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Arginine metabolism is a biomarker of red blood cell and human aging.
Get PDFIncreasing global life expectancy motivates investigations of molecular mechanisms of aging and age-related diseases. This study examines age-associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age-dependent changes in RBC metabolism. Over 15,700 specimens from 13,757 humans were examined, a major expansion over previous studies of RBCs in aging. Multi-omics approaches identified chronological age-related alterations in the arginine pathway with increased arginine utilization in RBCs from older individuals. These changes were consistent across healthy and sickle cell disease cohorts and were influenced by genetic variation, sex, and body mass index. Integrating multi-omics data and metabolite quantitative trait loci (mQTL) in humans and 525 diversity outbred mice functionally linked metabolism of arginine during RBC storage to increased vesiculation-a hallmark of RBC aging-and lower post-transfusion hemoglobin increments. Thus, arginine metabolism is a biomarker of RBC and organismal aging, suggesting potential new targets for addressing sequelae of aging
Introducing Identification Probability for Automated and Transferable Assessment of Metabolite Identification Confidence in Metabolomics and Related Studies.
Get PDFMethods for assessing compound identification confidence in metabolomics and related studies have been debated and actively researched for the past two decades. The earliest effort in 2007 focused primarily on mass spectrometry and nuclear magnetic resonance spectroscopy and resulted in four recommended levels of metabolite identification confidence─the Metabolite Standards Initiative (MSI) Levels. In 2014, the original MSI Levels were expanded to five levels (including two sublevels) to facilitate communication of compound identification confidence in high resolution mass spectrometry studies. Further refinement in identification levels have occurred, for example to accommodate use of ion mobility spectrometry in metabolomics workflows, and alternate approaches to communicate compound identification confidence also have been developed based on identification points schema. However, neither qualitative levels of identification confidence nor quantitative scoring systems address the degree of ambiguity in compound identifications in the context of the chemical space being considered. Neither are they easily automated nor transferable between analytical platforms. In this perspective, we propose that the metabolomics and related communities consider identification probability as an approach for automated and transferable assessment of compound identification and ambiguity in metabolomics and related studies. Identification probability is defined simply as 1/N, where N is the number of compounds in a database that matches an experimentally measured molecule within user-defined measurement precision(s), for example mass measurement or retention time accuracy, etc. We demonstrate the utility of identification probability in an in silico analysis of multiproperty reference libraries constructed from a subset of the Human Metabolome Database and computational property predictions, provide guidance to the community in transparent implementation of the concept, and invite the community to further evaluate this concept in parallel with their current preferred methods for assessing metabolite identification confidence
A ventilated perfused lung model platform to dissect the response of the lungs to viral infection.
No full textIn this study, we developed a 3D lung model that incorporated alveolar and vascular components, allowing for the investigation of lung physiology and responses to infection. We investigated the role of ventilation in formation of the alveolar epithelial layer and its response to viral infections. We subjected our perfused model to a continuous respiratory cycle at the air-liquid interface (ALI) for up to 10 days. The results revealed that ventilation increased tight-junction formation with better epithelial barrier function over time. Two viruses, influenza and respiratory syncytial virus (RSV), were tested, where ventilation enhanced infectivity with an increased progression of viral spread over time while sensitizing the epithelium for viral recognition. Ventilation also attenuated the production of key proinflammatory chemokines. Our findings represent a critical step forward in advancing our understanding of lung-specific viral responses and respiratory infections in response to ventilation, shedding light on vital aspects of pulmonary physiology and pathobiology
An Isoform-Specific RUNX1C-BTG2 Axis Governs AML Quiescence and Chemoresistance.
Get PDFAberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted rRNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of rRNAs increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineated an isoform-specific transcriptional circuit that governed chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence. Significance: This study identifies RUNX1C as a contributor to AML chemoresistance and an inducer of quiescence through BTG2. Targeting RUNX1C with RNA-based approaches disrupts this state and improves chemotherapy response, highlighting RUNX1C inhibition as a promising strategy to overcome resistance and enhance treatment efficacy in AML
Strengthening Insights Into MAMDC2: Functional Characterization Of A Dystrophic Mouse Model
No full textMAMDC2 is a recently identified gene implicated in a novel form of autosomal dominant muscular dystrophy, yet its functional role in skeletal muscle remains unknown. This study aims to characterize the biological function of MAMDC2 by assessing muscle regenerative capacity and tissue integrity in a mouse model carrying a patient derived E668Ter truncating mutation. Baseline histological analysis revealed no signs of dystrophic pathology in the gastrocnemius muscle of wild-type (WT), heterozygous (HET) or homozygous (HOM) mice. To assess regenerative capacity under acute stress, WT mice underwent barium chloride (BaCl2) induced-muscle injury followed by time-course analysis at 3, 5, 15, and 28 days post injury (DPI) to the tibialis anterior muscle, which confirmed stereotypical stages of degeneration and regeneration. Separately, WT, HET and HOM cohorts were evaluated at 5 and 15 DPI to determine whether MAMDC2 deficiency impacts regenerative outcome. Across genotypes, all groups displayed comparable regenerative trajectories, as assessed by hematoxylin and eosin staining, centrally nucleated fiber (CNF) size, normalized TA muscle weights, and CD45+ immune cell infiltration. Muscle fiber type distribution (at homeostasis) in the soleus and extensor digitorum longus muscles, along with echocardiographic measures of cardiac function were also preserved across groups. These findings suggest that loss of MAMDC2 does not overtly impair early regeneration or homeostatic muscle composition in young adult mice. Future studies consist of applying this model on aged cohorts, assessing additional proximal muscles such as the iliopsoas, and culturing primary myoblasts to examine differentiation as a means to uncover potential delayed or tissue-specific phenotypes
Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics.
