Genomic epidemiology reveals early transmission of SARS-CoV-2 and mutational dynamics in Nanning, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are a fatal pathogen resulting in substantial morbidity and mortality, and posing a great threat to human health with epidemics and pandemics. METHODS: Next-generation sequencing (NGS) was performed to investigate the SARS-CoV-2 genomic characterization. Phylogenetic analysis of SARS-CoV-2 genomes was used to probe the evolutionary. Homology protein structure modelling was done to explore potential effect of the mutations. RESULTS: The eighty genome sequences of SARS-CoV-2 obtained from the thirty-nine patients with COVID-19. A novel variant with mutation H625R concomitant with S50L in spike glycoprotein had been identified. Phylogenetic analysis revealed that SARS-CoV-2 variants belong to several distinct lineages. Homology modelling indicated that variant with mutation H625R and S50L increases flexibility of S1 subunit. CONCLUSIONS: SARS-CoV-2 genomes are constantly evolving by accumulation of point mutations. The amino acid H625R in combination with S50L may have a significant impact on the interaction between spike glycoprotein and ACE2.

Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function.

PML nuclear bodies (NB) are disrupted in PML-RARA-driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% of patients with APL, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid-liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB assembly, PML sumoylation, and PML-RARA degradation, mechanistically explaining clinical ATO resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML that could pave the way to novel cancer drugs. SIGNIFICANCE: Arsenic curative effects in APL rely on PML targeting. We report a PML B-box-2 structure that drives trimer assembly, positioning a cysteine trio to form an arsenic-binding pocket, which is disrupted in resistant patients. Identification of this ROS-sensitive triad controlling PML dynamics and functions could yield novel drugs. See related commentary by Salomoni, p. 2505. This article is featured in Selected Articles from This Issue, p. 2489.

Structural characterization of human RPA70N association with DNA damage response proteins.

The heterotrimeric Replication protein A (RPA) is the ubiquitous eukaryotic single-stranded DNA (ssDNA) binding protein and participates in nearly all aspects of DNA metabolism, especially DNA damage response. The N-terminal OB domain of the RPA70 subunit (RPA70N) is a major protein-protein interaction element for RPA and binds to more than 20 partner proteins. Previous crystallography studies of RPA70N with p53, DNA2 and PrimPol fragments revealed that RPA70N binds to amphipathic peptides that mimic ssDNA. NMR chemical-shift studies also provided valuable information on the interaction of RPA70N residues with target sequences. However, it is still unclear how RPA70N recognizes and distinguishes such a diverse group of target proteins. Here, we present high-resolution crystal structures of RPA70N in complex with peptides from eight DNA damage response proteins. The structures show that, in addition to the ssDNA mimicry mode of interaction, RPA70N employs multiple ways to bind its partners. Our results advance the mechanistic understanding of RPA70N-mediated recruitment of DNA damage response proteins.

Synthesis and bioactive evaluation of N-((1-methyl-1H-indol-3-yl)methyl)-N-(3,4,5-trimethoxyphenyl)acetamide derivatives as agents for inhibiting tubulin polymerization.

Based on the inhibitory effect of CA-4 analogues and indoles on tubulin polymerization, we designed and synthesized a series of N-((1-methyl-1H-indol-3-yl)methyl)-2-(1H-pyrazol-1-yl or triazolyl)-N-(3,4,5-trimethoxyphenyl)acetamides. All the synthesized compounds were evaluated for their in vitro antiproliferative activities against HeLa, MCF-7 and HT-29 cancer cell lines, and some of the target compounds demonstrated effective activities towards the three tumour cell lines. Among them, compound 7d exhibited the most potent activities against HeLa (IC50 = 0.52 µM), MCF-7 (IC50 = 0.34 µM) and HT-29 (IC50 = 0.86 µM). Mechanistic studies revealed that compound 7d induced cell apoptosis in a dose-dependent manner, arrested the cells in the G2/M phase and inhibited polymerization of tubulin via a consistent way with colchicine. Therefore, 7d is a potential agent for the further development of tubulin polymerization inhibitors.

Structure and mechanism for streptococcal fatty acid kinase (Fak) system dedicated to host fatty acid scavenging.

