bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamical models reveal anatomically reliable attractor landscapes embedded in resting state brain networks
Authors: Chen Ruiqi , Singh Matthew , Braver Todd S. , Ching ShiNung 
Published: January 2024

Analyses of functional connectivity (FC) in resting-state brain networks (RSNs) have generated many insights into cognition. However, the mechanistic underpinnings of FC and RSNs are still not well-understood. It remains debated whether resting state activity is best characterized as noise-driven fluctuations around a single stable state, or instead, as a nonlinear dynamical system with nontrivial attractors embedded in the RSNs. Here, we provide evidence for the latter, by constructing whole-brain dynamical systems models from individual resting-state fMRI (rfMRI) recordings, using the Mesoscale Individualized NeuroDynamic (MINDy) platform. The MINDy models consist of hundreds of neural masses representing brain parcels, connected by fully trainable, individualized weights. We found that our models manifested a diverse taxonomy of nontrivial attractor landscapes including multiple equilibria and limit cycles. However, when projected into anatomical space, these attractors mapped onto a limited set of canonical RSNs, including the default mode network (DMN) and frontoparietal control network (FPN), which were reliable at the individual level. Further, by creating convex combinations of models, bifurcations were induced that recapitulated the full spectrum of dynamics found via fitting. These findings suggest that the resting brain traverses a diverse set of dynamics, which generates several distinct but anatomically overlapping attractor landscapes. Treating rfMRI as a unimodal stationary process (i.e., conventional FC) may miss critical attractor properties and structure within the resting brain. Instead, these may be better captured through neural dynamical modeling and analytic approaches. The results provide new insights into the generative mechanisms and intrinsic spatiotemporal organization of brain networks.Significance StatementOur brain remains active even when not engaged in cognitively demanding tasks. However, the processes that determine such ‘resting state’ activity are still not well-understood. Using a large (n > 1000) functional neuroimaging dataset and new techniques for computationally modeling brain activity, we found that the resting brain possesses several distinct mechanisms by which activity can be generated. These mechanisms, or dynamics, vary moment to moment, but result in the activation of similar anatomical regions across different individuals. Our results suggest that the resting brain is neither idle, nor monolithic in its governing mechanisms, but rather possesses a diverse but consistent taxonomy of ways in which it can activate and hence transition to cognitive tasks.
The mechanosensitive Pkd2 channel modulates the recruitment of myosin II and actin to the cytokinetic contractile ring
Authors: Chowdhury Pritha , Sinha Debatrayee , Poddar Abhishek , Chetluru Madhurya , Chen Qian 
Published: January 2024

AbstractCytokinesis, the last step in cell division, separate daughter cells through the force produced by an actomyosin contractile ring assembled at the equatorial plane. In fission yeast cells, the ring helps recruit a mechanosensitive ion channel Pkd2 to the cleavage furrow, whose activation by membrane tension promotes calcium influx and daughter cell separation. However, it is unclear how the activities of Pkd2 may affect the actomyosin ring. Here, through both microscopic and genetic analyses of a hypomorphic mutant of the essentialpkd2gene, we examine its potential role in assembling and constricting the contractile ring. Thepkd2-81KDmutation significantly increased the number of type II myosin heavy chain Myo2 (+20%), its regulatory light chain Rlc1 (+37%) and actin (+20%) molecules in the ring, compared to the wild type. Consistent with a regulatory role of Pkd2 in the ring assembly, we identified a strong negative genetic interaction betweenpkd2-81KDand the temperature-sensitive mutantmyo2-E1. Thepkd2-81KD myo2-E1cells often failed to assemble a complete contractile ring. We conclude that Pkd2 modulates the recruitment of type II myosin and actin to the contractile ring, suggesting a novel calcium- dependent mechanism regulating the actin cytoskeletal structures during cytokinesis.
Cbfβ regulates Wnt/β-catenin, Hippo/Yap, and TGFβ signaling pathways in articular cartilage homeostasis and protects from ACLT surgery-induced osteoarthritis
Authors: Chen Wei , Lu Yun , Zhang Yan , Wu Jinjin , McVicar Abigail , Chen Yilin , Zhu Siyu , Zhu Guochun , Lu You , Zhang Jiayang , McConnell Matthew , Li Yi-Ping 
Published: January 2024

