bluuebunny/crossref_metadata_2025_split huggingface dataset:
How do stochastic processes and genetic threshold effects explain incomplete penetrance and inform causal disease mechanisms?
Authors: Jenkins Dagan 
Published: October 2023

AbstractIncomplete penetrance is the rule rather than the exception in Mendelian disease. In syndromic monogenic disorders, phenotypic variability can be viewed as the combination of incomplete penetrance for each of multiple independent clinical features. Within genetically identical individuals, such as isogenic model organisms, stochastic variation at molecular and cellular levels is the primary cause of incomplete penetrance according to a genetic threshold model. By defining specific probability distributions of causal biological readouts and genetic liability values, stochasticity and incomplete penetrance provide information about threshold values in biological systems. Ascertainment of threshold values has been achieved by simultaneous scoring of relatively simple phenotypes and quantitation of molecular readouts at the level of single cells. However, this is much more challenging for complex morphological phenotypes using experimental and reductionist approaches alone, where cause and effect are separated temporally and across multiple biological modes and scales. Here I consider how causal inference, which integrates observational data with high confidence causal models, might be used to quantify the relative contribution of different sources of stochastic variation to phenotypic diversity. Collectively, these approaches could inform disease mechanisms, improve predictions of clinical outcomes and prioritise gene therapy targets across modes and scales of gene function.
Heterogeneity in Functional Connectivity: Dimensional Predictors of Individual Variability during Rest and Task fMRI in Psychosis
Authors: Secara Maria T. , Oliver Lindsay D. , Gallucci Julia , Dickie Erin W. , Foussias George , Gold James , Malhotra Anil K. , Buchanan Robert W. , Voineskos Aristotle N. , Hawco Colin 
Published: October 2023

AbstractBackgroundIndividuals with schizophrenia spectrum disorders (SSD) often demonstrate cognitive impairments, associated with poor functional outcomes. While neurobiological heterogeneity has posed challenges when examining social cognition in SSD, it provides a unique opportunity to explore brain-behavior relationships. We examined the relationship between behavioral data and individual variability of functional connectivity at rest and during an emotional-processing task.MethodsNeuroimaging and behavioral data were analyzed for 193 individuals with SSD and 155 controls (total n = 348). Individual variability was quantified through mean correlational distance (MCD) of functional connectivity between participants; MCD was defined as a global ‘variability score’. Hierarchical regressions were performed on variability scores derived from resting state and Empathic Accuracy (EA) task functional connectivity data to determine potential predictors (e.g., age, sex, neurocognitive and social cognitive scores) of individual variability.ResultsSSD showed greater MCD during rest (p = 0.00013) and task (p = 0.022). In the hierarchical regression, diagnosis remained significant when social cognition was included during rest (p = 0.008), but not during task (p = 0.50); social cognition was significant during both rest and task (both p = 0.01).ConclusionsDiagnostic differences were more prevalent during unconstrained resting scans, whereas the task pushed participants into a more common pattern which better emphasized transdiagnostic differences in cognitive abilities. Focusing on variability may provide new opportunities for interventions targeting specific cognitive impairments to improve functional outcomes.
Samsung Galaxy Watch5 Pro and Withings Body+ generate electrical interference on CRT-Ds
Authors: Hansen Nathan , Ha Gia-Bao , Colvin Penny , Freedman Roger A. , Bayés-Genís Antoni , Steinberg Benjamin A. , Sanchez Benjamin 
Published: October 2023

ABSTRACTSmart consumer devices with bioimpedance sensing technology apply an electrical current to the body for health and wellness. However, whether these smart devices interfere with cardiac implantable electronic devices (CIEDs) remains unknown. We report electrical interference with benchtop testing from the Galaxy Watch5 Pro and smart scale Body+ to cardiac resynchronization therapy device generators from different manufacturers. These results highlight the need of establishing standard testing procedures to assess the safety of smart devices with bioimpedance sensing in patients with CIEDs.
Asthma severity and corticosteroid response depend on variable type 1 and type 2 inflammation in the airway
Authors: Fahy John V. , Jackson Nathan D. , Sajuthi Satria P. , Pruesse Elmar , Moore Camille M. , Everman Jamie L. , Rios Cydney , Tang Monica , Gauthier Marc , Wenzel Sally E. , Bleecker Eugene R. , Castro Mario , Comhair Suzy A. , Erzurum Serpil C. , Hastie Annette T. , Moore Wendy , Israel Elliot , Levy Bruce D. , Denlinger Loren , Jarjour Nizar N. , Johansson Mats W. , Mauger David T. , Phillips Brenda R. , Sumino Kaharu , Woodruff Prescott G. , Peters Michael C. , Seibold Max A. ,   the National Heart, Lung, and Blood Institute Severe Asthma Research Program-3
Published: October 2023

