The Role of Ubiquitination and the E3 Ligase Nedd4 in Regulating Corneal Epithelial Wound Healing.

Purpose: Ubiquitination serves as a fundamental post-translational modification in numerous cellular events. Yet, its role in regulating corneal epithelial wound healing (CEWH) remains elusive. This study endeavored to determine the function and mechanism of ubiquitination in CEWH. Methods: Western blot and immunoprecipitation were used to discern ubiquitination alterations during CEWH in mice. Interventions, including neuronally expressed developmentally downregulated 4 (Nedd4) siRNA and proteasome/lysosome inhibitor, assessed their impact on CEWH. In vitro analyses, such as the scratch wound assay, MTS assay, and EdU staining, were conducted to gauge cell migration and proliferation in human corneal epithelial cells (HCECs). Moreover, transfection of miR-30/200 coupled with a luciferase activity assay ascertained their regulatory mechanism on Nedd4. Results: Global ubiquitination levels were markedly increased during the mouse CEWH. Importantly, the application of either proteasomal or lysosomal inhibitors notably impeded the healing process both in vivo and in vitro. Furthermore, Nedd4 was identified as an essential E3 ligase for CEWH. Nedd4 expression was significantly upregulated during CEWH. In vivo studies revealed that downregulation of Nedd4 substantially delayed CEWH, whereas further investigations underscored its role in regulating cell proliferation and migration, through the Stat3 pathway by targeting phosphatase and tensin homolog (PTEN). Notably, our findings pinpointed miR-30/200 family members as direct regulators of Nedd4. Conclusions: Ubiquitination holds pivotal significance in orchestrating CEWH. The critical E3 ligase Nedd4, under the regulatory purview of miR-30 and miR-200, facilitates CEWH through PTEN-mediated Stat3 signaling. This revelation sheds light on a prospective therapeutic target within the realm of CEWH.

Molecular genetic characterization analysis of a novel HIV-1 circulating recombinant form (CRF156_0755) in Guangdong, China.

Introduction: The characteristic of human immunodeficiency virus type 1 (HIV-1) is its susceptibility to erroneous replication and recombination, which plays a crucial role in the diverse and dynamic variation of HIV-1. The spread of different subtypes in the same population often leads to the emergence of circulating recombination forms (CRFs). At present, the main recombinant subtypes of HIV-1 in China are CRF07_BC, CRF01_AE, CRF08_BC and B' subtypes, while CRF55_01B has become the fifth major epidemic strain in China after rapid growth in recent years since it was first reported in 2013. In this study, we obtained five nearly full-length genomes (NFLGs) and one half-length genome from five different cities in Guangdong. Here, we focused on analyzing their characteristics, parental origin and drug resistance. Methods: Plasma samples were collected from six HIV-1 infected patients in Guangdong Province who had no epidemiological association with each other. The NFLGs of HIV-1 were amplified in two overlapping segments by the near-terminal dilution method. The positive products were sequenced directly to obtain genomic sequences. The recombinant patterns and breakpoints of the NFLGs were determined using the Simplot software and confirmed by the maximum likelihood trees for segments using the IQ-TREE and BEAST software. The genotypic resistance profiles of the protease reverse transcriptase and integrase were resolved by the Stanford HIV drug resistance database. Results: The six genomes shared highly similar recombinant pattern, with the CRF55_01B backbone substituted by CRF07_BC segments, therefore assigned as CRF156_0755. The evolutionary analysis of the segments showed that CRF07_BC segments were not clustered with the Chinese MSM variants in the CRF07_BC lineage. All the five NFLGs were identified with the non-nucleoside reverse-transcription inhibitors (NNRTIs) resistance mutation V179E. Discussion: With the accumulation and evolution of recombination between CRF55_01B and CRF 07_BC, the prevalence of more recombinant strains of CRF55_01B and CRF 07_BC may occur. Therefore, it is necessary to strengthen the identification and monitoring of the recombination of CRF55_01B and CRF 07_BC.

Identification of a novel HIV-1 third-generation circulating recombinant form (CRF126_0755) in Guangdong, China.

