Abstract Carboxypeptidase A4 (CPA4) is a member of the metallocarboxypeptidase family. Current studies have identified the roles of CPA4 in cancer biology and insulin sensitivity. However, the roles of CPA4 in other diseases are not known. In the present study, we investigated the roles of CPA4 in cardiac hypertrophy. The expression of CPA4 was significantly increased in the hypertrophic heart tissues of human patients and isoproterenol (ISO)-induced hypertrophic heart tissues of mice. We next knocked down Cpa4 with shRNA or overexpressed Cpa4 using adenovirus in neonatal rat cardiomyocytes and induced cardiomyocyte hypertrophy with ISO. We observed that Cpa4 overexpression promoted whereas Cpa4 knockdown reduced ISO-induced growth of cardiomyocyte size and overexpression of hypertrophy marker genes, such as myosin heavy chain β (β-Mhc), atrial natriuretic peptide (Anp), and brain natriuretic peptide (Bnp). Our further mechanism study revealed that the mammalian target of rapamycin (mTOR) signaling was activated by Cpa4 in cardiomyocytes, which depended on the phosphoinositide 3-kinase (PI3K)-AKT signaling. Besides, we showed that the PI3K-AKT-mTOR signaling was critically involved in the roles of Cpa4 during cardiomyocyte hypertrophy. Collectively, these results demonstrated that CPA4 is a regulator of cardiac hypertrophy by activating the PI3K-AKT-mTOR signaling, and CPA4 may serve as a promising target for the treatment of hypertrophic cardiac diseases.
Abstract With the aging of the global population, older people living with HIV (OPLWH) have emerged as a focal point in HIV/AIDS research. Although antiretroviral therapy has demonstrated positive effects in OPLWH, concerns persist regarding overall poor immune reconstitution and elevated rates of age-related comorbidities, such as cardiovascular disease, bone disease, and cognitive impairment. This review aims to elucidate the mechanisms underlying immunosenescence and the interaction of immunosenescence with HIV infection, further exploring its role in the pathogenesis of HIV infection during aging. Aging-induced involution of the immune system, along with chronic inflammation and infection, can induce immunosenescence, leading to immune dysfunction that impairs the effective control of HIV infection. In addition, HIV infection induces immunosenescence through persistent inflammation and immune activation, even under treatment. The combined effects of aging and HIV infection accelerate the progression of immunosenescence in OPLWH, increasing their susceptibility to multiple age-related diseases. The unfavorable prognosis observed among OPLWH is largely attributed to increased levels of immunosenescence. A comprehensive understanding of the relationship between immunosenescence and HIV infection is crucial for developing targeted therapeutic strategies for this vulnerable population.
As the initial stage for children to receive knowledge systematically, pre-school education not only affects the quality of family life and happiness index, but also is an important indicator to measure the level of urban education development. Kindergarten is the main facility carrier of pre-school education. This study uses population census data and kindergarten degree and other multi-source data, based on the street scale, presents a systematic analysis of the spatial distribution of kindergarten, the relationship between the supply and demand of educational resources, accessibility, fairness in 51 streets in the central city of Lanzhou. The research is of great significance for optimizing the spatial distribution of preschool resources and adjusting the supply and equitable allocation of street-scale preschool resources. The results show that: 1) the spatial distribution of kindergartens is relatively uniform, showing the characteristics of ‘one core, four centres’ and east-west belt-shaped distribution. 2) The spatial distribution of school-age children roughly coincides with kindergartens, the overall mismatch between the supply of kindergarten places and the demand for the number of school-age children. with 13 streets are under supply of pre-school education resources and 38 streets are oversupply of pre-school education resources. 3) Within 300m, the number of streets with accessibility index of 0 accounted for 84.31%, and within 500m, the number of streets with accessibility index of 0 accounted for 58.82%. Along with the expansion of the search distance, the opportunity of enrolment increases, and the value of accessibility increases as well. 4) Lanzhou City preschool education resources in the range of 300-500m show inter-district overall equity and intra-district local imbalance, and in the range of 1000-1500m show inter-district overall imbalance and intra-district local equity. Finally, due to the limitations of data sources and precision, we have only discussed the allocation of preschool education resources at the street scale, and we have not been able to further analyses the differences in the access to preschool education resources, opportunities for enrolment in kindergartens, and the quality of education enjoyed by children of families from different strata at the residential scale. In the future, we will combine family income and other socio-economic factors to study social stratification and equal opportunities in preschool education resources, with a view to providing reference for strengthening the rational spatial distribution and coordinated development of preschool education resources in Lanzhou City.
