bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational models reveal how chloride dynamics determine the optimal distribution of inhibitory synapses to minimise dendritic excitability
Authors: Currin Christopher Brian , Raimondo Joseph Valentino 
Published: December 2021

AbstractMany neurons in the mammalian central nervous system have complex dendritic arborisations and active dendritic conductances that enable these cells to perform sophisticated computations. How dendritically targeted inhibition affects local dendritic excitability is not fully understood. Here we use computational models of branched dendrites to investigate where GABAergic synapses should be placed to minimise dendritic excitability over time. To do so, we formulate a metric we term the “Inhibitory Level” (IL), which quantifies the effectiveness of synaptic inhibition for reducing the depolarising effect of nearby excitatory input. GABAergic synaptic inhibition is dependent on the reversal potential for GABAA receptors (EGABA), which is primarily set by the transmembrane chloride ion (Cl-) concentration gradient. We, therefore, investigated how variable EGABA and dynamic chloride affects dendritic inhibition. We found that the inhibitory effectiveness of dendritic GABAergic synapses combines at an encircled branch junction, “inhibitory accumulation”. The extent of inhibitory accumulation is dependent on the number of branches and location of synapses but is independent of EGABA. This inhibitory accumulation occurs even for very distally placed inhibitory synapses when they are hyperpolarising – but not when they are shunting. When accounting for Cl- fluxes and dynamics in Cl- concentration, we observed that Cl- loading is detrimental to inhibitory effectiveness. This enabled us to determine the most inhibitory distribution of GABAergic synapses which is close to – but not at – a shared branch junction. This distribution balances a trade-off between a stronger combined inhibitory influence when synapses closely encircle a branch junction with the deleterious effects of increased Cl- loading that occurs when inhibitory synapses are co-located.
RNA2Immune: A Manually Curated Database of Experimentally Supported Data Linking Noncoding RNA Regulation to the Immune System
Authors: Wang Jianjian , Li Shuang , Wang Tianfeng , Xu Si , Wang Xu , Kong Xiaotong , Lu Xiaoyu , Zhang Huixue , Li Lifang , Feng Meng , Ning Shangwei , Wang Lihua 
Published: December 2021

AbstractNon-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), have emerged as important regulators of the immune system and are involved in the control of immune cell biology, disease pathogenesis as well as vaccine responses. A repository of ncRNA−immune associations will facilitate our understanding of ncRNA-dependent mechanisms in the immune system and advance the development of therapeutics for immune disorders as well as vaccines. Here, we describe a comprehensive database, RNA2Immune, which aims to provide a high-quality resource of experimentally supported database linking ncRNA regulatory mechanisms to immune cell function, immune disease, cancer immunology, and vaccines. The current version of RNA2Immune documents 50,433 immune−ncRNA associations in 42 host species, including: (i) 6690 ncRNA associations with immune functions involving 31 immune cell types; (ii) 38,672 ncRNA associations with 348 immune diseases; (iii) 4833 ncRNA associations with cancer immunology; and (iv) 238 ncRNA associations with vaccine responses involving 26 vaccine types targeting 22 diseases. RNA2Immune provides a user-friendly interface for browsing, searching and downloading ncRNA−immune system associations. Collectively, RNA2Immune provides important information about how ncRNAs influence immune cell function, the pathological consequences of dysregulation of these ncRNAs (immune diseases and cancers), and how ncRNAs affect immune responses to vaccines. RNA2Immune is available at http://bio-bigdata.hrbmu.edu.cn/rna2immune/home.jsp.
Enabling complex fibre geometries using 3D printed axon-mimetic phantoms
Authors: Kuehn Tristan K. , Mushtaha Farah N. , Khan Ali R. , Baron Corey A. 
Published: December 2021

