bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rates, risks and routes to reduce vascular dementia (R4VaD), a UK-wide multicentre prospective observational cohort study of cognition after stroke: baseline data and statistical analysis plan (ISRCTN18274006)
Authors: Bath Philip M , Backhouse Ellen , Brown Rosalind , Woodhouse Lisa J , Doubal Fergus , Quinn Terence J , Markus Hugh S , McManus Richard , O’Brien John T , Robinson Thompson , Werring David J , Sprigg Nikola , Parry-Jones Adrian , Touyz Rhian M , Williams Steven , Mah Yee-Haur , Emsley Hedley , Wardlaw Joanna M ,   the R4VaD Investigators
Published: May 2024

ABSTRACTBackgroundStroke is often followed by vascular cognitive impairment and vascular dementia; these are the most feared complication of stroke. However, there is limited understanding of post-stroke cognitive impairment.MethodsRates, Risks and Routes to Reduce Vascular Dementia (R4VaD) is an observational cohort study of post-stroke cognition. Patients with haemorrhagic or ischaemic stroke, or transient ischaemic attack, were recruited within six weeks of stroke from hospitals across the UK. Consent was obtained from patients with capacity or from relatives/friends in those without capacity. The primary outcome is cognition and its severity assessed using a 7-level ordinal outcome. Final cognition will be compared in those with mild stroke/TIA (worst NIHSS <=7) versus severe stroke (NIHSS >7). Secondary outcomes will include function, mood and quality of life.ResultsWe recruited 2441 patients from 50 hospitals. Of these, 2437 (99.8%) had a qualifying event of stroke or TIA. The mean age was 68.2 years (standard deviation 13.5), females 981 (40.3%), onset to recruitment 6 days [interquartile range 3-13] and diagnosis ICH 193 (7.9%), ischaemic stroke 2101 (86.2%), TIA 143 (5.9%). The distribution of cognition at baseline was: normal 1256 (51.6%), minor neurocognitive disorder-single domain 530 (21.8%), minor neurocognitive disorder-multi domain 320 (13.1%), major neurocognitive disorder-mild 237 (9.7%), major neurocognitive disorder-moderate 90 (3.7%) and major neurocognitive disorder-severe 3 (0.1%). We provide the statistical analysis plan in the appendix.ConclusionWe provide baseline data and the SAP. Final follow-up will be completed in quarter 2 2024. The data highlight the substantial under-appreciated cognitive burden of stroke, even in the first few days and weeks.
C9orf72repeat expansions modify risk for secondary motor and cognitive-behavioral symptoms in behavioral-variant frontotemporal degeneration and amyotrophic lateral sclerosis
Authors: Spencer Barbara E. , Xie Sharon X. , Elman Lauren , Quinn Colin C. , Amado Defne , Baer Michael , Lee Edward B. , Van Deerlin Vivianna M. , Dratch Laynie , Massimo Lauren , Irwin David J. , McMillan Corey T. 
Published: May 2024

AbstractIn behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), secondary motor or cognitive-behavioral symptoms, respectively, are associated with shorter survival. However, factors influencing secondary symptom development remain largely unexplored.We performed a retrospective evaluation of the entire disease course of individuals with ALS (n=172) and bvFTD (n=69). Only individuals who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or aC9orf72hexanucleotide repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether each was modified by the presence of aC9orf72expansion or initial clinical syndrome.Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [95% CI 1.97-9.14], p<0.001) and an increased hazard (HR= 4.77 [95% CI 2.33-9.79], p<0.001) for developing secondary symptoms in those with aC9orf72expansion compared to those without. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary symptoms.These data highlight the need for clinician vigilance to detect the onset of secondary motor and cognitive-behavioral symptoms in patients carrying aC9orf72expansion, regardless of initial clinical syndrome.C9orf72clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.
TheαC helix is a central regulator of PKR activation
Authors: Feinstein Aaron G. , Cole James L. , May Eric R. 
Published: May 2024

AbstractProtein kinase R (PKR) functions in the eukaryotic innate immune system as a first-line defense against viral infections. PKR binds viral dsRNA, leading to autophosphorylation and activation. In its active state, PKR can phosphorylate its primary substrate, eIF2α, which blocks initiation of translation in the infected cell. It has been established that PKR activation occurs when the kinase domain dimerizes in a back-to-back configuration. However, the mechanism by which dimerization leads to enzymatic activation is not fully understood. Here, we investigate the structural mechanistic basis and energy landscape for PKR activation, with a focus on theαC helix – a kinase activation and signal integration hub – using all-atom equilibrium and enhanced sampling molecular dynamics simulations. By employing window-exchange umbrella sampling, we compute free energy profiles of activation which show that back-to-back dimerization stabilizes a catalytically competent conformation of PKR. Key hydrophobic residues in the homodimer interface contribute to stabilization of theαC helix in an active conformation and the position of its glutamate residue. Using linear mutual information analysis, we analyze allosteric communication connecting the protomers’ N-lobes and theαC helix dimer interface with theαC helix.
Electrophysiological responses to appetitive and consummatory behavior in the rostral nucleus tractus solitarius in awake, unrestrained rats
Authors: Pilato Stephen A. , O’Connell Flynn P. , Victor Jonathan D. , Di Lorenzo Patricia M. 
Published: May 2024