Abstract Although antiretroviral therapy (ART) can reduce the viral load in the plasma to undetectable levels in human immunodeficiency virus (HIV)-infected individuals, ART alone cannot completely eliminate HIV due to its integration into the host cell genome to form viral reservoirs. To achieve a functional cure for HIV infection, numerous preclinical and clinical studies are underway to develop innovative immunotherapies to eliminate HIV reservoirs in the absence of ART. Early studies have tested adoptive T-cell therapies in HIV-infected individuals, but their effectiveness was limited. In recent years, with the technological progress and great success of chimeric antigen receptor (CAR) therapy in the treatment of hematological malignancies, CAR therapy has gradually shown its advantages in the field of HIV infection. Many studies have identified a variety of HIV-specific CAR structures and types of cytolytic effector cells. Therefore, CAR therapy may be beneficial for enhancing HIV immunity, achieving HIV control, and eliminating HIV reservoirs, gradually becoming a promising strategy for achieving a functional HIV cure. In this review, we provide an overview of the design of anti-HIV CAR proteins, the cell types of anti-HIV CAR (including CAR T cells, CAR natural killer cells, and CAR-encoding hematopoietic stem/progenitor cells), the clinical application of CAR therapy in HIV infection, and the prospects and challenges in anti-HIV CAR therapy for maintaining viral suppression and eliminating HIV reservoirs.
HIV-1/Treponema pallidum (T. pallidum) coinfection has become a global challenge, and three monocyte subsets express varying levels of the chemokine receptors CCR2 and CX3CR1. We recently evaluated the association between monocyte subsets and regulatory T cells in HIV-infected individuals with syphilis. Currently, the dynamic changes of CCR2 and CX3CR1 on monocyte subsets during HIV-1 and syphilis coinfection have not been fully investigated. In this study, cell surface staining was used to explore CCR2 and CX3CR1 expression on three monocyte subsets during HIV-1/T. pallidum coinfection. We found that CCR2 densities on the classical monocyte subsets decreased in acute HIV-1 infected (AHI) patients, chronic HIV-1-infected individuals without antiviral therapy (ART) (CHI+ART-), chronic HIV-1-infected individuals receiving ART (CHI+ART+), rapid plasma reagin-positive (RPR+) individuals, CHI+ART- plus RPR+ (CHI+RPR+ART-) individuals, and CHI+ART+ plus RPR+ (CHI+RPR+ART+) individuals. CX3CR1 density increased on the three monocyte subsets during HIV-1 and/or T. pallidum infection. CX3CR1 density on the intermediate and nonclassical monocyte subsets in CHI+ART- individuals was lower than that in CHI+ART+ individuals, and CX3CR1 density on the three monocyte subsets in CHI+ART+ individuals was higher than that in CHI+RPR+ART+ individuals. Our data provide new insight into the roles of CCR2 and CX3CR1 on three monocyte subsets in HIV-1 and T. pallidum pathogenesis.
Objective: To estimate 18~60 year-old adults’ demand for hepatitis B vaccine in the rural area of China.Methods: 17 071 individuals between 18 and 60 were selected from 35 villages in 6 provinces.Questionnaire survey about vaccination was conducted.Nested logit model was employed to analyze the data.Results: Among the alternatives variables,distance and fee have significant influences on the demand for hepatitis B vaccine.Individual level characters,age,education,occupation,income and knowledge of HBV have significant influence on the demand.Conclusions: Improving accessibility and knowledge level of HBV could increase the demand for hepatitis B vaccine.
F-box and WD repeat domain–containing 7 (FBXW7) is an E3-ubiquitin ligase, which serves as one of the components of the SKP1, CUL1, and F-box protein type ubiquitin ligase (SCF) complex. Previous studies reveal that FBXW7 participates in cancer, inflammation and Parkinson's disease. FBXW7 also contributes to angiogenesis of endothelial cells. However, the function of FBXW7 in cardiac homeostasis remains to elucidate. Here we identified the critical role of FBXW7 during cardiac hypertrophy in humans and rodents. Quantitative real-time PCR (qRT-PCR) and Western blot revealed that the mRNA and protein levels of FBXW7 were upregulated significantly in hypertrophic hearts in human and mouse as well as Angiotensin II (Ang II)-induced hypertrophic neonatal rat cardiomyocytes (NRCM). Gain-of-function (adenovirus) and loss-of-function (siRNA) experiments provided evidence that FBXW7 promoted Ang II-induced cardiomyocyte hypertrophy as demonstrated by the increase in the size of cardiomyocytes and overexpression of hypertrophic fetal genes myosin heavy chain 7 (Myh7) natriuretic peptide a (Nppa), brain natriuretic peptide (Nppb). Further mechanism study revealed that FBXW7 promoted the expression of sine oculis homeobox homolog 1 (SIX1) in cardiomyocytes, which relied on regulation of the stability of the histone methyltransferase EZH2 (Enhancer of zeste homolog 2). Previous work revealed the pro-hypertrophic role of the EZH2-SIX1 axis in rodents. Indeed, our genetic and pharmacological evidence showed that the EZH2-SIX1 signaling was critically involved in FBXW7 functions in Ang II-induced cardiomyocyte hypertrophy. Therefore, we identified FBWX7 as an important regulator of cardiac hypertrophy via modulating the EZH2-SIX1 axis.
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