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The impact of co-housing on murine aging studies.
Get PDFAnalysis of preclinical lifespan studies often assume that outcome data from co-housed animals are independent. In practice, treatments, such as controlled feeding or putative life-extending compounds, are applied to whole housing units, and as a result, the outcomes are potentially correlated within housing units. We consider intra-class (here, intra-cage) correlation in three published and two unpublished lifespan studies of aged mice encompassing more than 20,000 observations. We show that the independence assumption underlying common analytic techniques does not hold in these data, particularly for traits associated with frailty. We describe and demonstrate various analytical tools available to accommodate this study design and highlight a limitation of standard variance components models (i.e., linear mixed models) which are the usual statistical tools for handling correlated errors. Through simulations, we examine the statistical biases resulting from intra-cage correlations with similar magnitudes as observed in these case studies and discuss implications for power and reproducibility
Chapter 27 - The Mouse Developmental Anatomy Ontology (EMAPA) and the Gene Expression Database for Mouse Development (GXD)
No full textPodoplanin-positive cell-derived small extracellular vesicles contribute to cardiac amyloidosis after myocardial infarction.
Get PDFCardiac amyloidosis is a secondary phenomenon of an already pre-existing chronic condition. Whether car- diac amyloidosis represents one of the complications post myocardial infarction (MI) has yet to be fully under- stood. Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage- derived serum amyloid A 3 (SAA3) monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from cardiac stromal cells (CSCs), which, in response to MI, activate the expression of a platelet aggregation-inducing type I transmembrane glycoprotein, Podoplanin (PDPN). CSC PDPN+ -derived small extracellular vesicles (sEVs) are enriched in SAA3, and exosomal SAA3 engages with macrophage by Toll-like receptor 2, triggering overproduction with consequent impaired clearance and aggregation of SAA3 monomers into rigid fibers. SAA3 amyloid deposits reduce cardiac contractility and increase scar stiff- ness. Inhibition of SAA3 aggregation by retro-inverso D-peptide, specifically designed to bind SAA3 mono- mers, prevents the deposition of SAA3 amyloid fibrils and improves heart function post MI
Single-cell and bulk transcriptional profiling of mouse ovaries reveals novel genes and pathways associated with DNA damage response in oocytes.
Get PDFImmature oocytes enclosed in primordial follicles stored in female ovaries are under constant threat of DNA damage induced by endogenous and exogenous factors. Checkpoint kinase 2 (CHEK2) is a key mediator of the DNA damage response (DDR) in all cells. Genetic studies have shown that CHEK2 and its downstream targets, p53, and TAp63, regulate primordial follicle elimination in response to DNA damage. However, the mechanism leading to their demise is still poorly characterized. Single-cell and bulk RNA sequencing were used to determine the DDR in wild-type and Chek2-deficient ovaries. A low but oocyte-lethal dose of ionizing radiation induces ovarian DDR that is solely dependent on CHEK2. DNA damage activates multiple response pathways related to apoptosis, p53, interferon signaling, inflammation, cell adhesion, and intercellular communication. These pathways are differentially employed by different ovarian cell types, with oocytes disproportionately affected by radiation. Novel genes and pathways are induced by radiation specifically in oocytes, shedding light on their sensitivity to DNA damage, and implicating a coordinated response between oocytes and pregranulosa cells within the follicle. These findings provide a foundation for future studies on the specific mechanisms regulating oocyte survival in the context of aging, therapeutic and environmental genotoxic exposures
Workshop Report-Heterogeneity and Successful Aging Part I: Heterogeneity in Aging-Challenges and Opportunities.
No full textHistorically, aging research has focused primarily on the study of differences in means of varied measures obtained at different ages. However, growing evidence has shown that for many parameters, variability in measurements obtained both between- and within-age groups increases with aging. Moreover, growing heterogeneity may become especially apparent when examined via longitudinal as opposed to cross-sectional aging data. Efforts to deconvolute and better understand such heterogeneity present remarkable translational opportunities for developing targeted and more effective interventions into aging. Here, we present Part I, a summary of the NIA Heterogeneity and Successful Aging workshop virtually held in May 2023
Chromatin State Maps of Blood Pressure-Relevant Renal Segments Reveal Potential Regulatory Role for SNPs.
