Taming AID mutator activity in somatic hypermutation.

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) by introducing base substitutions into antibody genes, a process enabling antibody affinity maturation in immune response. How a mutator is tamed to precisely and safely generate programmed DNA lesions in a physiological process remains unsettled, as its dysregulation drives lymphomagenesis. Recent research has revealed several hidden features of AID-initiated mutagenesis: preferential activity on flexible DNA substrates, restrained activity within chromatin loop domains, unique DNA repair factors to differentially decode AID-caused lesions, and diverse consequences of aberrant deamination. Here, we depict the multifaceted regulation of AID activity with a focus on emerging concepts/factors and discuss their implications for the design of base editors (BEs) that install somatic mutations to correct deleterious genomic variants.

Comprehensive evaluation of inactivated SARS-CoV-2 vaccination on sperm parameters and sex hormones.

Background: The inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine has made significant contributions to fighting the epidemic in the past three years. However, the rapid development and application raised concerns about its safety in reproductive health, especially after several studies had observed a decrease in semen parameters following two doses of mRNA SARS-CoV-2 vaccination. Thus, it is necessary to comprehensively evaluate the effect of inactivated SARS-CoV-2 vaccine on male fertility. Methods: A retrospective cohort study was conducted in the Center for Reproductive Medicine of the Affiliated Hospital of Jining Medical University between July 2021 and March 2023. A total of 409 men with different vaccination status and no history of SARS-CoV-2 infection were included in this study. Their sex hormone levels and semen parameters were evaluated and compared separately. Results: The levels of FSH and PRL in one-dose vaccinated group were higher than other groups, while there were no significant changes in other sex hormone levels between the control and inactivated SARS-CoV-2 vaccinated groups. Most semen parameters such as volume, sperm concentration, total sperm count, progressive motility and normal forms were similar before and after vaccination with any single dose or combination of doses (all P > 0.05). Nevertheless, the total motility was significantly decreased after receiving the 1 + 2 doses of vaccine compared to before vaccination (46.90 ± 2.40% vs. 58.62 ± 2.51%; P = 0.001). Fortunately, this parameter was still within the normal range. Conclusion: Our study demonstrated that any single dose or different combined doses of inactivated SARS-CoV-2 vaccination was not detrimental to male fertility. This information could reassure men who want to conceive after vaccination and be incorporated into future fertility recommendations.

Effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus (COVID-19) vaccination on male fertility.

Coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global public health challenge. This disease causes damage not only to the respiratory system, affecting the normal physiological function of the lungs, but also to other vital organs, such as the heart and testicles. Existing studies have shown that co-expression of angiotensin-converting enzyme 2 and transmembrane serine protease 2 is the main mechanism by which SARS-CoV-2 invades host cells. Angiotensin-converting enzyme 2-expressing cells are widespread in the corpus cavernosum, reproductive tract and testis of men, which has raised concerns. Furthermore, abnormal sex hormone levels and decreased semen parameters were observed in coronavirus disease 2019 patients. This study comprehensively assessed the effects of SARS-CoV-2 infection on the testis, semen parameters, sex hormone levels and erectile function, and discussed possible transmission routes during sexual intercourse and the effect of vaccination on male fertility.

C-to-G editing generates double-strand breaks causing deletion, transversion and translocation.

Base editors (BEs) introduce base substitutions without double-strand DNA cleavage. Besides precise substitutions, BEs generate low-frequency 'stochastic' byproducts through unclear mechanisms. Here, we performed in-depth outcome profiling and genetic dissection, revealing that C-to-G BEs (CGBEs) generate substantial amounts of intermediate double-strand breaks (DSBs), which are at the centre of several byproducts. Imperfect DSB end-joining leads to small deletions via end-resection, templated insertions or aberrant transversions during end fill-in. Chromosomal translocations were detected between the editing target and off-targets of Cas9/deaminase origin. Genetic screenings of DNA repair factors disclosed a central role of abasic site processing in DSB formation. Shielding of abasic sites by the suicide enzyme HMCES reduced CGBE-initiated DSBs, providing an effective way to minimize DSB-triggered events without affecting substitutions. This work demonstrates that CGBEs can initiate deleterious intermediate DSBs and therefore require careful consideration for therapeutic applications, and that HMCES-aided CGBEs hold promise as safer tools.

Vaccine inequity-induced COVID-19 dilemma: Time to sober up.

