bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA hypomethylation promotes the expression of CASPASE-4 which exacerbates neuroinflammation and amyloid-β deposition in Alzheimer’s disease The Ohio State University College of Medicine
Authors: Daily Kylene P. , Badr Asmaa , Eltobgy Mostafa , Estfanous Shady , Whitham Owen , Tan Michelle H. , Carafice Cierra , Krause Kathrin , McNamara Andrew , Hamilton Kaitlin , Houle Samuel , Gupta Spandan , Gupta Gauruv A. , Madhu Shruthi , Fitzgerald Julie , Saadey Abbey A. , Laster Brooke , Yan Pearlly , Webb Amy , Zhang Xiaoli , Pietrzak Maciej , Kokiko-Cochran Olga N. , Ghoneim Hazem E. , Amer Amal O. 
Published: September 2023

AbstractAlzheimer’s Disease (AD) is the 6th leading cause of death in the US. It is established that neuroinflammation contributes to the synaptic loss, neuronal death, and symptomatic decline of AD patients. Accumulating evidence suggests a critical role for microglia, innate immune phagocytes of the brain. For instance, microglia release pro-inflammatory products such as IL-1β which is highly implicated in AD pathobiology. The mechanisms underlying the transition of microglia to proinflammatory promoters of AD remain largely unknown. To address this gap, we performed Reduced Representation Bisulfite Sequencing (RRBS) to profile global DNA methylation changes in human AD brains compared to no disease controls. We identified differential DNA methylation of CASPASE-4 (CASP4), which when expressed, can be involved in generation of IL-1β and is predominantly expressed in immune cells. DNA upstream of the CASP4 transcription start site was hypomethylated in human AD brains, which was correlated with increased expression of CASP4. Furthermore, microglia from a mouse model of AD (5xFAD) express increased levels of CASP4 compared to wild-type (WT) mice. To study the role of CASP4 in AD, we developed a novel mouse model of AD lacking the mouse ortholog of CASP4, CASP11, which is encoded by mouseCaspase-4(5xFAD/Casp4-/-). The expression of CASP11 was associated with increased accumulation of pathologic protein aggregate amyloid-β (Aβ) and increased microglial production of IL-1β in 5xFAD mice. Utilizing RNA sequencing, we determined that CASP11 promotes unique transcriptomic phenotypes in 5xFAD mouse brains, including alterations of neuroinflammatory and chemokine signaling pathways. Notably,in vitro, CASP11 promoted generation of IL-1β from macrophages in response to cytosolic Aβ through cleavage of downstream effector Gasdermin D (G SDMD). We describe a role for CASP11 and GSDMD in the generation of IL-1β in response to Aβ and the progression of pathologic inflammation in AD. Overall, our results demonstrate that overexpression of CASP4 due to differential methylation in AD microglia contributes to the progression of AD pathobiology, thus identifying CASP4 as a potential target for immunotherapies for the treatment of AD.
Natural genomic variation in rice blast genomes is associated with specific heterochromatin modifications
Authors: Rowe David , Huang Jun , Zhang Wei , Mishra Divya , Jordan Katherine , Valent Barbara , Liu Sanzhen , Cook David E. 
Published: September 2023

ABSTRACTGenome organization in eukaryotes exhibits non-random patterns tied to transcription, replication, and chromatin. However, the driving forces across these processes, and their impacts on genome evolution remain unclear. To address this, we analyzed sequence data from 86Magnaporthe oryzaeisolates, a globally important plant pathogenic fungus, alongside new reference genomes, to investigate DNA sequence variation and the epigenome. Histone modification profiles were obtained through genome-wide chromatin immunoprecipitation-sequencing of the four new reference strains, which revealed that repressive histone marks (H3K27me3, H3K9me3) were associated with SNP and INDEL frequency. Densely grouped SNPs were found to reside in heterochromatin, often outside transposable elements, highlighting the link between heterochromatin and DNA variation. Even when controlling for selection, silent SNP frequency/kb was higher in H3K27me3-associated genes. Effector genes, key to pathogenicity, also displayed this trend. Comparing the reference strains, euchromatic regions were often syntenic, while heterochromatic regions trended towards non-syntenic. Heterochromatin emerged as a major factor associated with diverse DNA variations inM. oryzaepopulations, even when accounting for selective pressure. This underscores heterochromatin’s pivotal role in shaping genetic diversity in these mainly asexually reproducing fungi.
Early life adversity has sex-dependent effects on survival across the lifespan in rhesus macaques
Authors: Patterson Sam K. , Andonov Ella , Arre Alyssa M. , Martínez Melween I. , Negron-Del Valle Josué E. , Petersen Rachel M. , Phillips Daniel , Rahman Ahaylee , Ruiz-Lambides Angelina , Villanueva Isabella , Lea Amanda J. , Snyder-Mackler Noah , Brent Lauren J.N. , Higham James P. 
Published: September 2023

