bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal loss ofGalnt2Impairs O-glycosylation and Leads to Neurobehavioral Deficits Mimicking GALNT2-CDG
Authors: Edmondson Andrew C. , Yu Melody , Villarosa Alvin , Shiplett Emily J. , Schjoldager Katrine T. , Zhou Zhaolan 
Published: October 2024

AbstractGALNT2-CDG is a multi-system genetic disorder due to biallelic pathogenic mutations inGALNT2, which encodes a ubiquitously expressed Golgi-localized glycosyltransferase that initiates mucin-type O-glycosylation. Affected individuals exhibit dysmorphic facial features, short stature, decreased HDL-C, and notable impairments in brain function. GALNT2-CDG patients show global developmental delay without speech development, childhood epilepsy, autistic-like features, and white-matter brain abnormalities. The extent of O-glycosylation in brain development and function remains poorly understood. To address this question, we selectively ablatedGalnt2from pan-neuronal cells in the brain and found that conditional knockout mice exhibit deficits across numerous behavioral domains, including locomotion, motor coordination, sociability, learning, and memory, as well as experience spontaneous seizures, recapitulating characteristic neurological manifestations of GALNT2-CDG. Given the catalytic activity of GALNT2 to initiate mucin-type O-glycosylation, we used glycoproteomics to identify disrupted O-glycosylation in synaptosomes purified from cortical tissues. We ascertained a non-redundant, isoform-specific contribution of GALNT2 to the cortical synaptosomal O-glycoproteome, identifying candidate glycoproteins and disrupted O-glycosites that accompany behavioral abnormalities in knockout mice. These findings demonstrate functional impact of O-glycosylation in neurons, implicating roles of O-glycosylation in diverse molecular and cellular pathways related to neuronal function and provide new opportunities to gain insights into the neurological pathophysiology of GALNT2-CDG.
A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases
Authors: Qiao Longliang , Niu Lingxue , Wang Meiyan , Wang Zhihao , Kong Deqiang , Yu Guiling , Ye Haifeng 
Published: October 2024

AbstractRed light optogenetic systems are in high demand for the precise control of gene expression for gene- and cell-based therapies. Here, we report ared/far-red light-induciblephotoswitch (REDLIP) system based on the chimeric photosensory protein FnBphP (Fn-REDLIP) or PnBphP (Pn-REDLIP) and their interaction partner LDB3, which enables efficient dynamic regulation of gene expression with a timescale of seconds without exogenous administration of a chromophore in mammals. We used the REDLIP system to establish the REDLIP-mediated CRISPR-dCas9 (REDLIPcas) system, enabling optogenetic activation of endogenous target genes in mammalian cells and mice. The REDLIP system is small enough to support packaging into adeno-associated viruses (AAVs), facilitating its therapeutic application. Demonstrating its capacity to treat metabolic diseases, we show that an AAV-delivered Fn-REDLIP system achieved optogenetic control of insulin expression to effectively lower blood glucose levels in type 1 diabetes model mice and control an anti-obesity therapeutic protein (thymic stromal lymphopoietin, TSLP) to reduce body weight in obesity model mice. REDLIP is a compact and sensitive optogenetic tool for reversible and non-invasive control that can facilitate basic biological and biomedical research.
Exploring New Horizons: A Novel Cdk5 Inhibitor Restoring Cognitive Function and Alleviating Type 2 Diabetes
Authors: Paul Sangita , Remya Chandran , Dileep K.V. , Bhardwaj Juhi , Singh Praveen , Poornima S , Srinivas C , Sajith A.M. , Binukumar BK 
Published: October 2024