The genetic recombination patterns and genetic distribution of HIV-1 are valuable for elucidating the epidemic and genetic diversity of HIV. Numerous HIV-1 circulating recombinant forms (CRFs) have recently emerged and disseminated rapidly. In China, at least 32 CRFs have been reported to account for more than 80% of all HIV infections. However, CRFs derived from the CRF07_BC and CRF55_01B lineages have never been recorded. Here, a novel third-generation CRF involving HIV-1 was identified in four HIV-1-infected patients in Guangdong, China, who had no epidemiological association with each other. Phylogenetic and recombinant analyses confirmed that these strains shared highly similar recombination patterns, with the CRF07_BC backbone substituted by a CRF55_01B segment; therefore, these strains were classified as CRF126_0755. This is the first study of a CRF derived from CRF07_BC and CRF55_01B. Bayesian phylogenetic inference suggested that CRF126_0755 originated in approximately 2005-2007. The present findings reveal that the genotype composition of HIV-1 has become more complex than that of other viruses and highlight the urgent need for continuous molecular screening and epidemic surveillance within HIV-1-infected populations to advance our understanding of viral transmission mechanisms.

Factors associated with immunological non-response after ART initiation: a retrospective observational cohort study.

BACKGROUND: Among people living with HIV (PLHIV) on antiretroviral therapy (ART), the mortality of immunological non-responders (INRs) is higher than that of immunological responders (IRs). However, factors associated with immunological non-response following ART are not well documented. METHODS: We obtained data for HIV patients from the National Free Antiretroviral Treatment Program database in China. Patients were grouped into IRs (CD4 cell count ≥ 350 cells/µl after 24 months' treatment), immunological incomplete responders (ICRs) (200-350 cells/µl) and INRs (< 200 cells/µl). Multivariable logistic regression was used to assess factors associated with immunological non-response. RESULTS: A total of 3900 PLHIV were included, among whom 2309 (59.2%) were IRs, 1206 (30.9%) ICRs and 385 (9.9%) INRs. In multivariable analysis, immunological non-response was associated with being male (2.07, 1.39-3.09), older age [40-49 years (vs. 18-29 years): 2.05, 1.29-3.25; 50-59 years: 4.04, 2.33-7.00; ≥ 60 years: 5.51, 2.84-10.67], HBV co-infection (1.63, 1.14-2.34), HCV co-infection (2.01, 1.01-4.02), lower CD4 + T cell count [50-200 cells/µl (vs. 200-350 cells/µl): 40.20, 16.83-96.01; < 50 cells/µl: 215.67, 85.62-543.26] and lower CD4/CD8 ratio (2.93, 1.98-4.34) at baseline. Compared with patients treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) based regimens, those receiving protease inhibitors (PIs) based regimens were less likely to be INRs (0.47, 0.26-0.82). CONCLUSIONS: We found a sizable immunological non-response rate among HIV-infected patients. Being male, older age, coinfection with HBV and HCV, lower CD4 + T cell count and lower CD4/CD8 ratio are risk factors of immunological non-response, whereas PIs-based regimens is a protective factor.

Genetic characteristics of a novel HIV-1 circulating recombinant form (CRF128_07B) identified among MSM in Guangdong Province, China.

OBJECTIVE: To obtain and investigate the genetic characteristics of four HIV-1 near full-length genome sequences (NFLGs), aiming at a description of a novel circulating recombinant form (CRF) in Guangdong China. METHODS: Plasma samples were collected from HIV-1 infected MSM patients in Guangdong Province who had no epidemiological association with each other. The NFLGs were amplified with two overlapping halves and phylogenetic analyses were performed using Mega V11.0.1. Recombination analyses were comprehensively screened with the jpHMM, RIP, and BootScan analyses. Finally, the Bayesian phylogenetic analyses were performed using Beast V1.10.4 to estimate the origin time. RESULTS: Phylogenetic analyses revealed the four NFLGs formed a distinct monophyletic cluster distinguished from other known subtypes in the Neighbor-joining tree. Recombinant analyses revealed they shared a highly similar recombinant pattern, with the CRF07_BC backbone substituted by three subtype B segments. Subregion phylogenetic analyses confirmed them to be a novel CRF composed of CRF07_BC and subtype B, therefore, designed as CRF128_07B. According to the Bayesian phylogenetic analyses, CRF128_07B was inferred to approximately originated around 2005-2006. CONCLUSIONS: These findings described a novel HIV-1 CRF identified from MSM in Guangdong Province. This is the first detection of a CRF comprising CRF07_BC and subtype B. The present finding highlights the urgent need for continuous molecular screening and the epidemic surveillance within the MSM populations.

