Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.

Dynamic m6 A profiles reveal the role of YTHDC2-TLR2 signaling axis in Talaromyces marneffei infection.

Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N6 -methyladenosine (m6 A) plays important roles in host immune response to various pathogen infections, yet its role in TM and HIV/TM coinfection remains largely unexplored. Here we reported genome-wide transcriptional m6 A profiles of TM mono-infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m6 A levels and upregulation of the m6 A reader YTH N6 -methyladenosine RNA binding protein C2 (YTHDC2) in TM-infected macrophages. Knockdown of YTHDC2 in TM-infected cells showed an elevated expression of TLR2 through m6 A-dependence, along with upregulation of TNF-α and IL1-ß. Overall, we characterized the m6 A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m6 A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases.

Critical roles of mitochondrial fatty acid synthesis in tomato development and environmental response.

Plant mitochondrial fatty acid synthesis (mtFAS) appears to be important in photorespiration based on the reverse genetics research from Arabidopsis (Arabidopsis thaliana) in recent years, but its roles in plant development have not been completely explored. Here, we identified a tomato (Solanum lycopersicum) mutant, fern-like, which displays pleiotropic phenotypes including dwarfism, yellowing, curly leaves, and increased axillary buds. Positional cloning and genetic and heterozygous complementation tests revealed that the underlying gene FERN encodes a 3-hydroxyl-ACP dehydratase enzyme involved in mtFAS. FERN was causally involved in tomato morphogenesis by affecting photorespiration, energy supply, and the homeostasis of reactive oxygen species. Based on lipidome data, FERN and the mtFAS pathway may modulate tomato development by influencing mitochondrial membrane lipid composition and other lipid metabolic pathways. These findings provide important insights into the roles and importance of mtFAS in tomato development.

Spectrum and mortality of opportunistic infections among HIV/AIDS patients in southwestern China.

We describe the opportunistic infections (OIs) of HIV/AIDS to understand the spectrum, mortality, and frequency of multiple coinfected OIs among HIV/AIDS patients in southern China, where OIs are severe. We carried out a retrospective cohort study of hospitalized HIV-infected individuals at the Fourth People's Hospital of Nanning, Guangxi, China, from Jan. 2011 to May. 2019. The chi-square test was used to analyze cross-infection; the Kaplan‒Meier analysis was used to compare mortality. A total of 12,612 HIV-infected patients were admitted to this cohort study. Among them, 8982 (71.2%) developed one or more OIs. The overall in-hospital mortality rate was 9.0%. Among the patients, 35.6% coinfected one OI, and 64.4% coinfected more than two OIs simultaneously. Almost half of the patients (60.6%) had CD4 + T-cell counts < 200 cells/µL. Pneumonia (39.8%), tuberculosis (35.3%), and candidiasis (28.8%) were the most common OIs. Coinfected cryptococcal meningitis and dermatitis are the most common combined OIs. The rate of anaemia (17.0%) was highest among those common HIV-associated complications. Multiple OIs are commonly found in hospitalized HIV/AIDS patients in southwestern China, which highlights the need for improved diagnosis and treatment.

Acceptance of COVID-19 vaccination and influencing factors among people living with HIV in Guangxi, China: a cross-sectional survey.

BACKGROUND: Vaccination has been proven to be an effective approach against the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to determine the acceptance rate and factors influencing acceptance of COVID-19 vaccination among people living with HIV (PLWH) in Guangxi, China. METHODS: A cross-sectional survey was carried out in five cities in Guangxi, China from May 7 to June 1, 2021. Questionnaires on the acceptance of COVID-19 vaccination and the related factors were conducted among PLWH recruited by simple random sampling. Univariate and multivariate logistic regression analyses were performed to identify factors associated with acceptance of COVID-19 vaccination. RESULTS: Of all valid respondents (n = 903), 72.9% (n = 658) were willing to receive COVID-19 vaccination. Fear of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was the main reason for being willing to receive vaccination (76.0%), while the main reasons for not willing were the concerns about vaccine safety (54.7%) and the vaccination's effect on antiretroviral therapy (ART) (50.6%). The most important factors influencing acceptance were the perception that vaccination is unsafe for HIV-infected people (aOR = 0.082, 95% CI = 0.024-0.282) and the poor efficacy in preventing SARS-CoV-2 infection in HIV-infected people (aOR = 0.093, 95% CI = 0.030-0.287). Other factors associated with acceptance included Zhuang ethnicity (aOR = 1.653, 95% CI = 1.109-2.465), highest education level of middle school, high school or above (aOR = 1.747, 95% CI = 1.170-2.608; aOR = 2.492, 95% CI = 1.326-4.682), and the vaccination having little effect on ART efficacy (aOR = 2.889, 95% CI = 1.378-6.059). CONCLUSIONS: Acceptance rate of the COVID-19 vaccination is relatively low among PLWH compared to the general population in China, although some patients refused vaccination due to concerns about vaccine safety and vaccination affecting ART efficacy. More research is needed to investigate the impact of the COVID-19 vaccines on ART efficacy and the effectiveness in preventing SARS-CoV-2 infection among PLWH.

