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Stathmin-2 enhances motor axon regeneration after injury independent of its binding to tubulin.
Full text linkStathmin-2 (also known as SCG10) is encoded by the STMN2 gene, whose mRNA is one of the most abundantly expressed in human motor neurons. In almost all instances of ALS and other TDP-43 proteinopathies, stathmin-2 encoding mRNAs are cryptically spliced and polyadenylated in motor neurons, a pathogenic consequence of nuclear loss of function of the RNA binding protein TDP-43. While stathmin-2 has been shown to enhance regeneration after axonal injury to axons of cultured motor neurons, here, we show that after crush injury within the adult murine nervous system of wild-type or stathmin-2-null mice, the presence of stathmin-2 reduces axonal and neuromuscular junction degeneration and stimulates reinnervation and functional recovery. Mechanistically, although stathmin-2 has been proposed to function through direct binding to α/β tubulin heterodimers and correspondingly to affect microtubule assembly and dynamics, stathmin-2’s role in axon regeneration after axotomy is shown to be independent of its tubulin binding abilities
Placental and Cord Blood DNA Methylation Changes Associated With Gestational Diabetes Mellitus in a Marginalized Population: The Untold Role of Saturated Fats.
Full text linkThe role of DNA methylation (DNAm) and its modulation by dietary factors in gestational diabetes mellitus (GDM) remains underexplored, particularly in marginalized populations. This study investigates DNAm alterations in GDM-exposed cord blood and placenta and their association with maternal dietary quality and single nutrient intake in a low-income population from the Myanmar-Thailand border. A matched case-control design (GDM: n = 38, controls: n = 34) was selected from a Myanmar-Thailand pregnancy cohort. Dietary intake was assessed via 24-h recalls and analyzed using Nutritionist Pro, with dietary quality evaluated by the healthy eating index (HEI). DNAm was profiled in 72 cord blood and 72 placental samples using the Infinium MethylationEPIC array. Significant differences in dietary vitamin D, total folate, and saturated fat intake were observed between the groups. RnBeads analyses revealed hypomethylation as the predominant DNAm pattern in GDM, particularly at ADORA2B (placenta) and ZFP57 (cord blood) promoters. The excessive intake of saturated fats was associated with GDM hypomethylation profiles and negatively correlated with ZFP57 methylation levels. This study highlights the influence of saturated fat intake on epigenetic changes in pregnancy, revealing potential biomarkers for GDM and emphasizing the need for tailored, population-specific nutritional interventions to mitigate transgenerational health impacts
An epithelial cell culture model for sturgeon integument responds sensitively to 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure.
Full text linkSturgeon species are threatened or endangered worldwide due to habitat loss and increasing pollution. An epithelial cell culture model promises to help investigate hazardous environmental exposures. Stratified squamous integument of green and white sturgeons (Acipenser medirostris and transmontanus, respectively) and cells cultured from their epithelia expressed substantial levels of TGM1-like transglutaminases, types I and II keratins and aryl hydrocarbon receptor (AHR) proteins analogous to those in mammalian integument. Epithelial cells cultured from the rim of the mouth, oral cavity and ampullae of Lorenzini exhibited dramatic growth suppression upon exposure to environmentally relevant levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a model compound for ubiquitous environmental combustion products that activate the AHR. The rho kinase inhibitor Y27632 markedly increased cell growth in culture and, surprisingly, prevented growth suppression by TCDD. Thus, these epithelial cell cultures provide an intriguing model for studying the mechanism by which activation of the AHR produces adverse effects. Evidently, contributions from genome duplication, gene duplication, gene loss and complications of polyploidization have endowed sturgeon with multiple forms of AHR, in this case 3 pairs of closely related genes. AHR1 and AHR2 are predicted to bind TCDD with high affinity, which could help rationalize the cellular sensitivity to AHR activation
Molecular landscape of respiratory infection: A large-scale, multi-centre blood transcriptome dataset.
