76555 research outputs found
Sort by
Discovery of genomic loci for liver health and steatosis reveals overlap with glutathione redox genetics.
Get PDFNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition in the United States, encompassing a wide spectrum of liver pathologies including steatosis, steatohepatitis, fibrosis, and cirrhosis. Despite its high prevalence, there are no medications currently approved by the Food and Drug Administration for the treatment of NAFLD. Recent work has suggested that NAFLD has a strong genetic component and identifying causative genes will improve our understanding of the molecular mechanisms contributing to NAFLD and yield targets for future therapeutic investigations. Oxidative stress is known to play an important role in NAFLD pathogenesis, yet the underlying mechanisms accounting for disturbances in redox status are not entirely understood. To better understand the relationship between the glutathione redox system and signs of NAFLD in a genetically-diverse population, we measured liver weight, serum biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and graded liver pathology in a large cohort of Diversity Outbred mice. We compared hepatic endpoints to those of the glutathione redox system previously measured in the livers and kidneys of the same mice, and we screened for statistical and genetic associations using the R/qtl2 software. We discovered several novel genetic loci associated with markers of liver health, including loci that were associated with both liver steatosis and glutathione redox status. Candidate genes within each locus point to possible new mechanisms underlying the complex relationship between NAFLD and the glutathione redox system, which could have translational implications for future studies targeting NAFLD pathology
Age, sex and Alzheimer\u27s disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer\u27s patients.
Get PDFBACKGROUND: Aging and sex are major risk factors for developing late-onset Alzheimer\u27s disease. Compared to men, women experience worse neuropathological burden and cognitive decline despite living longer with the disease. Similarly, male 3xTg-AD mice, developed to model Alzheimer\u27s disease, no longer consistently exhibit standard Alzheimer\u27s neuropathology yet experience higher rates of mortality - providing a unique opportunity to further elucidate this dichotomy. We hypothesized that sex differences in the biological aging process yield distinct pathological and molecular Alzheimer\u27s disease signatures in males and females, which could be harnessed for therapeutic and biomarker development.
METHODS: We aged male and female, 3xTg-AD and B6129 control mice across their respective lifespans (n = 3-8 mice per sex, strain, and age group) and longitudinally assessed neuropathological hallmarks of Alzheimer\u27s disease, markers of hepatic inflammation, splenic mass and morphology, as well as plasma cytokine levels. We conducted RNA sequencing analysis on bulk brain tissue and examined differentially expressed genes (DEGs) between 3xTg-AD and B6129 samples and across ages in each sex. We also examined DEGs between clinical Alzheimer\u27s and control parahippocampal gyrus brain tissue samples from the Mount Sinai Brain Bank study in each sex.
RESULTS: 3xTg-AD females significantly outlived 3xTg-AD males and exhibited progressive Alzheimer\u27s neuropathology, while 3xTg-AD males demonstrated progressive hepatic inflammation, splenomegaly, circulating inflammatory proteins, and minimal Alzheimer\u27s neuropathological hallmarks. Instead, 3xTg-AD males experienced an accelerated upregulation of immune-related gene expression in the brain relative to females. Our clinical investigations revealed that individuals with Alzheimer\u27s disease develop similar sex-specific alterations in neuronal and immune function. In diseased males of both species, we observed greater upregulation of complement-related gene expression, and lipopolysaccharide was predicted as the top upstream regulator of DEGs.
CONCLUSIONS: Our data demonstrate that chronic inflammation and complement activation are associated with increased mortality, indicating that age-related changes in immune response contribute to sex differences in Alzheimer\u27s disease trajectories. We provide evidence that aging and transgene-driven disease progression trigger a widespread inflammatory response in 3xTg-AD males, which mimics the impact of lipopolysaccharide stimulation despite the absence of infection
Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy.