AbstractPurposeTo introduce a method to create 3D-printed axon-mimetic phantoms with complex fibre orientations to characterize the performance of diffusion MRI models and representations in the presence of orientation dispersion.MethodsAn extension to an open source 3D printing package was created to 3D print a set of five 3D-printed axon-mimetic (3AM) phantoms with various combinations of bending and crossing fibre orientations. A two-shell diffusion MRI scan of the five phantoms in water was performed at 9.4T. Diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), the ball and stick model, neurite orientation density and dispersion imaging (NODDI), and Bingham-NODDI were all fit to the resulting diffusion MRI data. A fiducial in each phantom was used to register a ground truth map of that phantom’s crossing angles and/or arc radius to the diffusion-weighted images. Metrics from each model and representation were compared to the ground-truth maps, and a quadratic regression model was fit to each combination of output metric and ground-truth metric.ResultsThe mean diffusivity (MD) metric defined by DTI was insensitive to crossing angle, but increased with fibre curvature. Axial diffusivity (AD) decreased sharply with increasing crossing angle. DKI’s diffusivity metrics replicated the trends seen in DTI, and its mean kurtosis (MK) metric, decreased with fibre curvature, except in regions with high crossing angles. The estimated stick volume fraction in the ball and stick model decreased with increasing fibre curvature and crossing angle. NODDI’s intra-neurite volume fraction was insensitive to crossing angle, and its orientation dispersion index (ODI) was strongly correlated to crossing angle. Bingham-NODDI’s intra-neurite volume fraction was also insensitive to crossing angle, while its primary ODI (ODIP) was also strongly correlated to crossing angle and its secondary ODI (ODIS) was insensitive to crossing angle. For both NODDI models, the volume fractions of the extra-neurite and CSF compartments had low reliability with no clear relationship to crossing angle.ConclusionsThis study demonstrates that inexpensive 3D-printed axon-mimetic phantoms can be used to investigate the effect of fibre curvature and crossings on diffusion MRI representations and models of diffusion signal. As a proof of concept, the dependence of several representations and models on fibre dispersion/crossing were investigated. As expected, Bingham-NODDI was best able to characterize planar fibre dispersion in the phantoms.
Single cell gene expression profiling of nasal ciliated cells reveals distinctive biological processes related to epigenetic mechanisms in patients with severe COVID-19
Authors: Diambra Luis , Alonso Andres M , Sookoian Silvia , Pirola Carlos J 
Published: December 2021

ABSTRACTObjectiveTo explore the molecular processes associated with cellular regulatory programs in patients with COVID-19, including gene activation or repression mediated by epigenetic mechanisms. We hypothesized that a comprehensive gene expression profiling of nasopharyngeal epithelial cells might expand understanding of the pathogenic mechanisms of severe COVID-19.MethodsWe used single-cell RNA sequencing (scRNAseq) profiling of ciliated cells (n = 12725) from healthy controls (SARS-CoV-2 negative n =13) and patients with mild/moderate (n =13) and severe (n =14) COVID-19. ScRNAseq data at the patient level were used to perform gene set and pathway enrichment analyses. We prioritized candidate miRNA-target interactions and epigenetic mechanisms.ResultsPathways linked to mitochondrial function, misfolded proteins, and membrane permeability were upregulated in patients with mild/moderate disease compared to healthy controls. Besides, we noted that compared to mild/moderate disease, cells derived from severe COVID-19 patients had downregulation of sub-networks associated with epigenetic mechanisms, including DNA and histone H3K4 methylation and chromatin remodeling regulation. We found 11-ranked miRNAs that may explain miRNA-dependent regulation of histone methylation, some of which share seed sequences with SARS-CoV-2 miRNAs.ConclusionOur results may provide novel insights into the epigenetic mechanisms mediating the clinical course of SARS-CoV-2 infection.
Risk of hospitalization and mortality after breakthrough SARS-CoV-2 infection by vaccine type and previous SARS-CoV-2 infection utilizing medical claims data
Authors: Kshirsagar Meghana , Mukherjee Sumit , Nasir Md , Becker Nicholas , Ferres Juan Lavista , Richardson Barbra A. 
Published: December 2021

