bluuebunny/crossref_metadata_2025_split huggingface dataset:
Location-biased β-arrestin conformations direct GPCR signaling
Authors: Pham Uyen , Chundi Anand , Stępniewski Tomasz Maciej , Darbha Srikrishna , Eiger Dylan Scott , Gazula Sonia , Gardner Julia , Hicks Chloe , Selent Jana , Rajagopal Sudarshan 
Published: September 2024

ABSTRACTβ-arrestins are multifunctional intracellular proteins that regulate the desensitization, internalization and signaling of over 800 different G protein-coupled receptors (GPCRs) and interact with a diverse array of cellular partners1,2. Beyond the plasma membrane, GPCRs can initiate unique signaling cascades from various subcellular locations, a phenomenon known as “location bias”3,4. Here, we investigate how β-arrestins direct location-biased signaling of the angiotensin II type I receptor (AT1R). Using novel bioluminescence resonance energy transfer (BRET) conformational biosensors and extracellular signal-regulated kinase (ERK) activity reporters, we reveal that in response to the endogenous agonist Angiotensin II and the β-arrestin-biased agonist TRV023, β-arrestin 1 and β-arrestin 2 adopt distinct conformations across different subcellular locations, which are intricately linked to differential ERK activation profiles. We also uncover a population of receptor-free catalytically activated β-arrestins in the plasma membrane that exhibits insensitivity to different agonists and promotes ERK activation on the plasma membrane independent of G proteins. These findings deepen our understanding of GPCR signaling complexity and also highlight the nuanced roles of β-arrestins beyond traditional G protein pathways.
ADENYLATE CYCLASE 3 MEDIATES CAROTID BODY ACTIVATION AND AUTONOMIC DYSFUNCTION IN A SLEEP APNEA MODEL
Authors: Peng Ying-Jie , Nanduri Jayasri , Wang Ning , Su Xiaoyu , Hildreth Matthew , Prabhakar Nanduri R. 
Published: September 2024

ABSTRACTPatients with obstructive sleep apnea (OSA) experience chronic intermittent hypoxia (CIH). OSA patients and CIH-treated rodents exhibit autonomic dysfunction, characterized by overactive sympathetic nervous system and hypertension, mediated through hyperactive carotid body (CB) chemoreflex. Activation of olfactory receptor 78 (Olfr78) by hydrogen sulfide (H2S) is implicated in CB activation and autonomic responses to CIH, but the downstream signaling pathways remain unknown. Given that odorant receptor signaling is coupled to adenylyl cyclase 3 (Adcy3), we hypothesized that Adcy3-dependent cAMP contributes to CB and autonomic responses to CIH. Our findings show that CIH increases cAMP levels in the CB, a response absent inAdcy3,Cth, andOlfr78null mice. CBs fromCthandOlfr78mutant mice lacked persulfidation response to CIH, indicating that Adcy3 activation by CIH requires Olfr78 activation by H2S. CIH also enhanced glomus cell Ca2+influx, an effect absent inCnga2andAdcy3mutants, suggesting that CIH-induced cAMP mediates enhanced Ca2+responses through cyclic nucleotide-gated channels. Furthermore,Adcy3null mice did not exhibit neither CB activation nor autonomic dysfunction by CIH. These results demonstrate that Adcy3-dependent cAMP is a downstream signaling pathway to H2S/Olfr78, mediating CIH-induced CB activation and autonomic dysfunction.
Differential roles of cyclin-CDK1 complexes in cell migration and invasion
Authors: Hetmanski Joseph H R , Jones Michael J , Caswell Patrick T , Jones Matthew C 
Published: September 2024