Full text linkRespiratory infections pose significant challenges to global health, impacting millions of individuals annually. Understanding the molecular mechanisms underlying the pathogenicity of these infections is crucial for developing effective interventions. RNA sequencing provides insights into a patient\u27s global transcriptome changes, facilitating the identification of host gene signatures in response to infection and potential therapeutic targets. Here we present an extensive whole blood transcriptome dataset from a demographically diverse cohort of 502 patients with infections including COVID-19, seasonal coronavirus, influenza A or influenza B, sepsis, septic shock, and co-infections (Viral/Viral, Bacterial/Viral, Bacterial/Viral/Fungal, Viral/Fungal, Viral/ Viral/Fungal). The cohort size and depth of data showcase its potential to unravel respiratory infection pathogenesis for the development of better diagnostics, treatments, and preventive strategies for respiratory infections and future global health crises
mzrtsim: Raw Data Simulation for Reproducible Gas/Liquid Chromatography-Mass Spectrometry-Based Nontargeted Metabolomics Data Analysis.
No full textReproducibility of data analysis is pivotal in the context of nontargeted metabolomics based on mass spectrometry coupled with chromatography. While various algorithms have been proposed for feature or peak extraction, their validation often revolves around a limited set of known compounds or standards. While data simulation is widely used in other omics studies, simulations are focused on the feature level, neglecting uncertainties inherent in the feature or peak extraction process for metabolomics mass spectrometry data. In this technique note, we introduce an R package called mzrtsim \u27 to simulate gas/liquid chromatography full scan raw data in the mzML format. Unlike simulations solely based on virtual features, our approach leverages experimental spectral data from MassBank of North America (MoNA) and the human metabolome database (HMDB). We developed algorithms to simulate chromatographic peaks, accounting for the tailing factor. The results of our study demonstrate the potential of this tool for comparing established metabolomics software (e.g., XCMS, mzMine, and OpenMS) against ground truth. We found that the investigated software introduced false positive peaks and/or loss of compounds with fewer peaks. They also showed different sensitivity to the tailing and leading peaks. This R package is free and available online (https://github.com/yufree/mzrtsim)
Plot twist: TET2 clones save the brain.
No full textWhile clonal hematopoiesis (CH) is associated with protection from Alzheimer’s disease (AD), a limited understanding of the mechanisms by which this occurs has been a barrier to therapeutic intervention. In a new study, Matatall et al. discover protective mechanisms by which TET2-mutant, but not DNMT3A-mutant, CH impacts dementia pathology and cognition
The 2023 medical genetics workforce in the United States.
No full textPURPOSE: To characterize the 2023 medical genetics and genomics workforce in the United States-comprising clinical geneticists, genetic counselors, genetic nurses, genetic physician assistants, laboratory geneticists, and metabolic dietitians-to inform genetics workforce efforts.
METHODS: National genetics membership or board-certification organizations distributed an electronic survey to medical genetics professionals in early 2023. Questions were derived from prior workforce surveys and by a workgroup led by the National Coordinating Center for the Regional Genetics Networks.
RESULTS: Of the 3070 medical genetics professionals who responded, 66.0% were genetic counselors, 15.4% were clinical geneticists, 12.2% were laboratory geneticists, 4.7% were metabolic dietitians, and 1.7% were genetic nurses or physician assistants. The respondents identified as White (76.1%) and women (84.7%); there were statistically significant differences between disciplines. Forty percent worked in academic centers; 55.3% worked 41+ hours per week. Nearly 11% of respondents provided services in a language other than English. Despite 34.7% of respondents experiencing some burnout, most had no plans to leave the field (94.4%) within the next year.
