USP7 reduction leads to developmental failure of mouse early embryos.

As a member of Ubiquitin-specific protease subfamily, ubiquitin specific protease 7 (USP7) has been reported to participate in a variety of cellular processes, including cell cycle, apoptosis, DNA damage response, and epigenetic modification. However, its function in preimplantation embryos is still obscure. To investigate the functions of USP7 during preimplantation embryo development, we used siRNA to degrade endogenous USP7 messenger RNA. We found that USP7 knockdown significantly decreased the development rate of mouse early embryos. Moreover, depletion of USP7 induced the accumulation of the DNA lesions and apoptotic blastomeres in early embryos. In addition, USP7 knockdown caused an abnormal H3K27me3 modification in 2-cell embryos. Overall, our results indicate that USP7 maintains genome stability perhaps via regulating H3K27me3 and DNA damage, consequently controlling the embryo quality.

Epidemiology of multimorbidity associated with atherosclerotic cardiovascular disease in the United States, 1999-2018.

BACKGROUND: The multimorbidity of Atherosclerotic cardiovascular disease (ASCVD) and many other chronic conditions is becoming common. This study aimed to assess multimorbidity distribution in ASCVD among adults in the United States from 1999 to 2018. METHODS: This cross-sectional survey from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 using stratified multistage probability design. Among the 53,083 survey respondents during the study period, 5,729 US adults aged ≥ 20 years with ASCVD. Joinpoint regression was used to assess the statistical significance of prevalence trends in the prevalence of ASCVD stratified by multimorbidity. The Apriori association rule mining algorithm was used to identify common multimorbidity association patterns in ASCVD patients. RESULTS: Overall, 5,729 of 53,083 individuals had ASCVD, and the prevalence showed a slow declining trend (biannual percentage change = -0.81%, p = 0.035, average 7.71%). The prevalence of ASCVD significantly decreased in populations without dyslipidemia, diabetes mellitus (DM), hypertension, asthma, chronic obstructive pulmonary disease (COPD), and arthritis (all groups, p < 0.05). Additionally, 65.6% of ASCVD patients had at least four of the 12 selected chronic conditions, with four and five being the most common numbers of conditions (17.9% and 17.7%, respectively). The five most common chronic conditions were (in order) dyslipidemia, hypertension, arthritis, chronic kidney disease, and DM. The coexistence of hypertension and dyslipidemia had the highest support in association rules (support = 0.63), while the coexistence of dyslipidemia, hypertension, metabolic syndrome, and DM had the highest lift (lift = 1.82). CONCLUSIONS: During the 20-year survey period, there was a significant decrease in the overall prevalence of ASCVD. However, this reduction was primarily observed in individuals without dyslipidemia, DM, hypertension, asthma, COPD, and arthritis. Among populations with any of the evaluated chronic conditions, the prevalence of ASCVD remained unchanged. Most of ASCVD patients had four or more concurrent chronic conditions.

Nephrotic Syndrome Complicated with Familial Hypocalciuric Hypercalcemia in an Infant: A Case Report and Comprehensive Literature Review.

Background: Nephrotic syndrome, a prevalent childhood glomerular disorder, manifests with proteinuria, hypoalbuminemia, edema, and hypercholesteremia. Hypercalcemia, though rare, occasionally complicates these cases. Familial hypocalciuric hypercalcemia, an autosomal dominant disorder, is characterized by lifelong hypercalcemia, hypocalciuria, and normal or elevated parathyroid hormone levels due to loss-of-function mutations. Case Presentation: We detail a 2-year-old girl with nephrotic syndrome whose proteinuria responded effectively to steroid therapy without side effects. Hypercalcemia emerged after one month, prompting a familial history investigation, revealing a predisposition to hypercalcemia. Genetic analysis identified a heterozygous mutation c.1394G>A (p.R465Q) in the calcium-sensing receptor gene, shared among the patient, her grandmother, her father, and one sister. Notably, hypercalcemia required no intervention. Conclusions: This case report is the first documenting familial hypocalciuric hypercalcemia in a child with primary nephrotic syndrome and delineates the familial pedigree. While familial hypocalciuric hypercalcemia is infrequent, our findings affirm its generally benign nature. A critical aspect of patient care involves monitoring for potential complications, including acute pancreatitis or chondrocalcinosis. The indispensability of genetic studies in both diagnosis and the differentiation of related conditions is underscored, emphasizing their pivotal role in enhancing our understanding of this rare yet clinically significant disease. Continued research is imperative for advancing knowledge and improving clinical management.