AbstractType 2 diabetes (T2D) is a metabolic disorder frequently associated with cognitive decline, making T2D patients susceptible to dementia. Often referred to as type 3 diabetes, Alzheimer’s disease (AD) shares a close association with hyperglycemia and insulin dysregulation. Despite this, anti-diabetic medications have proven beneficial in reducing cognitive impairment induced by T2D. Previous research, including our own, has highlighted the dysregulation of Cdk5 activity in both T2D and AD, with downstream consequences contributing to the progression of pathophysiological changes in both disorders. Therefore, targeting the kinase Cdk5 may offer a more effective approach to treating T2D and cognitive deterioration. In our study, we present evidence supporting Cdk5 as a significant mediator between T2D and cognitive decline. Through the screening of the KINACore library, we identified novel brain-penetrant Cdk5 inhibitors, BLINK11 and BLINK15. Our study further validated the efficacy of these inhibitors in a high-fat diet-induced T2D model, demonstrating their rescue effects on T2D pathogenesis, including blood glucose levels, obesity, and cognitive impairment as assessed through behavioral studies. Notably, BLINK11 emerges as a promising Cdk5 inhibitor for improving the T2D phenotype and addressing cognitive impairment in T2D conditions.Graphical abstract
Reduced Synaptic Heterogeneity in a Tetanus Toxin Model of Epilepsy: Insights from Computational Modeling
Authors: Eskikand Parvin Zarei , Cook Mark J. , Burkitt Anthony N. , Grayden David B. 
Published: October 2024

AbstractA neural mass model was used to assess connectivity strength across diverse populations by fitting the model to background EEG data obtained from a Tetanus Toxin rat model of epilepsy. Our findings reveal a notable decline in the variability of estimated parameters when using EEG data recorded from rats in the Tetanus Toxin group compared with the control group. A detailed comparison of standard deviations in estimated parameters between day 1 and day 20 recordings, coinciding with a heightened number of seizures, underscores the impact of Tetanus Toxin on diminishing synaptic strength variability across recordings. This study supports electrophysiological studies suggesting that epileptogenesis induces a reduction in biophysical heterogeneity, potentially leading to an increase in network synchrony associated with epilepsy. Furthermore, our computational model establishes a foundation for future explorations of the implications of this diminished variability.
Depth diagnosis of colorectal cancer located on a colorectal fold by quantitative evaluation of a width of colorectal - fold lateral contour using a lateral split-view computed tomographic air-contrast enema image
Authors: Miyasaka Mitsutoshi , Muraki Toshio , Nishimuta Yusuke , Oki Eiji , Ishigami Kousei , Tsurumaru Daisuke 
Published: October 2024

AbstractPurposeTo investigate the usefulness of quantitative evaluation of a width of lateral contour on a lateral split-view computed tomographic air-contrast enema (CT enema) image for diagnosing the invasion depth of colorectal cancer (CRC) located on a colorectal fold.MethodsThe cases of 22 patients with 22 fold-located CRCs (12 early CRCs and 10 advanced CRCs) who underwent a pretherapeutic computed tomographic colonography were retrospectively examined. T1-stage CRCs were classified into two categories according to the Japanese guideline: T1a-stage, carcinoma invading the superficial submucosa (< 1000 um); and T1b-stage, carcinoma invading the deeper submucosa (≥ 1000 um). The maximum width of a lateral contour of the colorectal fold on which the CRC was located, i.e., the gap distance between the two adjacent haustrations, was calculated from the lateral split-view CT enema image by two gastrointestinal radiologists. These values were compared between the intramucosal / T1a CRCs and the T1b / more deeply invading CRCs. The inter-rater intraclass correlation coefficients were also evaluated for reliability.ResultsThe maximum widths of a lateral contour of the colorectal fold were significantly higher in the T1b / more deeply invading CRCs than in the intramucosal / T1a CRCs (p<0.0001). The optimum cut-off value of the maximum width of a lateral contour of the colorectal fold for differentiating the former from the latter was 6.0 mm, with a sensitivity and specificity of 100% and 100%, respectively. The inter-rater intraclass correlation coefficient for measurement of a lateral contour of the colorectal fold was 0.958.ConclusionsWe demonstrated for the first time that quantitative evaluation of a width of lateral contour using a lateral split-view CT enema image can improve the diagnostic accuracy of the invasion depth for CRCs located on a colorectal fold.
Typical indicators of neighborhood change used to define gentrification have opposing associations with infant mortality
Authors: Murosko Daria , Passarella Molly , Montoya-Williams Diana , Mehdipanah Roshanak , Lorch Scott 
Published: October 2024

