bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Variations and Altered Blood mRNA Level of Circadian Genes and BDNF as Risk Factors of Post-Stroke Cognitive Impairment among Eastern Indians
Authors: Sadhukhan Dipanwita , Biswas Arindam , Mishra Smriti , Maji Daytee , Mitra Parama , Mukherjee Priyanka , Podder Gargi , Ray Biman Kanti , Biswas Atanu , Banerjee Tapas Kumar , Hui Subhra Prakash , Deb Ishani 
Published: July 2023

ABSTRACTBackgroundPost-stroke cognitive impairment (PSCI) is a clinical outcome in around 30% of post-stroke survivors. BDNF is a major gene in this regard. It regulates and being regulated by circadian rhythm. The circadian genes are correlated with stroke timings at molecular level. However, studies suggesting the role of these on susceptibility to PSCI is limited.AimWe aim here to determine a) genetic risk variants in circadian clock genes,BDNFand b) dysregulation in expression level ofCLOCK, BMAL1 andBDNF, that may be associated with PSCI.MethodsBDNF (rs6265G/A, rs56164415C/T), CLOCK (rs1801260T/C, rs4580704G/C) and CRY2 (rs2292912C/G) genes variants were genotyped among 119 post-stroke survivors and 292 controls from Eastern part of India. In addition, we analysed their gene expression in PBMC from 15 PSCI cases and 12 controls. The mRNA data for BDNF was further validated by its plasma level through ELISA.ResultsAmong the studied variants, only rs4580704/CLOCKshowed an overall association with PSCI (P = 0.001) and lower BMSE score. Its ‘C’ allele showed a correlation with attention deficiency. The language and memory impairments showed association with rs6265/BDNFwhile the ‘CC’ genotype of rs2292912/CRY2negatively influenced language and executive function. A significant decrease in gene expression forCLOCKandBDNFin PBMC (influenced by specific genotypes) of PSCI patients was observed than controls. Unlike, Pro-BDNF, plasma level mBDNF was also lower in them.ConclusionsOur results suggest that the circadian genes andBDNFplay a role in PSCI on both genetic and transcript level.
Identification of Spinster Homolog 3 as a novel putative LL-37 receptor
Authors: Corrêa Alana Bazán , de Lima Thais Martins , Ariga Suely Kubo , Pinheiro da Silva Fabiano 
Published: July 2023

AbstractBackgroundAntimicrobial Peptides are primitive components of the innate immune response. LL-37, a human antimicrobial peptide, has been researched for its therapeutic potential in immune-inflammatory diseases. This study aimed to identify novel LL-37 receptors.Methods and ResultsUsing the phage display technique, the sequence GNWSFV was selected and found to bind to LL-37. BLAST analysis revealed that this sequence has a high degree of similarity to a portion of human transmembrane protein Spinster Homolog 3.ConclusionOur study suggests that Spinster Homolog 3 may be a potential therapeutic target for LL-37-related diseases.
Prevalence and Associated Risk Factors of Scabies and Impetigo: A Cross-Sectional Study in the Nata Catchment Areas of Tutume District, Botswana
Authors: Nthibo Leungo Audrey , Molefi Tuduetso Leka , Kololo Sidney Otladisa , Leeme Tshepo Botho , Selemogo Mpho , Molefi Mooketsi 
Published: July 2023