Drug Resistance Profile Among HIV-1 Infections Experiencing ART with Low-Level Viral Load in Guangdong China During 2011-2022: A Retrospective Study.

Background: Antiretroviral therapy (ART) efficiently reduces the morbidities and mortalities caused by HIV-1 infection and prevents the HIV epidemic. However, virologic failure (VF) occurs in some patients receiving ART experience, especially increases in those patients with intermittent or persistent low-level viremia (LLV). The presence of drug resistance mutations (DRMs) in LLV was a strong predictor of subsequent VF. The data on drug resistance (DR) or DRMs for HIV-1 infections at low-level viral load (LLVL) are limited in China. Objective: To monitor the prevalence of HIV-1 drug resistance and to evaluate the risk factors associated with drug resistance in LLVL HIV-1 infections during ART in Guangdong, China. Methods: Plasma samples with LLVL during ART in Guangdong Province between Jan 2011 and Dec 2022 were subjected to a modified reverse-transcription PCR with a pre-step of virus concentration by ultracentrifugation before extraction and the Sanger sequencing. Then, the genotypic resistance test was performed and DR was analyzed by the Stanford HIVDB program. Finally, DR-associated factors were identified by logistic regression analysis. Results: We found that CRF01_AE (53.57%) and CRF07_BC (25.07%) were the dominant HIV-1 genotypes in LLVL in Guangdong between 2011 and 2022 but that the percentage of CRF01_AE showed a trend of decrease over time. M46 (1.49%), M184 (30.91%), and K103 (21.46%) were the dominant PI-, NRTI-, and NNRTI-associated mutations, respectively. The total DR rate was 47.06%. Specifically, PI (3.71%) showed a significantly lower DR rate than NNRTI (40.74%) and NRTI (34.14%). Duration of ART, initial ART regimen, ethnicity, and WHO clinical stages were associated with DR. Conclusion: The drug resistance rate among the LLVL during ART in Guangdong, China is high. The risk factors associated with HIV drug resistance should be seriously considered for better control.

Drug Resistance to Integrase Strand-Transfer Inhibitors among HIV-1-Infected Adults in Guangdong, China.

BACKGROUND: Integrase strand-transfer inhibitor (INSTI)-containing regimens have gradually been administered in Guangdong Province, China beginning in 2016, and INSTI-related drug resistance (DR) may occur and should be monitored among HIV-1-infected patients. OBJECTIVE: To investigate the prevalence of INSTI-related resistance among HIV-1-infected individuals in Guangdong and provide evidence for the optimal administration of INSTIs. METHODS: This study recruited 1208 HIV-1-infected patients (including 404 ART-naive and 804 ART-experienced patients) between June 2021 and April 2022. The entire integrase gene was amplified from blood plasma. Demographic and epidemiological information were collected. INSTI mutations and susceptibility were interpreted using the Stanford HIV Drug Resistance Database HIVdb program. RESULTS: Of the 1208 enrolled individuals, 2.65% (32/1208) carried at least one INSTI major or accessory drug resistance mutation (DRM), with 1.49% (6/404) being from ART-naive individuals and 3.23% (26/804) from ART-experienced individuals. Among them, seven polymorphic major mutations were detected. Although no INSTI drug resistance was found among treatment-naive patients, seven ART-experienced patients (0.87%, 7/804) carried mutations conferring resistance to INSTIs. CONCLUSION: The overall prevalence of INSTI DRMs and DR was comparatively low among ART-naive and ART-treated populations in Guangdong; however, INSTI-related polymorphic mutations were observed. Surveillance should be reinforced before transfer to INSTI-containing regimens.