ABSTRACTThe prevalence, inter-relationships, and longitudinal behavior of type 1 (T1) and type 2 (T2) immune responses in asthma are uncertain, as is the role of viruses as determinants of these responses. Here, we performed whole transcriptome network analysis on sputum cells collected from Severe Asthma Research Program (SARP)-3 patients before and after treatment with intramuscular corticosteroid and again at 1 and 3-year follow-up visits. We used network analysis to analyze whole-transcriptome gene expression and metagenomic analysis of these RNA-seq data to detect viruses. We identified T1 and T2 airway networks, the expression of which showed that 26% and 44% of patients had T1-high and T2-high asthma at baseline, respectively. Asthma severity outcomes were worse in T2-high asthma than in T1-high asthma and most severe in the subgroup of patients (14%) with combined T1- and T2-high disease. Corticosteroid treatment suppressed T2 but not T1 gene expression, and corticosteroid-associated improvements in FEV1 occurred only in patients with T1-L/T2-H disease and not in T1-H/T2-H patients. Although T1 and T2 inflammation at baseline was a significant predictor of T1 and T2 inflammation at follow-up visits, most patients had variable rather than persistent expression of T1 and T2 network genes. Viral metagenomic analyses uncovered that 24% of asthma sputum samples tested positive for a virus and high viral carriage was associated with an 11-fold increased risk of T1-high disease. Together our results uncover a relatively high burden of T1-high and T1/T2-high disease subtypes in severe asthma, which are corticosteroid-resistant and manifest with sub-clinical viral infection.
Polygenic associations with clinical and neuropathological trait heterogeneity across TDP-43 proteinopathies
Authors: Spencer Barbara E. , Irwin David J. , Van Deerlin Vivianna M. , Suh EunRan , Lee Edward B. , Elman Lauren B. , Quinn Colin C. , Amado Defne , Baer Michael , Grossman Murray , Wolk David A. , McMillan Corey T. 
Published: October 2023

ABSTRACTObjectiveTDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), and limbic-predominant age-related TDP-43 encephalopathy, encompass a spectrum of clinical and neuropathological traits. Despite mounting evidence for shared genetic risk across TDP-43 proteinopathies, the modifiers of individual-level traits are unknown. We aimed to identify polygenic contributions to trait heterogeneity across TDP-43 proteinopathies.MethodsWe used weighted correlation analysis of GWAS summary statistics for ALS, FTLD-TDP, and hippocampal sclerosis of aging (HS-Aging) to identify data-driven modules of highly correlated single nucleotide polymorphisms (SNPs). We performed gene ontology enrichment analysis for each identified module. We derived module-specific polygenic scores and evaluated their association with clinical and neuropathological traits in an independently evaluated sample of individuals who met neuropathological and/or genetic criteria for FTLD-TDP or ALS (n=260).ResultsWe identified 5 distinct data-driven modules, including 3 GWAS phenotype-specific modules (FTLD-TDP, ALS, HS-Aging) and 2 modules representing the overlap between a pair of GWAS phenotypes (ALS-FTLD and FTLD-HS). Pathway analysis revealed biologically meaningful associations including distinct GWAS phenotype-specific processes within modules. Module-specific ALS and FTLD-TDP polygenic risk each associated with individual-level clinical traits, even within the context of autosomal dominant mutation carriers, where higher ALS polygenic risk associated with neuromuscular impairment and higher FTLD-TDP polygenic risk associated with cognitive-behavioral impairment. Moreover, higher FTLD-TDP polygenic risk associated with higher TDP-43 burden within characteristic FTLD-TDP brain regions.Interpretation:We suggest that there are polygenic modifiers of clinical and neuropathological traits across TDP-43 proteinopathies that may contribute to individual-level differences, including likelihood for developing FTLD or ALS.
The Effects of Intensive Antihypertensive Treatment Targets on Cerebral Blood Flow and Orthostatic Hypotension in Frail Older Adults
Authors: Weijs Ralf W.J. , de Roos Bente M. , Thijssen Dick H.J. , Claassen Jurgen A.H.R. 
Published: October 2023