AbstractTwo key hallmarks of cancer are dysregulated proliferation and metastasis, which are co- ordinated at the single cell level by regulation of cell-cycle progression and invasive cell migration respectively. We have previously described a central role for CDK1 at the nexus of adhesion signalling and cell cycle progression, demonstrating that CDK1 has a non-canonical role in regulating integrin adhesion complexes and in the migration of cancer cells in 3D interstitial matrix. Here we show that the CDK1 binding partners cyclinB1 and cyclinA2 also have roles in cell migration and invasion in both cancer and non-transformed cells. CyclinB1 plays a key role in RhoA activation to promote rear retraction in a membrane tension dependent manner, while cyclinA2 has a general role in promoting motility. Knockdown of either cyclin significantly perturbs migration with contrasting phenotypes, while knockdown of both together has an additive effect which arrests both migration and division. We find that the cell migration specific role of CDK1 is independent of cell-cycle phase, with inhibition or knockdown of CDK1 perturbing migration in G0/G1 arrested cells, while CDK1-cyclin expression correlates strongly with invasive potential of bladder cancer cell lines. Our findings therefore describe how cyclin-CDK1 complexes orchestrate migration as well as division of cells and that cyclinA2-CDK1 and cyclinB1-CDK1 complexes play distinct roles in motility. Furthermore, these findings suggest that targeting CDK1 signalling in aggressive and invasive tumours may have an unexpected dual potential to combat metastasis in addition to proliferation.
RanBALL: An Ensemble Random Projection Model for Identifying Subtypes of B-Cell Acute Lymphoblastic Leukemia
Authors: Li Lusheng , Xiao Hanyu , Wu Xinchao , Tang Zhenya , Khoury Joseph D. , Wang Jieqiong , Wan Shibiao 
Published: September 2024

AbstractAs the most common pediatric malignancy, B-cell acute lymphoblastic leukemia (B-ALL) has multiple distinct subtypes characterized by recurrent and sporadic somatic and germline genetic alterations. Identifying B-ALL subtypes can facilitate risk stratification and enable tailored therapeutic design. Existing methods for B-ALL subtyping primarily depend on immunophenotyping, cytogenetic tests and genomic profiling, which would be costly, complicated, and laborious. To overcome these challenges, we presentRanBALL(an ensembleRandom projection-based model for identifyingB-ALLsubtypes), an accurate and cost-effective model for B-ALL subtype identification. By leveraging random projection (RP) and ensemble learning, RanBALL can preserve patient-to-patient distances after dimension reduction and yield robustly accurate classification performance for B-ALL subtyping. Benchmarking results based on >1700 B-ALL patients demonstrated that RanBALL achieved remarkable performance (accuracy: 0.93, F1-score: 0.93, and Matthews correlation coefficient: 0.93), significantly outperforming state-of-the-art methods like ALLSorts in terms of all performance metrics. In addition, RanBALL performs better than tSNE in terms of visualizing B-ALL subtype information. We believe RanBALL will facilitate the discovery of B-ALL subtype-specific marker genes and therapeutic targets to have consequential positive impacts on downstream risk stratification and tailored treatment design. To extend its applicability and impacts, a Python-based RanBALL package is available athttps://github.com/wan-mlab/RanBALL.
LOCAS: Multi-label mRNALocalization with Supervised Contrastive Learning
Authors: Abir Abrar Rahman , Tahmid Md Toki , Rahman M. Saifur 
Published: September 2024

AbstractTraditional methods for mRNA subcellular localization often fail to account for multiple compartmentalization. Recent multi-label models have improved performance, but still face challenges in capturing complex localization patterns. We introduce LOCAS (Localization with Supervised Contrastive Learning), which integrates an RNA language model to generate initial embeddings, employs supervised contrastive learning (SCL) to identify distinct RNA clusters, and uses a multi-label classification head (ML-Decoder) with cross-attention for accurate predictions. Through extensive ablation studies and multi-label overlapping threshold tuning, LOCAS achieves state-of-the-art performance across all metrics, providing a robust solution for RNA localization tasks.
Auto-antibodies against interferons are common in people living with chronic hepatitis B virus infection and associate with PegIFN non-response
Authors: Fink DL , Etoori D , Hill R , Idilli O , Kartikapallil N , Payne O , Griffith S , Bradford HF , Mauri C , Kennedy PTF , McCoy LE , Maini MK , Gill US 
Published: September 2024