AbstractBackgroundScabies is a poorly understood disease in the developing world, particularly in regions with high disease burden. Lack of epidemiological data, especially in sub-Saharan Africa, hampers our understanding of the disease’s occurrence and impact. This study aimed to estimate the prevalence and associated risk factors of scabies and impetigo in the Nata catchment areas of Tutume district.MethodologyA cross-sectional study was conducted in the Nata catchment area, targeting the settlements of Manxhotae, Malelejwe, Ndutshaa, and Tshwaane. Participants were randomly selected from randomly selected households. Data were collected using questionnaires, and scabies was confirmed by skin examination using the International Alliance for the Control of Scabies (IACS) consensus criteria. Statistical significance was set at p<0.05, with a 95% confidence interval for precision.ResultsA total of 429 participants were enrolled across the four settlements. The highest prevalence of scabies was in Manxhotae at 27.1% (21.2-34.0) and Ndutshaa at 23.4% (13.4-37.3). Malelejwe and Tshwaane had lower prevalence of 10.4% (6.2-16.8) and 3.4% (0.8-12.7), respectively. Only five(5) cases of impetigo were identified. Multivariable logistic regression analysis using the IACS criteria revealed that younger age and a household member with an itch were strongly associated with scabies, with adjusted odds ratios (AOR) of 5.69 [3.16-10.26] and 5.31 [2.76-10.21], respectively, however, a less sensitive criterion also included less frequent bathing as a significant exposure, AOR of 3.3 [1.9-5.8]ConclusionThe prevalence of scabies in the Nata catchment area was unexpectedly high. The risk factors included younger age, a household member with an itch, and less frequent bathing. Prospective studies are needed to explore household disease transmission dynamics and risk factors specific to the youth.Author SummaryThis study was carried out in the Nata catchment area in Tutume district, Botswana. It aimed to assess the burden, risk factors informing effective disease control programs. The survey involved interviews and skin examination by a health worker. Findings revealed a higher incidence of scabies cases, while impetigo cases were less prevalent. These results highlight the need for community-wide interventions to mitigate the disease’s impact. Identified risk factors include younger age, residing with an individual experiencing itchiness, and infrequent bathing. Overall, this study supports advocating for scabies as a neglected tropical disease.
Multigenerational effects of tire wear particle leachate through trophic transfer from producer to primary consumer
Authors: Chai Yanchao , Wang Haiqing , Yang Jiaxin 
Published: July 2023

AbstractTire wear particle (TWP) and their leachate have been known toxic for aquatic organism due to additives released from the rubber matrix. However, it is not clear whether the ecotoxicity of TWP leachate could be transferred through algae-zooplankton food chain especially after multi generations. In this work, the effect of different concentrations TWP leachate on growth of microalgae,Chlorella pyrenoidesa, was studied. Subsequently, those algae were fed to zooplankton rotifer,Brachionus calyciflorus, which continuously lasted for ten generations to explore multigenerational accumulation of TWP leachate ecotoxicity through food-chain transfer. The results showed that the TWP leachate displayed growth inhibition for algae with evident concentration effect. For rotifer fed with those contaminated microalgae, though the first two generations showed hormesis, the ecotoxicity exhibited after 2 generations, characterized by reduction of lifespan and offspring number. The ecological effects of TWP leachate were transferred from algae to rotifer. In addition, the ecotoxicity gradually aggravated along with generation passage and exposure concentration of algae. What was even more, population passage of rotifer collapsed totally with no offspring after 5-generations feed by algae exposed to high concentration TWP leachate. Based on those, it is summarized that the ecological effects of TWP leachate indeed can be transferred from low to high trophic level in food chain, and accumulate across generations passage. The indirect non-contact exposure through food chain should be considered at the risk assessment of TWP. Single generation exposure will underestimate their ecological risk from long term.
Beta-subunit-eliminated eHAP expression (BeHAPe) cells reveal new properties of the cardiac voltage-gated sodium channel
Authors: Minard Annabel Y , Clark Colin J , Ahern Christopher A , Piper Robert C 
Published: July 2023