Staphylococcus and Streptococcus, two groups of major human pathogens, are equipped with a fatty acid kinase (Fak) machinery to scavenge host fatty acids. The Fak complex is contains an ATP-binding subunit FakA, which interacts with varied FakB isoforms, and synthesizes acyl-phosphate from extracellular fatty acids. However, how FakA recognizes its FakB partners and then activates different fatty acids is poorly understood. Here, we systematically describe the Fak system from the zoonotic pathogen, Streptococcus suis. The crystal structure of SsFakA complexed with SsFakB2 was determined at 2.6 Å resolution. An in vitro system of Fak-PlsX (phosphate: acyl-ACP transacylase) was developed to track acyl-phosphate intermediate and its final product acyl-ACP. Structure-guided mutagenesis enabled us to characterize a mechanism for streptococcal FakA working with FakB partners engaged in host fatty acid scavenging. These findings offer a comprehensive description of the Fak kinase machinery, thus advancing the discovery of attractive targets against deadly infections with Streptococcus.

Job load, job stress, and job exhaustion among Chinese junior middle school teachers: Job satisfaction as a mediator and teacher's role as a moderator.

Job exhaustion is not uncommon among Chinese middle school teachers, but the key antecedents of job exhaustion and the underlying mechanisms in this historically underrepresented population remain poorly understood. This study examined the association between job demand and exhaustion, and tested the mediating role of job satisfaction and the moderating role of teachers' role (i.e., homeroom versus subject) in this association. The two-wave, China Education Panel Survey data from 701 Chinese junior middle school teachers (M age = 30.05 years old, SD age = 7.86; 78.75% females) were used. Primary hypotheses were tested using structural equation modelling. Results indicated that job load rather than job stress at Wave 1 was positively associated with job exhaustion at Wave 2 indirectly through its negative association with job satisfaction at Wave 2 only among subject teachers; in contrast, for homeroom teachers, job satisfaction at Wave 2 was the only factor that was identified to be negatively associated with job exhaustion at Wave 2. Notably, all significant associations emerged after controlling for a number of covariates, including job exhaustion at Wave 1. Such findings shed initial light on the complexity inherent within the phenomena of middle school teachers' occupational health in a Chinese cultural context. Reducing teachers' work load associated with long working hours and promoting teachers' job satisfaction may be effective ways to relieve and prevent job exhaustion, especially for Chinese subject teachers.

Viral Dynamic Surveillance in COVID-19 Patients: A Cohort Study.

Background: Coronavirus disease 2019 (COVID-19) is a potentially fatal pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially those of novel SARS-CoV-2 variants and infection has affected over 700 million people globally. Methods: This retrospective, descriptive study included 118 patients admitted with SARS-CoV-2 infection as confirmed by real-time reverse transcription polymerase chain reaction. Results: The median duration of detectable SARS-CoV-2 infection in patients with high ALT, AST, and PLT/LYMPH, or low CD4+, CD8+, and PLT/MONO was considerably longer. In the risk factor model, multivariate analysis was performed for the estimation of ALT (HR, 0.54; 95% CI, 0.36-0.81), AST (HR, 0.56; 95% CI, 0.34-0.93), CD4+ (HR,0.77; 95% CI, 0.48-1.24), CD8+ (HR,0.64; 95% CI, 0.37-1.11), PLT/LYMPH (HR, 1.16; 95% CI, 0.76-1.77), and PLT/MONO (HR, 0.64; 95% CI, 0.43-0.94). Conclusions: The longer viral RNA duration was associated with a higher International Prognostic Index score (p = 0.0013), demonstrating for the first time that multivariate features of the bioindicators closely associated with SARS-CoV-2-infected patients clear the virus.

Serum Exosomal microRNA Profiling in AIDS Complicated with Talaromyces marneffei Infection.