ABSTRACTAs the most common degenerative joint disease, osteoarthritis (OA) contributes significantly to pain and disability during aging. Several genes of interest involved in articular cartilage damage in OA have been identified. However, the direct causes of OA are poorly understood. Evaluating the public human RNA-seq dataset showed thatCbfβ,(subunit of a heterodimeric Cbfβ/Runx1,Runx2, or Runx3 complex) expression is decreased in the cartilage of patients with OA. Here, we found that the chondrocyte-specific deletion ofCbfβin tamoxifen-inducedCbfβf/fCol2α1-CreERTmice caused a spontaneous OA phenotype, worn articular cartilage, increased inflammation, and osteophytes. RNA-sequencing analysis showed thatCbfβdeficiency in articular cartilage resulted in reduced cartilage regeneration, increased canonical Wnt signaling and inflammatory response, and decreased Hippo/YAP signaling and TGF-β signaling. Immunostaining and western blot validated these RNA-seq analysis results. ACLT surgery-induced OA decreasedCbfβand Yap expression and increased active β-catenin expression in articular cartilage, while local AAV-mediatedCbfβoverexpression promoted Yap expression and diminished active β-catenin expression in OA lesions. Remarkably, AAV-mediatedCbfβoverexpression in knee joints of mice with OA showed the significant protective effect ofCbfβon articular cartilage in the ACLT OA mouse model. Overall, this study, using loss-of-function and gain-of-function approaches, uncovered that low expression ofCbfβmay be the cause of OA. Moreover, Local admission ofCbfβmay rescue and protect OA through decreasing Wnt/β-catenin signaling, and increasing Hippo/Yap signaling and TGFβ/Smad2/3 signaling in OA articular cartilage, indicating that localCbfβoverexpression could be an effective strategy for treatment of OA.
Opioid-driven disruption of the septal complex reveals a role for neurotensin-expressing neurons in withdrawal
Authors: Simon Rhiana C. , Fleming Weston T. , Senthilkumar Pranav , Briones Brandy A. , Ishii Kentaro K. , Hjort Madelyn M. , Martin Madison M. , Hashikawa Koichi , Sanders Andrea D. , Golden Sam A. , Stuber Garret D. 
Published: January 2024

AbstractBecause opioid withdrawal is an intensely aversive experience, persons with opioid use disorder (OUD) often relapse to avoid it. The lateral septum (LS) is a forebrain structure that is important in aversion processing, and previous studies have linked the lateral septum (LS) to substance use disorders. It is unclear, however, which precise LS cell types might contribute to the maladaptive state of withdrawal. To address this, we used single-nucleus RNA-sequencing to interrogate cell type specific gene expression changes induced by chronic morphine and withdrawal. We discovered that morphine globally disrupted the transcriptional profile of LS cell types, but Neurotensin-expressing neurons (Nts; LS-Ntsneurons) were selectively activated by naloxone. Using two-photon calcium imaging andex vivoelectrophysiology, we next demonstrate that LS-Ntsneurons receive enhanced glutamatergic drive in morphine-dependent mice and remain hyperactivated during opioid withdrawal. Finally, we showed that activating and silencing LS-Ntsneurons during opioid withdrawal regulates pain coping behaviors and sociability. Together, these results suggest that LS-Ntsneurons are a key neural substrate involved in opioid withdrawal and establish the LS as a crucial regulator of adaptive behaviors, specifically pertaining to OUD.
A call for a unified and multimodal definition of cellular identity in the enteric nervous system
Authors: Majd Homa , Cesiulis Andrius , Samuel Ryan M , Richter Mikayla N , Elder Nicholas , Guyer Richard A , Hao Marlene M. , Stamp Lincon A. , Goldstein Allan M , Fattahi Faranak 
Published: January 2024