Drug resistance and genetic transmission characteristics of HIV-1 CRF59_01B in infected patients in Guangdong Province, China.

OBJECTIVES: To comprehensively analyse the prevalence of drug resistance and the transmission characteristics of CRF59_01B strains in infected patients in Guangdong, China. METHODS: CRF59_01B-infected individuals were recruited, and the HIV-1 pol region was amplified. Drug resistance-associated mutations (DRMs) and antiretroviral susceptibility were examined using the Stanford University HIV Drug Resistance Database to analyse pretreatment drug resistance (PDR) and acquired drug resistance (ADR). Genetic transmission networks were extracted from the maximum likelihood phylogenetic tree with Cluster Picker and visualized with Cytoscape. RESULTS: Two hundred and twenty-five CRF59_01B-infected individuals, comprising 35 ART-experienced and 190 ART-naive individuals, were recruited. No patients harboured PI DRMs, 5.33% (12/225) of the patients harboured NRTI DRMs and 11.11% (25/225) of the patients harboured NNRTI DRMs. The overall prevalence of strains with ADR was 51.43% (18/35), while the prevalence of strains with PDR was 2.63% (5/190). A total of 20 transmission networks, involving 25.78% (58/225) database-derived sequences, were identified. The networks ranged in size from 2 to 10 individuals, of which most (55.00%, 11/20) were made up of two individuals. Among the 225 study subjects, 9.78% (22/225) had 1 link and 16.00% (36/225) had ≥2 links. CONCLUSIONS: The overall prevalence of CRF59_01B strains with ADR among the ART-experienced patients was high. Although the overall prevalence of CRF59_01B strains with PDR among the ART-naive patients was low, it is necessary to remain vigilant regarding some important DRMs.

Development and external validation of a prognostic model for survival of people living with HIV/AIDS initiating antiretroviral therapy.

Background: Most existing prognostic models for people living with HIV/AIDS (PLWHA) were derived from cohorts in high-income settings established a decade ago and may not be applicable for contemporary patients, especially for patients in developing settings. The aim of this study was to develop and externally validate a prognostic model for survival in PLWHA initiating ART based on a large population-based cohort in China. Methods: We obtained data for patients from the Chinese National Free Antiretroviral Treatment Program database. The derivation cohort consisted of PLWHA treated between February 2004 and December 2019 in a tertiary center in Guangzhou, South China, and validation cohort of patients treated between February 2004 to December 2018 in another tertiary hospital in Shenyang, Northeast China. We included ART-naive patients aged above 16 who initiated a combination ART regimen containing at least three drugs and had at least one follow-up record. We assessed 20 candidate predictors including patient characteristics, disease characteristics, and laboratory tests for an endpoint of death from all causes. The prognostic model was developed from a multivariable cox regression model with predictors selected using the least absolute shrinkage and selection operator (Lasso). To assess the model's predictive ability, we quantified the discriminative power using the concordance (C) statistic and calibration accuracy by comparing predicted survival probabilities with observed survival probabilities estimated with the Kaplan-Meier method. Findings: The derivation cohort included 16481 patients with a median follow-up of 3·41 years, among whom 735 died. The external validation cohort comprised 5751 participants with a median follow-up of 2·71 years, of whom 185 died. The final model included 10 predictors: age, body mass index, route of HIV acquisition, coinfection with tuberculosis, coinfection with hepatitis C virus, haemoglobin, CD4 cell count, platelet count, aspartate transaminase, and plasma glucose. The C-statistic was 0·84 (95% confidence interval 0·82-0·85) in internal validation after adjustment of optimism and 0·84 (0·82-0·87) in external validation, which remained consistently above 0·75 in all landmark time points within five years of follow up when using time-updated laboratory measurements. The calibration accuracy was satisfactory in both derivation and validation cohorts. Interpretation: We have developed and externally validated a model to predict long-term survival in PLWHA on ART. This model could be applied to individualized patient counseling and management during treatment, and future innovative trial design. Funding: Natural Science Foundation of China Excellent Young Scientists Fund, Natural Science Foundation of China International/Regional Research Collaboration Project, Natural Science Foundation of China Young Scientist Fund, the National Science and Technology Major Project of China,National Special Research Program of China for Important Infectious Diseases, 13th Five-Year Key Special Project of Ministry of Science and Technology, and the Joint-innovation Program in Healthcare for Special Scientific Research Projects of Guangzhou.