AbstractBackground and aimsType one (T1) and three interferons (T3IFNs) are implicated in Chronic Hepatitis B (CHB) immunopathogenesis. IFN remains the only licenced immune modulating therapy for CHB. We measured the prevalence of auto-antibodies (auto-Abs) against T1 and T3IFNs to examine the hypothesis that they impact Hepatitis B Virus (HBV) control and treatment response, as highlighted by COVID-19.MethodsOur multi-centre retrospective longitudinal study accessed two CHB cohorts, auto-Ab levels and neutralisation status were measured against T1IFN and T3IFN. Associations were tested against HBV clinical parameters.ResultsOverall, 11.9% (33/276) of CHB patients had any detectable anti-IFN auto-Abs and 9.8% (27/276) anti-T3IFN auto-Abs, with high incidence of PegIFNα-inducedde novoauto-Ab (25.7%, 9/35). However, only a minority of auto-Ab-positive sera demonstrated neutralisationin vitro(3/33, 9.1%). Auto-Ab-positivity correlated with higher median HBsAg levels (p=0.0024). All individuals with detectable auto-Ab were PegIFNαnon-responders including those without auto-Ab against IFNαspecifically.ConclusionsNon-neutralising anti-IFN auto-Abs are common in CHB and associate with higher median HBsAg levels. Further prospective study of anti-cytokine auto-Ab in CHB are required to characterise association with long-term outcomes.Impact and implicationsHBV and PegIFNαindividually may induce broad auto-reactivity associated with dysregulated anti-viral immune responses. Auto-Ab screening pre-PegIFNαand other immunotherapies may have a critical role in stratifying patient selection.
Specific Within-Domain Cognitive Impairments Predict Depression Severity Six-Months After Stroke
Authors: Kelleher Kyle , Demeyere Nele , Kusec Andrea 
Published: September 2024

AbstractBackgroundFollowing stroke, chronic cognitive impairments across multiple domains have been associated with depression. Currently, it is unknown if specific subtypes of cognitive impairments differentially relate to post-stroke depression severity. This study aimed to explore the differential associations between within-domain cognitive impairment to depression severity six-months after stroke.MethodParticipants (n= 385, AgeM= 73.86 years [SD= 12.51], National Institutes of Health Stroke SeverityM= 6.83 [SD= 6.01]) were recruited from an acute stroke ward. Participants completed a self-report mood measure (Hospital Anxiety and Depression Scale; HADS) and a stroke-specific cognitive assessment (Oxford Cognitive Screen; OCS). Separate multiple regressions predicting depression were conducted across 1) OCS domain-specific cognitive impairments of language, memory, attention, praxis, numeracy and executive function, and 2) the novel subtask-specific impairments within each OCS domain. Anxiety severity and years of education attained were included as covariates.ResultsWithin-domain impairments that were uniquely associated with depression severity were calculation (b(.57)= 1.44, 95%CI[0.31, 2.56],p= .012), episodic memory (b(.52)= 1.36, 95%CI[0.34, 2.37],p= .009), picture naming (b(.45)= 1.18, 95%CI[0.31, 2.06],p= .008), number writing (b(.46)= 2.54, 95%CI[0.26, 2.07],p= .012), and visuospatial attention (b(.35)= 1.24, 95%CI[0.54, 1.93],p= .001). Analysis in pooled multiply imputed data (N= 430) corroborated complete case analysis findings.ConclusionsSpecific within-domain cognitive impairments have differential relationships with post-stroke depressive symptomology. Accommodating for these impairments in post-stroke depression interventions may potentially enhance therapeutic outcomes.
Development and evaluation of patient-centred polygenic risk score reports for glaucoma screening
Authors: Hollitt Georgina L , Hassall Mark M , Siggs Owen M , Craig Jamie E , Souzeau Emmanuelle 
Published: September 2024