AbstractBackgroundGuidelines recommend restrictive antihypertensive treatment (AHT) in hypertensive frail older adults, as intensive AHT is assumed to cause cerebral hypoperfusion and orthostatic hypotension (OH). However, studies directly examining these assumptions in older, frail individuals are lacking.MethodsFourteen frail hypertensive patients (six females; age 80.3±5.2 years; Clinical Frailty Scale 4-7; unattended SBP ≥150 mmHg) underwent measurements before and after a median of 7-weeks AHT (SBP target ≤140 mmHg). Transcranial Doppler measurements of middle cerebral artery velocity (MCAv), reflecting changes in cerebral blood flow (CBF), were combined with finger plethysmography recording of continuous BP. Transfer function analysis assessed cerebral autoregulation (CA). ANCOVA analyzed AHT-induced changes in CBF and CA, and evaluated non-inferiority of the relative change in CBF (margin: -10%; covariates: pre-AHT values and AHT-induced relative mean BP change). McNemar-tests analyzed whether the prevalence of (initial) OH, assessed by sit/supine-to-stand challenges, increased with AHT.ResultsUnattended mean arterial pressure decreased by 15 mmHg following AHT. Ten (71%) participants had good quality TCD assessments. Non-inferiority was confirmed for the relative change in MCAv (95%CI -2.7, 30.4). CA was normal and remained unchanged following AHT (P>0.05). None of the 14 participants had an increase in the prevalence of OH or initial OH (P≥0.655).ConclusionsWe found that AHT in frail, older patients does not reduce CBF, is not associated with impaired CA, and does not increase (initial) OH prevalence. These observations may open doors for more intensive AHT targets upon individualized evaluation and monitoring of hypertensive frail patients.Clinical Trial RegistrationClinicalTrials.gov(NCT05529147) and EudraCT (2022-001283-10).
Computational divergence analysis reveals the existence of regulatory degeneration and supports HDAC1 as a potential drug target for Alzheimer’s disease
Authors: Wang Qun , Zhao Zhenzhen , Lu Dong , Xu Hong , Xia Jianhua , Zhang Weidong , Meng Guofeng 
Published: October 2023

AbstractEpigenetic dysregulation has been widely reported in patients of Alzheimer’s disease (AD) and epigenetic drugs are gaining particular interest as a potential candidate therapy target. However, it is less clear how epigenetic dysregulation contributes to AD development. In this work, we performed regulatory divergence analysis using large-scale AD brain RNA-seq data and reported a widespread existence of regulatory degeneration among AD patients. It seems that transcription factor (TF)-mediated regulations get weakened or lost during AD development, resulting in disruption of normal neuronal function, especially including protein degradation, neuroinflammation, mitochondria and synaptic dysfunction. The regulatory degeneration burden (RDB) is well correlated with the detrimental clinical manifestations of AD patients. Studies of epigenetic marks, including histone modification, open chromatin accessibility and three TF binding sites supported the existence of regulatory degeneration. It suggested that epigenetic dysregulation contributed to regulatory degeneration, which also explained the consequence of epigenetic dysregulation. Among the epigenetic regulators, HDAC1 was proposed as a potential participator in such a process. Overall, our computational analysis suggested a novel causal mechanism of AD development and proposed HDAC1 as a drug target to treat AD.
Securing diagonal integration of multimodal single-cell data against ambiguous mapping
Authors: Zhou Han , Cao Kai , Lu Yang Young 
Published: October 2023