No full textBACKGROUND: Hypertension or elevated blood pressure (BP) is a worldwide clinical challenge and the leading primary risk factor for kidney dysfunctions, heart failure, and cerebrovascular disease. The kidney is a central regulator of BP by maintaining sodium-water balance. Multiple genome-wide association studies revealed that BP is a heritable quantitative trait, modulated by several genetic, epigenetic, and environmental factors. The SNPs identified in genome-wide association studies predominantly (\u3e95%) reside within noncoding genomic regions, making it difficult to understand how they regulate BP. Given the central role of the kidney in regulating BP, we hypothesized that chromatin-accessible regions in renal tissue would be enriched for BP-associated single nucleotide polymorphisms.
METHODS: We manually dissected 2 important kidney segments that maintain the sodium-water balance: proximal tubules and medullary thick ascending limbs from the human and rat kidneys. To delineate their chromatin and transcriptomic profiles, we performed the assay for transposase-accessible chromatin and RNA sequencing, respectively.
RESULTS: The chromatin accessibility maps revealed the shared and unique
CONCLUSIONS: Collectively, this study lays a foundation for interrogating how intergenic single nucleotide polymorphisms may regulate polygenic traits such as BP
FYN regulates aqueous humor outflow and IOP through the phosphorylation of VE-CADHERIN.
Get PDFSchlemm\u27s canal endothelial cells (SECs) serve as the final barrier to aqueous humor (AQH) drainage from the eye. SECs adjust permeability to AQH outflow to modulate intraocular pressure (IOP). The broad identification of IOP-related genes implicates SECs in glaucoma. However, the molecular mechanisms by which SECs sense and respond to pressure changes to regulate fluid permeability and IOP remain largely undefined. We hypothesize that mechano-responsive phosphorylation of the cell adhesion molecule VE-CADHERIN (CDH5) in SECs, by FYN and possibly other SRC family kinases, regulates adherens junction (AJ) permeability to AQH in response to IOP. On experimentally raising IOP in mouse eyes, AJ permeability, CDH5 phosphorylation, and FYN activation at the AJ all increase. FYN null mutant mice display disrupted IOP regulation and reduced AQH outflow. These findings demonstrate an important role of mechanotransducive signaling within SECs in maintaining IOP homeostasis and implicate FYN as a potential target for developing IOP-lowering treatments
CASCADES, a novel SOX2 super-enhancer-associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma.
Get PDFGlioblastoma is the most common primary malignant brain tumor in adults, with a median survival of just over 1 year. The failure of available treatments to achieve remission in patients with glioblastoma (GBM) has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence. In fact, the property of stemness itself may be responsible for treatment resistance. In this study, we identify a novel long noncoding RNA (lncRNA), cancer stem cell-associated distal enhancer of SOX2 (CASCADES), that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in isocitrate dehydrogenase (IDH)-wild-type GBM and is significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer-associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs that represents a novel epigenetic and therapeutic target for disrupting the CSC compartment in glioblastoma
Spatiotemporal metabolic mapping of ex-situ preserved hearts subjected to dialysis by integration of bio-SPME sampling with non-targeted metabolipidomic profiling.
Get PDFBACKGROUND: Normothermic ex situ heart perfusion (ESHP) has emerged as a valid modality for advanced cardiac allograft preservation and conditioning prior to transplantation though myocardial function declines gradually during ESHP thus limiting its potential for expanding the donor pool. Recently, the utilization of dialysis has been shown to preserve myocardial and coronary vasomotor function. Herein, we sought to determine the changes in myocardial metabolism that could support this improvement.
RESULTS: Male Yorkshire porcine hearts were subjected to ESHP for 8 h with or without dialysis. Alterations in metabolism were studied with an innovative in vivo solid-phase microextraction (SPME) technology coupled with global metabolite profiling at 15 min, 1.5, 4, and 8 h of perfusion. Bio-SPME sampling was performed by inserting SPME fibres coated with a PAN-based extraction phase containing mixed-mode (C8+benzenesulfonic acid) functionalities into the myocardium to a depth of their entire 8 mm coating or immersing them in the perfusate, followed by a 20-min extraction period for the analytes of interest. Dialyzed hearts demonstrated improved bioenergetics as evidenced by accelerated purine metabolism and less pronounced accumulation of intermediates of fatty acid β/ω-oxidation. Metabolic waste accumulation such as pro-inflammatory lipid mediators (e.g., leukotrienes) was mitigated thereby supporting the process of resolution of inflammation through excretion of specialized pro-resolving mediators (resolvins D1/D2, E2, protecin D1).
SIGNIFICANCE: Through implementing the unique analytical pipeline we demonstrated that the addition of dialysis may preserve cardiac metabolism allowing for prolonged ESHP. This strategy has the potential to facilitate high-risk donor organs\u27 reconditioning prior to transplantation