Molecular cluster, transmission characteristics, origin and dynamics analysis of HIV-1 CRF59_01B in China: A molecular epidemiology study.

PURPOSE: This study investigated for the HIV-1 CRF59_01B epidemic's spatiotemporal dynamics and its transmission networks in China. METHODS: Between 2007 and 2020, a total of 250 partial pol gene sequences of HIV-1 CRF59_01B were collected from four regions (10 Chinese provinces). Phylogenetic tree construction and cluster identification were then performed. The Bayesian skyline and birth-death susceptible-infected-removed models were employed for the phylodynamic analyses of subtypes and large clusters, respectively. Phylogenetic analyses and trait diffusion of these sequences were performed using Bayesian phylogenetic methods (beast-classic package). Distance-based molecular network analyses were performed to identify putative relationships. RESULTS: Using a genetic distance threshold of 1.3 %, We identified 45 clusters that included 62.40 % (156/250) of the sequences. Three clusters (6.67 %, 3/45) had 10 or more sequences, and were considered "large clusters". Six clusters (13.33 %) included sequences from different regions (Southeast, Northeast, Southeast, and Central China). Thirteen clusters (28.89 %) included sequences of men who had sex with men only, three clusters (6.67 %) included sequences of heterosexuals only, and 12 clusters (26.67 %) included sequences of both groups. The substitution rate of CRF59_01B was 1.91 × 10-3 substitutions per site per year [95 % highest posterior density (HPD) interval: 1.39 × 10-3-2.49 × 10-3)], the time to the most recent common ancestor of CRF59_01B was to be 1992.83 (95 % HPD: 1977.97-2002.81). A Bayesian skyline plot revealed that the effective population size of CRF59_01B increased from 2000 to 2015 and remained stable after 2015. The large clusters showed continuous growth from 2013 to 2020. Phylogeographic analysis showed that CRF59_01B B most likely originated in Southeast China, with a posterior probability of 97.44 %, and then spread to other regions. CONCLUSIONS: Our study revealed the temporal and geographical origins of HIV-1 CRF59_01B as well as the process of transmission among various regions and risk groups in China, which can help develop targeted HIV prevention strategies.

Impact of Awareness of Sexual Partners' HIV Serostatus on the HIV Acquisition among Men Who Have Sex with Men in Guangzhou, China: A Nested Case-Control Study.

This study aimed to investigate the impact of sexual partners' HIV serostatus awareness on the HIV acquisition among men who have sex with men (MSM) in Guangzhou, China. A nested case-control study was conducted based on a prospective cohort of MSM in Guangzhou. Within the cohort, individuals who underwent HIV seroconversion were identified as the case group, and each case was matched with four controls from the non-seroconverted participants. Information regarding the awareness of sexual partners' HIV serostatus over the preceding 6 months was gathered. Of the 161 participants, 36.0% were aware of the HIV serostatus of all their sexual partners. The practice of engaging in condomless anal sex with partners of unknown HIV serostatus and being aware of the HIV serostatus of only some casual partners were positively correlated with an elevated risk of acquiring HIV. Conversely, being fully aware of the HIV serostatus of all sexual partners, including regular ones, was associated with a diminished risk of HIV incidence. Regular communication with sexual partners regarding HIV testing outcomes, honest disclosure of one's own HIV serostatus, and refusal of sexual contact with partners of unknown HIV serostatus can potentially mitigate the risk of acquiring HIV among MSM.

Evolving molecular HIV clusters revealed genotype-specific dynamics in Guangzhou, China (2008-2020).