AbstractExposure to adversity during early life is linked to lasting detrimental effects on evolutionary fitness across many taxa. However, due to the challenges of collecting longitudinal data, especially in species where one sex disperses, direct evidence from long-lived species remains relatively scarce. Here we test the effects of early life adversity on male and female longevity in a free-ranging population of rhesus macaques (Macaca mulatta) at Cayo Santiago, Puerto Rico. We leveraged six decades of data to quantify the relative importance of ten forms of early life adversity for 6,599 macaques (3,230 male, 3,369 female), with a smaller sample size (N=299) for one form of adversity (maternal social isolation) which required high-resolution behavioral data. We found that individuals who experienced more early life adversity died earlier than those who experienced less adversity. Mortality risk was highest during early life, defined as birth to four years old, suggesting acute survival effects of adversity, but heightened mortality risk was also present in macaques who survived to adulthood. Females and males were affected differently by some forms of adversity, and these differences might be driven by varying energetic demands, female philopatry, and male dispersal. By leveraging data on thousands of macaques collected over decades, our results show that the fitness consequences of early life adversity are not uniform across individuals but vary as a function of the type of adversity, timing, and social context, and thus contribute to our limited but growing understanding of the evolution of early life sensitivities in long-lived species.Significance StatementExposure to early life adversity, even when conditions subsequently improve, can have profound and persistent consequences for human health. Negative effects of early life adversity appear widespread across the animal kingdom. To date, however, direct evidence from long-lived species is relatively scarce due to the difficulties of collecting data from early life till death. We leverage six decades of observations on thousands of free-ranging male and female rhesus macaques to examine the complex ways early life adversity impacts survival. Our results suggest that the type of adversity and life history factors intersect to impact immediate and downstream survival. By studying early life adversity across environments, cultures, contexts, and species, we can better understand the evolutionary underpinnings of early life sensitivities.
Heterotypic stressors unmask behavioral influences of PMAT deficiency in mice
Authors: Weber Brady L , Nicodemus Marissa M , Hite Allianna K , Spalding Isabella R , Beaver Jasmin N , Scrimshaw Lauren R , Kassis Sarah K , Reichert Julie M , Ford Matthew T , Russell Cameron N , Hallal Elayna M , Gilman T Lee 
Published: September 2023

AbstractCertain life stressors having enduring physiological and behavioral consequences, in part by eliciting dramatic signaling shifts in monoamine neurotransmitters. High monoamine levels can overwhelm selective transporters like the serotonin transporter. This is when polyspecific transporters like plasma membrane monoamine transporter (PMAT, Slc29a4) are hypothesized to contribute most to monoaminergic signaling regulation. Here, we employed two distinct counterbalanced stressors – fear conditioning, and swim stress – in mice to systematically determine how reductions in PMAT function affect heterotypic stressor responsivity. We hypothesized male heterozygotes would exhibit augmented stressor responses relative to female heterozygotes. Decreased PMAT function enhanced context fear expression, an effect unexpectedly obscured by a sham stress condition. Impaired cued fear extinction retention and enhanced context fear expression in males were conversely unmasked by a sham swim condition. Abrogated corticosterone levels in male heterozygotes that underwent swim stress after context fear conditioning did not map on to any measured behaviors. In sum, male heterozygous mouse fear behaviors proved malleable in response to preceding stressor or sham stress exposure. Combined, these data indicate reduced male PMAT function elicits a form of stress-responsive plasticity. Future studies should assess how PMAT is differentially affected across sexes and identify downstream consequences of the stress-shifted corticosterone dynamics.
Exploring the Conformational Landscape of Cryo-EM Using Energy-Aware Pathfinding Algorithm
Authors: Lin Teng-Yu , Chung Szu-Chi 
Published: September 2023

