Transcription factor Dmrt1 triggers the SPRY1-NF-κB pathway to maintain testicular immune homeostasis and male fertility.

Bacterial or viral infections, such as Brucella, mumps virus, herpes simplex virus, and Zika virus, destroy immune homeostasis of the testes, leading to spermatogenesis disorder and infertility. Of note, recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells, leading to male reproductive dysfunction. Due to the many side effects associated with antibiotic therapy, finding alternative treatments for inflammatory injury remains critical. Here, we found that Dmrt1 plays an important role in regulating testicular immune homeostasis. Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed that Dmrt1 positively regulated the expression of Spry1, an inhibitory protein of the receptor tyrosine kinase (RTK) signaling pathway. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) analysis indicated that SPRY1 binds to nuclear factor kappa B1 (NF-κB1) to prevent nuclear translocation of p65, inhibit activation of NF-κB signaling, prevent excessive inflammatory reaction in the testis, and protect the integrity of the blood-testis barrier. In view of this newly identified Dmrt1- Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis, our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.

Ubiquitin C-terminal hydrolase L1 (UCHL1), a double-edged sword in mammalian oocyte maturation and spermatogenesis.

BACKGROUND: Recent studies have shown that ubiquitin-mediated cell apoptosis can modulate protein interaction and involve in the progress of oocyte maturation and spermatogenesis. As one of the key regulators involved in ubiquitin signal, ubiquitin C-terminal hydrolase L1 (UCHL1) is considered a molecular marker associated with spermatogonia stem cells. However, the function of UCHL1 was wildly reported to regulate various bioecological processes, such as Parkinson's disease, lung cancer, breast cancer and colon cancer, how UCHL1 affects the mammalian reproductive system remains an open question. METHODS: We identified papers through electronic searches of PubMed database from inception to July 2022. RESULTS: Here, we summarize the important function of UCHL1 in controlling mammalian oocyte development, regulating spermatogenesis and inhibiting polyspermy, and we posit the balance of UCHL1 was essential to maintaining reproductive cellular and tissue homeostasis. CONCLUSION: This study considers the 'double-edged sword' role of UCHL1 during gametogenesis and presents new insights into UCHL1 in germ cells.

Long-Term Changes of HIV/AIDS Incidence Rate in China and the U.S. Population From 1994 to 2019: A Join-Point and Age-Period-Cohort Analysis.

Although HIV caused one of the worst epidemics since the late twentieth century, China and the U.S. has made substantial progress to control the spread of HIV/AIDS. However, the trends of HIV/AIDS incidence remain unclear in both countries. Therefore, this study aimed to highlight the long-term trends of HIV/AIDS incidence by gender in China and the U.S. population. The data were retrieved from the Global Burden of Disease (GBD) database since it would be helpful to assess the impact/role of designed policies in the control of HIV/AIDS incidence in both countries. The age-period-cohort (APC) model and join-point regression analysis were employed to estimate the age-period-cohort effect and the average annual percentage change (AAPC) on HIV incidence. Between 1994 and 2019, we observed an oscillating trend of the age-standardized incidence rate (ASIR) in China and an increasing ASIR trend in the U.S. Despite the period effect in China declined for both genders after peaked in 2004, the age effect in China grew among the young (from 15-19 to 25-29) and the old age groups (from 65-69 to 75-79). Similarly, the cohort effect increased among those born in the early (from 1924-1928 to 1934-1938) and the latest birth groups (from 1979-1983 to 2004-2009). In the case of the U.S., the age effect declined after it peaked in the 25-29 age group. People born in recent birth groups had a higher cohort effect than those born in early groups. In both countries, women were less infected by HIV than men. Therefore, besides effective strategies and awareness essential to protect the young age groups from HIV risk factors, the Chinese government should pay attention to the elderly who lacked family support and were exposed to HIV risk factors.

Development of multivalent nanobodies blocking SARS-CoV-2 infection by targeting RBD of spike protein.

BACKGROUND: The outbreak and pandemic of coronavirus SARS-CoV-2 caused significant threaten to global public health and economic consequences. It is extremely urgent that global people must take actions to develop safe and effective preventions and therapeutics. Nanobodies, which are derived from single­chain camelid antibodies, had shown antiviral properties in various challenge viruses. In this study, multivalent nanobodies with high affinity blocking SARS-CoV-2 spike interaction with ACE2 protein were developed. RESULTS: Totally, four specific nanobodies against spike protein and its RBD domain were screened from a naïve VHH library. Among them, Nb91-hFc and Nb3-hFc demonstrated antiviral activity by neutralizing spike pseudotyped viruses in vitro. Subsequently, multivalent nanobodies were constructed to improve the neutralizing capacity. As a result, heterodimer nanobody Nb91-Nb3-hFc exhibited the strongest RBD-binding affinity and neutralizing ability against SARS-CoV-2 pseudoviruses with an IC50 value at approximately 1.54 nM. CONCLUSIONS: The present study indicated that naïve VHH library could be used as a potential resource for rapid acquisition and exploitation of antiviral nanobodies. Heterodimer nanobody Nb91-Nb3-hFc may serve as a potential therapeutic agent for the treatment of COVID-19.