Experience of rehabilitation specialist nurses in providing bowel care for stroke patients: A qualitative study.

AIMS: This study aims to explore the experiences of rehabilitation specialist nurses in providing bowel care to stroke patients and to identify the factors that either facilitate or hinder their practice. DESIGN: This was a descriptive qualitative design study. METHODS: Between May 2022 and October 2022, we conducted in-depth and semi-structured interviews with 12 rehabilitation specialist nurses from two tertiary hospitals in Changsha, China. Thematic analysis was employed to analyse the interview transcripts. FINDINGS: Three key themes were revealed from our analysis: (1) acceptance of bowel care as a process, (2) high level of recognition improves the experience and (3) challenges stemming from limited knowledge and rights. Acceptance of bowel care as a dynamic process, coupled with a high level of recognition, enabled nurses to prioritize the health and safety of patients over personal feelings and achieve professional accomplishments. However, they encountered challenges in terms of professional development and restricted prescribing rights for bowel care. CONCLUSION: The experiences of rehabilitation specialist nurses in providing bowel care are dynamic. These findings have important implications for healthcare improvement, including the need for collaboration with healthcare professionals and nurturing nurses' self-identity, comprehensive training plans, innovative programs and expanding the scope of rehabilitation specialist nurses' rights. IMPACT: This study enhances our understanding of the challenges faced by rehabilitation specialist nurses caring for stroke patients with neurogenic bowel dysfunction. The findings provide insights into how to enhance bowel care experience and develop further in this field. REPORTING METHOD: This study adhered to the EQUATOR guideline and utilized the COREQ checklist. PATIENT OR PUBLIC CONTRIBUTIONS: This study involved participants who were registered nurses, and there were no contributions from patients or public.

Oxygen-doped NiCoP derived from Ni-MOFs for high performance asymmetric supercapacitor.

Oxygen doping strategy is one of the most effective methods to improve the electrochemical properties of nickel-cobalt phosphide (NiCoP)-based capacitors by adjusting its inherent electronic structure. In this paper, O-doped NiCoP microspheres derived from porous nanostructured nickel metal-organic frameworks (Ni-MOFs) were constructed through solvothermal method followed by phosphorization treatment. The O-doping concentration has a siginificant influence on the rate performance and cycle stability. The optimized O-doped NiCoP electrode material shows a specific capacitance of 632.4 F-g-1at 1 A-g-1and a high retention rate of 56.9% at 20 A g-1. The corresponding NiCoP-based asymmetric supercapacitor exhibits a high energy density of 30.1 Wh kg-1when the power density is 800.9 W kg-1, and can still maintain 82.1% of the initial capacity after 10 000 cycles at 5 A g-1.

A Transparent Additive-Free Fibrous Facial Mask for Skin Moisturizing.

Most sheet facial masks for skincare are made of nonwovens and loaded with liquid active ingredients, which are usually opaque and require additives for long-term preservation. Herein, a Transparent Additive-Free Fibrous (TAFF) facial mask is reported for skin moisturizing. The TAFF facial mask consists of a bilayer fibrous membrane. The inner layer is fabricated by electrospinning functional components of gelatin (GE) and hyaluronic acid (HA) into a solid fibrous membrane to get rid of additives, the outer layer is an ultrathin PA6 fibrous membrane that is highly transparent, especially after absorbing water. The results indicate that the GE-HA membrane can quickly absorb water and become a transparent hydrogel film. By employing the hydrophobic PA6 membrane as the outer layer, directional water transport is achieved, which enables TAFF facial mask with excellent skin moisturizing effect. The skin moisture content is up to 84% ± 7% after placing the TAFF facial mask on the skin for 10 min. In addition, the relative transparency of the TAFF facial mask on the skin reaches 97.0% ± 1.9% when ultrathin PA6 membrane is used as the outer layer. The design of the transparent additive-free facial mask may serve as a guideline for developing new functional facial masks.

Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy.

BACKGROUND: Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children. Exploring the correlation between the phenotype and genotype of NPHP-RC is helpful for early diagnosis and management. We investigated the phenotype and genotype spectra of NPHP-RC in a Chinese multicentre cohort. METHODS: Crosss-ectional and longitudinal data of 60 patients from 57 families with pathogenic NPHP-RC gene mutations distributed in 22 regions of China were collected into a unified, anonymous database. The mean observation time of this cohort was 3.5±3.1 years. RESULTS: Mutations in NPHP1 and NPHP3 were the most common genetic defects. Overall, 45% of patients presented with isolated nephronophthisis (NPH), and 55% exhibited the extrarenal phenotype, which frequently involved the liver (41.7%, n=25), central nervous system (26.7%, n=16), eyes (26.7%, n=16) and skeletal system (11.7%, n=7). Accidental detection of elevated serum creatinine and non-specific symptoms caused by chronic kidney disease occurred in 65% of patients. Patients carrying NPHP1 mutations mainly presented with isolated NPH (90%, 18/20) and progressed to ESRD at a mean age of 12.9±0.5 years. The mean age of ESRD onset in the non-NPHP1 group was lower than that in the NPHP1 group (6.2±1.4 years, p<0.001), especially for patients carrying NPHP3 mutations (3.1±1.2 years), showing a heterogeneous phenotype characterised by Bardet-Biedl syndrome (12.5%, n=5), Joubert syndrome (7.5%, n=3), COACH syndrome (2.5%, n=1), Mainzer-Saldino syndrome (2.5%, n=1), short-rib thoracic dysplasia (2.5%, n=1) and unclassified symptoms (32.5%, n=13). CONCLUSIONS: The Chinese Children Genetic Kidney Disease Database registry characterised the spectrum of the phenotype and genotype of NPHP-RC in the Chinese population. NPHP1 and NPHP3 were the most common pathogenic genes. Rapid progression to ESRD and liver involvement were noted in patients with NPHP3 mutations.

Uptake of an App-Based Case Management Service for HIV-Positive Men Who Have Sex With Men in China: Process Evaluation Study.

BACKGROUND: Men who have sex with men (MSM) in China are disproportionately affected by the HIV epidemic, and medication adherence to antiretroviral treatment in this vulnerable population is suboptimal. To address this issue, we developed an app-based case management service with multiple components, informed by the Information Motivation Behavioral skills model. OBJECTIVE: We aimed to conduct a process evaluation for the implementation of an innovative app-based intervention guided by the Linnan and Steckler framework. METHODS: Process evaluation was performed alongside a randomized controlled trial in the largest HIV clinic in Guangzhou, China. Eligible participants were HIV-positive MSM aged ≥18 years planning to initiate treatment on the day of recruitment. The app-based intervention had 4 components: web-based communication with case managers, educational articles, supportive service information (eg, information on mental health care and rehabilitation service), and hospital visit reminders. Process evaluation indicators of the intervention include dose delivered, dose received, fidelity, and satisfaction. The behavioral outcome was adherence to antiretroviral treatment at month 1, and Information Motivation Behavioral skills model scores were the intermediate outcome. Logistic and linear regression was used to investigate the association between intervention uptake and outcomes, controlling for potential confounders. RESULTS: A total of 344 MSM were recruited from March 19, 2019, to January 13, 2020, and 172 were randomized to the intervention group. At month 1 follow-up, there was no significant difference in the proportion of adherent participants between the intervention and control groups (66/144, 45.8% vs 57/134, 42.5%; P=.28). In the intervention group, 120 participants engaged in web-based communication with case managers and 158 accessed at least 1 of the delivered articles. The primary concern captured in the web-based conversation was the side effects of the medication (114/374, 30.5%), which was also one of the most popular educational articles topics. The majority (124/144, 86.1%) of participants that completed the month 1 survey rated the intervention as "very helpful" or "helpful." The number of educational articles accessed was associated with adequate adherence in the intervention group (odds ratio 1.08, 95% CI 1.02-1.15; P=.009). The intervention also improved the motivation score after adjusting for baseline values (ß=2.34, 95% CI 0.77-3.91; P=.004). However, the number of web-based conversations, regardless of conversation features, was associated with lower motivation scores in the intervention group. CONCLUSIONS: The intervention was well-received. Delivering educational resources of interest may enhance medication adherence. The uptake of the web-based communication component could serve as an indicator of real-life difficulties and could be used by case managers to identify potential inadequate adherence. TRIAL REGISTRATION: Clinicaltrial.gov NCT03860116; https://clinicaltrials.gov/ct2/show/NCT03860116. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12889-020-8171-5.