AbstractCryo-electron microscopy (cryo-EM) is a powerful technique for studying macromolecules and holds the potential for identifying kinetically preferred transition sequences between conformational states. Typically, these sequences are explored within two-dimensional energy landscapes. However, due to the complexity of biomolecules, representing conformational changes in two dimensions can be challenging. Recent advancements in reconstruction models have successfully extracted structural heterogeneity from cryo-EM images using higher-dimension latent space. Nonetheless, creating high-dimensional conformational landscapes in the latent space and then searching for preferred paths continues to be a formidable task. This study introduces an innovative framework for identifying preferred trajectories within high-dimensional conformational landscapes. Our method encompasses the search for the shortest path in the graph, where edge weights are determined based on the energy estimation at each node using local density. The effectiveness of this approach is demonstrated by identifying accurate transition states in both synthetic and real-world datasets featuring continuous conformational changes.
HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells
Authors: Wu Hao , Zhao Xiufeng , Hochrein Sophia M. , Eckstein Miriam , Gubert Gabriela F. , Knöpper Konrad , Mansilla Ana Maria , Öner Arman , Doucet-Ladevèze Remi , Schmitz Werner , Ghesquière Bart , Theurich Sebastian , Dudek Jan , Gasteiger Georg , Zernecke-Madsen Alma , Kobold Sebastian , Kastenmüller Wolfgang , Vaeth Martin 
Published: September 2023

ABSTRACTFunctional exhaustion of T cells in cancer and persistent infections is characterized by the upregulation of inhibitory receptors, the progressive decline in cytokine secretion and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex) with phenotypic features of memory T cells and a stem-like capacity to self-renew. However, the metabolic principles of Tpex maintenance and the regulatory circuits that control the exhaustion of their progeny remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics and metabolomic analyses, we here show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the T cell exhaustion program. At the molecular level, we found that diminished mitochondrial respiration and metabolic remodeling cause oxidative stress, which inhibits the proteasomal degradation ofhypoxia inducible factor 1 alpha(HIF-1α) in Tpex cells. HIF-1α mediates the transcriptional-glycolytic reprogramming of Tpex cells as an initial step towards terminal differentiation and functional exhaustion. Finally, we show that enhancing respiration by limiting the glycolytic activity of CAR T cells is a feasible metabolic intervention strategy to preserve the stemness of Tpex cells during chronic viral infection and cancer immunotherapy.
Belt and braces: two escape ways to maintain the cassette reservoir of large chromosomal integrons
Authors: Richard Egill , Darracq Baptiste , Littner Eloi , Millot Gael , Conte Valentin , Cokelaer Thomas , Engelstädter Jan , Rocha Eduardo P.C. , Mazel Didier , Loot Céline 
Published: September 2023

AbstractIntegrons are adaptive devices that capture, stockpile, shuffle and express gene cassettes thereby sampling combinatorial phenotypic diversity. Some integrons called sedentary chromosomal integrons (SCIs) can be massive structures containing hundreds of cassettes. Since most of these cassettes are non-expressed, it is not clear how they remain stable over long evolutionary timescales. Recently, it was found that the experimental inversion of the SCI ofVibrio choleraeled to a dramatic increase of the cassette excision rate associated to a fitness defect. Here, we question the evolutionary sustainability of this apparently counter selected genetic context through experimental evolution. We find that the integrase is rapidly inactivated and that the inverted SCI can recover its original orientation by homologous recombination between two insertion sequences (ISs) present in the array. These two outcomes of SCI inversion restore the normal growth and prevent the loss of cassettes, enabling SCIs to retain their roles as reservoirs of functions. These results illustrate an interesting interplay between gene orientation, genome rearrangement, bacterial fitness and demonstrate how integrons can benefit from their embedded ISs.
Identification and copy number variant analysis of enhancer regions of genes causing spinocerebellar ataxia
Authors: Ghorbani Fatemeh , de Boer Eddy N. , Fokkens Michiel R. , de Boer-Bergsma Jelkje , Verschuuren-Bemelmans Corien C. , Wierenga Elles , Kasaei Hamidreza , Noordermeer Daan , Verbeek Dineke S. , Westers Helga , van Diemen Cleo C. 
Published: September 2023