AbstractAs the intermediate nucleus in the brainstem receiving information from the tongue and transmitting information upstream, the rostral portion of the nucleus tractus solitarius (rNTS) is most often described as a “taste relay”. Although recent evidence implicates the NTS in a broad neural circuit involved in regulating ingestion, there is little information about how cells in this structure respond when an animal is eating solid food. Here, single cells in the rNTS were recorded in awake, unrestrained rats as they explored and ate solid foods (Eating paradigm) chosen to correspond to the basic taste qualities: milk chocolate for sweet, salted peanuts for salty, Granny Smith apples for sour and broccoli for bitter. A subset of cells was also recorded as the animal licked exemplars of the five basic taste qualities: sucrose, NaCl, citric acid, quinine and MSG (Lick paradigm). Results showed that most cells were excited by exploration of a food-filled well, sometimes responding prior to contact with the food. In contrast, cells that were excited by food well exploration became significantly less active while the animal was eating the food. Most cells were broadly tuned across foods, and those cells that were recorded in both the Lick and Eating paradigms showed little correspondence in their tuning across paradigms. The preponderance of robust responses to the appetitive versus the consummatory phase of ingestion suggests that multimodal convergence onto cells in the rNTS may be used in decision making about ingestion.Significance StatementThe rostral part of the NTS has traditionally, but perhaps narrowly, been thought of as a “taste relay”. While it is true that this structure receives and transmits information about tastants in the mouth to higher order structures in the central gustatory pathway, data presented here show that its function is more diverse. Specifically, in addition to the responses to liquid tastants in the mouth, its responses to approach and exploration of solid food define a significant role for the rNTS in the appetitive phase of eating. Moreover, responses to food consumption, albeit weaker than those during appetitive behavior, buttress the idea that the rNTS is part of the larger hindbrain circuit guiding energy regulation.
A brain-enriched circRNA blood biomarker can predict response to SSRI antidepressants
Authors: Papageorgiou Grigorios , Ibrahim El-Cherif , Maxson Gabriella , Gorgievski Victor , Lozano Evelyn , Belzeaux Raoul , Carmody Thomas , Tzavara Eleni T. , Trivedi Madhukar H. , Mellios Nikolaos 
Published: May 2024

AbstractMajor Depressive Disorder (MDD) is a debilitating psychiatric disorder that currently affects more than 20% of the adult US population and is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the inherent complexity and heterogeneity of the disease and the “trial and error” approach in choosing the most effective antidepressant treatment for each patient, allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, to cross the blood-brain-barrier, and to be highly sensitive to changes in neuronal activity or activation of various neuronal receptors. Here we present evidence of a brain-enriched circRNA that is regulated by Serotonin 5-HT2A and Brain-Derived Neurotrophic Factor (BDNF) receptor activity and whose expression in the blood can predict response to SSRI treatment. We present data using circRNA-specific PCR in baseline whole blood samples from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) study, showing that before treatment this circRNA is differentially expressed between future responders and non-responders to sertraline. We further show that the expression of this circRNA is upregulated following sertraline treatment and that its trajectory of change post-treatment is associated with long-term remission. Furthermore, we show that the biomarker potential of this circRNA is specific to SSRIs, and not associated with prediction of response or remission after Placebo or Bupropion treatment. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting that the same circRNA is enriched in the brain and is regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment.
Contrasting the development of larval and adult body plans during the evolution of biphasic lifecycles in sea urchins
Authors: McDonald Brennan D. , Massri Abdull J. , Escobar Alejandro Berrio , Byrne Maria , McClay David R. , Wray Gregory A. 
Published: May 2024