Effect and Mechanism of Cotrimoxazole Against Talaromyces marneffei in vitro.

BACKGROUND: Talaromyces marneffei (formerly Penicillium marneffei) is an important thermally dimorphic fungus endemic which is characterized by one of the most frequent opportunistic infections in HIV/AIDS patients, mainly prevalent in Southeast Asia, southern China, and northeastern India. Cotrimoxazole(CTX) inhibits folic acid synthesis which is important for the survival of many bacteria, protozoa, and fungi, thereby commonly used to prevent several opportunistic infections among HIV/AIDS patients. In addition to preventing other HIV-associated opportunistic infections, CTX prophylaxis are considered to have the potential to prevent T. marneffei infection in HIV/AIDS patients receiving antiretroviral therapy (ART). However, the effect of cotrimoxazole towards T. marneffei fungus in vitro remains unclear. METHODS: Human THP-1 macrophages were used as cell model in vitro to explore the effect and mechanism of cotrimoxazole resistance towards T. marneffei. Cell viability assay and drug sensitivity colony forming units (CFU) experiments were conducted to determine the minimum inhibitory concentration (MIC) of cotrimoxazole inside and outside THP-1 macrophages respectively. Enzyme-linked immunosorbent assay (Elisa) was used to measure the concentration of Dihydropteroic acid synthetase (DHPS), Dihydrofolate synthetase (DHFS) and Dihydrofolate reductase (DHFR) between T. marneffei adding TMP/SMX and without adding TMP/SMX group respectively. Real-time fluorescence quantitative PCR(qPCR) was performed to detect the mRNA expression levels in Dectin-1 mediated signaling pathway and downstream inflammatory cytokines including IL-6, IL-10, IL-23A, CXCL8 and TNF-α released by T. marneffei-infected macrophages between adding TMP/SMX and without adding TMP/SMX group respectively. RESULTS: Cotrimoxazole can inhibit the proliferation of T. marneffei within safe concentration inside and outside THP-1 macrophages. Drug susceptibility results showed the minimal inhibit concentration(MIC) of 1:5 TMP/SMX was ranging from 14/70 to 68/340 µg/ml. The MIC of SMX was ranging from 100 to 360 µg/ml. The MIC of TMP was ranging from 240 to 400 µg/ml outside macrophages. The MIC of TMP/SMX was ranging from 36/180 to 68/340 µg/ml. The MIC of SMX was ranging from 340 to 360 µg/ml. The MIC of TMP was ranging from 320 to 400 µg/ml inside macrophages. The synergistic interaction of 1:5 TMP/SMX was more effective in inhibiting T. marneffei than separate SMX and TMP. DHPS, DHFS and DHFR can be inhibited by cotrimoxazole within safe and effective concentration. Dectin-1 expression is increased following T. marneffei infection, leading to the increase of IL-6, IL-10, IL-23A and the decrease of CXCL8 and TNF-α. Conversely, cotrimoxazole decrease the levels of Dectin-1, IL-6, IL-10, IL-23A and increase the levels of CXCL8 and TNF-α, thereby enhancing the intracellular killing-T. marneffei capacity of macrophages. CONCLUSIONS: Our findings indicated that cotrimoxazole directly inhibited T. marneffei growth by blocking DHPS, DHFS and DHFR and indirectly inhibited T. marneffei growth perhaps by regulating the Dectin-1 signaling pathway, which may effectively interfere with the defense ability of the host against T. marneffei infection.

Multiresidue Pesticide Analysis in Tea Using GC-MS/MS to Determine 12 Pesticide Residues (GB 2763-2021).

Pesticides are widely used on tea plants, and pesticide residues are of significant concern to consumers. The National Food Safety Standard Maximum Residue Limits for Pesticides in Food (GB 2763-2021) was recently amended. However, detection methods for pesticides newly added to the list of residues in beverages have not yet been established. For that reason, this study developed a solid-phase extraction (SPE) and gas chromatography-tandem mass spectrometry (GC-MS/MS) method for determining the residues of 12 pesticides, including four newly added, in black and green tea. Sample preparation processes (sample extraction, SPE clean-up, elution solvent, and elution volume) were optimized to monitor these residues reliably. Multiple reaction monitoring (MRM) was used for GC-MS/MS electron impact (EI) mode determination. Finally, satisfactory recoveries (70.7-113.0% for green tea and 72.0-99.1% for black tea) were achieved at three concentrations (10 µg/kg, 20 µg/kg, and 100 µg/kg). The LOQs were 0.04-8.69 µg/kg, and the LODs were 0.01-3.14 µg/kg. This study provides a reliable and sensitive workflow for determining 12 pesticide residues in tea, filling a gap in the newly revised National Standards.

Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design.

SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM-GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.

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.

Effect of AIDS-defining events at initiation of antiretroviral therapy on long-term mortality of HIV/AIDS patients in Southwestern China: a retrospective cohort study.

OBJECTIVE: To evaluate the impact of AIDS-defining events (ADE) on long-term mortality of HIV positive individuals on antiretroviral therapy (ART), a retrospective HIV/AIDS treatment cohort study performed in Southwestern China. METHODS: The retrospective cohort was conducted among 6757 HIV/AIDS patients on ART (2NRTIs + 1NNRTI, 2NRTIs + 1PI and Single or two drugs) recruited in Guigang city, Guangxi, China, from January 2004 to December 2018. Participants were divided into ADE and non-ADE groups, and were followed-up every six months to observe treatment outcomes. Comparison of mortality between groups was performed using the log-rank test and Kaplan-Meier analysis. Cox proportional hazard regression was used to explore the risk factors of mortality. 1:1 propensity score matching (PSM) was used to balance confounding factors and adjust the mortality risk. RESULTS: Of 6757 participants with 29,096.06 person-years of follow-up, 16.86% (1139/6757) belonged to ADE group while the others (83.14%) belonged to the non-ADE group. The most common cause of death by ADE was disseminated mycosis (31.65%), followed by recurrent severe bacterial pneumonia (28.48%), herpes zoster (17.72%), and extra-pulmonary tuberculosis (8.86%). The mortality of the ADE group was significantly higher than that of the non-ADE group [3.45/100 person-years (95% CI 2.92-3.97) vs. 2.34/100 person-years (95% CI 2.15-2.52), P<0.001]. The death risk of the ADE group was also higher than that of the non- ADE group [adjusted hazard ratio (aHR) = 1.291, 95% CI 1.061-1.571, P = 0.011], which was confirmed by PSM analysis (aHR = 1.581, 95% CI 1.192-2.099, P = 0.002). Cox analysis indicated that ADE, older age, male gender, previous non-use of cotrimoxazole, advanced WHO clinical stage, and low baseline CD4+ cell count were the risk factors for death. CONCLUSIONS: Even on ART, the mortality risk of HIV positive individuals with ADE was higher than those without ADE. Active testing, earlier diagnosis, and timely therapy with ART may reduce the death risk of ADE.

HIV late presentation and advanced HIV disease among patients with newly diagnosed HIV/AIDS in Southwestern China: a large-scale cross-sectional study.

OBJECTIVE: This study aimed to investigate the prevalence of HIV late presentation and advanced HIV disease and to identify the factors associated with HIV late presentation and advanced HIV disease among patients with newly diagnosed HIV/AIDS in the Guangxi Zhuang Autonomous Region, in Southwestern China. METHODS: Patients with newly diagnosed HIV registered in the HIV surveillance system of Guangxi Centers for Disease Control between January 2012 and December 2016 were included in this study. RESULTS: Of 45,118 newly diagnosed patients, 70.2% had late presentation, and 45.1% had advanced HIV disease. A higher prevalence of late presentation and advanced HIV disease was found in male heterosexuals and female people who use drugs (PWID). Heterosexuals (OR 2.11 [95% CI 1.90-2.34]) and PWID (OR 1.55 [95% CI 1.30-1.84]) had a higher risk of late presentation than men who have sex with men (MSM). Blood testing of the blood receivers (OR 1.75 [95% CI 1.36-2.26]) and diagnosed in hospital (OR 1.74 [95% CI 1.65-1.84]) had an increased risk of late presentation compared to those who diagnosis in voluntary counseling and testing (VCT). Heterosexuals (OR 2.86 [95% CI 2.51-3.27]), PWID (OR 2.23 [95% CI 1.83-2.71]), blood testing of the blood receivers (OR 1.58 [95% CI 1.29-1.94]) and diagnosed in hospital (OR 1.85 [95% CI 1.76-1.94]) were also independent risk factors associated with advanced HIV disease. Older age, lower level of education and being divorced or widowed were also associated with late presentation and advanced HIV disease. CONCLUSIONS: Late presentation and advanced HIV disease were very common among patients with newly diagnosed HIV in Guangxi, China during 2012-2016. Targeted programs are urgently required to reduce HIV late diagnosis in Guangxi, especially for male heterosexuals, PWID, and patients with characteristics such as older age, lower level of education, divorced or widowed.