AbstractRecent advances in single-cell multimodal omics technologies enable the exploration of cellular systems at unprecedented resolution, leading to the rapid generation of multimodal datasets that require sophisticated integration methods. Diagonal integration has emerged as a flexible solution for integrating heterogeneous single-cell data without relying on shared cells or features. However, the absence of anchoring elements introduces the risk of artificial integrations, where cells across modalities are incorrectly aligned due to ambiguous mapping. To address this challenge, we propose SONATA, a novel diagnostic method designed to detect potential artificial integrations resulting from ambiguous mappings in diagonal data integration. SONATA identifies ambiguous alignments by quantifying cell-cell ambiguity within the data manifold, ensuring that biologically meaningful integrations are distinguished from spurious ones. It is worth noting that SONATA is not designed to replace any existing pipelines for diagonal data integration; instead, SONATA works simply as an add-on to an existing pipeline for achieving more reliable integration. Through comprehensive evaluation on both simulated and real multimodal single-cell datasets, we observe that artificial integrations in diagonal data integration are widespread yet surprisingly overlooked, occurring across all mainstream diagonal integration methods. We demonstrate SONATA’s ability to safeguard against misleading integrations and provide actionable insights into potential integration failures across mainstream methods. Our approach offers a robust framework for ensuring the reliability and interpretability of multimodal single-cell data integration.1
Conditional Requirement for Dimerization of the Membrane-Binding Module of BTK
Authors: Eisen Timothy J. , Ghaffari-Kashani Sam , Groves Jay T. , Weiss Arthur , Kuriyan John 
Published: October 2023

AbstractBruton’s tyrosine kinase (BTK) is a major drug target in immune cells. The membrane-binding pleckstrin-homology and tec-homology (PH–TH) domains of BTK are required for signaling. In vitro, dimerization of the PH–TH module strongly stimulates BTK kinase activity. Whether BTK dimerizes in cells via the PH–TH module, and whether this dimerization is necessary for signaling, is unknown. To address this question, we developed high-throughput mutagenesis assays for BTK function in B cells and T cells. We measured the fitness costs for thousands of point mutations in the PH–TH module and kinase domain, allowing us to assess whether dimerization of the PH–TH module and BTK kinase activity are necessary for function. In Ramos B cells we find that neither PH–TH dimerization nor kinase activity is required for BTK signaling. Instead, in Ramos cells, BTK signaling is enhanced by mutations in the PH–TH module that increase membrane adsorption, even at the cost of reduced PH–TH dimerization. In contrast, in Jurkat T cells, we find that BTK signaling depends on both PH–TH dimerization and kinase activity. Evolutionary analysis shows that BTK proteins in fish and lower organisms, like all Tec kinases other than BTK, lack PH–TH dimerization but have active kinase domains. Thus, PH–TH dimerization is not intrinsically required for Tec-kinase activity, and is a special feature that evolved to exert stricter regulatory control on BTK kinase activity as adaptive immune systems gained increased complexity.
Healthcare and long-term care for older people with cognitive impairment in the US: A latent transition analysis
Authors: Hu Bo , Wang Pengyun , Chen Xi 
Published: October 2023

AbstractBackgroundHealthcare and long-term care are crucial to the well-being of people with mild cognitive impairment (MCI) or dementia. This study investigates the clustering patterns of healthcare and long-term care use in people with MCI or dementia and the relationships between changes in cognitive functioning and transitions of care.MethodsThe study used longitudinal data from three recent waves of the Health and Retirement Study (HRS 2014-2018, N=10,152). MCI and dementia were measured based on the Langa-Weir Classifications. The outcome measures included five types of healthcare and three types of long-term care services. Latent transition analyses were conducted to identify the clustering patterns of care use and map out the transition pathways between different care classes over time. Multilevel regression analyses were conducted to investigate the relationships between changes in cognitive functioning and care transitions.ResultsWe identified three user groups: medium healthcare and low long-term care (MM-LC, 56%, n=5,653), high healthcare and high long-term care (HM-HC, 37%, n=3,743), and low healthcare and low long-term care (LM-LC, 7%, n=736). The progression of cognitive impairment was associated with a higher probability of transitioning from MM-LC to HM-HC class (β=0.070; p<0.001). An improvement in cognitive functioning was associated with a higher probability of transitioning from HM-HC to MM-LC class (β=0.039, p<0.05).ConclusionsOur findings underscore the importance of integration between healthcare and long-term care. Changes in cognitive functioning are useful indicators for care planning, resource allocation, and care coordination from diverse care providers.Key pointsThree classes of healthcare and long-term care services were identified in the latent transition analyses.The progression of cognitive impairment was associated with transitioning to a class characterized by more use of healthcare and long-term care services,An improvement in cognitive functioning was associated with transitioning to a class characterized by less use of care in both sectors.
Genomics in nephrology: identifying informatics opportunities to improve diagnosis of genetic kidney disorders using a human-centered design approach
Authors: Romagnoli Katrina M. , Salvati Zachary M. , Johnson Darren K. , Ramey Heather M. , Chang Alexander R. , Williams Marc S. 
Published: October 2023