AbstractVoltage-gated sodium (NaV) channels drive the upstroke of the action potential and are comprised of a pore-forming α-subunit and regulatory β-subunits. The β-subunits modulate the gating, trafficking, and pharmacology of the α-subunit. These functions are routinely assessed by ectopic expression in heterologous cells. However, currently available expression systems may not capture the full range of these effects since they contain endogenous β-subunits. To better reveal β-subunit functions, we engineered a human cell line devoid of endogenous NaVβ-subunits and their immediate phylogenetic relatives. This new cell line, β-subunit-eliminated eHAP expression cells (BeHAPe), were derived from haploid eHAP cells by engineering inactivating mutations in SCN1B, SCN2B, SCN3B, SCN4B, MPZL1, MPZL2, MPZL3, MPZ and JAML. In diploid BeHAPe cells, the cardiac NaVα-subunit, NaV1.5, was highly sensitive to β-subunit modulation and revealed that each β-subunit and even MPZ imparted unique gating properties. Furthermore, combining β1 and β2 with NaV1.5 generated a sodium channel with hybrid properties, distinct from the effects of the individual subunits. Thus, this approach revealed an expanded ability of β-subunits to regulate NaV1.5 activity and can be used to improve the characterization of other α/β NaVcomplexes.
TheSORL1p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer’s disease
Authors: Jensen Anne Mette G. , Raska Jan , Fojtik Petr , Monti Giulia , Lunding Melanie , Vochyanova Simona , Pospisilova Veronika , van der Lee Sven J. , Dongen Jasper Van , Bossaerts Liene , Broeckhoven Christine Van , Dols Oriol , Lléo Alberto , Benussi Luisa , Ghidoni Roberta , Hulsman Marc , Sleegers Kristel , Bohaciakova Dasa , Holstege Henne , Andersen Olav M. 
Published: July 2023

ABSTRACTTruncating genetic variants ofSORL1, encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer’s disease (AD). However, most genetic variants observed inSORL1are missense variants, for which it is complicated to determine the pathogenicity level because carriers come from pedigrees too small to be informative for penetrance estimations. Here, we describe three unrelated families in which theSORL1coding missense variant rs772677709, that leads to a p.Y1816C substitution, segregates with Alzheimer’s disease. Further, we investigate the effect of SORLA p.Y1816C on receptor maturation, cellular localization and trafficking in cell-based assays. Under physiological circumstances, SORLA dimerizes within the endosome, allowing retromer-dependent trafficking from the endosome to the cell surface, where the luminal part is shed into the extracellular space (sSORLA). Our results showed that the p.Y1816C mutant impairs SORLA dimerization in the endosome leading to a strong decrease in trafficking to the cell surface, resulting in decreased sSORLA shedding. Furthermore, we find that iPSC-derived neurons with engineered p.Y1816C mutation have enlarged endosomes, a defining cytopathology of AD.Our studies provide genetic as well as functional evidence that theSORL1p.Y1816C variant is causal for AD. The high penetrance of the mutation suggests this mutation should be considered in clinical genetic screening of multiplex early-onset AD families.
Estimating the instantaneous reproduction number (Rt)by using particle filter
Authors: Won Yong Sul , Son Woo-Sik , Choi Sunhwa , Kim Jong-Hoon 
Published: July 2023

AbstractBackgroundMonitoring the transmission of coronavirus disease 2019 (COVID-19) requires accurate estimation of the effective reproduction number (Rt). However, existing methods for calculatingRtmay yield biased estimates if important real-world factors, such as delays in confirmation, pre-symptomatic transmissions, or imperfect data observation, are not considered.MethodTo include real-world factors, we expanded the susceptible-exposed-infectious-recovered (SEIR) model by incorporating pre-symptomatic (P) and asymptomatic (A) states, creating the SEPIAR model. By utilizing both stochastic and deterministic versions of the model, and incorporating predetermined time series ofRt, we generated simulated datasets that simulate real-world challenges in estimatingRt. We then compared the performance of our proposed particle filtering method for estimatingRtwith the existing EpiEstim approach based on renewal equations.ResultsThe particle filtering method accurately estimatedRteven in the presence of data with delays, pre-symptomatic transmission, and imperfect observation. When evaluating via the root mean square error (RMSE) metric, the performance of the particle filtering method was better in general and was comparable to the EpiEstim approach if perfectly deconvolved infection time series were provided, and substantially better whenRtexhibited short-term fluctuations and the data was right truncated.ConclusionsThe SEPIAR model, in conjunction with the particle filtering method, offers a reliable tool for predicting the transmission trend of COVID-19 and assessing the impact of intervention strategies. This approach enables enhanced monitoring of COVID-19 transmission and can inform public health policies aimed at controlling the spread of the disease.
A machine-learning evaluation of biomarkers designed for the future of precision medicine
Authors: Climer Sharlee 
Published: July 2023