SummaryThe enteric nervous system (ENS) is a tantalizing frontier in neuroscience. With the recent emergence of single cell transcriptomic technologies, this rare and poorly understood tissue has begun to be better characterized in recent years. A precise functional mapping of enteric neuron diversity is critical for understanding ENS biology and enteric neuropathies. Nonetheless, this pursuit has faced considerable technical challenges. By leveraging different methods to compare available primary mouse and human ENS datasets, we underscore the urgent need for careful identity annotation, achieved through the harmonization and advancements of wet lab and computational techniques. We took different approaches including differential gene expression, module scoring, co-expression and correlation analysis, unbiased biological function hierarchical clustering, data integration and label transfer to compare and contrast functional annotations of several independently reported ENS datasets. These analyses highlight substantial discrepancies stemming from an overreliance on transcriptomics data without adequate validation in tissues. To achieve a comprehensive understanding of enteric neuron identity and their functional context, it is imperative to expand tissue sources and incorporate innovative technologies such as multiplexed imaging, electrophysiology, spatial transcriptomics, as well as comprehensive profiling of epigenome, proteome, and metabolome. Harnessing human pluripotent stem cell (hPSC) models provides unique opportunities for delineating lineage trees of the human ENS, and offers unparalleled advantages, including their scalability and compatibility with genetic manipulation and unbiased screens. We encourage a paradigm shift in our comprehension of cellular complexity and function in the ENS by calling for large-scale collaborative efforts and research investments.
Generational differences in physical health and disability in the United States and Europe
Authors: Gimeno Laura , Goisis Alice , Dowd Jennifer B. , Ploubidis George B. 
Published: January 2024

AbstractObjectivesDeclines in mortality have typically been associated with improvements in physical health across generations. While life expectancy in most high-income countries continues to increase, there is evidence that younger generations, particularly in the United States (US), are less healthy than previous generations at the same age. We compared generational trends in physical health in the US, England, and continental Europe to explore whether other regions have experienced a similar pattern of worsening health across cohorts.MethodsUsing data from nationally representative studies of adults aged ≥50 years from the US (Health and Retirement Study,n=26,939), England (English Longitudinal Study of Ageing,n=14,992) and 11 continental European countries (Survey of Health, Ageing and Retirement in Europe,n=72,595), we estimated differences in the age-adjusted prevalence of self-reported chronic disease and disability and observer-measured health indicators across pseudo-birth cohorts (born <1925, 1925-1935, 1936-1945, 1946-1954, 1955-1959).ResultsAge-adjusted prevalence of doctor-diagnosed chronic disease increased across cohorts in all regions. Trends in disability prevalence were more regionally varied. Still, in both the US and Europe, we observed a structural break in disability trends, with declines observed in pre-war cohorts slowing, stalling, or reversing for cohorts born since 1945.DiscussionIn all regions, we found evidence for worsening health across cohorts, particularly for those born since 1945. While more chronic disease in younger cohorts need not necessarily translate to worse quality of life or higher rates of functional limitation, there is some suggestion that worsening chronic disease morbidity may be spilling over into worsening disability.
Routine Labs in Hospital Patients: Iatrogenic Anemia and Missed Acute Kidney Injury
Authors: Dean Dawson 
Published: January 2024

AbstractGuidelines recommend avoiding unnecessary laboratory tests to minimize risks of anemia in hospitalized patients as well as reduce costs. Avoiding routine labs, however, may introduce new risks of missing conditions that do not have physical exam or history findings, such as Acute Kidney Injury. This study analyzes retrospective data for routine laboratory results and simulates different strategies for skipping labs. It estimates potential benefits from avoiding iatrogenic anemia as well as costs from increased risk of Acute Kidney Injury. In a simplified estimate of pure dollar costs, the costs of daily labs appear to significantly outweigh the costs of missing Acute Kidney Injury, but there are costs to skipping routine labs.
Early developmental milestone clusters of autistic children based on electronic health records
Authors: Ben-Sasson Ayelet , Guedalia Joshua , Ilan Keren , Shefer Galit , Cohen Roe , Gabis Lidia V 
Published: January 2024