Accelerated English Teaching Methods: The Role of Digital Technology.

This article presents the impact of digital teaching method in the form of Rosetta Stone program on the quality of English language acquisition. The study involved 320 third-year students who study in the People's Republic of China. Group B post-assessment results show an increase in scores on the four assessment criteria: reading, listening, writing, and speaking after the Rosetta Stone intervention. Reading skills increased by 33.6%, listening by 26.0%, writing by 48.6%, and speaking by 20.5%. Students from group B who were additionally Rosetta Stone users had a 7.4% higher average achievement rate than the control group, which proves the effectiveness of the program in the context of English language learning. Correlations were calculated between the cumulative score of the specific criteria and the general criteria as well as the individual assessment categories, all correlations were positive, weak, medium, or strong.

Effects of combined antibiotics on nitrification, bacteria and antibiotic resistance genes in activated sludge: Insights from legacy effect of antibiotics.

The effect of combined antibiotics exposure on nitrogen removal, microbial community assembly and proliferation of antibiotics resistance genes (ARGs) is a hotspot in activated sludge system. However, it is unclear that how the historical antibiotic stress affects the subsequent responses of microbes and ARGs to combined antibiotics. In this study, the effects of combined sulfamethoxazole (SMX) and trimethoprim (TMP) pollution on activated sludge under legacy of SMX or TMP stress with different doses (0.005-30 mg/L) were investigated to clarify antibiotic legacy effects. Nitrification activity was inhibited under higher level of combined exposure but a high total nitrogen removal (∼70%) occurred. Based on the full-scale classification, the legacy effect of past antibiotic stress had a marked effect on community composition of conditionally abundant taxa (CAT) and conditionally rare or abundant taxa (CRAT). Rare taxa (RT) were the keystone taxa in the microbial network, and the responses of hub genera were also affected by the legacy of antibiotic stress. Nitrifying bacteria and genes were inhibited by the antibiotics and aerobic denitrifying bacteria (Pseudomonas, Thaurea and Hydrogenophaga) were enriched under legacy of high dose, as were the key denitrifying genes (napA, nirK and norB). Furthermore, the occurrences and co-selection relationship of 94 ARGs were affected by legacy effect. While, some shared hosts (eg., Citrobacter) and hub ARGs (eg., mdtD, mdtE and acrD) were identified. Overall, antibiotic legacy could affect responses of activated sludge to combined antibiotic and the legacy effect was stronger at higher exposure levels.

Histological image color normalization using a skewed normal distribution mixed model.