No full textMetabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive liver disease that encompasses a spectrum of steatosis, steatohepatitis (or MASH), and fibrosis. Evidence suggests that dietary restriction (DR) and sleeve gastrectomy (SG) can lead to remission of hepatic steatosis and inflammation through weight loss, but it is unclear whether these procedures induce distinct metabolic or immunological changes in MASLD livers. This study aims to elucidate the intricate hepatic changes following DR, SG or sham surgery in rats fed a high-fat diet as a model of obesity-related MASLD, in comparison to a clinical cohort of patients undergoing SG. Single-cell and single-nuclei transcriptome analysis, spatial metabolomics, and immunohistochemistry revealed the liver landscape, while circulating biomarkers were measured in serum samples. Artificial intelligence (AI)-assisted image analysis characterized the spatial distribution of hepatocytes, myeloid cells and lymphocytes. In patients and experimental MASLD rats, SG improved body mass index, circulating liver injury biomarkers and triglyceride levels. Both DR and SG attenuated liver steatosis and fibrosis in rats. Metabolism-related genes
Tuberculosis in otherwise healthy adults with inherited TNF deficiency.
Get PDFSevere defects in human IFNγ immunity predispose individuals to both Bacillus Calmette–Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1 . Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte–macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette–Guérin disease and tuberculosis3 . Human TNF is required for respiratory- burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents
Development and Application of Genetic Ancestry Reconstruction Methods to Study Diversity of Patient-Derived Models in the NCI PDXNet Consortium.
Get PDFPrecision medicine holds great promise for improving cancer outcomes. Yet, there are large inequities in the demographics of patients from whom genomic data and models, including patient-derived xenografts (PDX), are developed and for whom treatments are optimized. In this study, we developed a genetic ancestry pipeline for the Cancer Genomics Cloud, which we used to assess the diversity of models currently available in the National Cancer Institute-supported PDX Development and Trial Centers Research Network (PDXNet). We showed that there is an under-representation of models derived from patients of non-European ancestry, consistent with other cancer model resources. We discussed these findings in the context of disparities in cancer incidence and outcomes among demographic groups in the US, as well as power analyses for biomarker discovery, to highlight the immediate need for developing models from minority populations to address cancer health equity in precision medicine. Our analyses identified key priority disparity-associated cancer types for which new models should be developed.
SIGNIFICANCE: Understanding whether and how tumor genetic factors drive differences in outcomes among U.S. minority groups is critical to addressing cancer health disparities. Our findings suggest that many additional models will be necessary to understand the genome-driven sources of these disparities
Chemokines in the tumor microenvironment: implications for lung cancer and immunotherapy.
Get PDFThe tumor microenvironment (TME) is a complex interconnected network of immune cells, fibroblasts, blood vessels, and extracellular matrix surrounding the tumor. Because of its immunosuppressive nature, the TME can pose a challenge for cancer immunotherapies targeting solid tumors. Chemokines have emerged as a crucial element in enhancing the efficacy of cancer immunotherapy, playing a direct role in immune cell signaling within the TME and facilitating immune cell migration towards cancer cells. However, chemokine ligands and their receptors exhibit context-dependent diversity, necessitating evaluation of their tumor-promoting or inhibitory effects based on tumor type and immune cell characteristics. This review explores the role of chemokines in tumor immunity and metastasis in the context of the TME. We also discuss current chemokine-related advances in cancer immunotherapy research, with a particular focus on lung cancer, a common cancer with a low survival rate and limited immunotherapy options
Large changes in detected selection signatures after a selection limit in mice bred for voluntary wheel-running behavior.
Get PDFIn various organisms, sequencing of selectively bred lines at apparent selection limits has demonstrated that genetic variation can remain at many loci, implying that evolution at the genetic level may continue even if the population mean phenotype remains constant. We compared selection signatures at generations 22 and 61 of the High Runner mouse experiment, which includes 4 replicate lines bred for voluntary wheel-running behavior (HR) and 4 non-selected control (C) lines. Previously, we reported multiple regions of differentiation between the HR and C lines, based on whole-genome sequence data for 10 mice from each line at generation 61, which was \u3e31 generations after selection limits had been reached in all HR lines. Here, we analyzed pooled sequencing data from ~20 mice for each of the 8 lines at generation 22, around when HR lines were reaching limits. Differentiation analyses of allele frequencies at ~4.4 million SNP loci used the regularized T-test and detected 258 differentiated regions with FDR = 0.01. Comparable analyses involving pooling generation 61 individual mouse genotypes into allele frequencies by line produced only 11 such regions, with almost no overlap among the largest and most statistically significant peaks between the two generations. These results implicate a sort of genetic churn that continues at loci relevant for running. Simulations indicate that loss of statistical power due to random genetic drift and sampling error are insufficient to explain the differences in selection signatures. The 13 differentiated regions at generation 22 with strict culling measures include 79 genes related to a wide variety of functions. Gene ontology identified pathways related to olfaction and vomeronasal pathways as being overrepresented, consistent with generation 61 analyses, despite those specific regions differing between generations. Genes Dspp and Rbm24 are also identified as potentially explaining known bone and skeletal muscle differences, respectively, between the linetypes
Meeting report of the fifth annual workshop on Principles and Techniques for Improving Preclinical to Clinical Translation in Alzheimer\u27s Disease Research.