AbstractASD children vary in symptoms, co-morbidities and response to interventions. This study aimed to identify clusters of ASD children with a distinct pattern of attaining early developmental milestones. Clustering of 5,836 ASD children was based on attainment of 43 gross motor, fine motor, language and social developmental milestones in the first three years of life as recorded in baby wellness visits.K-means cluster analysis detected 4 Early Developmental Milestone (EDM) clusters: typical (n=1,686); mild (n=1,691); moderate (n=2,265); and severe (n=194). Most prominent cluster differences were in the language domain. The severe cluster showed earlier and greater developmental delay across domains, unique early gross motor delays, and more were born preterm via cesarian section. Moderate cluster had poor language development prominently in the second year of life, later fine motor delays. Mild cluster had language delays in the third year of life. The typical cluster mostly passed milestones. EDM clusters differed demographically, with higher socioeconomic status in typical cluster and lowest in severe cluster. Moderate cluster had more immigrant and non-Jewish mothers followed by the mild cluster. The rates of parental concerns and provider developmental referrals were significantly higher in the severe, followed by the moderate, mild, and typical EDM clusters.ASD children’s language and motor delay in the first three years can be grouped by common magnitude and onset profiles as distinct groups that may link to specific etiologies (like prematurity or genetics) and to specific intervention programs. Early ASD screening should be tailored to these different developmental profiles.
The Dearth of Representation in FDA Approved Drug Trials
Authors: Ibilibor Christine , Armbruster Shannon , Parker Rell , Yu Jia-Ray , Barros Andrew 
Published: January 2024

AbstractThe generalizability of data derived from randomized controlled trials is of paramount importance given their utility in the Food & Drug Administration (FDA) drug approval process. An essential part of this process is the inclusion of reliably reported gender, race and ethnicity data in trials that lead to FDA drug approval. Despite previous mandates by the FDA andClinicaltrials.gov, gender and race-specific data remains under reported. We reviewed 100 most recently approved FDA medications, and abstracted the clinical trial data fromClinicaltrials.govthat supported their approval. We then compared these FDA approved trials to non-FDA approved trials from the same year and of similar size. We found that 40% of the FDA trials were missing race/ethnicity information, while 24% of these trials did not include gender information. We demonstrate that there remains a significant amount of missing gender and racial/ethnic data in trials that lead to FDA-approved medications.
Cohort profile: a multicenter European study of acute respiratory infections: the MERMAIDS-ARI 2.0 cohort study
Authors: de Hoog Marieke L.A. , Prat-Aymerich Cristina , Troeman Darren P.R. , Lee James , Ieven Greet , Horby Peter , Leus Frank , Bonten Marc J. M. , Goossens Herman J.A. , Bruijning-Verhagen Patricia C.J.L. 
Published: January 2024

ABSTRACTPurposeMulti-centre EuRopean study of MAjor Infectious Disease Syndromes – Acute Respiratory Infections (MERMAIDS-ARI) cohort study is a European prospective cohort study. It was originally launched in 2016 as MERMAIDS-ARI to study acute respiratory infections. When the COVID-19 pandemic hit, the study re-started inclusion under an amended protocol as MERMAIDS-ARI 2.0 focusing on SARS-CoV-2. The objectives of this study were to describe the disease spectrum, clinical features, and outcomes of SARS-CoV-2 infections in hospital care, to determine relevant risk factors and the assess prevalence and within hospital spread compared to other respiratory infections. An important second objective was to establish an extensive biobank supplemented with detailed clinical data to be able to address future virological, immunological, and clinical research questions.MethodsPatients with either 1) ARI presenting to hospital care during the SARS-CoV-2 epidemic (including both COVID-19 and non-COVID-19 patients) or 2) confirmed COVID-19 infection, but with atypical presentation (non-ARI) or with nosocomial acquisition were included. Clinical data and biological samples were collected on enrolment day and repeatedly thereafter until discharge. A subset of COVID-19 patients was also followed up to 12 months post-discharge to study clinical recovery and long-term sequelae.Findings to dateIn total 297 patients from 8 countries and 11 sites were recruited between June 2020 and September 2021. We reached high sample completeness for most sample types (>97% for single samples and >86% for serial samples). 294 (99.0%) patients were admitted to hospital with SARS-CoV-2. The population primarily consists of patients (median age 61 years) of Caucasian ethnicity, with the majority being male (62.0%) and having ≥1 comorbidities (67.3%). The median hospital stay was 10 days, and most patients (87.5%) received treatment with systemic corticosteroids and respiratory support (81.4%). A total of 64 (21.7%) patients were admitted to the Intensive Care Unit (ICU), and 6.5% died during hospitalization. Long-term follow-up of 94 patients revealed that most individuals resumed their regular activities and work within three months, with improvements observed in mobility and personal care over time. Instances of severe and extreme pain and anxiety were rarely reported (≤1.1%).ConclusionThis pan-European study offers a valuable resource for conducting in-depth virological, immunological, and pathophysiological investigations pertaining to SARS-CoV-2.
The transgenerational consequences of paternal social isolation and predation exposure in threespined sticklebacks
Authors: Hellmann Jennifer , Rogers Michaela 
Published: January 2024