Transmitted drug resistance and transmission clusters among HIV-1 treatment-naïve patients in Guangdong, China: a cross-sectional study.

BACKGROUND: Transmitted drug resistance (TDR) that affects the effectiveness of the first-line antiretroviral therapy (ART) regimen is becoming prevalent worldwide. However, its prevalence and transmission among HIV-1 treatment-naïve patients in Guangdong, China are rarely reported. We aimed to comprehensively analyze the prevalence of TDR and the transmission clusters of HIV-1 infected persons before ART in Guangdong. METHODS: The HIV-1 treatment-naïve patients were recruited between January 2018 and December 2018. The HIV-1 pol region was amplified by reverse transcriptional PCR and sequenced by sanger sequencing. Genotypes, surveillance drug resistance mutations (SDRMs) and TDR were analyzed. Genetic transmission clusters among patients were identified by pairwise Tamura-Nei 93 genetic distance, with a threshold of 0.015. RESULTS: A total of 2368 (97.17%) HIV-1 pol sequences were successfully amplified and sequenced from the enrolled 2437 patients. CRF07_BC (35.90%, 850/2368), CRF01_AE (35.56%, 842/2368) and CRF55_01B (10.30%, 244/2368) were the main HIV-1 genotypes circulating in Guangdong. Twenty-one SDRMs were identified among fifty-two drug-resistant sequences. The overall prevalence of TDR was 2.20% (52/2368). Among the 2368 patients who underwent sequencing, 8 (0.34%) had TDR to protease inhibitors (PIs), 22 (0.93%) to nucleoside reverse transcriptase inhibitors (NRTIs), and 23 (0.97%) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Two (0.08%) sequences showed dual-class resistance to both NRTIs and NNRTIs, and no sequences showed triple-class resistance. A total of 1066 (45.02%) sequences were segregated into 194 clusters, ranging from 2 to 414 sequences. In total, 15 (28.85%) of patients with TDR were included in 9 clusters; one cluster contained two TDR sequences with the K103N mutation was observed. CONCLUSIONS: There is high HIV-1 genetic heterogeneity among patients in Guangdong. Although the overall prevalence of TDR is low, it is still necessary to remain vigilant regarding some important SDRMs.

Critical appraisal and external validation of a prognostic model for survival of people living with HIV/AIDS who underwent antiretroviral therapy.

BACKGROUND: HIV/AIDS remains a leading cause of death worldwide. Recently, a model has been developed in Wenzhou, China, to predict the survival of people living with HIV/AIDS (PLWHA) who underwent antiretroviral therapy (ART). We aimed to evaluate the methodological quality and validate the model in an external population-based cohort. METHODS: Prediction Model Risk of Bias Assessment Tool (PROBAST) was used to assess the risk of bias of the Wenzhou model. Data were from the National Free Antiretroviral Treatment Program database. We included PLWHA treated between February 2004 and December 2019 in a tertiary hospital in Guangzhou city, China. The endpoint was all-cause deaths and assessed until January 2020. We assessed the discrimination performance of the model by Harrell's overall C-statistics and time-dependent C-statistics and calibration by comparing observed survival probabilities estimated with the Kaplan-Meier method versus predicted survival probabilities. To assess the potential prediction value of age and gender which were precluded in developing the Wenzhou model, we compared the discriminative ability of the original model with an extended model added with age and gender. RESULTS: Based on PROBAST, the Wenzhou model was rated as high risk of bias in three out of the four domains (selection of participants, definition of outcome, and methods for statistical analysis) mainly because of the misuse of nested case-control design and propensity score matching. In the external validation analysis, 16758 patients were included, among whom 743 patients died (mortality rate 11.41 per 1000 person-years) during follow-up (median 3.41 years, interquartile range 1.64-5.62). The predictor of HIV viral load was missing in 14361 patients (85.7%). The discriminative ability of the Wenzhou model decreased in the external dataset, with the Harrell's overall C-statistics being 0.76, and time-dependent C-statistics dropping from 0.81 at 6 months to 0.48 at 10 years after ART initiation. The model consistently underestimated the survival, and the level was 6.23%, 10.02%, and 14.82% at 1, 2, and 3 years after ART initiation, respectively. The overall and time-dependent discriminative ability of the model improved after adding age and gender to the original model. CONCLUSION: The Wenzhou prognostic model is at high risk of bias in model development, with inadequate model performance in external validation. Thereby, we could not confirm the validity and extended utility of the Wenzhou model. Future prediction model development and validation studies need to comply with the methodological standards and guidelines specifically developed for prediction models.