Get PDFThe evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there a consistent longitudinal trajectory across the cohort. Nevertheless, specific trajectories were enriched in subsets of patients. Changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem. Our study provides a blueprint of GBM\u27s diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them
Patterns of Associations with Epidemiologic Factors by High-Grade Serous Ovarian Cancer Gene Expression Subtypes.
Get PDFBACKGROUND: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes.
METHODS: We pooled data from 11 case-control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis consortium. The PrOTYPE-validated NanoString-based 55-gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 controls using multivariable-adjusted polytomous regression models.
RESULTS: Among the 2,070 HGSC cases, 556 (27%) were classified as C1.MES, 340 (16%) as C5.PRO, 538 (26%) as C2.IMM, and 636 (31%) as C4.DIF. The key factors, including oral contraceptive use, parity, breastfeeding, and family history of ovarian cancer, were similarly associated with all subtypes. Heterogeneity was observed for several factors. Former smoking [OR = 1.25; 95% confidence interval (CI) = 1.03, 1.51] and genital powder use (OR = 1.42; 95% CI = 1.08, 1.86) were uniquely associated with C2.IMM. History of endometriosis was associated with C5.PRO (OR = 1.46; 95% CI = 0.98, 2.16) and C4.DIF (OR = 1.27; 95% CI = 0.94, 1.71) only. Family history of breast cancer (OR = 1.44; 95% CI = 1.16, 1.78) and current smoking (OR = 1.40; 95% CI = 1.11, 1.76) were associated with C4.DIF only.
CONCLUSIONS: This study observed heterogeneous associations of epidemiologic and modifiable factors with HGSC molecular subtypes.
IMPACT: The different patterns of associations may provide key information about the etiology of the four subtypes
Workplace perk or pitfall? A qualitative study of genetic counselors\u27 perspectives and experiences with workplace genetic testing.
Get PDFSome employers offer genetic testing for increased cancer and cardiovascular disease risk, as well as pharmacogenetic variants, as a wellness benefit, which presents unique considerations for genetic counseling. Our ethical, legal, and social implications (ELSI) of genomics study, positioned in a post-positivist paradigm, aimed to qualitatively assess the perspectives and experiences of genetic counselors (GCs) who had counseled on workplace genetic testing (wGT). Semi-structured interviews were conducted with 18 US GCs who either worked in the wGT industry (i.e., role-directed wGT experience) or provided post-test counseling in a clinical setting (i.e., patient-directed wGT experience). Interviews were analyzed following the principles of codebook thematic analysis using a codebook developed from key domains from the interview guide and emergent themes that were identified during data collection. De-identified transcripts were double-coded. Both role-directed and patient-directed GCs recognized the potential benefits of wGT such as increasing access to genetic services and thereby improving health outcomes. However, patient-directed GCs had more concerns about the lack of access to follow-up care and increasing healthcare disparities. Role-directed GCs were generally more supportive of wGT and were more likely to endorse the benefits. Overall, both role- and patient-directed GCs emphasized the need for guardrails, particularly adequate pre- and post-test education, to mitigate potential harms of wGT, such as lack of informed decision-making, psychological distress, false reassurance, and decisional regret. GCs spontaneously drew parallels between wGT and population genomic screening efforts, noting that wGT similarly attempts to increase access to genetic testing for the general population. GCs\u27 perspectives on strategies to maximize the benefits and minimize the harms of wGT may inform ELSI considerations when developing population genomic screening efforts and other programs that aim to expand access to genetic testing for the general population
Perceived understanding and psychosocial outcomes: employees\u27 responses to learning results of workplace genetic testing.
No full textAIMS: This study explored employees\u27 understanding of, and psychosocial responses to, workplace genetic testing (wGT) results.
MATERIALS & METHODS: Employees of a US healthcare system who underwent wGT (hereditary cancer/heart disease risk, pharmacogenomics) and received results were surveyed. We ascertained pretest education engagement, test understanding, and psychosocial responses. Regression analyses identified predictors of scores on a modified Feelings About genomiC Test Results questionnaire (positive feelings, negative emotions, and uncertainty after wGT).
RESULTS:
CONCLUSIONS: wGT was associated with low levels of measured psychosocial harm among participants. However, results suggested a greater likelihood of negative psychosocial responses among those with increased risk of cancer/heart disease and non-Hispanic African American/Black employees. Future studies should explore strategies to ensure all employees undergoing wGT have educational and psychosocial support
The rare-to-common disease journey: a winding road to new therapies.
No full textThe study of genetic variants that cause rare diseases has been a central strategy of genetic research for the last century, but the contribution of rare variants to the multifactorial inheritance of common diseases has only recently emerged as an avenue to accelerate functional mapping of the human genome. This perspective defines rare and common diseases, surveys prospects for integrating their study to decipher pathogenic mechanisms, and cites current clinical hurdles of disease translation. We discuss the premise that research into rare disease etiology can inform our understanding of common illnesses and vice versa, identify impediments to progress in translating rare disease findings into common disease treatments, and offer suggestions for realizing the benefits of global health research in the discovery of rare disease variants