INTRODUCTION: In order to find the early diagnostic markers of AIDS combined with TM infection, we detected and analyzed the serum exosomal miRNAs of AIDS patients with or without TM infection. MATERIALS AND METHODS: We profiled the expression levels of miRNAs via RNA sequencing in serum exosomes from the pooled samples of 17 AIDS patients combined without TM infection and 15 AIDS combined with TM infection patients. For external validation, we validated these results using real-time quantification polymerase chain reaction (qRT-PCR) in an independent cohort of 35 AIDS patients combined without TM infection and 33 AIDS combined with TM infection patients. Finally, bioinformatics was used to predict the target genes and pathways of meaningful miRNAs. RESULTS: A total of 131 serum exosomal miRNAs including 73 up-regulated and 59 down-regulated miRNAs were found to be differentially expressed (log2FC≥1 and FDR <0.01) in the two groups. A validation analysis revealed that three miRNAs (miR-192-5p, miR-194-5p and miR-1246) were upregulated in exosomes from AIDS combined with TM infection patients. ROC analyses showed that the AUC in combined diagnosis of the three miRNAs was 0.742, and the diagnostic sensitivity and specificity were 0.568 and 0.861, respectively. In the biological process analysis, all the 3 miRNAs were involved in transcription, DNA-templated and positive regulation of transcription from RNA polymerase II promoter. At the same time, the related pathways were involved in TGF-ß signaling pathway, AMPK signaling pathway, Wnt signaling pathway, MAPK signaling pathway, cGMP-PKG and cAMP signaling pathway, etc. CONCLUSION: miR-192-5p, miR-194-5p and miR-1246 in serum exosomes might be a potential biomarker for AIDS combined with TM infection patients, which may be involved in TGF-ß signaling pathway, AMPK signaling pathway, Wnt signaling pathway, MAPK signaling pathway, cGMP-PKG and cAMP signaling pathway, etc. Further research is needed on the biological functions and mechanisms of these miRNAs.

New insights into the antibacterial and quorum sensing inhibition mechanism of Artemisia argyi leaf extracts towards Pseudomonas aeruginosa PAO1.

This study aimed to investigate the anti-quorum sensing (QS) activity of Artemisia argyi leaf extracts (AALE) towards Pseudomonas aeruginosa PAO1 as well as the underlying molecular mechanisms. Using a biosensor Chromobacterium violaceum CV026, AALE were found to have anti-QS activity as AALE treatment significantly inhibited the violacein production of C. violaceum CV026 while produced little effect on the cell growth. Beyond that a higher dosage of AALE inhibited cell growth, sub-MIC of AALE significantly reduced the production of QS-regulated virulence factors (pyocyanin, elastase, and rhamnolipid), biofilm formation, and the swarming and swimming motility in P. aeruginosa PAO1 with a dosage-dependent manner. Quantitative real-time PCR (qRT-PCR) analysis did not detect the direct inhibitory effect of AALE on the expression of QS genes (lasI, lasR, rhlI, and rhlR). By iTRAQ-based quantitative proteomic analysis, 129 proteins were found to be differentially expressed upon AALE treatment, with 85 upregulated and 44 downregulated proteins, respectively. Functional enrichment analysis of the differential proteins revealed that AALE exerted anti-QS activity towards P. aeruginosa PAO1 by upregulating the expression of the global regulator CsrA, inducing oxidative stress, and perturbing protein homeostasis. Moreover, the inhibitory effect of AALE on the virulence of P. aeruginosa PAO1 was likely to be achieved by attenuating the expression of QS-regulated genes instead of QS genes. Collectively, the results of this study provide a basis for the future use of AALE as a preservative in controlling food spoilage caused by P. aeruginosa. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02663-5.

Interparental Hostility Interacts with Interparental Cooperative Conflict to Predict Adolescent Social Competence Through Parent-Child Relationship Quality.

An emerging (yet still scant) body of research has linked interparental hostility to youth compromised social competence over time among adolescents. Moreover, little is known about the conditions under which and the processes through which this association might occur. Using prospective data from 878 youth (50.23% females) and their parents and teachers, this study examined how interparental hostility and cooperative conflict might work in conjunction with each other to predict youth social competence over time via parent-child relationship quality. Results demonstrated that interparental cooperative conflict at grade 5 buffered the negative association between interparental hostility at grade 5 and mother-child but not father-child relationship quality at grade 6. Mother-child relationship quality, in turn, was associated positively with youth social competence at age 15. As such, interparental hostility at grade 5 was negatively related to youth social competence at age 15 via mother-child relationship quality at grade 6 only when interparental cooperative conflict at grade 5 was low. This study represents a more nuanced and specific examination of the implications of interparental hostility for child later social development by highlighting underlying moderating and mediating mechanisms. Relevant implications for the development of more targeted and effective interventions are also discussed.