AbstractPrecision medicine is cognizant of the impact of genetics and environments on subtypes of heterogeneous diseases and aims to identify, diagnose, and treat each subtype appropriately. Real-valued biomarkers, such as protein levels in plasma, are key for practical subtype diagnoses and hold potential to elucidate subtypes and illuminate promising drug targets. Biomarkers that are common across all subtypes have been discovered using fold change (FC) and the area under the receiver operating characteristic curve (AUC). However, FC and AUC fail to identify biomarkers for subtypes when they comprise less than half of the disease group. We present here a machine-learning biomarker evaluation method based on clustering of the data points, referred to as Difference in Bicluster Distances (DBD). We contribute efficient, yet optimal, software coupled with rigorous validation techniques, and demonstrate our approach on a late-onset Alzheimer disease (AD) gene expression dataset. Our trials produced four significant genes and appropriate thresholds for biomarker diagnostics. While none of these genes were identified as significant by either FC or AUC for the given dataset, the genes have been independently associated with AD or neurological disorders by other groups using completely independent means. In summary, DBD provides a unique and effective method for screening real-valued data to identify biomarkers associated with subtypes of heterogeneous diseases.
Systems biology and machine learning approaches identify metabolites that influence dietary lifespan and healthspan responses across flies and humans
Authors: Hilsabeck Tyler A.U. , Narayan Vikram P. , Wilson Kenneth A. , Carrera Enrique , Raftery Daniel , Promislow Daniel , Brem Rachel B. , Campisi Judith , Kapahi Pankaj 
Published: July 2023

SummaryDietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data fromDrosophilaGenetic Reference Panel strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. Employing two computational methods across species—random forest modeling within the DGRP and Mendelian randomization in the UK Biobank—we pinpointed key traits with cross-species relevance that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and counteracted DR effects in flies, while threonine extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.
Learning and memory deficits produced by aspartame are heritable via the paternal lineage
Authors: Jones Sara K. , McCarthy Deirdre M. , Stanwood Gregg D. , Schatschneider Chris , Bhide Pradeep G. 
Published: July 2023

AbstractEnvironmental exposures produce heritable traits that can linger in the population for one or two generations. Millions of individuals consume substances such as artificial sweeteners daily that are declared safe by regulatory agencies without evaluation of their potential heritable effects. We show that consumption of aspartame, an FDA-approved artificial sweetener, daily for up to 16-weeks at doses equivalent to only 7-15% of the FDA recommended maximum daily intake value (equivalent to 2-4 small, 8 oz diet soda drinks per day) produces significant spatial learning and memory deficits in mice. Moreover, the cognitive deficits are transmitted to male and female descendants along the paternal lineage suggesting that aspartame’s adverse cognitive effects are heritable, and that they are more pervasive than current estimates, which consider effects in the directly exposed individuals only. Traditionally, deleterious environmental exposures of pregnant and nursing women are viewed as risk factors for the health of future generations. Environmental exposures of men are not considered to pose similar risks. Our findings suggest that environmental exposures of men can produce adverse impact on mental health of future generations and demonstrate the need for considering heritable effects via the paternal lineage as part of the regulatory evaluations of artificial sweeteners.
Multi-organ Metabolic Model ofZea maysConnects Temperature Stress with Thermodynamics-Reducing Power-Energy Generation Axis
Authors: Chowdhury Niaz Bahar , Decouard Berengere , Quillere Isabelle , Rigault Martine , Sajeevan Karuna Anna , Acharya Bibek , Chowdhury Ratul , Hirel Bertrand , Dellagi Alia , Maranas Costas , Saha Rajib 
Published: July 2023