ABSTRACTBackgroundGenomic conditions in nephrology often have a long lag between onset of symptoms and diagnosis. To design a real time genetic diagnosis process that meets the needs of nephrologists, we need to understand the current state of the diagnostic process of genomic kidney disorders, barriers and facilitators nephrologists experience, and identify areas of opportunity for improvement and innovation.MethodsQualitative in-depth interviews were conducted with 16 nephrologists from 7 health systems across the US, with variable levels of experience with genetic testing and diagnosis. Rapid analysis identified themes in the interviews. Themes were then used to develop service blueprints (visual diagrams representing relationships between components of a service) and process maps depicting the current state of genetic diagnosis of kidney disease, helping visualize the current state, along with associated barriers and facilitators.ResultsThemes from the interviews included the importance of trustworthy resources, guidance on how to order tests, and evidence-based recommendations on what to do with results. Barriers included lack of knowledge, lack of access, and complexity surrounding the case and disease. Facilitators, based on current genetic testing services used by participants, included good user experience, straightforward diagnoses, and support from colleagues.DiscussionThe current state of diagnosis of genetic kidney diseases is suboptimal, with information gaps, complexity of genetic testing process, and complexity of disease impeding efficiency. This study highlights opportunities for improvement and innovation to address these barriers and empower clinicians who treat nephrological disease to access and use real time genetic information.
Manipulation of natural transformation by AbaR-type islands promotes fixation of antibiotic resistance inAcinetobacter baumanniipopulations
Authors: Tuffet Rémi , Carvalho Gabriel , Godeux Anne-Sophie , Laaberki Maria-Halima , Venner Samuel , Charpentier Xavier 
Published: October 2023

AbstractThe opportunistic pathogenAcinetobacter baumannii, a major global public health concern, has developed multiple variants of AbaR-type genomic islands that confer multidrug resistance. The mechanisms facilitating the persistence of these potentially costly islands withinA. baumanniipopulations have remained enigmatic. In this study, we employed a combination of investigative methods to shed light on the factors contributing to their selective advantage and long-term persistence. The dissemination of AbaR islands is intricately linked to their horizontal transfer via natural transformation, a process through which bacteria can import and recombine exogenous DNA, facilitating allelic recombination, genetic acquisition, and deletion. In experimental populations, we first quantified the rate at which natural transformation events occur between individuals. Our findings indicate that the rate of AbaR deletion events is marginally higher than the rate of their acquisition. When this result is integrated into a model of population dynamics not exposed to antibiotic selection pressure, it leads to the swift removal of AbaRs from the population, a pattern that stands in contrast to AbaR prevalence in genomes. Yet, genomic analyses show that nearly all AbaRs-carryingA. baumanniihave at least one AbaR disruptingcomM, a gene encoding a helicase critical for natural transformation. We discovered that such disruption differentially inhibits the rate of genetic acquisition and deletion. Specifically, they significantly impede the removal of AbaRs while still enabling the host cell to acquire and recombine short sequences, such as allelic variants. Through mathematical evolutionary modeling, we demonstrate that AbaRs inserted intocomMgain a selective advantage over AbaRs inserted in sites that do not inhibit or completely inhibit transformation, in line with the genomic observations. The persistence of AbaRs within populations can be ascribed to their targeted integration into a gene, substantially diminishing the likelihood of their removal from the bacterial genome. In contrast, this integration enables the host cell to preserve the ability to acquire and eliminate various short heterologous sequences, enabling the host bacterium - and thus its AbaR - to adapt to the unpredictability of the environment and persist over the long term. This work underscores how AbaRs, and potentially other Mobile Genetic Elements (MGEs), can manipulate natural transformation to ensure their persistence in populations, ultimately leading to the high prevalence of multidrug resistance.