AbstractInfant mortality (IM), or death prior to the first birthday, is a key public health metric that increases with neighborhood structural inequities. However, neighborhood exposures shift as communities undergo gentrification, a pattern of neighborhood change defined by increasing affluence (in wealth, education, and housing costs). Gentrification has inconsistent associations with infant health outcomes like IM, which may be due to differing relationships between its composite measures and such outcomes. We designed a retrospective cohort analysis of all births and deaths from 2010-2019 across 4 metropolitan areas in Michigan to determine how gentrification and its neighborhood-change components are associated with risk of IM, using multilevel multivariable logistic regression models. Among 672,432 infants, 0.52% died before 1 year. IM was not associated with gentrification. Census tracts with greater increases in income and education had lower rates of IM, but tracts with greater increases in rent costs had higher rates of IM. In unadjusted models, odds of IM were 40% and 15% lower for infants living in tracts in the top quartile increase in household income and college completion, respectively, compared to infants from tracts with the least amount of change. Odds of IM were also increased 29% in infants from tracts with the most increases in rent, though these differences were attenuated when adjusting for individual social factors. Indicators of increasing community affluence have opposing relationships with IM. Policies and interventions that address rising housing costs may reduce IM.
Spatial and temporal changes in choroid morphology associated with long-duration spaceflight
Authors: Bélanger Nzakimuena Charles , Masís Solano Marissé , Marcotte-Collard Rémy , Lesk Mark Richard , Costantino Santiago 
Published: October 2024

PurposeThe development of neuro-ophthalmic symptoms during long-duration spaceflight presents major risks to astronauts and their missions. Amid efforts to understand spaceflight associated neuro-ocular syndrome (SANS), uncovering the role of the choroid in its etiology is challenged by the accuracy of image segmentation. The present study extends deep learningbased choroid quantification from optical coherence tomography (OCT) to the characterization of pulsatile and topological changes in the macular plane and investigates changes in response to prolonged microgravity exposure.MethodsWe analyzed OCT macular videos and volumes acquired from astronauts before, during and after long-duration spaceflight. Deep learning models were fine-tuned for choroid segmentation and combined with further image processing towards vascularity quantification. Statistical analysis was performed to determine changes in time-dependent and spatially averaged variables from preflight baseline for OCT data.ResultsFor 13 astronauts with a mean age of 47±9 years, there were significant increases in choroid thickness (CT) and luminal area (LA) of 14±25 µm (P = 0.01) and 0.11±0.2 mm2(P = 0.009) and no significant change in choroid vascularity index (CVI) averaged over OCT macular video segments. There was no significant change in the amplitude of pulsatile CT fluctuation (ΔCT), but significant increases in both pulsatile LA (ΔLA) and CVI (ΔCVI) of 0.077±0.14 mm2(P = 0.009) and 0.03±0.06 (P = 0.01), respectively. For a subgroup of 6 astronauts for which inflight imaging was available, choroid volume, luminal volume and CVI over the macular region all increased significantly during spaceflight with the greatest differences reached at 90 days following launch.ConclusionsThe findings show that localized choroid pulsatile changes occur following prolonged microgravity exposure. They suggest that the choroid vessels expand in a manner similar to the choroid layer across the macular region during spaceflight, accompanied by a relative increase in the space they occupy. The methods developed provide new tools and avenues for studying and establishing effective countermeasures to risks associated with long-duration spaceflight.
Subphenotypes of youth-onset type 2 diabetes mellitus and their association with distal symmetrical polyneuropathy
Authors: Guo Jiali , Li Zhongyu , Carrillo-Larco Rodrigo M. , Hsia Daniel S. , Harding Jessica L , Ali Mohammed K. , Varghese Jithin Sam 
Published: October 2024

