ABSTRACT
Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.
Subject(s)
Mice , Animals , Transcriptome , Aging/metabolism , Cochlea , Stria Vascularis , PresbycusisABSTRACT
Under the background of " Internet+ medical treatment" and the continuous deepening of face recognition technology research, the face recognition industry has continued to mature, and face recognition has been initially applied in medical fields such as hospital management, auxiliary medical care, and epidemic prevention and control. At the same time, face recognition technology brings problems including error risk, technical cracking risk, privacy risk, equality risk, abuse risk, and other issues in practice, which seriously threaten the personal and property rights and interests of the public. On the basis of summarizing the specific application direction of face recognition technology in hospitals, the authors sorted out the legal regulation of face recognition in China, and proposed that it should be based on technology research and development, strengthen the " gatekeeper" responsibility of medical institutions, improve legal system and recommendations for strengthening judicial leadership in order to improve the legal regulations of face recognition technology, reduce the risk of infringement by medical institutions in the application of face recognition technology, and protect the legitimate rights and interests of citizens.
ABSTRACT
The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.
ABSTRACT
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-κB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient's iPSCs. Importantly, the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.
ABSTRACT
RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem cells. Altogether, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.
ABSTRACT
Objective To study the percentage of HBV specific CD3 + T cells in the peripheral blood of chronic hepatitis B patients. Methods HLA A 2 patients were screened by MHC:Ig dimer reagent. HLA A 2 restricted HBV core, polymerase, and surface peptides were added to T cells of chronic hepatitis B patients, followed by double staining with anti CD3 antibodies and antibodies reactive with the heavy chain of Ig. FACS was used for monitoring HBV specific T cell percentage. Results 23/54 (42.6%) patients belonged to HLA A 2. Fifteen of them were reacted with HBV peptides. CD3 + T cells of five patients showed higher percentage of binding with the HBV peptides than that in the controls. Four patients showed CD3 + T cells binding with S peptide, one with P peptide and one binding with both S and P peptide. Conclusions The percentage of T cells which could bind with HBV peptide was low in chronic hepatitis B and the binding efficiency was low as well. The MHC:Ig dimer reagent is convenient for counting the number of HBV specific T cells, but the nonspecific staining background seems to be relatively high. However, this technology is useful to monitor changes of immune responses in chronic hepatitis B patients during immuno therapy.