AbstractWe compare the risks of hospitalization (n=1121) and mortality (n=138) in a cohort of 17,881 breakthrough SARS-CoV-2 infections for the Pfizer, Moderna and Janssen vaccines for those with and without SARS-CoV-2 infections prior to vaccination. Cox regression analysis results in a lower hazard ratio for breakthroughs receiving the Moderna vaccine, but a significantly higher hazard ratio for breakthroughs receiving the Janssen vaccine, as compared to breakthroughs who got the Pfizer vaccine. Further, the risk of hospitalization (P<0.001) and death (P<0.05) were lower among breakthroughs who had a SARS-CoV-2 infection prior to vaccination, independent of age, sex, comorbidities, and vaccine type.NoteWe do not study the role of natural immunity in SARS-CoV-2 infections, as our cohort does not contain unvaccinated individuals.
Deep learning-driven risk-based subtyping of cognitively impaired individuals
Authors: Romano Michael F. , Zhou Xiao , Balachandra Akshara R. , Jadick Michalina F. , Qiu Shangran , Nijhawan Diya A. , Joshi Prajakta S. , Lee Peter H. , Smith Maximilian J. , Paul Aaron B. , Mian Asim Z. , Small Juan E. , Chin Sang P. , Au Rhoda , Kolachalama Vijaya B. 
Published: December 2021

AbstractQuantifying heterogeneity in Alzheimer’s disease (AD) risk is critical for individualized care and management. Recent attempts to assess AD heterogeneity have used structural (magnetic resonance imaging (MRI)-based) or functional (Aβ or tau) imaging, which focused on generating quartets of atrophy patterns and protein spreading, respectively. Here we present a computational framework that facilitated the identification of subtypes based on their risk of progression to AD. We used cerebrospinal fluid (CSF) measures of Aβ from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n=544, discovery cohort) as well as the National Alzheimer’s Coordinating Center (NACC) (n=508, validation cohort), and risk-stratified individuals with mild cognitive impairment (MCI) into quartiles (high-risk (H), intermediate-high risk (IH), intermediate-low risk (IL), and low-risk (L)). Patients were divided into subgroups utilizing patterns of brain atrophy found in each of these risk-stratified quartiles. We found H subjects to have a greater risk of AD progression compared to the other subtypes at 2- and 4-years in both the discovery and validation cohorts (ADNI: H subtype versus all others, p < 0.05 at 2 and 4 years; NACC: H vs. IL and LR at 2 years, p < 0.05, and a trend toward higher risk vs. IH, and p < 0.05 vs. IH, and L risk groups at 48 months with a trend toward lower survival vs. IL). Using MRI-based neural models that fused various deep neural networks with survival analysis, we then predicted MCI to AD conversion. We used these models to identify subtype-specific regions that demonstrate the largest levels of atrophy-related importance, which had minimal overlap (Average pairwise Jaccard Similarity in regions between the top 5 subtypes, 0.25±0.05 (± std)). Neuropathologic changes characteristic of AD were present across all subtypes in comparable proportions (Chi-square test, p>0.05 for differences in ADNC, n=31). Our risk-based approach to subtyping individuals provides an objective means to intervene and tailor care management strategies at early stages of cognitive decline.
Pulmonary Embolism Readmission Trend Over the Years: A National Readmission Database Study
Authors: Murthi Mukunthan , Velagapudi Sujitha , Park Dae Yong , Shaka Hafeez 
Published: December 2021