OBJECTIVE: The aim of the study was to discuss the catastrophic consequences of inequitable vaccine distribution and analyze the main challenges to address it, helping to guide efforts to address inequities in vaccine coverage. METHODS: All published papers written in English were searched through PubMed, Web of Science, and Google Scholar with the combination of relevant terms of COVID-19 vaccine inequity. RESULTS: In this paper, we first outlined the scope of inequitable vaccine distribution and identify its truly catastrophic consequences. Next, from the perspectives of political will, free markets, and profit-driven enterprises based on patent and intellectual property protection, we analyzed in depth the root causes of why this phenomenon is so difficult to combat. In addition, some specific and crucial solutions that should be undertaken in the long term were also put forward in order to provide a useful reference for the authorities, stakeholders, and researchers involved in addressing this worldwide crisis and the next one. CONCLUSIONS: Achieving COVID-19 vaccine equity faces funding gaps, vaccine nationalism, and barriers to access to intellectual property and technology. Thus, the scope of global vaccine inequity is immense, and its repercussions will continue to be felt worldwide, especially among the world's most vulnerable residents, both adults and children. Beyond fundamental issues, the growing vaccine hesitancy and unreliable distribution in low-income countries must be addressed.

Reflections on the dynamic zero-COVID policy in China.

The coronavirus disease 2019 (COVID-19) pandemic has posed a serious threat to global healthcare and economy. In order to curb its spread, China adopted the dynamic zero-COVID policy, aiming to diagnose and isolate cases and close contacts as soon as possible. However, there is a controversy about the impact of isolation measures on social order, including the economy, personal employment and public mental health. Therefore, this review discusses and analyzes in detail the advantages and challenges of implementing dynamic zero-COVID policy. Although this public health policy might cause a shock to the economy in the short term, China still achieved a continued healthy economic performance with stable unemployment and strong export growth. Moreover, the rates of infection and mortality in China were lower than those in the United States and the European Union. However, due to the high transmissibility and low pathogenicity of the Omicron variant and prolonged lockdown-induced psychological damage, people questioned the effectiveness and necessity of this policy. Now that China has adjusted its policy in a timely manner, but many problems still remain unsolved. Some practical suggestions in terms of mental health, vaccine development, drugs supply, and economic recovery are put forward at the end of our paper to minimize negative impacts and provide a reference for future efforts.

Trinickia dinghuensis sp. nov. and Trinickia fusca sp. nov., isolated from forest soil.

Two Gram-stain-negative, aerobic, non-spore forming and rod-shaped bacterial strains, designated DHOM06T and 7MK8-2T, were isolated from forest soil sampled at Dinghushan Biosphere Reserve, Guangdong Province, PR China. Strain DHOM06T grew at 12-37 °C (optimum, 28-33 °C), pH 4.5-7.5 (pH 5.5) and in the presence of 0-0.5 % NaCl (w/v); while strain 7MK8-2T grew at 12-42 °C (28-33 °C), pH 4.0-8.5 (pH 4.5-5.5) and in the presence of 0-1.0 % NaCl (w/v). Strains DHOM06T and 7MK8-2T each has a 16S rRNA gene sequence similarity of 97.1-98.9 % as well as 97.4-97.9 % to Trinickia strains, respectively. In the 16S rRNA gene sequence phylogram, both strains and all five currently described Trinickia species formed a clade but they were all distinct from each other. The average nucleotide identity and digital DNA-DNA hybridization values for strains DHOM06T and 7MK8-2T and all Trinickia species were in the range of 77.4-82.6 % and 21.7-26.2 %, respectively. The DNA G+C content of DHOM06T and 7MK8-2T was 63.2 and 63.5 mol%, respectively, based on total genome calculations. These two strains contained ubiquinone 8 as the major respiratory quinone and C16 : 0, C17 : 0cyclo, C19 : 0cyclo ω8c, summed feature 3 (C16 : 1ω7c/C16 : 1ω6c) and summed feature 8 (C18 : 1ω7c/C18 : 1ω6c) as the major cellular fatty acids. The major polar lipids of DHOM06T and 7MK8-2T were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. On the basis of phenotypic, chemotaxonomic, phylogenetic and genomic analysis data, strains DHOM06T and 7MK8-2T represent two novel species of the genus Trinickia, for which the names Trinickia dinghuensis sp. nov. (type strain DHOM06T=GDMCC 1.1280T=LMG 30259T) and Trinickia fusca sp. nov. (type strain 7MK8-2T=GDMCC 1.1449T=KCTC 62469T) are proposed.