AbstractParents routinely encounter stress in the ecological environment that can affect offspring development (transgenerational plasticity: TGP); however, parents’ interactions with conspecifics may alter how parents respond to ecological stressors.During social buffering, the presence of conspecifics can reduce the response to or increase the speed of recovery from a stressor. This may have cascading effects on offspring if conspecifics can mitigate parental responses to ecological stress in ways that blunt the transmission of stress-induced transgenerational effects.Here, we simultaneously manipulated both paternal social isolation and experience with predation risk prior to fertilization in threespined stickleback (Gasterosteus aculeatus). We generated offspring via in-vitro fertilization to allow us to isolate paternal effects mediated via sperm alone (i.e., in the absence of paternal care). If social buffering mitigates TGP induced by paternal exposure to predation risk, then we expect the transgenerational effects of predation exposure to be weaker when a conspecific is present compared to when the father is isolated.Offspring of predator-exposed fathers showed reduced anxiety-like behavior and tended to be captured faster by the predator. Fathers who were socially isolated also had offspring that were captured faster by a live predator, suggesting that paternal social isolation may have maladaptive effects on how offspring respond to ecological stressors. Despite additive effects of paternal social isolation and paternal predation risk, we found no evidence of an interaction between these paternal treatments, suggesting that the presence of a conspecific did not buffer fathers and/or offspring from the effects of predation risk.Our results suggest that socially-induced stress is an important, yet underappreciated, mediator of TGP and can elicit transgenerational effects even in species that do not form permanent social groups. Future studies should therefore consider how the parental social environment can affect both within and trans-generational responses to ecological stressors.
Does early-stage Alzheimer’s disease affect the dynamics of motor adaptation?
Authors: Sutter K , Oostwoud Wijdenes L , van Beers RJ , Claassen JAHR , Kessels RPC , Medendorp WP 
Published: January 2024

AbstractAlzheimer’s disease (AD) is characterized by an initial decline in declarative memory, while non-declarative memory processing remains relatively intact. Error-based motor adaptation is traditionally seen as a form of non-declarative memory, but recent findings suggest that it involves both fast, declarative and slow, non-declarative adaptive processes. If the declarative memory system shares resources with the fast process in motor adaptation, it can be hypothesized that the fast, but not the slow, process is disturbed in AD patients. To test this, we studied 20 early-stage AD patients and 21 age-matched controls of both sexes using a reach adaptation paradigm that relies on spontaneous recovery after sequential exposure to opposing force fields. Adaptation was measured using error clamps and expressed as an adaptation index (AI). Although patients with AD showed slightly lower adaptation to the force field than the controls, both groups demonstrated effects of spontaneous recovery. The time course of the AI was fitted by a hierarchical Bayesian two-state model in which each dynamic state is characterized by a retention and learning rate. Compared to controls, the retention rate of the fast process was the only parameter that was significantly different (lower) in the AD patients, confirming that the memory of the declarative, fast process is disturbed by AD. The slow adaptive process was virtually unaffected. Since the slow process learns only weakly from error, our results provide neurocomputational evidence for the clinical practice of errorless learning of everyday tasks in people with dementia.