AbstractIntroductionAcute pulmonary embolism (PE) is known to be associated with significant short-term and long-term complications. However, with the evolution of PE management, the outcomes of PE-related complications and the need for readmission have not been well studied. The aim of this study is to see the trend in readmissions in PE patients from the years 2010 to 2018.MethodsWe utilized the National Readmission Database from 2010 to 2018 to identify hospitalized patients with a principal diagnosis of acute pulmonary embolism. Identified the total number of readmissions for acute PE from 2010 to 2018. A multivariate cox regression model was used to identify independent predictors of readmission.ResultsThe number of patients with 30-day readmissions has gradually increased from 14,508 in 2010 to 19,703 in 2018. The proportion of females admitted was higher than males in all years. The 30-day all-cause readmission after principal admission for PE decreased from 11.2% to 9.7% from 2010 to 2014 but increased to 11.8% in 2018 (p<0.001). Risk-adjusted readmission specific for PE showed a decrease from 1.2 to 1% (p=0.023) from 2010 to 2018. When adjusted to age and gender, an increase in the proportion of readmissions with intracranial bleeding was seen among both the 30-day (0.7% in 2010 to 1.2% in 2018, aOR 1.06, p<0.001) and 90-day (0.7% in 2010 to 1.2% in 2018, aOR 1.06, p-trend 0.003) cohorts. Similarly, an increasing trend of readmissions for UGI bleed was seen among both 30-day (0.9% vs 4.3%, aOR=1.26, p-trend <0.001) and 90-day readmissions (0.7% vs 3.8%, aOR=1.27, p-trend <0.001). The units of blood transfusion required per readmission reduced in both cohorts during the study period.ConclusionOur study suggests that there is a statistically significant decrease in PE-specific readmission from 2010 to 2018, but an increase in all-cause readmissions. We also report an increase in non-major bleeding during readmissions, including ICH and UGI bleed. These findings warrant further studies to elucidate the mechanism for decreasing PE-specific readmission but possible causes for the increase in all-cause readmission in the hope of optimizing management and continuing improving outcomes.
Stress-impaired reward pathway promotes distinct feeding behavior patterns
Authors: Fujioka Yusuke , Kawai Kaori , Endo Kuniyuki , Ishibashi Minaka , Iwade Nobuyuki , Tuerde Dilina , Kaibuchi Kozo , Yamashita Takayuki , Yamanaka Akihiro , Katsuno Masahisa , Watanabe Hirohisa , Ishigaki Shinsuke , Sobue Gen 
Published: December 2021

AbstractPsychosocial stress can impact feeding behavior outcomes. Although many studies have examined alterations to food intake, little is known about how stress affects feeding behavior patterns. To determine the impact of psychological stress on feeding behavior patterns, mice were subjected to various psychosocial stressors (social isolation, intermittent high-fat-diet, or physical restraint) prior to timed observations in a feeding arena that incorporated multiple bait loci. In addition, in vivo microdialysis was used to assess the effects of stressors on the reward system by measuring dopamine levels in the nucleus accumbens (NAcc) shell. Impaired feeding behavior patterns characterized by significant deviations in bait selection (i.e. fixated feeding) and prolonged periods of eating (i.e. protracted feeding) were observed in stressed mice relative to non-stressed controls. In addition to clear behavioral effects, the stressors also negatively impacted dopamine levels at the nucleus accumbens shell. Normalization of dopamine reversed the fixated feeding behavior, whereas specifically inhibiting neuronal activity in the dopaminergic neurons of the ventral tegmental area that project to the nucleus accumbens shell caused similar impairments in feeding. Given that the deviations were not consistently accompanied by changes in the amount of bait consumed, body weight, or metabolic factors, the qualitative effects of psychosocial stressors on feeding behavior likely reflect perturbations to a critical pathway in the mesolimbic dopamine system. These findings provide compelling evidence that aberrations in feeding behavior patterns can be developed as sensitive biomarkers of psychosocial stress and possibly a prodromal state of neuropsychiatric diseases.Significance StatementFeeding behavior can be affected by neuropsychiatric disorders including psychosocial stressors, and the evaluation of eating behavior was mainly based on food intake. However, it is speculated that not only food intake but also feeding behavior patterns can be affected in such disorders. The biological processes underlying the feeding behavior patterns have not been clarified yet. We found that aberrant feeding behaviors in mice characterized by fixated feeding were provoked by psychosocial stressors. The qualitative effects of psychosocial stressors on feeding behavior reflect perturbations in the mesolimbic dopamine system. These findings provide compelling evidence that aberrations in feeding behavior patterns can be developed as sensitive biomarkers of psychosocial stress and possibly a prodromal state of neuropsychiatric diseases.
Hypergravity is more challenging than microgravity for the human sensorimotor system
Authors: Chomienne L. , Sainton P. , Sarlegna F. , Bringoux L. 
Published: December 2021

