient risk groups using a Random-Forest classifier model based on sociodemographic information, pre-existing medical conditions, vaccination status, and the VOC as predictive variables. Third, we explore the key features influencing the classification.ResultsThe unsupervised clustering identified three severity risk profile groups. The classification model effectively distinguished these groups, with age, gender, COVID-19 vaccination, VOC, and presence of comorbidities as top predictive features. A high number and longer duration of symptoms were associated with younger age groups, males, unvaccinated individuals, Omicron infections, and those with comorbidities. These results are consistent with evidence of severe COVID-19 in infants, older children with comorbidities, and unvaccinated children.ConclusionOur classification model has the potential to provide clinicians with insights into the children’s risk profile of COVID-19 using readily available data. This approach can support public health efforts by clarifying disease burden and improving patient care strategies. Furthermore, it underscores the importance of integrating risk classification models to monitor and manage infectious diseases.
Monitoring sexual hormones in women going to high altitude – a pilot study
Authors: Taalaibekova Aijan , Meyer Michelle , Ulrich Stefanie , Mirzalieva Gulzada , Mademilov Maamed , Lichtblau Mona , Betschart Cornelia , Sooronbaev Talant M. , Ulrich Silvia , Bloch Konrad E. , Furian Michael 
Published: December 2024

AbstractBackgroundThe susceptibility to acute mountain sickness (AMS) in relation to sexual hormones in women remains elusive, partly because hormones could not be conveniently measured. We evaluated a novel kit for self-monitoring sexual hormones in women and recorded AMS incidence during high-altitude sojourns.MethodsTwo groups of healthy, premenopausal women, mean±SD age 23.1±2.3 y, residing <1,000m underwent baseline evaluations at 760 m before travelling to and staying for 2 days and nights (48 hours) at 3,100 m or 3,600 m, respectively. Participants self-monitored morning urine sexual hormone concentrations (estrone-1-glucuronide, E1G, pregnanediol-3-alpha-glucuronide, PdG, and luteinizing hormone, LH) daily for 30d including altitude sojourns using the simple“Proov”kit (MFB Fertility Inc). Follicular and luteal menstrual cycle phases detected by LH peak, altitude-related adverse health effects (ARAHE), AMS (Lake Louise score 2018 [LLS] ≥ 3 points including headache) and pulse oximetry (SpO2) were assessed.Results1,172 of 1,250 (93.8%) hormone measurements were successful, 78 of 1,250 (6.2%) failed due to nonadherence or technical failure. At 3,600 m, mean differences in urinary PdG concentration were 3.8 mcg/ml (95%CI, 0.6 to 7.1) between luteal and follicular cycle phases. At 3,100 m, corresponding difference was 8.5 mcg/ml (95%CI, 5.0 to 12.0). At 3,100 m, 9 of 21 (43%) women were diagnosed with AMS with SpO2of 93.0±1.6% and LLS of 0.3±1.4 in the morning after the first night. At 3,600 m, 12 of 21 (57%) women had AMS (p=0.355 versus 3,100 m) with SpO2of 86.8±1.8% (p<0.05 vs. 3,100 m) and LLS of 1.9±1.4 (p<0.05 vs. 3,100 m).ConclusionSelf-monitoring female sexual hormones during high-altitude field studies with the employed kit is feasible and provides physiologically plausible trends of hormone levels over the menstrual cycle. Our data provide a valuable basis for designing further studies to evaluate AMS susceptibility in women.