Color variation between histological images may influence the performance of computer-aided histological image analysis. Therefore, among the most essential and challenging tasks in histological image analysis are the reduction of the color variation between images and the preservation of the histological information contained in the images. In recent years, many methods have been introduced with respect to the color normalization of histological images. In this study, we introduce a new clustering method referred to as the skewed normal distribution mixed model clustering algorithm. Realizing that the color distribution of hue values approximates the combination of several skewed normal distributions, we propose to use the skewed normal distribution mixture model to analyze the hue distribution. The proposed skewed normal distribution mixture model clustering algorithm includes saturation-weighted hue histograms because it takes into account the saturation and hue information of a particular histogram image, which can diminish the influence of achromatic pixels. Finally, we conducted extensive experiments based on three data sets and compared them with commonly used color normalization methods. The experiments show that the proposed algorithm has better performance in stain separation and color normalization compared to other methods.

Association between childhood friendship and cognitive ageing trajectory in later life: evidence from the China Health and Retirement Longitudinal Study (CHARLS).

BACKGROUND: Childhood experience has been suggested to affect cognitive function in later life. However, the association between childhood friendship status and cognitive ageing trajectory in middle-aged and older adults has not been fully assessed. This study examined the association between childhood friendship status and cognitive ageing trajectory and identified factors modifying this association. METHODS: We used four waves of data from the China Health and Retirement Longitudinal Study (CHARLS), a national representative longitudinal study of adults aged 45 years or older, 2011-2018. The CHARLS included surveys on childhood friendship and cognitive assessments. Childhood friendship status was categorised as poor, fair, and good. To examine the association between childhood friendship and cognitive ageing trajectory in later life, we applied multilevel linear regression models, and explored potential influences of sociodemographic factors, health status and behaviours, and childhood conditions on this association. RESULTS: Of the 4,350 participants, 1,919 (44.1%) were women. The mean age was 56.29 ± 7.80 years. We found childhood friendship was significantly associated with cognitive ageing trajectory in later life, with a dose-response relationship. After adjusting for covariates, comparing to participants with poor childhood friendships, those with better childhood friendships had lower rates of cognitive decline (ß = 0.12, 95% confidence interval [CI]: 0.03 to 0.22 [interaction term of fair friendship and time]; ß = 0.19, 95% CI: 0.10 to 0.28 [interaction term of good friendship and time]) and higher level of cognitive functions (ß = 0.40, 95% CI: 0.22 to 0.58 [fair friendships]; ß = 0.61, 95% CI: 0.43 to 0.79 [good friendships]). These associations were stronger for those who were female, less educated, and had experienced more adverse childhood experiences. CONCLUSIONS: Childhood friendship is associated with cognitive ageing in later life. Enhancing childhood friendships can play an important role to promote healthy ageing in the future.

Storage tank as a pretreatment unit for rainwater cleaner production: Role of biofilm bacterial communities and functional genera in water quality improvement.

This study investigated the water purification function and mechanism of biofilm in storage tank, with a view to using it as a pretreatment unit for rainwater cleaner production. Shortening the hydraulic retention time (HRT) of storage tank from 12 to 4 h improved the pollutants removal performance and reduced the suspended bacteria counts. The accumulation of abundant taxa and succession of rare taxa were observed with biofilm development. Positive correlations within and across different bacterial taxa were dominant in the network, and some rare genera (Ralstonia and Micropruina) were identified as hub bacteria. Candidatus Nitrospira nitrosa and Nitrospira sp. ENR4 were two identified complete ammonia oxidizers. Denitrifying bacteria tended to enrich and formed more complex interactions over time. The main nitrogen metabolism pathways may be ammonia assimilatory, complete denitrification and dissimilatory/assimilatory nitrate reduction. HRT was negatively correlated with most dominant genera, and contributed 20.35% to the variation of functional taxa. This study highlights the self-purification function and micro-ecology of storage tank, and provides a new insight for its role in rainwater cleaner production process.

The repair of endo/exogenous DNA double-strand breaks and its effects on meiotic chromosome segregation in oocytes.