AbstractCurrently, routine diagnostics for spinocerebellar ataxia (SCA) consist of analyses that look for polyQ repeat expansions and conventional variations affecting the proteins encoded by known SCA genes. Despite all the effort, ∼40% of the patients still remain without a genetic diagnosis after routine tests. Increasing evidence suggests that variations in the enhancer regions of genes involved in neurodegenerative disorders can also be disease-causing. Since the enhancers of SCA genes are not yet known, it remains to be determined whether variations in these regions are a cause of SCA. In this pilot project, we aimed to identify the enhancers of the SCA genesATXN1, ATXN3, TBPandITPR1in human cerebellum using 4C-seq experiments, publicly available datasets, reciprocal 4C-seq and luciferase assays. We then screened these enhancers for copy number variants (CNVs) in a cohort of genetically undiagnosed SCA patients. We identified two active enhancers for each of the four SCA genes in human cerebellar tissue. In addition, forTBPandITPR1, we observed interactions between the putative enhancers of each gene. CNV analysis did not reveal any CNVs in the active enhancers of the four SCA genes in any of the genetically undiagnosed SCA patients. However, in one patient, we noted a CNV deletion with unknown clinical significance near one of the active enhancers ofITPR1. These results not only reveal elements involved in regulation of SCA genes, they can also lead to the discovery of novel SCA-causing genetic variants. As enhancer variations are increasingly recognized to cause brain disorders, screening the enhancers ofATXN1, ATXN3, TBPandITPR1for variations other than CNVs and identifying and screening enhancers of other SCA genes might elucidate the genetic cause in genetically undiagnosed patients.
Profiling plasma extracellular vesicle-derived microRNAs for noninvasive diagnosis of alpha-1 antitrypsin deficiency associated liver disease
Authors: Oshins Regina , Huo Zhiguang , Poole Brittney , Clark Virginia , Zhou Huiping , West Jesse , Wheeler Matthew , Aghaee Mahya , He Mei , Brantly Mark , Khodayari Nazli 
Published: September 2023

ABSTRACTAlpha-1 antitrypsin deficiency (AATD) is a rare genetic disease characterized by reduced circulating levels of alpha-1 antitrypsin (AAT) due to the retention of misfolded AAT in the hepatocytes. The toxic AAT aggregates in hepatocytes cause liver fibrosis, cirrhosis, and hepatocellular carcinoma. Most patients remain asymptomatic until the final stage in which liver transplantation becomes the only treatment. Timely diagnosis of AATD liver disease plays a critical role in intervention and finding curative solutions. Assessing the prevalence and severity of AATD liver disease remains challenging due to limitations in current methods. Liver biopsy, the gold standard for evaluating the hepatic AAT accumulation, the initiating stage for AATD liver disease, is hindered by invasiveness and sampling errors. To address these limitations, we conducted a study using unique and precious clinical samples. We analyzed plasma extracellular vesicle (EV) derived miRNAs and liver transcriptomes from AATD individuals to develop a sensitive and noninvasive diagnostic approach for AATD liver disease. In the testing stage of our study, we enrolled 17 AATD individuals with different stages of liver disease, as determined by liver biopsy, and 20 controls. We identified differential expression of 178 miRNAs within the AATD group compared to controls by miRNA sequencing. Among those miRNAs, we selected miR-223-3p, miR-23a-3p, miR-15b-5p, let-7a-5p, let-7f-5p, and miR-374a-5p for further validation in an independent cohort of 45 AATD individuals. Using a logistic model that combined three miRNAs, we achieved an AUC of 0.737 for detecting AATD liver disease. Adding a fourth miRNA into this model increased the AUC to 0.751. The changes in EV miRNAs are correlated to dysregulated expression of liver mRNAs in AATD individuals with different stages of liver disease. We propose that plasma-circulating EV exhibit distinct miRNAs in AATD individuals and could serve as clinically significant biomarkers for the early detection of AATD liver disease.
Detecting signals of critical transition in inclusive teaching in biology education: A computational text analysis ofCourseSource
Authors: Mangane Sokona , Zhao Yuhao , Eaton Carrie Diaz 
Published: September 2023

AbstractWe examine every Inclusive Teaching section in articles published by the journalCourseSource- undergraduate biology teaching materials and related essays - from 2014 to 2022 to understand the evolution of inclusive teaching ideas as expressed through language. We find a rapid shift in attention to inclusive teaching occurs between 2018 and 2019, marked by an increase in section length, increased use of inclusive teaching keywords, and an increase in complexity of ideas in the semantic network. This critical transition occurs before many of the recent events in 2020 which have renewed conversation on equity in education. Some effect is associated with Writing Workshop Faculty Mentoring Networks, which provide participants with authoring resources and support. However, this alone is not enough to explain the observed shift, suggesting that many other structures, conversations, and investments were already providing the fertile ground for educational equity in biology education.
Characterization of an EG.5.1 clinical isolatein vitroandin vivo
Authors: Uraki Ryuta , Kiso Maki , Iwatsuki-Horimoto Kiyoko , Yamayoshi Seiya , Ito Mutsumi , Chiba Shiho , Sakai-Tagawa Yuko , Imai Masaki , Kashima Yukie , Koga Michiko , Fuwa Noriko , Okumura Nobumasa , Hojo Masayuki , Iwamoto Noriko , Kato Hideaki , Nakajima Hideaki , Ohmagari Norio , Yotsuyanagi Hiroshi , Suzuki Yutaka , Kawaoka Yoshihiro 
Published: September 2023