AbstractWhile recent findings demonstrated the importance of contextual estimates about gravity for optimal motor control, it remains unclear how gravitational changes are taken into account by the central nervous system to perform complex motor skills. Here, we investigated the effect of microgravity and hypergravity on the neuromuscular control of whole-body reaching movements compared to normogravity. Standing participants (n=9) had to reach toward visual targets during parabolic flights, which allowed us to test the influence of gravity level on sensorimotor planning and control processes. Also, to specifically test the efficiency of online motor control mechanisms, unexpected mechanical perturbations were used. Whole-body kinematics and muscular activity were adjusted in microgravity, allowing arm reaching to be as accurate as in normogravity. In contrast, systematic undershooting was observed in hypergravity, where main parameters of whole-body kinematics remained unchanged and muscle activations insufficiently adjusted to keep the same accuracy as in normogravity. Conversely, muscular synergies exhibited during whole-body reaching were found similar in the various gravitational contexts, as were local muscular adjustments in response to unexpected mechanical perturbations. This suggests that online feedback control remains functional across very distinct gravitational environments. Overall, our findings demonstrates that hypergravity creates challenges that the human sensorimotor system is unable to solve rapidly, contrary to microgravity.
Novel and known transcriptional targets of ALS/FTD protein TDP-43: Meta-analysis and interactive graphical databases
Authors: Cao Maize C. , Scotter Emma L. 
Published: December 2021

AbstractTDP-43 proteinopathy is the major pathological hallmark of amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal dementia (FTD). Mounting evidence implicates a loss of normal TDP-43 function in neurodegeneration, either resultant from or independent of TDP-43 aggregation. TDP-43 knockdown is therefore a common paradigm for modelling ALS and FTD. However, because TDP-43 can interact directly with thousands of mRNA targets and regulate the function of other RNA binding proteins, the phenotype of TDP-43 depletion is likely to differ depending on the proteomic and transcriptomic profile of the model cell type. Here, we conducted a meta-analysis of publicly available RNA-sequencing datasets that utilized TDP-43 knockdown to model ALS or FTD, and validated these against RNA-sequencing data from TDP-43-immunonegative neuronal nuclei from ALS/FTD brain. We present these analyses as easy-to-use interactive graphical databases. Of 9 TDP-43-knockdown datasets identified, 4 showed significant depletion of TARDBP (human HeLa and SH-SY5Y cell lines, induced human motor neurons, and mouse striatal tissue). There was little overlap in differentially expressed genes between TDP-43-knockdown model cell types, but PFKP, RANBP1, KIAA1324, ELAVL3, and STMN2 were among the common TDP-43 targets. Similarly, there were few genes that showed common patterns of differential exon usage between cell types and which validated in TDP-43-immunonegative neurons, but these included well-known targets POLDIP3, RANBP1, STMN2, and UNC13A, and novel targets EXD3, CEP290, KPNA4, and MMAB. Enrichment analysis showed that TDP-43 knockdown in different cell types affected a unique range of biological pathways. Together, these data identify novel TDP-43 targets, validate known TDP-43 targets, and show that TDP-43 plays both conserved and cell-type-specific roles in the regulation of gene expression and splicing. Identification of cell-type-specific TDP-43 targets will enable sensitive mapping of cell-autonomous TDP-43 dysfunction beyond just neurons, while shared TDP-43 targets are likely to have therapeutic value across myriad cell types.