Un número cada vez mayor (aunque aún escaso) de investigaciones han vinculado la hostilidad interparental con la competencia social comprometida de los jóvenes conforme avanza el tiempo entre adolescentes. Además, se sabe poco acerca de las condiciones en las cuales podría producirse esta asociación, así como acerca de los procesos por los cuales podría producirse. Utilizando datos prospectivos de 878 jóvenes (el 50.23 % de sexo femenino) y de sus padres y maestros, este estudio analizó cómo la hostilidad interparental y el conflicto cooperativo podrían funcionar en conjunto para predecir la competencia social de los jóvenes conforme avanza el tiempo mediante la calidad de la relación entre padres e hijos. Los resultados demostraron que el conflicto cooperativo interparental en el grado 5 amortiguó la asociación negativa entre la hostilidad interparental en el grado 5 y una menor calidad de la relación entre madre e hijo, pero no entre padre e hijo, en el grado 6. La calidad de la relación entre madre e hijo, a su vez, estuvo asociada positivamente con la competencia social de los jóvenes a los 15 años. Como tal, la hostilidad interparental en el grado 5 estuvo asociada negativamente con la competencia social de los jóvenes a los 15 años mediante la calidad de la relación entre madre e hijo en el grado 6 solo cuando el conflicto cooperativo interparental en el grado 5 fue bajo. Este estudio representa un análisis más matizado y específico de las implicancias de la hostilidad interparental para el desarrollo social posterior de los niños destacando un posible factor moderador y mecanismo de mediación. Se debaten algunas implicancias relevantes para el desarrollo de intervenciones más dirigidas y eficaces.

No Increase in HIV Drug Resistance Mutations among Injecting Drug Users on Methadone Maintenance Therapy: A Prospective Cohort Study.

BACKGROUND: Whether HIV-positive injecting drug users (IDUs) are at higher risk of developing drug resistance mutations (DRMs) after methadone maintenance therapy (MMT) than any other HIV-positive population is unclear. OBJECTIVE: To compare the incidence of new DRMs in two population groups: antiretroviraltreatment (ART) HIV-positive IDUs and non-drug users. METHODS: A prospective cohort of ART HIV-positive patients including IDUs who received MMT (MMT group) and non-drug users (N-MMT group) was established from April 2016 to December 2017 in Guangxi, China. RESULTS: Of the 80 participants, 43 were in the MMT group and 37 were in the N-MMT group. Compared with the N-MMT group, the HRs of PIs, NRTIs and NNRTIs for new DRMs in the MMT group was 1.55 (95%CI: 0.28-8.64; P = 0.616), 1.51 (95%CI: 0.44-5.20; P = 0.512) and 0.45 (95%CI: 0.15-1.35; P = 0.155), respectively. There was no dose-response relationship between MMT and new DRMs for PIs, NRTIs and NNRTIs (P > 0.05). The new DRM incidence for NRTIs (138.23 per 104 person-months) was higher than for PIs (94.16 per 104 person-months) and NNRTIs (95.41per 104 person-months) in the MMT group, while the new DRM incidence for NNRTIs (208.24 per 104 person-months) was higher than for PIs (44.13 per 104 person-months) and NRTIs (91.78 per 104 person-months) in the N-MMT group. CONCLUSION: Among ART HIV-positive patients, there is no significant difference in the incidence of new DRMs between IDUs receiving MMT and non-drug users. MMT has little impact on the development of DRMs among IDUs.

Design, Synthesis and Bioactive Evaluation of Oxime Derivatives of Dehydrocholic Acid as Anti-Hepatitis B Virus Agents.

