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Connecting research and clinical practice: training the next generation of translational scientists.
No full textAmerican Hair Research Society Mentorship Grant Program: Short-Term Training Opportunities with Experts.
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Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.
Get PDFAging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveals co-localization of aged immune and epithelial cells in situ. Lastly, we found transcriptional signatures of aging mammary cells in human breast tumors, suggesting possible links between aging and cancer. Together, these data uncover that epithelial, immune and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment and neoplasia risk
Multidisciplinary stakeholder-informed identification of key characteristics for implementation of workplace genetic testing.
Get PDFWorkplace genetic testing (wGT) is an evolving model for genetic testing where employees are offered consumer genetic testing through employer-sponsored wellness programs. However, the potential harms, benefits, and key characteristics for best implementation practices for wGT have yet to be defined. To address this issue, we conducted a three-round modified Delphi process, including multiple rounds of survey and a virtual deliberative workshop, with purposely chosen wGT stakeholders (employees, employers, ethical, legal, and social implications [ELSI] professionals, genetic testing industry representatives, and healthcare professionals) to share their perspectives. From the modified Delphi process, we identified 12 key characteristics for the implementation of wGT that were perceived to increase the potential for benefit while reducing the risk of potential harms. Most participants agreed that privacy/security, voluntariness, transparency, understanding and education, anti-discrimination, employee control, and evidence-based testing measures were both important (\u3e90%) and necessary (\u3e75%) for the implementation of wGT. However, some participants also expressed a lack of confidence in the likelihood of achieving these characteristics in wGT programs. Overall, stakeholders expressed qualified support for wGT at the conclusion of the modified Delphi process. Their perspectives on the topic varied over the course of the process and were at least partially contingent on whether the aforementioned 12 key characteristics were met. These findings help inform the establishment of a normative framework for wGT assessment
AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome.
No full textMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here we present BioMapAI, a supervised deep neural network trained on a 4-year, longitudinal, multi-omics dataset from 249 participants, which integrates gut metagenomics, plasma metabolomics, immune cell profiling, blood laboratory data and detailed clinical symptoms. By simultaneously modeling these diverse data types to predict clinical severity, BioMapAI identifies disease- and symptom-specific biomarkers and classifies ME/CFS in both held-out and independent external cohorts. Using an explainable AI approach, we construct a unique connectivity map spanning the microbiome, immune system and plasma metabolome in health and ME/CFS adjusted for age, gender and additional clinical factors. This map uncovers altered associations between microbial metabolism (for example, short-chain fatty acids, branched-chain amino acids, tryptophan, benzoate), plasma lipids and bile acids, and heightened inflammatory responses in mucosal and inflammatory T cell subsets (MAIT, γδT) secreting IFN-γ and GzA. Overall, BioMapAI provides unprecedented systems-level insights into ME/CFS, refining existing hypotheses and hypothesizing unique mechanisms-specifically, how multi-omics dynamics are associated to the disease\u27s heterogeneous symptoms
Correlation Measures in Metagenomic Data: The Blessing of Dimensionality
Get PDFMicrobiome analysis has revolutionized our understanding of various biological processes, spanning human health and epidemiology (including antimicrobial resistance and hor- izontal gene transfer), as well as environmental and agricultural studies. At the heart of microbiome analysis lies the characterization of microbial communities through the quantification of microbial taxa and their dynamics. In the study of bacterial abundances, it is becoming more relevant to consider their relationship, to embed these data in the framework of network theory, allowing characterization of features like node relevance, pathways, and community structure. In this study, we address the primary biases encoun- tered in reconstructing networks through correlation measures, particularly in light of the compositional nature of the data, within-sample diversity, and the presence of a high number of unobserved species. These factors can lead to inaccurate correlation estimates. To tackle these challenges, we employ simulated data to demonstrate how many of these is- sues can be mitigated by applying typical transformations designed for compositional data. These transformations enable the use of straightforward measures like Pearson’s correlation to correctly identify positive and negative relationships among relative abundances, espe- cially in high-dimensional data, without having any need for further corrections. However, some challenges persist, such as addressing data sparsity, as neglecting this aspect can result in an underestimation of negative correlations
Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.
Get PDFPathogenic variants in the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (∼40 % of patients) and p.E815K (∼25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of the two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research
Statistical Power to Detect QTL Peaks in Genetic Modifier Crosses
No full textMonogenic diseases often display broad variation in age of onset and severity. This variation may be due to environmental or genetic factors. The genetic causes of this variation can be identified using a “modifier screen”, in which mice carrying a dominant disease-causing gene are crossed with genetically diverse mice. Genetic diversity can be introduced through recombinant inbred lines, such as the BXD or Collaborative Cross (CC), or outcross mice, such as the Diversity Outbred (DO) to create an F1 mouse population in which investigators perform quantitative trait locus (QTL) mapping. We ran QTL mapping simulations with varying heritability, effect size, and sample size in BXD, CC, DO, BXD-F1, CC-F1, and DO-F1 mouse populations to determine the power and precision to detect QTL peaks in these populations. We found that the power in the F1 populations is half that of the power in the corresponding parent populations. We also found that the support interval was larger in the F1 and that the QTL position was more variable in the F1. Modifier mapping studies require more mice than mapping studies with the parent populations, and the findings in this study can assist investigators in determining the necessary sample size
Preclinical use of a clinically-relevant scAAV9/SUMF1 vector for the treatment of multiple sulfatase deficiency.
Get PDFBACKGROUND: Multiple Sulfatase Deficiency (MSD) is a rare inherited lysosomal storage disorder characterized by loss of function mutations in the SUMF1 gene that manifests as a severe pediatric neurological disease. There are no available targeted therapies for MSD.
METHODS: We engineered a viral vector (AAV9/SUMF1) to deliver working copies of the SUMF1 gene and tested the vector in Sumf1 knock out mice that generally display a median lifespan of 10 days. Mice were injected as pre-symptomatic neonates via intracerebroventricular administration, or as post-symptomatic juveniles via intrathecal alone or combination intrathecal and intravenous delivery. Cohorts were assessed for survival, behavioral outcomes, and post-mortem for sulfatase activity.
RESULTS: We show that treatment of neonates extends survival up to 1-year post-injection. Importantly, delivery of SUMF1 through cerebral spinal fluid at 7 days of age alleviates MSD symptoms. The treated mice show wide distribution of the SUMF1 gene, no signs of toxicity or neuropathy, improved vision and cardiac function, and no behavioral deficits. One-year post treatment, tissues show increased sulfatase activity, indicating functional SUMF1. Further, a GLP toxicology study conducted in rats demonstrates favorable overall safety of this approach.
CONCLUSIONS: These preclinical studies highlight the potential of our AAV9/SUMF1 vector, the design of which is directly translatable for clinical use, as a gene replacement therapy for MSD patients