OBJECTIVES: This study investigated the genotype-specific dynamics of molecular HIV clusters (MHCs) in Guangzhou, China, aiming to enhance HIV control. METHODS: HIV pol sequences from people with HIV (PWH) in Guangzhou (2008-2020) were obtained for genotyping and molecular network creation. MHCs were identified and categorized into three types: emerging, growing, or stable. Clustering rates, proportions of cluster types, and members within each type were calculated and their trends were assessed using joinpoint regression. RESULTS: Among 8395 PWH, the most prevalent HIV-1 genotypes were CRF07_BC (39.7%) and CRF01_AE (32.6%). The genotype composition has been stable since 2012 (Ps > 0.05). The overall clustering rate was 43.3%, with significant variations across genotypes (P < 0.001), indicating genotype-specific transmission fitness. Significant declines in overall and genotype-specific clustering rates toward the end of 2020 (Ps < 0.05), potentially offer support for HIV control efforts in reducing local infections. The continuously increasing proportions of stable clusters and the gradually decreasing proportions of emerging and growing clusters (either Ps < 0.05 or Ps > 0.05) suggest a trend toward stable molecular network structure. However, growing clusters exhibited CRF55_01B, CRF07_BC, and CRF59_01B dominance that indicate their priority for interventions. CONCLUSION: The evolving MHCs highlight the genotype-specific cluster dynamics, providing fresh insights for enhanced prevention and control strategies.

The origin and spread of HIV-1 CRF59_01B epidemic in China: A molecular network and phylogeographic analysis.

Human immunodeficiency virus type 1 CRF59_01B, identified in China in 2013, has been detected nationwide, exhibiting notably high prevalence in Guangzhou and its vicinity. This study aimed to unravel its origin and migration. A data set was established, incorporating all available CRF59_01B pol gene sequences and their metadata from Guangzhou and the public database. Bayesian phylogeographic analysis demonstrated that CRF59_01B originated in Shenzhen, the neighboring city of Guangzhou, around 1998 with posterior probability of 0.937. Molecular network analysis detected 1131 transmission links and showed a remarkably high clustering rate (78.9%). Substantial inter-city transmissions (26.5%, 300/1131) were observed between Shenzhen and Guangzhou while inter-region transmissions linked Guangzhou with South (46) and Southwest (64) China. The centre of Guangzhou was the hub of CRF59_01B transmission, including the inflow from Shenzhen (3.57 events/year) and outflow to the outskirts of Guangzhou (>2 events/year). The large-scale analysis revealed significant migration from Shenzhen to Guangzhou (5.08 events/year) and North China (0.59 events/year), and spread from Guangzhou to Central (0.47 events/year), East (0.42 events/year), South (0.76 events/year), Southwest China (0.76 events/year) and Shenzhen (1.89 events/year). Shenzhen and Guangzhou served as the origin and the hub of CRF59_01B circulation, emphasizing inter-city cooperation and data sharing to confine its nationwide diffusion.

The ARK2N-CK2 complex initiates transcription-coupled repair through enhancing the interaction of CSB with lesion-stalled RNAPII.

Transcription is extremely important for cellular processes but can be hindered by RNA polymerase II (RNAPII) pausing and stalling. Cockayne syndrome protein B (CSB) promotes the progression of paused RNAPII or initiates transcription-coupled nucleotide excision repair (TC-NER) to remove stalled RNAPII. However, the specific mechanism by which CSB initiates TC-NER upon damage remains unclear. In this study, we identified the indispensable role of the ARK2N-CK2 complex in the CSB-mediated initiation of TC-NER. The ARK2N-CK2 complex is recruited to damage sites through CSB and then phosphorylates CSB. Phosphorylation of CSB enhances its binding to stalled RNAPII, prolonging the association of CSB with chromatin and promoting CSA-mediated ubiquitination of stalled RNAPII. Consistent with this finding, Ark2n-/- mice exhibit a phenotype resembling Cockayne syndrome. These findings shed light on the pivotal role of the ARK2N-CK2 complex in governing the fate of RNAPII through CSB, bridging a critical gap necessary for initiating TC-NER.

PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation.