Germ cell-derived genomic structure variants not only drive the evolution of species but also induce developmental defects in offspring. The genomic structure variants have different types, but most of them are originated from DNA double-strand breaks (DSBs). It is still not well known whether DNA DSBs exist in adult mammalian oocytes and how the growing and fully grown oocytes repair their DNA DSBs induced by endogenous or exogenous factors. In this study, we detected the endogenous DNA DSBs in the growing and fully grown mouse oocytes and found that the DNA DSBs mainly localized at the centromere-adjacent regions, which are also copy number variation hotspots. When the exogenous DNA DSBs were introduced by Etoposide, we found that Rad51-mediated homologous recombination (HR) was used to repair the broken DNA. However, the HR repair caused the chromatin intertwined and impaired the homologous chromosome segregation in oocytes. Although we had not detected the indication about HR repair of endogenous centromere-adjacent DNA DSBs, we found that Rad52 and RNA:DNA hybrids colocalized with these DNA DSBs, indicating that a Rad52-dependent DNA repair might exist in oocytes. In summary, our results not only demonstrated an association between endogenous DNA DSBs with genomic structure variants but also revealed one specific DNA DSB repair manner in oocytes.

The differentiation of colorectal cancer is closely relevant to m6A modification.

The occurrence and development of tumors cannot be separated from the influence of differentiation at different stages and levels. Our study found that E-cadherin was significantly increased in cell model induced by sodium butyrate and cell density, while METTL3, METTL16 and WTAP were decreased during the differentiation of cells. In the clinicopathological tissues, E-cadherin was low expressed in poorly differentiated tumor tissues and above three regulators were highly expressed in poorly differentiated tissues. At the levels of clinicopathological differentiation, tissue differentiation and cell differentiation, the result indicated that the poor prognosis of colorectal cancer (CRC) may be closely related to high expression of total m6A level and high expression of METTL3, METTL16 and WTAP.

Prevalence and associated factors of sexualized drug use in sex work among transgender women sex workers in China.

Sexualized drug use (SDU) is associated with a higher risk of HIV transmission. There is a dearth of study investigating the association between sex work characteristics and SDU in sex work among transgender women sex workers. To address these gaps, we conducted a secondary analysis of a cross-sectional study among 220 transgender women sex workers in Shenyang, China. The prevalence of SDU in sex work was 20.9% in the past month. After adjustment for age, HIV status, education, monthly income and duration of stay in Shenyang, performing sex work mainly in hotel rooms, charging higher per episode of commercial sex, depressive symptoms and anxiety symptoms were associated with higher likelihood of SDU in sex work. Future SDU prevention programmes SDU targeting transgender women sex workers should focus on those who charged higher and performed sex work in hotel rooms, and integrate mental health promotion as an essential component.

Gut Microbiota Dysbiosis Drives the Development of Colorectal Cancer.

BACKGROUND: The gut microbiota is a diverse community of microbes that maintain the stability of the intestinal environment. Dysbiosis of the gut microbiota has been linked to gastrointestinal diseases, such as colorectal cancer (CRC) - a leading cause of death for cancer patients. SUMMARY: Candidate pathogens have been identified using bacterial culture and high-throughput sequencing techniques. Currently, there is evidence to show that specific intestinal microbes drive CRC development and progression, yet their pathogenic mechanisms are still unclear. Key Messages: In this review, we describe the known healthy gut microbiota and its changes in CRC. We especially focus on exploring the pathogenic mechanisms of gut microbiota dysbiosis in CRC. This is crucial for explaining how gut microbiota dysbiosis drives the process of colorectal carcinogenesis and tumor progression. Evaluation of changes in the gut microbiota during CRC development and progression offers a new strategy for the diagnosis and treatment of this disease.

Nickel-vanadium layered double hydroxide nanosheets as the saturable absorber for a passively Q-switched 2 µm solid-state laser.