USP49 potently stabilizes APOBEC3G protein by removing ubiquitin and inhibits HIV-1 replication.

The antiviral activity of host factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) and its degradation mediated by human immunodeficiency virus type 1 (HIV-1) Vif protein are important topics. Although accumulating evidence indicates the importance of deubiquitination enzymes (DUBs) in innate immunity, it is unknown if they participate in A3G stability. Here, we found that USP49 directly interacts with A3G and efficiently removes ubiquitin, consequently increasing A3G protein expression and significantly enhancing its anti-HIV-1 activity. Unexpectedly, A3G degradation was also mediated by a Vif- and cullin-ring-independent pathway, which was effectively counteracted by USP49. Furthermore, clinical data suggested that USP49 is correlated with A3G protein expression and hypermutations in Vif-positive proviruses, and inversely with the intact provirus ratio in the HIV-1 latent reservoir. Our studies demonstrated a mechanism to effectively stabilize A3G expression, which could comprise a target to control HIV-1 infection and eradicate the latent reservoir.

The Double Burdens of Mental Health Among AIDS Patients With Fully Successful Immune Restoration: A Cross-Sectional Study of Anxiety and Depression in China.

Background: Anxiety and depression continue to be significant comorbidities for people with HIV infection. We investigated the prevalence of and factors associated with anxiety and depression among adult HIV-infected patients across China. Methods: In this cross-sectional study, we described clinical and psychosocial variables related to depression and anxiety in 4103 HIV-infected persons. Doctors assessed anxiety and depression by asking patients whether they had experienced anxiety or depression in the prior month. Patients also self-administered the Hospital Anxiety and Depression (HAD) scale; those with score ≥8 on HAD-A/D were considered to be at high risk of anxiety or depression. Results: Associations between socio-demographic, psychosocial, and ART-related clinical factors and risk of depression or anxiety were investigated using multivariable logistic regression. Among patients assessed between 9/2014 and 11/2015, 27.4% had symptoms of anxiety, 32.9% had symptoms of depression, and 19.0% had both. Recentness of HIV diagnoses (P = 0.046) was associated with elevated odds of anxiety. Older age (P = 0.004), higher educational attainment (P < 0.001), employment (P = 0.001), support from family / friends (P < 0.001), and sleep disturbance (P < 0.001), and number of ART regimen switches (P = 0.046) were associated with risk of depression, while neither sex nor transmission route showed any associations. There were no significant associations with HIV-specific clinical factors including current CD4+ T cell count and current viral load. Conclusions: Prevalence of symptoms of anxiety and depression is high in this cohort of treatment-experienced HIV patients. Psychological and social-demographic factors, rather than HIV disease status, were associated with risk of depression and anxiety. This finding highlights the need to deliver interventions to address the mental health issues affecting HIV-infected persons with fully successful immune restoration across China.

Burden of sleep disturbances and associated risk factors: A cross-sectional survey among HIV-infected persons on antiretroviral therapy across China.