ABSTRACTBackgroundPolygenic risk scores (PRS), which provide an individual probabilistic estimate of genetic susceptibility to develop a disease, have shown effective risk stratification for glaucoma onset. However, there is limited best practice evidence for reporting PRS and patient-friendly reports for communicating effectively PRS are lacking. Here we developed patient-centred PRS reports for glaucoma screening based on the literature and evaluated them with participants using a qualitative research approach.MethodsWe first reviewed existing PRS reports and literature on probabilistic risk communication. This informed the development of a draft glaucoma screening PRS report for a hypothetical high risk individual from the general population. We designed three versions of the report to illustrate risk using a pictograph, a pie chart and a bell curve. We then conducted semi-structured interviews to assess preference of visual risk communication aids, understanding of risk, content, format and structure of the reports. Participants were invited from an existing study, which aims to evaluate the clinical validity of glaucoma among individuals >50 years from the general population. Numeracy and literacy levels were assessed.ResultsWe interviewed 12 individuals (50% female, 42% university education). Numeracy (mean 2.1±0.9, range 0-3), graph literacy (mean 2.8±0.8, range 0-4) and genetic literacy (mean 24.2±6.2, range -20-+46) showed a range of levels. We analysed the reports under three main themes: visual preferences, understanding risk and reports formatting. The visual component was deemed important to understanding risk, with the pictograph being the preferred visual risk representation, followed by the pie chart and the bell curve. Participants expressed preference for absolute risk in understanding risk, along with the written content explaining the results. The importance of follow-up recommendations and time to glaucoma onset were highlighted. Participants expressed varied opinions in the level of information and the colours used, which informed revisions of the report.ConclusionsOur study revealed preferences for reporting PRS information in the context of glaucoma screening, to support the development of clinical PRS reporting. Further research is needed to assess PRS communication in other contexts and with other target audiences (e.g. referring clinicians), and its potential psychosocial impact in the wider community.
Gastrointestinal Dysmotility, Autonomic Function and Small Intestinal Bacterial Overgrowth Among People with Well-Controlled HIV
Authors: Robinson-Papp Jessica , Mehta Mitali , Mueller Bridget R. , Neupane Niyati , Zhao Zhan , Cedillo Gabriela , Coyle Kaitlyn , Campbell Maya , George Mary Catherine , Benn Emma KT , Lee Gina , Semler Jack 
Published: September 2024

AbstractIntroductionGastrointestinal dysfunction, including microbiome changes and increased translocation across a compromised gastrointestinal barrier plays a role in the chronic inflammation experienced by people with HIV (PWH). It is unknown whether autonomic neuropathy (AN) may contribute to these mechanisms by altering gastrointestinal motility.MethodsThis is a cross-sectional study of 100 PWH and 89 controls. All participants underwent assessment of gastrointestinal transit times using a wireless motility capsule (WMC). All PWH and a subset of controls also underwent: a standardized battery of autonomic function tests summarized as the Modified Composite Autonomic Severity Score (MCASS) and its adrenergic, cardiovagal and sudomotor sub-scores, breath testing for small intestinal bacterial overgrowth (SIBO), and the Patient Assessment of Upper Gastrointestinal Disorders Symptoms (PAGI-SYM) and Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaires.ResultsPWH displayed shorter gastric emptying times (GET) and longer small bowel and colonic transit times (SBTT, CTT) compared to controls. Among PWH, GET was associated with PAGI-SYM score. The MCASS and its sudomotor sub-score (reflecting peripheral sympathetic function) were associated with SBTT but not GET or CTT. PWH with prolonged SBTT (>6h) were more likely to have SIBO.ConclusionGastrointestinal motility is altered in PWH. This study provides preliminary evidence that changes in autonomic function may influence SBTT in PWH and that prolonged SBTT may contribute to the development of SIBO. Future studies are needed to more fully elucidate the pathophysiologic links between HIV-associated AN, altered gastrointestinal motility, the gastrointestinal microbiome, chronic inflammation, and resulting morbidity and mortality among PWH.
Patient-centered Transcriptomic and Multimodal Neuroimaging Determinants of Clinical Progression, Physical Activity and Treatment Needs in Parkinson’s Disease
Authors: Adewale Quadri , Khan Ahmed Faraz , Lin Sue-Jin , Baumeister Tobias R. , Zeighami Yashar , Carbonell Felix , Ferreira Daniel , Iturria-Medina Yasser 
Published: September 2024

ABSTRACTParkinson’s disease is a complex and multifactorial disorder, but how its biological and clinical complexity emerge from molecular to macroscopic brain interactions remains poorly understood. Here, we use a personalized multiscale generative brain model to characterize direct spatiotemporal links between genes and multimodal neuroimaging-derived biological factors in PD. We identified a set of genes modulating PD-associated longitudinal changes in dopamine transporter level, neuronal activity, dendrite density and tissue atrophy. Inter-individual heterogeneity in the gene-mediated biological mechanisms is associated with five distinct configurations of PD motor and non-motor symptoms. Although characterized by distinctive biological pathways, all the symptom configurations are associated with cell cycle processes. Notably, the protein-protein interaction networks underlying these configurations revealed distinct hub genes includingMYC, CCNA2, CCDK1, SRC, STAT3andPSMD4. We also uncovered the biological mechanisms associated with physical activities performance in PD, and observed that leisure and work activities are principally related to neurotypical cholesterol homeostasis and inflammatory response processes, respectively. Finally, patient-tailoredin silicogene perturbations revealed a set of putative disease-modifying drugs with potential to effectively treat PD, most of which are associated with dopamine reuptake and anti-inflammation. Our study constitutes the first self-contained multiscale approach providing comprehensive insights into the complex multifactorial pathogenesis of PD, unravelling key biological modulators of physical and clinical deterioration, and serving as a blueprint for optimum drug selection at personalized level.
Why are telomeres the length that they are? Insight from a phylogenetic comparative analysis
Authors: Benson Derek M. , Padilla Perez Dylan J. , DeNardo Dale F. 
Published: September 2024