Nickel-vanadium (NiV)-layered double hydroxide (LDH) was fabricated into a novel saturable absorber (SA) by the liquid phase exfoliation method and utilized as the laser modulator for the first time, to our best knowledge. We investigated a passive Q-switched Tm:YAG ceramic laser at 2 µm with the NiV-LDH SA. Under an absorbed pump power of 7.2 W, the shortest pulse width of 398 ns was obtained with an average output power of 263 mW and a pulse repetition frequency of 101.8 kHz, corresponding to a single pulse energy at 2.30 µJ. The results indicate that the NiV-LDH SA has great research potential in the field of laser modulation.

HIV diagnosis period influences ART initiation: findings from a prospective cohort study in China.

BACKGROUND: We estimated the predictive effects of ART-related perceptions on the actual ART uptake behavior among ART naïve PLWH stratified by different time of HIV diagnosis under the new strategy. METHODS: A prospective cohort study was conducted among ART naïve PLWH in Guangzhou, China from June 2016 to June 2017. Cox regression model was used to evaluate the predictive effects of ART-related perceptions on ART initiation among PLWH stratified by different timepoint of HIV diagnosis (i.e., before or after the update of the new treatment policy). RESULTS: Among 411 participants, 150 and 261 were diagnosed before (pre-scaleup group) and after (post-scaleup group) the implementation of the new strategy, respectively. The ART initiation rate in the post-scaleup group (88.9%) was higher than that in the pre-scaleup group (73.3%) (p < 0.001). A significant difference of mean score was detected in each HBM construct between pre- and post-scaleup groups (p < 0.05). After adjusting for significant background variables, among all participants, only the self-efficacy [adjusted HR (HRa) = 1.23, 95% CI 1.06 to 1.43, p = 0.006], has a predictive effect on ART initiation; in pre-scaleup group, all constructs of HBM-related ART perceptions were predictors of ART initiation (HRa = 0.71 to 1.83, p < 0.05), while in post-scaleup group, no significant difference was found in each construct (p > 0.05). CONCLUSIONS: The ART initiation rate was high particularly among participants who diagnosed after the new treatment strategy. The important role of the time of HIV diagnosis on ART initiation identified in this study suggested that future implementation interventions may consider to modify the ART-related perceptions for HIV patients who diagnosed before the implementation of the new ART strategy, while expand the accessibility of ART service for those who diagnosed after the implementation of the new strategy.

Targeting RyR2 with a phosphorylation site-specific nanobody reverses dysfunction of failing cardiomyocytes in rats.

Chronic PKA phosphorylation of ryanodine receptor 2 (RyR2) has been shown to increase diastolic sarcoplasmic reticulum (SR) Ca2+ leakage and lead to cardiac dysfunction. We hypothesize that intracellular gene delivery of an RyR2-targeting phosphorylation site-specific nanobody could preserve the contractility of the failing myocardium. In the present study, we acquired RyR2-specific nanobodies from a phage display library that were variable domains of Camelidae heavy chain-only antibodies. One of the nanobodies, AR185, inhibited RyR2 phosphorylation in vitro and was chosen for further investigation. We investigated the potential of adeno-associated virus (AAV)9-mediated cardiac expression of AR185 to combat postischemic heart failure (HF). AAV gene delivery elevated the intracellular expression of the AR185 protein in a rat model of ischemic HF, and this treatment normalized the systolic and diastolic dysfunction of the failing myocardium in vivo by reversing myocardial Ca2+ handling. Furthermore, AR185 gene transfer to failing cardiomyocytes reduced the frequency of SR calcium leaks, thereby restoring the attenuated intracellular calcium transients and SR calcium load. Moreover, AR185 gene transfer inhibited the PKA-mediated phosphorylation of RyR2 in failing cardiomyocytes. Our results provide preclinical experimental evidence that the cardiac expression of RyR2 nanobodies with AAV9 vectors is a promising therapeutic strategy for HF.-Li, T., Shen, Y., Lin, F., Fu, W., Liu, S., Wang, C., Liang, J., Fan, X., Ye, X., Tang, Y., Ding, M., Yang, Y., Lei, C., Hu, S. Targeting RyR2 with a phosphorylation site-specific nanobody reverses dysfunction of failing cardiomyocytes in rats.