ABSTRACTContextIndividuals with youth-onset type 2 diabetes mellitus (T2DM) display substantial, but unexplained, heterogeneity in their clinical presentations and risk of complications such as diabetic neuropathy. Data-driven clustering may be useful in characterizing this heterogeneity.ObjectiveTo identify data-driven subphenotypes of newly diagnosed youth-onset T2DM and study their association with distal symmetric polyneuropathy (DSPN) at time of diagnosis.DesignCross-sectionalSettingUSAParticipants641 individuals with newly diagnosed T2DM aged 10-19 years from the SEARCH for Diabetes in Youth Study and the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.Exposure(s)Body mass index, HbA1c, fasting C-peptide, systolic blood pressure, diastolic blood pressure, LDL cholesterol and HDL cholesterolMain Outcome MeasuresData-driven subphenotypes were identified from k-means clustering. The cross-sectional association of subphenotypes with DSPN, based on expert examination scores (≥2.5) from the Michigan Neuropathy Screening Instrument, were assessed using Poisson regressions with robust standard errors.ResultsAmong 641 youth-onset T2DM, 58.2% were female, with 38.2% of participants ≤13 years having average BMI of 34.5 kg/m2(SD: 6.5 kg/m2), and average HbA1c of 6.1% (IQR: 5.6-7.0). Three youth-onset subphenotypes were identified: mild obesity related diabetes (yMOD, 48.5%), severe insulin deficient diabetes (ySIDD, 18.7%) and severe insulin resistant diabetes (ySIRD, 32.7%). After adjusting for covariates, the prevalence of abnormal DSPN were 2.58 (95%CI: 1.74, 3.81) and 2.02 (95%CI: 1.40, 2.93) times among those classified as the ySIDD and ySIRD subphenotypes, relative to the yMOD subphenotype.ConclusionsYouth-onset T2DM consisted of heterogeneous clinical subphenotypes with differences prevalence of DSPN. Management of youth-onset T2DM may need to consider strategies tailored to each subphenotype.
Probabilistic Graphical Models for Evaluating the Utility of Data-Driven ICD Code Categories in Pediatric Sepsis
Authors: Valdez Lourdes A. , Hernandez Edgar Javier , Matthews O’Connor , Mulvey Matthew A. , Crandall Hillary , Eilbeck Karen 
Published: October 2024

AbstractElectronic health records (EHRs) are digitalized medical charts and the standard method of clinical data collection. They have emerged as valuable sources of data for outcomes research, offering vast repositories of patient information for analysis. Definitions for pediatric sepsis diagnosis are ambiguous, resulting in delayed diagnosis and treatment, highlighting the need for precise and efficient patient categorizing techniques. Nevertheless, the use of EHRs in research poses challenges. EHRs, although originally created to document patient encounters, are now primarily used to satisfy billing requirements. As a result, EHR data may lack granularity, potentially leading to misclassification and incomplete representation of patient conditions. We compared data-driven ICD code categories to chart review using probabilistic graphical models (PGMs) due to their ability to handle uncertainty and incorporate prior knowledge. Overall, this paper demonstrates the potential of using PGMs to address these challenges and improve the analysis of ICD codes for sepsis outcomes research.
Comprehensive Systematic Review and Meta-Analysis of Solute Carrier Family 19, Member 1 (SLC19A1) G80A Gene Polymorphism and Its Association with Congenital Heart Defects in Fetal Development: Implications for Genetic Susceptibility and Prenatal Risk Assessment
Authors: Hernandez Josh Patrick , Batul Anjhela Isabel , Dela Cruz Jerald Wynnes , Siroma Kyle Gabriel 
Published: October 2024

AbstractCongenital heart defects (CHD) are a major cause of neonatal mortality, highlighting the importance of identifying genetic risk factors in fetal development. The SLC19A1 gene, encoding the reduced folate carrier, is critical for folate metabolism, essential for DNA synthesis during embryogenesis. The G80A polymorphism in SLC19A1 may influence folate transport efficiency and contribute to CHD risk. This meta-analysis aimed to investigate the association between SLC19A1 G80A polymorphism and CHD susceptibility. A systematic review of major databases, including PubMed and EMBASE, was conducted to identify relevant case-control studies. Genetic risk models, such as allele (A vs G), heterozygous (GA vs GG), homozygous (AA vs GG), dominant (GA + AA vs GG), and recessive (AA vs GG + GA), were analyzed using RevMan 5.4.1, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated. Initial results across most genetic models did not show a significant association between G80A polymorphism and CHD. However, after excluding outliers, a moderate association was observed between the GA genotype and increased CHD risk (OR: 1.34, CI: 1.07–1.66). These findings suggest a minimal genetic effect, warranting further research in diverse populations.
Separated attractors in neural landscape of motor cortex encoding motor learning
Authors: Liu Xuanting , Wu Yanzi , Ru Xiahan , Li Rongrong , Si Ke , Gong Wei 
Published: October 2024