Mutations in the BRCA2 tumor suppressor gene have been associated with an increased risk of developing prostate cancer. One of the paradoxes concerning BRCA2 is the fact that its inactivation affects genetic stability and is deleterious for cellular and organismal survival, while BRCA2-mutated cancer cells adapt to this detriment and malignantly proliferate. Therapeutic strategies for tumors arising from BRCA2 mutations may be discovered by understanding these adaptive mechanisms. In this study, we conducted forward genetic synthetic viability screenings in Caenorhabditis elegans brc-2 (Cebrc-2) mutants and found that Ceubxn-2 inactivation rescued the viability of Cebrc-2 mutants. Moreover, loss of NSFL1C, the mammalian ortholog of CeUBXN-2, suppressed the spindle assembly checkpoint (SAC) activation and promoted the survival of BRCA2-deficient cells. Mechanistically, NSFL1C recruited USP9X to inhibit the polyubiquitination of AURKB and reduce the removal of AURKB from the centromeres by VCP, which is essential for SAC activation. SAC inactivation is common in BRCA2-deficient prostate cancer patients, but PP2A inhibitors could reactivate the SAC and achieve BRCA2-deficient prostate tumor synthetic lethality. Our research reveals the survival adaptation mechanism of BRCA2-deficient prostate tumor cells and provides different angles for exploring synthetic lethal inhibitors in addition to targeting DNA damage repair pathways.

Development and utility of a close contact information management system for the COVID-19 pandemic.

BACKGROUND: Since the outbreak started in 2019, COVID-19 pandemic has a significant global impact. Due to the highly infective nature of SARS-CoV-2, the COVID-19 close contacts are at significant risk of contracting COVID-19. China's experience in successfully controlling COVID-19 emphasized the importance of managing close contacts because this strategy helps to limit potential infection sources, prevent the unconscious spread of COVID-19 and thus control this pandemic. As a result, to understand and consider the management of close contacts may be beneficial to other countries. However, managing close contacts is challenging owing to the huge number of close contacts and a lack of appropriate management tools and literature references. METHODS: A new system called the COVID-19 Close Contact Information Management System was developed. Here we introduced the design, use, improvement and achievements of this system. RESULTS: This system was designed from the standpoint of the Centers for Disease Control and Prevention in charge of managing close contacts. Two main functions and eight modules/themes were ultimately formed after two development stages. The system introduces what information need to be collected in the close contact management. Since the system allows information flow across cities, the geographical distance and administrative regional boundaries are no longer obstacles for managing close contacts, which promotes the management of each close contact. Moreover, when this system is used in conjunction with other data tools, it provides data assistance for understanding the COVID-19 characteristics and formulating targeted COVID-19 control policies. To date, the system has been widely used in Guangdong Province for over 1 year and has recorded tens of thousands of pieces of data. There is sufficient practical experience to suggest that the system is capable of meeting the professional work requirements for close contact management. CONCLUSIONS: This system provides a new way to manage close contacts and restrict the spread of COVID-19 by combining information technology with disease prevention and control strategies in the realm of public health. We hope that this system will serve as an example and guide for those anticipating similar work in other countries in response to current and future public health incidents.

The effect of cardiovascular disease and acute cardiac injury on fatal COVID-19: a meta-analysis.

BACKGROUND: With the continuance of the global COVID-19 pandemic, cardiovascular disease (CVD) and cardiac injury have been suggested to be risk factors for severe COVID-19. OBJECTIVE: The aim is to evaluate the mortality risks associated with CVD and cardiac injury among hospitalized COVID-19 patients, especially in subgroups of populations in different countries. METHODS: A comprehensive systematic literature search was performed using 9 databases from November 1, 2019 to November 9, 2020. Meta-analyses were performed for CVD and cardiac injury between non-survivors and survivors of COVID-19. RESULTS: Although the prevalence of CVD in different populations was different, hospitalized COVID-19 patients with CVD were at a higher risk of fatal outcomes (OR = 2.72; 95% CI 2.35-3.16) than those without CVD. Separate meta-analyses of populations in four different countries also reached a similar conclusion that CVD was associated with an increase in mortality. Cardiac injury was common among hospitalized COVID-19 patients. Patients with cardiac injury had a significantly higher mortality risk than those without cardiac injury (OR = 13.25; 95% CI: 8.56-20.52). CONCLUSIONS: Patients' CVD history and biomarkers of cardiac injury should be taken into consideration during the hospital stay and incorporated into the routine laboratory panel for COVID-19.