Oxime derivatives of dehydrocholic acid and its esters were designed for anti-hepatitis B virus (HBV) drugs according to principles of assembling active chemical fragments. Twelve compounds were synthesized from dehydrocholic acid by esterification and oxime formation, and their anti-hepatitis B virus (HBV) activities were evaluated with HepG 2.2.15 cells. Results showed that 5 compounds exhibited more effective inhibition of HBeAg than positive control, among them 2b-3 and 2b-1 showed significant anti-HBV activities on inhibiting secretion of HBeAg (IC50 (2b-3) = 49.39 ± 12.78 µM, SI (2b-3) = 11.03; IC50 (2b-1) = 96.64 ± 28.99 µM, SI (2b-1) = 10.35) compared to the Entecavir (IC50 = 161.24 µM, SI = 3.72). Molecular docking studies showed that most of these compounds interacted with protein residues of heparan sulfate proteoglycan (HSPG) in host hepatocyte and bile acid receptor.

Enhanced Signaling Through the TLR9 Pathway Is Associated With Resistance to HIV-1 Infection in Chinese HIV-1-Exposed Seronegative Individuals.

Innate immunity is the first line of defense against invading pathogens and may mediate HIV-1 resistance in HIV-1-exposed seronegative (HESN) individuals. This study aims to identify components of innate immunity that confer natural HIV-1 resistance in Chinese HESN individuals. Specifically, we compared the expression levels of Toll-like receptors (TLRs) and associated pathway molecules in peripheral blood mononuclear cells (PBMCs), monocytes/macrophages, and plasma obtained from HESN and control individuals. HESN individuals had higher expression of TLR9, IRF7, IFN-α/ß, RANTES, and MIP-1α/1ß in PBMCs and plasma than control subjects. Upon TLR9 stimulation, significantly higher expression of TLR9 and IRF7, as well as higher production of IFN-α/ß, RANTES, and MIP-1α/1ß, was observed in PBMCs and monocytes/macrophages from HESN individuals than in the corresponding cells from control individuals. More importantly, both with and without TLR9 stimulation, the levels of HIV-1 replication in monocyte-derived macrophages (MDMs) from HESN individuals were significantly lower than those in MDMs from control individuals. These data suggest that increased TLR9 activity and subsequent release of antiviral factors contribute to protection against HIV-1 in HESN individuals.

A four-wave, cross-lagged model of problematic internet use and mental health among Chinese college students: Disaggregation of within-person and between-person effects.

Based on 4 annual waves of data from a large sample of Chinese college students (N = 2,329, Mage = 18.40 years old, SD = .85; 63.10% females), this study examines the within-person and between-person effects in the association between problematic Internet use (PIU) and mental health issues. Results of analyses using the developmental equilibrium model (i.e., an autoregressive, cross-lagged panel model) demonstrate a reciprocal positive association between PIU and mental health issues consistently across waves. In contrast, results of analyses utilizing the random intercept, cross-lagged panel model (i.e., a model that can disaggregate within-person and between-person effects) indicate a unidirectional positive within-person effect from PIU to mental health issues (rather than the reverse) consistently over time, while controlling for the between-person effects that exist when comparing different individuals. Such findings highlight the importance of disaggregating within-person and between-person effects in understanding the nature of the temporal dynamics of the association between PIU and mental health. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Migrant female sex workers working at the Sino-Vietnamese border for a short time have a higher risk of HIV transmission: a consecutive cross-sectional study.

OBJECTIVES: For migrant female sex workers (FSWs) at the Sino-Vietnamese border, the impact of work time in their current location on the spread of HIV/AIDS is not clear. METHODS: Data were collected from the Sino-Vietnamese border cities of Guangxi, China. Migrant FSWs working in these cities were studied. FSWs who worked less than 6 months in their current location were assigned to the short-term work group (ST FSWs), and FSWs who worked equal to or longer than 6 months in their current location were assigned to the long-term work group (LT FSWs). Logistic regression was performed to examine the impact of work time in the current location and factors associated with HIV infection. RESULTS: Among the 1667 migrant FSWs, 586 (35.2%) and 1081 (64.9%) were assigned to the ST FSW and LT FSW groups, respectively. Compared to LT FSWs, ST FSWs were more likely to be of Vietnamese nationality, be less than 18 years old when they first engaged in commercial sex work, and have a low-level of HIV-related knowledge and had higher odds of using condoms inconsistently, having more male clients, having no regular male clients, and having a history of male clients who used aphrodisiacs but lower odds of receiving free condoms distribution and education/HIV counselling and testing programme. The analysis of factors associated with HIV infection revealed that Vietnamese FSWs, less than 18 years old when they first engaged in commercial sex work, having no regular male clients, and having lower average charge per sex transaction were correlated with HIV infection. CONCLUSION: FSWs with short-term work at the Sino-Vietnamese border had a higher risk of risky sex and were correlated with HIV risk factors. Vietnamese FSWs were at higher risk of HIV infection, and they were more likely to have short-term work. More targeted HIV prevention should be designed for new FSWs who recently began working in a locality to further control the spread of HIV, particularly cross-border FSWs.