AbstractAnimals gain motor learning via decrease of variation through repeated training. The secondary motor (M2) cortex shows an indispensable role in the learning process of the rotarod-learning task. Yet, it remains unclear how population decoding in M2 cortex guides the repetitive training to transform into motor enhancement. We recorded neuronal population activity using Ca2+ imaging during this enhancement revealing that neuronal population correlates of the persistent internal learning state evolves in the process of motor learning. With the behavioral micro-states analysis, we identify the growing periodicity, stability, and consistency with two gradually clearer point attractor in the M2 neural state space. The results show the evolution of attractors in M2 participate in decrease of training-acquisition behavior variation and provide a general framework for the mapping between arbitrary non-task motor learning and neural topological structure.
Effect heterogeneity reveals complex pleiotropic effects of rare coding variants
Authors: Lu Wenhan , Chen Siwei , Posthuma Danielle , Neale Benjamin M. , O’Connor Luke J. , Karczewski Konrad J. 
Published: October 2024

AbstractGenome-wide association studies (GWAS) and rare-variant association studies (RVAS) have identified thousands of genes and variants that affect multiple phenotypes. Here, using rare variant association results from the UK Biobank (UKB) data, we identify pervasive gene-level pleiotropy across diverse phenotypic domains and highlight genes with apparent allelic series that provide additional association support through disease pathways. We develop a statistical test, ALLSPICE, to explore allelic heterogeneity within pleiotropic genes and identify evidence for a heterogeneous effect of a subset of missense variants in theALBgene on albumin and calcium levels, which are further validated at protein structure level. In this way, we demonstrate potential shared and trait-specific biological pathways, providing insights into the genetic basis of pleiotropy in complex human traits.
A unique bacterial family strikes again!
Authors: Shukla Gyanesh , Sharma Gaurav 
Published: October 2024

AbstractIn a recent study, Rolf Müller and colleagues identified a novel myxobacterial family Pendulisporaceae, encompassing four new strains with biosynthetic gene clusters (BGCs) largely distinct from known families. These strains, sourced from 1980s soil samples, display unique genomic and chemical features, suggesting significant biotechnological and pharmaceutical potential. This study underscores the value of exploring underrepresented microbial taxa for novel natural products, highlighting the potential of the family Pendulisporaceae as a source of new antimicrobial and therapeutic agents.
Computational Modeling of Proactive, Reactive, and Attentional Dynamics in Cognitive Control
Authors: Mistry Percy K. , Warren Stacie L. , Branigan Nicholas K. , Cai Weidong , Menon Vinod 
Published: October 2024

AbstractWe developed a novel Proactive Reactive and Attentional Dynamics (PRAD) computational model designed to dissect the latent mechanisms of inhibitory control in human cognition. Leveraging data from over 7,500 participants in the NIH Adolescent Brain Cognitive Development study, we demonstrate that PRAD surpasses traditional models by integrating proactive, reactive, and attentional components of inhibitory control. Employing a hierarchical Bayesian framework, PRAD offers a granular view of the dynamics underpinning action execution and inhibition, provides debiased estimates of stop-signal reaction times, and elucidates individual and temporal variability in cognitive control processes. Our findings reveal significant intra-individual variability, challenging conventional assumptions of random variability across trials. By addressing nonergodicity and systematically accounting for the multi-componential nature of cognitive control, PRAD advances our understanding of the cognitive mechanisms driving individual differences in cognitive control and provides a sophisticated computational framework for dissecting dynamic cognitive processes across diverse populations.