AbstractBiphasic lifecycles are widespread among animals, but little is known about how the developmental transition between larvae and adults is regulated. Sea urchins are a unique system for studying this phenomenon because of the stark differences between their bilateral larval and pentaradial adult body plans. Here, we use single cell RNA-sequencing to analyze the development ofHeliocidaris erythrogramma(He), a sea urchin species with an accelerated, non-feeding mode of larval development. The sequencing time course extends from early embryogenesis to roughly a day before the onset of metamorphosis inHelarvae, which is a period that has not been covered by previous datasets. We find that the non-feeding developmental strategy ofHeis associated with several changes in the specification of larval cell types compared to sea urchins with feeding larvae, such as the loss of a larva-specific skeletal cell population. Furthermore, the development of the larval and adult body plans in sea urchins may utilize largely different sets of regulatory genes. These findings lay the groundwork for extending existing developmental gene regulatory networks to cover additional stages of biphasic lifecycles.Summary statementAnalysis of a new single cell transcriptomic atlas of sea urchin development reveals the rapid evolution of larval cell type trajectories and provides a candidate list of regulators for adult rudiment development.
Characterizing cell type specific transcriptional differences between the living and postmortem human brain
Authors: Vornholt Eric , Liharska Lora E. , Cheng Esther , Hashemi Alice , Park You Jeong , Ziafat Kimia , Wilkins Lillian , Silk Hannah , Linares Lisa M. , Thompson Ryan C. , Sullivan Brendan , Moya Emily , Nadkarni Girish N. , Sebra Robert , Schadt Eric E. , Kopell Brian H. , Charney Alexander W. , Beckmann Noam D. 
Published: May 2024

ABSTRACTSingle-nucleus RNA sequencing (snRNA-seq) is often used to define gene expression patterns characteristic of brain cell types as well as to identify cell type specific gene expression signatures of neurological and mental illnesses in postmortem human brains. As methods to obtain brain tissue from living individuals emerge, it is essential to characterize gene expression differences associated with tissue originating from either living or postmortem subjects using snRNA-seq, and to assess whether and how such differences may impact snRNA-seq studies of brain tissue. To address this, human prefrontal cortex single nuclei gene expression was generated and compared between 31 samples from living individuals and 21 postmortem samples. The same cell types were consistently identified in living and postmortem nuclei, though for each cell type, a large proportion of genes were differentially expressed between samples from postmortem and living individuals. Notably, estimation of cell type proportions by cell type deconvolution of pseudo-bulk data was found to be more accurate in samples from living individuals. To allow for future integration of living and postmortem brain gene expression, a model was developed that quantifies from gene expression data the probability a human brain tissue sample was obtained postmortem. These probabilities are established as a means to statistically account for the gene expression differences between samples from living and postmortem individuals. Together, the results presented here provide a deep characterization of both differences between snRNA-seq derived from samples from living and postmortem individuals, as well as qualify and account for their effect on common analyses performed on this type of data.
The influence of sensory noise, confidence judgments, and accuracy on pupil responses and associated behavioural adjustments in young and older people
Authors: Oliveira Sara F. , Gomes Catarina F. , Ribeiro Maria J. 
Published: May 2024

AbstractWe investigated the association between pupil responses, decision confidence and decision accuracy, their relationship with behavioural adjustments important for optimal task performance, and if these were altered in older adults.We tested young and older adults, including men and women, with a dot motion direction discrimination task, while measuring task-related pupil responses. Feedback was provided after each trial. Participants were instructed to report perceived motion direction and simultaneously their decision confidence.Older adults were overconfident in the presence of high sensory noise and in incorrect trials. Young people’s pupil responses reflected performance lapses. This effect was reduced in older people that showed blunted pupil responses to lapses and to negative feedback. Low confidence, errors, and larger pre-feedback pupil responses were associated with slower reaction time on the subsequent trial. The effects of errors and pupil were stronger in the older group.In conclusion, older people’s blunted pupil responses following lapses suggest reduced awareness of their own abilities and internal brain state and might impair adjustment of behaviour for optimal performance.
Engineering fluorescent reporters in human pluripotent cells and strategies for live imaging human neurogenesis
Authors: Dady Alwyn , Davidson Lindsay , Loyer Nicolas , Rappich Sophie , Findlay Greg , Sanders Timothy , Januschke Jens , Storey Kate G. 
Published: May 2024

AbstractInvestigation of cell behaviour and cell biological processes underlying human development is facilitated by creation of fluorescent reporters in human pluripotent stem cells, which can be differentiated into cell types of choice. Here we report use of a piggyBac transposon-mediated stable integration strategy to engineer human pluripotent stem cell reporter lines. These express a plasma membrane localised protein tagged with the fluorescent proteins eGFP or mKate2, the photoconvertible nuclear marker H2B-mEos3.2, or the cytoskeletal protein F-tractin tagged with mKate2. Focussing on neural development these lines were used to live image and quantify cell behaviours, including cell cycle progression and cell division orientation in spinal cord rosettes. Further, lipofection-mediated introduction of piggyBac constructs into human neural progenitors labelled single cells and small cell groups within rosettes, allowing individual cell behaviours including neuronal delamination to be monitored. Finally, using the F-tractin-mKate2 hiPSC line, novel actin dynamics were captured during proliferation in cortical neural rosettes. This study presents and validates new tools and techniques with which to interrogate human cell behaviour and cell biology using live imaging approaches.
Cell type and cell signaling innovations underlying mammalian pregnancy
Authors: Stadtmauer Daniel J. , Basanta Martínez Silvia , Maziarz Jamie D. , Cole Alison G. , Dagdas Gülay , Smith Gilbecca Rae , van Breukelen Frank , Pavličev Mihaela , Wagner Günter P. 
Published: May 2024

