Cardiac aging constitutes a significant risk factor for cardiovascular diseases prevalent among the elderly population. Urgent attention is required to prioritize preventive and management strategies for age-related cardiovascular conditions to safeguard the well-being of elderly individuals. In response to this critical challenge, the Aging Biomarker Consortium (ABC) of China has formulated an expert consensus on cardiac aging biomarkers. This consensus draws upon the latest scientific literature and clinical expertise to provide a comprehensive assessment of biomarkers associated with cardiac aging. Furthermore, it presents a standardized methodology for characterizing biomarkers across three dimensions: functional, structural, and humoral. The functional dimension encompasses a broad spectrum of markers that reflect diastolic and systolic functions, sinus node pacing, neuroendocrine secretion, coronary micro-circulation, and cardiac metabolism. The structural domain emphasizes imaging markers relevant to concentric cardiac remodeling, coronary artery calcification, and epicardial fat deposition. The humoral aspect underscores various systemic (N) and heart-specific (X) markers, including endocrine hormones, cytokines, and other plasma metabolites. The ABC’s primary objective is to establish a robust foundation for assessing cardiac aging, thereby furnishing a dependable reference for clinical applications and future research endeavors. This aims to contribute significantly to the enhancement of cardiovascular health and overall well-being among elderly individuals.
Sterile alpha and Toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is regarded as a key protein and a central executor of the self-destruction of injured axons. To identify novel molecular players and understand the mechanisms regulating SARM1 function, we investigated the interactome of SARM1 by proximity labeling and proteomic profiling. Among the SARM1-associated proteins, we uncovered that overexpression (OE) of ubiquitin-specific peptidase 13 (USP13) delayed injury-induced axon degeneration. OE of an enzyme-dead USP13 failed to protect injured axons, indicating that the deubiquitinase activity of USP13 was required for its axonal protective effect. Further investigation revealed that USP13 deubiquitinated SARM1, which increased the inhibitory interaction between the N-terminal armadillo repeat motif (ARM) and C-terminal Toll/interleukin-1 receptor (TIR) domains of the SARM1 protein, thereby suppressing SARM1 activation in axon injury. Collectively, these findings suggest that increase of USP13 activity enhances the self-inhibition of SARM1, which may provide a strategy to mitigate axon degeneration in injury and disease.
Synaptic vesicle (SV) exocytosis is orchestrated by protein machineries consisting of the SNARE complex, Ca2+ sensors, and their partners. Secretagogin (SCGN) is a Ca2+-binding protein involved in multiple forms of vesicle secretion. Although SCGN is implicated in multiple neurological disorders, its role in SV exocytosis in neurons remains unknown. Here, using knockout and knockdown techniques, we report that SCGN could regulate the asynchronous and spontaneous forms of excitatory but not inhibitory SV exocytosis in mouse hippocampal neurons. Furthermore, SCGN functioned in glutamate release via directly interacting with Doc2α, a high-affinity Ca2+ sensor specific for asynchronous and spontaneous SV exocytosis. Conversely, the interaction with SCGN is also required for Doc2α to execute its Ca2+ sensor function in SV release. Together, our study revealed that SCGN plays an important role in asynchronous and spontaneous glutamate release through its interaction with Doc2α.
DNA double-strand breaks (DSBs) induced by gene-editing tools are primarily repaired through non-homologous end joining (NHEJ) or homology-directed repair (HDR) using synthetic DNA templates. However, error-prone NHEJ may result in unexpected indels at the targeted site. For most genetic disorders, precise HDR correction using exogenous homologous sequence is ideal. But, the therapeutic application of HDR might be especially challenging given the requirement for the codelivery of exogenous DNA templates with toxicity into cells, and the low efficiency of HDR could also limit its clinical application. In this study, we efficiently repair pathogenic mutations in HBB coding regions of hematopoietic stem cells (HSCs) using CRISPR/Cas9-mediated gene conversion (CRISPR/GC) using the paralog gene HBD as the internal template. After transplantation, these edited HSCs successfully repopulate the hematopoietic system and generate erythroid cells with significantly reduced thalassemia propensity. Moreover, a range of pathogenic gene mutations causing β-thalassemia in HBB coding regions were effectively converted to normal wild-type sequences without exogenous DNA templates using CRISPR/GC. This highlights the promising potential of CRISPR/GC, independent of synthetic DNA templates, for genetic disease gene therapy.
Vitamin C is used to treat anaemia; however, the mechanism through which vitamin C promotes erythroid differentiation is not comprehensively understood. The in vitro erythroid differentiation induction system can reveal the differentiation mechanism and provide erythrocytes for clinical transfusion and anaemia treatment. This process can be promoted by adding small-molecule compounds. In this study, we added L-ascorbic acid 2-phosphate sesquimagnesium salt hydrate (AA2P), a derivative of vitamin C, to an erythroid differentiation system induced from umbilical cord blood haematopoietic stem and progenitor cells in vitro and detected its effect on erythroid differentiation using single-cell transcription sequencing technology combined with non-targeted metabolism detection. AA2P increased the proportion of late basophilic erythroblasts, upregulating the expression of erythroid-related regulatory molecules GATA1, KLF1, ALAS2, and the globins HBG and HBB. CA1 is a target gene of AA2P, and CA1 knockdown affected the expression of globin-related genes. AA2P also increased glycolysis and decreased oxidative phosphorylation to facilitate terminal erythroid differentiation and enhanced the proliferation of early erythroid progenitors by altering the cell cycle. These results provide a reliable basis for using vitamin C to improve the efficiency of erythropoiesis in vitro and for the clinical treatment of anaemia.