AbstractTelomeres are short repeating nucleotide sequences at the ends of chromosomes that shorten with every cellular replication. Despite the importance of keeping telomere length within a critical homeostatic range, adult telomere length can differ by two orders of magnitude across vertebrate species. Why telomere length varies so widely remains unknown, though popular hypotheses suggest that body size, lifespan, and endothermy are key variables that have coevolved with telomere length. To test the relationship among telomere length, telomerase activity (which extends telomeres), and these variables, we modeled the evolution of telomere length across 122 vertebrate species. We failed to find an influence of body mass, lifespan, or baseline metabolism on telomere length. However, we found a significant interactive effect between baseline metabolism and body mass. The presence of telomerase activity was positively correlated with telomere length across the 58 species where data for both existed. Taken together, our findings suggest that body mass may have differentially influenced the evolution of telomere length in endotherms and ectotherms and indicate that telomerase activity and telomere length may have coevolved.
An in vivo and in vitro spatiotemporal atlas of human midbrain development
Authors: Budinger Dimitri , Puigdevall Costa Pau , Hall George T. , Roth Charlotte , Xenakis Theodoros , Marrosu Elena , Jerber Julie , Di Domenico Alessandro , Kilpinen Helena , Castellano Sergi , Barral Serena , Kurian Manju A. 
Published: September 2024

AbstractThe dopaminergic system has key roles in human physiology and is implicated in a broad range of neurological and neuropsychiatric conditions that are increasingly investigated using induced pluripotent stem cell-derived midbrain models. To determine the similarity of such models to human systems, we undertook single cell and spatial profiling of first and second trimester fetal midbrain and compared it to in vitro midbrain models. Our initial histological analysis of second trimester fetal midbrain revealed structural complexity already similar to that of adult tissue, although this similarity did not fully extend to transcriptional activity. Moreover, we show that in vitro models recapitulate the transcriptional activity of late first trimester fetal midbrain, while 3D models replicate the spatial organization and cellular microenvironments of first and second trimester fetal midbrain. Understanding the extent of human tissue recapitulation in midbrain laboratory models is essential to justify their use as biological proxies.
Grasping the constraints of pure bacterial strains for the complete catabolism of micropollutants: a proteomic and kinetic study
Authors: Lopez Gordillo Ana P. , Trueba-Santiso Alba , Smith Kilian E.C. , Schäffer Andreas , Lema Juan M. 
Published: September 2024

ABSTRACTResearch into the microbial degradation of organic micropollutants (OMP) often involves monitoring depletion of the parent compound and analyzing the biotransformation pathways that can lead to the production of metabolites, some being toxic, and/or to their mineralization. For the antibiotic sulfamethoxazole (SMX), previous studies testing a range of SMX concentration (mg down to ng L−1), have shown incomplete biotransformation of the parent SMX. This occurred both during wastewater treatment with mixed microbial communities and in studies with pure bacterial strains acclimated to SMX. This study explores the mechanism of SMX biotransformation and relationships with the proteome profile as possible reasons for the incomplete degradation of the parent SMX.Microbacterium spBR1 served as an acclimated bacterial degrader of SMX in the range of µg L−1to ng L−1. Depletion of the SMX was incomplete whereas the metabolite 3-amino-5-methylisoxazole (3A5MI) accumulated. The activity of the enzymes for the initial transformation of the parent SMX (SadA) was higher than that of further biotransformation steps (SadB). These results showcase that even a highly sensitive and metabolically active strain at very low SMX concentrations may require complementary enzymatic machineries to degrade metabolites that have an inhibitory impact in the biodegradation and persistence of this antibiotic.SynopsisA complete removal of organic micropollutants from water is challenging. This article delves into the bacterial degradation of the antibiotic SMX and proteome analysis to clarify underlying causes of its incomplete elimination