AbstractHow fetal and maternal cell types have co-evolved to enable mammalian placentation poses a unique evolutionary puzzle. Here, we present a multi-species atlas integrating single-cell transcriptomes from six species bracketing therian mammal diversity. We find that invasive trophoblasts share a gene-expression signature across eutherians, and evidence that endocrine decidual cells evolved stepwise from an immunomodulatory cell type retained inTenrecwith affinity to human decidua of menstruation. We recover evolutionary patterns in ligand-receptor signaling: fetal and maternal cells show a pronounced tendency towards disambiguation, but a predicted arms race dynamic between them is limited. We reconstruct cell communication networks of extinct mammalian ancestors, finding strong integration of fetal trophoblast into maternal networks. Together, our results reveal a dynamic history of cell type and signaling evolution.SynopsisThe fetal-maternal interface is one of the most intense loci of cell-cell signaling in the human body. Invasion of cells from the fetal placenta into the uterus, and the corresponding transformation of maternal tissues called decidualization, first evolved in the stem lineage of eutherian mammals(1,2). Single-cell studies of the human fetal-maternal interface have provided new insight into the cell type diversity and cell-cell interactions governing this chimeric organ(3–5). However, the fetal-maternal interface is also one of the most rapidly evolving, and hence most diverse, characters among mammals(6), and an evolutionary analysis is missing. Here, we present and compare single-cell data from the fetal-maternal interface of species bracketing key events in mammal phylogeny: a marsupial (opossum,Monodelphis domestica), the afrotherianTenrec ecaudatus,and four Euarchontoglires - guinea pig and mouse (Rodentia) together with recent macaque and human data (primates) (4,5,7). We infer cell type homologies, identify a gene-expression signature of eutherian invasive trophoblast conserved over 99 million years, and discover a predecidual cell in the tenrec which suggests stepwise evolution of the decidual stromal cell. We reconstruct ancestral cell signaling networks, revealing the integration of fetal cell types into the interface. Finally, we test two long-standing theoretical predictions, the disambiguation hypothesis(8) and escalation hypothesis(9), at transcriptome-wide scale, finding divergence between fetal and maternal signaling repertoires but arms race dynamics restricted to a small subset of ligand-receptor pairs. In so doing, we trace the co-evolutionary history of cell types and their signaling across mammalian viviparity.
The dynamics of prion spreading is governed by the interplay between the non-linearities of tissue response and replication kinetics
Authors: Fornara Basile , Igel Angélique , Béringue Vincent , Martin Davy , Sibille Pierre , Pujo-Menjouet Laurent , Rezaei Human 
Published: May 2024

SummaryPrion diseases, or Transmissible Spongiform Encephalopathies (TSE), are neurodegenerative disorders caused by the accumulation of misfolded conformers (PrPSc) of the cellular prion protein (PrPC). During the pathogenesis, the PrPScseeds disseminate in the central nervous system and convert PrPCleading to the formation of insoluble assemblies. As for conventional infectious diseases, variations in the clinical manifestation define a specific prion strain which correspond to different PrPScstructures. In this work, we implemented the recent developments on PrPScstructural diversity and tissue response to prion replication into a stochastic reaction-diffusion model using an application of the Gillespie Algorithm. We showed that this combination of non-linearities can lead prion propagation to behave as a complex system, providing an alternative to the current paradigm to explain strain specific phenotypes, tissue tropisms and strain co-propagation while also clarifying the role of the connectome in the neuro-invasion process.
Representational similarity modulates neural and behavioral signatures of novelty
Authors: Becker Sophia , Modirshanechi Alireza , Gerstner Wulfram 
Published: May 2024

AbstractNovelty signals in the brain modulate learning and drive exploratory behaviors in humans and animals. While the perceived novelty of a stimulus is known to depend on previous experience, the effect of stimulus representations on novelty computation remains elusive. In particular, existing models of novelty computation fail to account for the effects of stimulus similarities that are abundant in naturalistic environments and tasks. Here, we present a unifying, biologically plausible model that captures how stimulus representations modulate novelty signals in the brain and influence novelty-driven learning and exploration. By applying our model to two publicly available data sets, we quantify and explain (i) how generalization across similar visual stimuli affects novelty responses in the mouse visual cortex, and (ii) how generalization across nearby locations impacts mouse exploration in an unfamiliar environment. Our model unifies and explains distinct neural and behavioral signatures of novelty, and enables theory-driven experiment design to investigate the neural mechanisms of novelty computation.