AbstractEG.5.1 is a subvariant of the SARS-CoV-2 Omicron XBB variant that is rapidly increasing in prevalence worldwide. EG.5.1 has additional substitutions in its spike protein (namely, Q52H and F456L) compared with XBB.1.5. However, the pathogenicity, transmissibility, and immune evasion properties of clinical isolates of EG.5.1 are largely unknown.In this study, we used wild-type Syrian hamsters to investigate the replicative ability, pathogenicity, and transmissibility of a clinical EG.5.1 isolate. Our data show that there are no obvious differences in growth ability and pathogenicity between EG.5.1 and XBB.1.5, and both EG.5.1 and XBB.1.5 are attenuated compared to a Delta variant isolate.We also found that EG.5.1 is transmitted more efficiently between hamsters compared with XBB.1.5. In addition, unlike XBB.1.5, we detected EG.5.1 virus in the lungs of four of six exposed hamsters, suggesting that the virus tropism of EG.5.1 is different from that of XBB.1.5 after airborne transmission.Finally, we assessed the neutralizing ability of plasma from convalescent individuals and found that the neutralizing activity against EG.5.1 was slightly, but significantly, lower than that against XBB.1.5 or XBB.1.9.2. This suggests that EG.5.1 effectively evades humoral immunity and that the amino acid differences in the S protein of EG.5.1 compared with that of XBB.1.5 or XBB.1.9.2 (i.e., Q52H, R158G, and F456L) alter the antigenicity of EG.5.1.Our data suggest that the increased transmissibility and altered antigenicity of EG.5.1 may be driving its increasing prevalence over XBB.1.5 in the human population.
S100A1’s single cysteine is an indispensable redox-switch for the protection against diastolic calcium leakage in cardiomyocytes
Authors: Seitz Andreas , Busch Martin , Kroemer Jasmin , Schneider Andrea , Simon Stephanie , Jungmann Andreas , Katus Hugo A. , Ritterhoff Julia , Most Patrick 
Published: September 2023

AbstractThe EF-hand calcium (Ca2+) sensor protein S100A1 combines inotropic with antiarrhythmic potency in cardiomyocytes (CM). Oxidative posttranslational modification (ox-PTM) of S100A1’s conserved, single cysteine residue (C85) via reactive nitrogen species (i.e. S-nitrosylation or glutathionylation) was proposed to modulate conformational flexibility of intrinsically disordered sequence fragments and to increase the molecule’s affinity towards Ca2+. In light of the unknown biological functional consequence, we aimed to determine the impact of the C85 moiety of S100A1 as a potential redox-switch.We first uncovered that S100A1 is endogenously glutathionylated in the adult heart in vivo. To prevent glutathionylation of S100A1, we generated S100A1 variants that were unresponsive to ox-PTMs. Overexpression of wildtype (WT) and C85-deficient S100A1 protein variants in isolated CM demonstrated equal inotropic potency, as shown by equally augmented Ca2+transient amplitudes under basal conditions and β-adrenergic receptor (βAR) stimulation. However, in contrast ox-PTM defective S100A1 variants failed to protect against arrhythmogenic diastolic sarcoplasmic reticulum (SR) Ca2+leak and ryanodine receptor (RyR2) hypernitrosylation during β-AR stimulation. Despite diastolic performance failure, C85-deficient S100A1 protein variants exerted similar Ca2+-dependent interaction with the RyR2 than WT-S100A1.Dissecting S100A1’s molecular structure-function relationship, our data indicate for the first time that the conserved C85 residue potentially acts as a redox-switch that is indispensable for S100A1’s antiarrhythmic but not its inotropic potency in CM. We therefore propose a model where C85’s ox-PTM determines S100A1’s ability to beneficially control diastolic but not systolic RyR2 activity.