Get PDFThe fifth annual workshop on Principles and Techniques for Improving Preclinical Translation of Alzheimer\u27s Disease Research was held in May 2023 at The Jackson Laboratory in Bar Harbor, Maine, USA. The workshop was established in 2018 to address training gaps in preclinical translational studies for Alzheimer\u27s disease (AD). In addition to providing fundamental knowledge and hands-on skills essential for executing rigorous in vivo studies that are designed to facilitate translation, each year the workshop aims to provide insight on state-of-the-field technological advances and new resources including novel animal models, publicly available datasets, novel biomarkers, and new medical imaging tracers. This innovative and comprehensive workshop continues to deliver training for the greater AD research community in order to provide investigators and trainees with the knowledge and skillsets essential for enabling improved preclinical to clinical translation and accelerate the process of advancing safe and effective therapeutic interventions for AD. HIGHLIGHTS: Translational research is not typically available as a course of study at academic institutions, yet there are fundamental skillsets and knowledge required to enable successful translation from preclinical experiments to clinical efficacy. It is important that there are resources and opportunities available to researchers planning preclinical translational experiments. Here we present proceedings from the fifth annual NIA-sponsored workshop focused on enabling improved preclinical to clinical translation for Alzheimer\u27s disease research that includes didactic lectures on state-of-the-field approaches and hands-on practicums for acquiring essential translational laboratory techniques
Impact and characterization of serial structural variations across humans and great apes.
Get PDFModern sequencing technology enables the systematic detection of complex structural variation (SV) across genomes. However, extensive DNA rearrangements arising through a series of mutations, a phenomenon we refer to as serial SV (sSV), remain underexplored, posing a challenge for SV discovery. Here, we present NAHRwhals ( https://github.com/WHops/NAHRwhals ), a method to infer repeat-mediated series of SVs in long-read genomic assemblies. Applying NAHRwhals to haplotype-resolved human genomes from 28 individuals reveals 37 sSV loci of various length and complexity. These sSVs explain otherwise cryptic variation in medically relevant regions such as the TPSAB1 gene, 8p23.1, 22q11 and Sotos syndrome regions. Comparisons with great ape assemblies indicate that most human sSVs formed recently, after the human-ape split, and involved non-repeat-mediated processes in addition to non-allelic homologous recombination. NAHRwhals reliably discovers and characterizes sSVs at scale and independent of species, uncovering their genomic abundance and suggesting broader implications for disease
Impaired axon initial segment structure and function in a model of
No full textDevelopmental and epileptic encephalopathies (DEE) are rare but devastating and largely intractable childhood epilepsies. Genetic variants in ARHGEF9, encoding a scaffolding protein important for the organization of the postsynaptic density of inhibitory synapses, are associated with DEE accompanied by complex neurological phenotypes. In a mouse model carrying a patient-derived ARHGEF9 variant associated with severe disease, we observed aggregation of postsynaptic proteins and loss of functional inhibitory synapses at the axon initial segment (AIS), altered axo-axonic synaptic inhibition, disrupted action potential generation, and complex seizure phenotypes consistent with clinical observations. These results illustrate diverse roles of ARHGEF9 that converge on regulation of the structure and function of the AIS, thus revealing a pathological mechanism for ARHGEF9-associated DEE. This unique example of a neuropathological condition associated with multiple AIS dysfunctions may inform strategies for treating neurodevelopmental diseases