Vietnamese female sex workers in rural cross-border areas of Guangxi, China: migration and HIV/STI risk behaviors.

China's HIV/AIDS epidemic continues to grow in rural and less developed areas. This consecutive cross-sectional study examines demographic and behavioral factors associated with HIV/STI infection, Hepatitis C (HCV) and other sexually transmitted infections (STIs) among Vietnamese female sex workers (FSW), a vulnerable population who cross into Guangxi, China. This study is a secondary data analysis of 303 Vietnamese and 4,348 Chinese FSWs recruited over seven years from two Chinese counties that border Vietnam. Logistic regression models compared demographics, HIV/STI status, HIV/AIDS-related knowledge, attitudes, and risk behaviors between Vietnamese FSWs and Chinese FSWs. Compared with Chinese FSWs, Vietnamese FSWs were younger, had attained lower education levels, were highly mobile, more likely to report using drugs, and were more vulnerable to HIV/STIs. Younger age, less educational attainment, shorter time in their current working location, no voluntary HIV testing in the last year, greater drug use, and not using condoms for all commercial sex in the last month were associated with higher HIV/STIs. In conclusion, several factors were associated with HIV/STI risk in Vietnamese cross-border FSWs. There is a pressing need to improve support systems for Vietnamese cross-border FSW and health system cooperation across the Chinese/Vietnamese border.

Deguelin inhibits HCV replication through suppressing cellular autophagy via down regulation of Beclin1 expression in human hepatoma cells.

AIMS: Deguelin, a natural compound derived from Mundulea sericea (Leguminosae) and some other plants exhibits an activity to inhibit autophagy, a cellular machinery required for hepatitis C virus (HCV) replication. This study aimed to illuminate the impact of deguelin on HCV replication and mechanism(s) involved. METHODS: HCV JFH-1-Huh7 infectious system was used for the investigation. Real time RT-PCR, Western blot, fluorescent microscopy assay were used to measure the expression levels of viral or cellular factors. Overexpression and silencing expression techniques were used to determine the role of key cellular factors. RESULTS: Deguelin treatment of Huh7 cells significantly inhibited HCV JFH-1 replication in a dose- and time-dependent manner. Deguelin treatment suppressed autophagy in Huh7 cells, evidenced by the decrease of LC3B-II levels, the conversion of LC3B-I to LC3B-II, and the formation of GFP-LC3 puncta as well as the increase of p62 level in deguelin-treated cells compared with control cells. HCV infection could induce autophagy which was also suppressed by deguelin treatment. Mechanism research reveals that deguelin inhibited expression of Beclin1, which is a key cellular factor for the initiation of the autophagosome formation in autophagy. Overexpression or silencing expression of Beclin1 in deguelin-treated Huh7 cells could weaken or enhance the inhibitory effect on autophagy by deguelin, respectively, and thus partially recover or further inhibit HCV replication correspondingly. CONCLUSIONS: Deguelin may serve as a novel anti-HCV compound via its inhibitory effect on autophagy, which warrants further investigation as a potential therapeutic agent for HCV infection.

Career-Related Parental Processes and Career Adaptability and Ambivalence Among Chinese Adolescents: A Person-Centered Approach.