This study evaluated the prevalence and factors associated with sleep disturbance in a large cohort of HIV-infected patients across China. A cross-sectional study was conducted among HIV-infected patients on antiretroviral therapy at 20 AIDS clinics. The Pittsburgh Sleep Quality Index was self-administered by subjects. Socio-demographic characteristics, medical history and HIV-related clinical data were collected. 4103 patients had complete data for analysis. Sleep disturbances were observed in 43.1% of patients. Associated factors in multivariable analysis included psychological factors: anxiety (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.44-4.00; P < 0.001), depression (OR, 2.09; 95% CI, 1.70-2.57; P < 0.001), and both anxiety and depression (OR, 5.90; 95% CI, 4.86-7.16; P < 0.001); sociodemographic factors: MSM (OR, 1.26; 95% CI, 1.04-1.52; P = 0.018), being single (OR, 1.45; 95%CI 1.21-1.74; P < 0.001), higher education (OR, 1.25; 95% CI, 1.03-1.53; P = 0.025); and clinical factors: suboptimal adherence (OR,1.51; 95% CI,1.23-1.85; P < 0.001), regimen-switching (OR, 1.94; 95% CI, 1.12-3.35; P = 0.018), and antidepressant use (OR, 1.98; 95% CI, 1.47-2.67; P = 0.044). Prevalence of sleep disturbance is high in this large Chinese cohort. Associated factors appear related to psychological and social-demographic factors. Health workers may consider routinely assessing sleep disturbances among HIV-infected patients, especially in the first three months after HIV diagnosis, and referring for mental health services, which may positively impact adherence to treatment.

The deubiquitinating enzyme Usp5 regulates Notch and RTK signaling during Drosophila eye development.

Usp5 belongs to the USP family of deubiquitinating enzymes (DUBs), which comprises the largest class of DUBs. We previously reported that loss of Usp5 impairs development of photoreceptors in Drosophila eyes, although the detailed mechanism remained unclear. In the present study, we demonstrate that Usp5 regulates both Notch and receptor tyrosine kinase (RTK) signaling. Loss of Usp5 results in upregulation of Notch signaling and downregulation of RTK signaling, leading to impaired photoreceptor development. Moreover, genetic rescue experiments with the DNA binding protein Suppressor of Hairless or Notch RNAi indicate that they mediate the regulation of RTK signaling by Usp5. The present study provides mechanistic insight into how Usp5 regulates photoreceptor differentiation by Notch and RTK signaling in the Drosophila eye.

Efficacy and Safety of Tenofovir and Lamivudine in Combination with Efavirenz in Patients Co-infected with Human Immunodeficiency Virus and Hepatitis B Virus in China.

BACKGROUND: The prevalence of hepatitis B virus (HBV) infection is high among individuals infected with human immunodeficiency virus (HIV) in China. Both HIV and HBV can be treated with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC), so we evaluated the safety and efficacy of combination antiretroviral therapy (ART) that included TDF, 3TC, and efavirenz (EFV) among ART-naive individuals who were co-infected with HIV and HBV. METHODS: One hundred HIV/HBV co-infected ARV-naive individuals were started on the regimen of TDF, 3TC, and EFV, and the levels of plasma HBV DNA, HIV RNA, and biochemical evaluation related to the function of liver and kidney were analyzed. RESULTS: Concerning efficacy, this study found that by week 48, the vast majority co-infected participants receiving this ART regimen had undetectable HBV DNA levels (71%) and/or HIV RNA levels (90%). Concerning safety, this study found that the median estimated glomerular filtration rate of participants decreased from baseline (109 ml·min-1·1.73 m-2) to week 12 (104 ml·min-1·1.73 m-2) but was almost back to baseline at week 48 (111 ml·min-1·1.73 m-2). CONCLUSION: This combination ART regimen is safe and effective for patients with HIV/HBV co-infection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01751555; https://clinicaltrials.gov/ct2/show/NCT01751555.

Hyperplastic discs differentially regulates the transcriptional outputs of hedgehog signaling.

Hedgehog (Hh) acts as a morphogen to activate the transcription of diverse target genes via its downstream effector Cubitus interruptus (Ci). Currently, it is less understood how Ci recruits co-factors to activate transcription. Here we report that hyperplastic discs (hyd), an E3 ubiquitin ligase, can differentially regulate the transcriptional outputs of Hh signaling. We show that loss of Hyd activity caused upregulation of some, but not all of Hh target genes. Importantly, Hyd does not affect the stability of Ci. Our data suggest that Hyd differentially restrains the transcriptional activity of Ci via selective association with respective promoters.