ABSTRACTGlobal climate change has severely impacted maize productivity. A holistic understanding of metabolic crosstalk among its organs is essential to address this issue. Thus, we reconstructed the first multi-organ maize genome-scale metabolic model,iZMA6517, and contextualized it with heat and cold stress-related transcriptomics data using the novelEXpression disTributedREAction fluxMeasurement (EXTREAM) algorithm. Furthermore, implementing metabolic bottleneck analysis on contextualized models revealed fundamental differences between these stresses. While both stresses had reducing power bottlenecks, heat stress had additional energy generation bottlenecks. To tie these signatures, we performed thermodynamic driving force analysis, revealing thermodynamics-reducing power-energy generation axis dictating the nature of temperature stress responses. Thus, for global food security, a temperature-tolerant maize ideotype can be engineered by leveraging the proposed thermodynamics-reducing power-energy generation axis. We experimentally inoculated maize root with a beneficial mycorrhizal fungus,Rhizophagus irregularis, and as a proof of concept demonstrated its potential to alleviate temperature stress. In summary, this study will guide the engineering effort of temperature stress-tolerant maize ideotypes.
DISCOVERY AND VALIDATION OF GENES DRIVING DRUG-INTAKE AND RELATED BEHAVIORAL TRAITS IN MICE
Authors: Roy Tyler A. , Bubier Jason A. , Dickson Price E. , Wilcox Troy D. , Ndukum Juliet , Clark James W. , Sukoff Rizzo Stacey J. , Crabbe John C. , Denegre James M. , Svenson Karen L. , Braun Robert E. , Kumar Vivek , Murray Stephen A. , White Jacqueline K. , Philip Vivek M. , Chesler Elissa J. 
Published: July 2023

AbstractSubstance use disorders (SUDs) are heritable disorders characterized by compulsive drug use, but the biological mechanisms driving addiction remain largely unknown. Genetic correlations reveal that predisposing drug-naïve phenotypes, including anxiety, depression, novelty preference, and sensation seeking, are predictive of drug-use phenotypes, implicating shared genetic mechanisms. Because of this relationship, high-throughput behavioral screening of predictive phenotypes in knockout (KO) mice allows efficient discovery of genes likely to be involved in drug use. We used this strategy in two rounds of screening in which we identified 33 drug-use candidate genes and ultimately validated the perturbation of 22 of these genes as causal drivers of substance intake. In our initial round of screening, we employed the two-bottle-choice paradigms to assess alcohol, methamphetamine, and nicotine intake. We identified 19 KO strains that were extreme responders on at least one predictive phenotype. Thirteen of the 19 gene deletions (68%) significantly affected alcohol use three methamphetamine use, and two both. In the second round of screening, we employed a multivariate approach to identify outliers and performed validation using methamphetamine two-bottle choice and ethanol drinking-in-the-dark protocols. We identified 15 KO strains that were extreme responders across the predisposing drug-naïve phenotypes. Eight of the 15 gene deletions (53%) significantly affected intake or preference for three alcohol, eight methamphetamine or three both (3). We observed multiple relations between predisposing behaviors and drug intake, revealing many distinct biobehavioral processes underlying these relationships. The set of mouse models identified in this study can be used to characterize these addiction-related processes further.
ENTRAIN: integrating trajectory inference and gene regulatory networks with spatial data to co-localize the receptor-ligand interactions that specify cell fate
Authors: Kyaw Wunna , Chai Ryan C. , Khoo Weng Hua , Goldstein Leonard D. , Croucher Peter I. , Murray John M. , Phan Tri Giang 
Published: July 2023

AbstractCell fate is commonly studied by profiling the gene expression of single cells to infer developmental trajectories based on expression similarity, RNA velocity, or statistical mechanical properties. However, current approaches do not recover microenvironmental signals from the cellular niche that drive a differentiation trajectory. We resolve this with environment-aware trajectory inference (ENTRAIN), a computational method that integrates trajectory inference methods with ligand-receptor pair gene regulatory networks to identify extracellular signals and evaluate their relative contribution towards a differentiation trajectory. The output from ENTRAIN can be superimposed on spatial data to co-localize cells and molecules in space and time to map cell fate potentials to cell-cell interactions. We validate and benchmark our approach on single-cell bone marrow and spatially resolved embryonic neurogenesis datasets to identify known and novel environmental drivers of cellular differentiation. ENTRAIN is available as a public package athttps://github.com/theimagelab/entrainand can be used on both single-cell and spatially resolved datasets.