Using latent profile analyses and based on two-wave data from 5,388 Chinese adolescents (Mage  = 15.79, SD = 0.66; 51.99% females), this study examined the variety of ways in which adolescents' perceived career-related parental processes (i.e., parental expectations, support, interference, barriers to engagement, and parent-child congruence) may be configured within families and how such configurations may be associated with adolescents' career adaptability and ambivalence one year later. Three meaningful profiles were identified: the "Supportive but not Intrusive" (SNI) profile, the "Unsupportive but not Permissive" (UNP) profile, and the "Ambivalent and Controlling" (AC) profile. Adolescents in the UNP profile reported higher levels of career ambivalence and lower levels of career adaptability than did those in either the SNI or the AC profiles. Implications for career development among Chinese adolescents were discussed.

Effects of cotrimoxazole prophylaxis on Talaromyces marneffei infection in HIV/AIDS patients receiving antiretroviral therapy: a retrospective cohort study.

The dimorphic fungus Talaromyces marneffei (TM) is a common cause of HIV-associated opportunistic infections in Southeast Asia. Cotrimoxazole (CTX) inhibits folic acid synthesis which is important for the survival of many bacteria, protozoa, and fungi and has been used to prevent several opportunistic infections among HIV/AIDS patients. We question whether CTX is effective in preventing TM infection. To investigate this question, we conducted an 11-year (2005-2016) retrospective observational cohort study of all patients on the Chinese national antiretroviral therapy (ART) programme in Guangxi, a province with high HIV and TM burden in China. Survival analysis was conducted to investigate TM cumulative incidence, and Cox regression and propensity score matching (PSM) were used to evaluate the effect of CTX on TM incidence. Of the 3359 eligible individuals contributing 10,504.66 person-years of follow-up, 81.81% received CTX within 6 months after ART initiation, and 4.73% developed TM infection, contributing 15.14/1,000 person-year TM incidence rate. CTX patients had a significantly lower incidence of TM infection than non-CTX patients (4.11% vs. 7.53%; adjusted hazard ratio (aHR) = 0.50, 95% CI 0.35-0.73). CTX reduced TM incidence in all CD4+ cell subgroups (<50 cells/µL, 50-99 cells/µL, 100-199 cells/µL), with the highest reduction observed in patients with a baseline CD4+ cell count <50 cells/µL in both Cox regression and the PSM analyses. In conclusion, in addition to preventing other HIV-associated opportunistic infections, CTX prophylaxis has the potential to prevent TM infection in HIV/AIDS patients receiving ART.

Berbamine exerts anticancer effects on human colon cancer cells via induction of autophagy and apoptosis, inhibition of cell migration and MEK/ERK signalling pathway.

PURPOSE: Berbamine is a plant-derived alkaloid with amazing and wide diversity of pharmacological properties which range from antimicrobial and anticancer. Nonetheless, the anticancer properties of Berbamine have not been thoroughly evaluated against colon cancer cells. This study was undertaken to evaluate the anticancer effects of Berbamine against human colon cancer cells (HT-29 colon cancer cells). Μethods: CCK-8 assay was used to determine the cell viability. DAPI and propidium iodide (PI) staining assays were used for the detection of apoptosis. Electron microscopy was used for the determination of autophagy. Wound healing assay was used to monitor cell migration. Protein expression was determined by western blotting. RESULTS: The results showed that Berbamine caused a remarkable decrease in the HT-29 cell viability with an IC50 of 14 µM, while the high IC50 of Berbamine against the normal CDD-18Co cells indicated low toxicity of this molecule against the normal cells. DAPI and PI staining assays showed nuclear fragmentation, indicative of apoptosis in HT-29 cells. Berbamine also caused activation of caspase-3 and 9 and increased the Bax/Bcl-2 ratio. Electron microscopic analysis showed that Berbamine triggered the development of autophagic vesicles in the HT-29 cells which was concomitant with the increase in protein levels of LC3B-I, ATG-5, ATG-12 and Beclin-1. Wound healing assay showed that Berbamine decreased the migration potential of the HT-29 and also blocked the MEK/ERK signalling pathway in colon cancer cells. CONCLUSION: Berbamine may prove an efficient lead molecule for the development of more potent anticancer agents through semi-synthetic approaches.