CONCLUSION: The medical genetics community needs to advance workforce initiatives to support current personnel and attract new and diverse individuals to the field to serve patients and their families
The Calcium Binding Gene Calb1 is an FGF23 target in Distal Convoluted Tubule in Sickle Cell Disease
No full textSickle cell disease (SCD) is a blood disorder characterized by red blood cell sickling and disrupted kidney calcium homeostasis, though the molecular mechanisms underlying calcium handling reprogramming in SCD remain largely unclear. Herein, using single cell transcriptomics and chromatin accessibilities profiling assays, we identify Calb1, a gene encoding a calcium-binding protein CALB1, to be strongly downregulated in SCD mouse models in the distal convoluted tubule cells, suggesting a misregulation of renal calcium handling via CALB1. Motif enrichment and chromatin accessibility analyses suggest that REST (RE1-silencing transcription factor) binds to the Calb1 promoter, acting as a transcriptional repressor. Further, we identify an upstream hormonal dependent pathway via fibroblast growth factor 23 (FGF23) as a potential modulator of REST–Calb1 axis in distal tubule (DT) cells. To support these findings, we examine chronic kidney disease (CKD) and acute kidney injury (AKI) mouse models, both of which show similar patterns of Calb1 repression associated with elevated FGF23. In addition, we reveal a kidney metabolic reprogramming occurring with SCD with a decrease of expression of enzymes involved Embden-Meyerhof-Parnas pathway and the increase of the enzyme BPGM that is associated with the Rapoport-Luebering Shunt pathway. Further, we found through in vitro studies that BPGM metabolite 2,3-diphosphoglycerate (2,3 DPG) impairs FGF23 signaling bioactivity characterized by decrease MAPK signaling-mediated EGR1 expression. Together, our findings highlight a new regulatory network involving FGF23, REST, Calb1, and Bpgm-2,3DPG axis that may contribute to calcium imbalance in SCD
The phenotypic impact of CSF1R enhancer fms-intronic regulatory element (FIRE) deletion in NSG mice
No full textThe study of neuroimmunology suffers from a lack of effective and translational model organisms due to intrinsic differences of biology between mouse models and human disease. This limitation spurred the need for a model organism which houses and expresses human neuroimmunological cells for effective study. The Shultz lab created the NSG-Csf1r FIRE KO/KO Mouse (NSG-FIRE KO/KO) in response to this need. This mouse model does not support several populations of resident macrophage cells, notably including microglia, which results in a complex phenotype characterized by a lowered lifespan and multiple observed phenotypic abnormalities. This project completed a series of clinical scorings on several NSG-FIRE KO/KO related genotypes and concluded that NSG-FIRE KO/KO mice expresses many observed neurological changes compared with NSG-FIRE WT/WT mice. Interestingly, most of these deficits were not present in NSG-FIRE KO/KO mice co-expressing the human SGM3 triple transgene despite continued microglia absence, which points to an impact on non-microglia myeloid cell populations in NSG-FIRE KO/KO mice. In vitro studies on murine bone marrow from FIRE KO/KO mice showed reduced levels of macrophage proteins related to macrophage activation and recruitment of T-cells. These data support the development of this model as human microglia xenograft recipients and use in understanding the role of FIRE in macrophage populations
Spatiotemporal Profiling of Patient Derived Xenograft Tumor Microenvironments
No full textTumors develop within a complex cellular environment that influences their growth and response to therapy. While this tumor microenvironment (TME) is known to affect treatment outcomes, its dynamic changes during therapy remain poorly characterized. Here, we used single-cell RNA sequencing and spatial transcriptomics data from patient-derived xenograft (PDX) models to investigate how the TME evolves under targeted treatment. We observed extensive microenvironmental remodeling throughout the course of therapy and these changes were found to be spatially organized. Notably, we identified spatially localized interactions between fibroblasts and macrophages with potential therapeutic relevance. Additionally, we found that TMEs in PDX models are largely conserved across cancer types and retain key features of endogenous TMEs, with variation by subtype and cell state. These findings offer new insights into the spatial and cellular dynamics of the TME during therapy and suggest avenues for improved treatment strategies