No Difference in Prevalence of Transmitted Drug Resistance between Injection Drug Users and Non-Injection Drug Users: A Cross-Sectional Study among Antiretroviral Treatment-Naïve HIV Patients.

OBJECTIVES: The epidemiological evidence is inconsistent about whether HIV-positive injection drug users (IDUs) are at higher risk of developing antiretroviral resistance than any other HIV-positive populations. This study aims to investigate and compare transmitted drug resistance (TDR) between IDUs and non-IDUs in Lingshan County, an HIV-hit region in Guangxi, China, where IDU and heterosexual transmission were the two dominant transmission routes and roughly equally contributed to the local HIV transmission. METHODS: A cross-sectional study was conducted among newly diagnosed and antiretroviral-treatment (ART)-naïve HIV-1 patients from Lingshan County. The pol gene of HIV-1 from the individuals was sequenced followed by genotyping and TDR analysis. RESULTS: Two dominant transmission routes, heterosexual contact and IDU, accounted for 49.2 and 45.9% of 183 HIV-1 infection cases, respectively. Three genotypes, including CRF08_BC (70.6%), CRF01_AE (24.4%), and CRF07_BC (5.0%), and three unique recombinant forms (1.6%), were identified. There was a significant difference in genotype distribution among the different transmission routes (F = 21.814, p < 0.001). The overall TDR prevalence was 5.5%. There were no significant differences in TDR prevalence among the different transmission routes (F = 1.420, p = 0.439). CONCLUSIONS: Injection drug use has little impact on TDR prevalence compared with other routes of transmission.

Epidemiological characteristics of asymptomatic Norovirus infection in a population from oyster (Ostrea rivularis Gould) farms in southern China.

The following paper investigates the prevalence and characteristics of asymptomatic norovirus infection in the population living around oyster farm sites. Two consecutive surveys were conducted from January 2014 to December 2014 and 4549 stool samples were screened during the same time period. The total asymptomatic infection rate was 4.04% (184/4549). Norovirus infection rate was 5.20% in oyster farming population which was significantly higher compared with non-farming population where the infection rate was 3.65% (χ2 = 5.49, P < 0.05). A total of 184 NoV positive samples were identified by real time-quantitative polymerase chain reaction (RT-qPCR) and semi-nested RT-PCR and 136 sequences were obtained. The sequences were clustered into 14 genotypes. GI strains were clustered into six genotypes, including GI.2, GI.3, GI.5, GI.6, GI.8 and GI.9; while GII strains were clustered into GII.2, GII.3, GII.4, GII.5, GII.6, GII.8 and GII.13. GI.9 and GII.17 were the predominant and most prevalent genotypes, respectively. The GII.17 genotype replaced GII.4 becoming the dominant genotype in the oyster farming area in 2014. To sum up, long-term monitoring of asymptomatic infection is crucial for the detection of new variant strains and for identifying outbreaks during the early stage.

[Norovirus infection surveillance in early warning of outbreaks in population in oyster farming areas].

OBJECTIVE: To have an insight into the prevalence tendency caused by Noroviruses( NoVs) in population of oyster farming areas, and evaluate the early warning signification of acute gastroenteritis( AGE) monitoring. METHODS: Between January and December in 2014, a retrospective household survey of AGE during past four weeks was conducted to residents using multi-stage sampling in oyster farming areas. Norovirus capsid genome was detected using real-time RT-PCR and semi-nested PCR, sequenced and phylogenetic analyzed. RESULTS: A total of 75 cases of AGE were reported. The incidence rate was 0. 10 per person-year, the detection rate of norovirus was 20. 0%( 15 /75). The dominant epidemic No Vs strain in oyster farming was still GII. 4 Sydney 2012. Furthermore, a newly GII. 17 variant was detected and early in March 2014. CONCLUSION: The GII. 4 Sydney 2012 genotype is still prevalent strain that caused AGE currently in the community residents of oyster farming areas. NoVs GII. 17 variant was found in sporadic patients of sentinel hospital AGE monitoring in March 2014 that have an early warning effect to the outbreaks of winter in 2014.

[Distribution of subtypes of pol gene in HIV-1 epidemic strains in Guangxi Zhuang Autonomous Region, 2010- 2012].

OBJECTIVE: To investigate the distribution and proportion of subtypes of pol gene in HIV-1 epidemic strains in Guangxi Autonomous Region. METHODS: 152 HIV-1 patients were enrolled from 11 cities in Guangxi Autonomous Region from 2010 to 2012 by convenient sampling. Inclusion criterias were listed as the fdlowing: HIV-1 infection was confirmed by Western blot, HIV-1 viral load >1 000 copies/ml, > 18 year-old, and without any serious illnesses. 5 ml of peripheral blood samples were obtained from each patient. The viral RNA was isolated from plasma and used for amplification of full-length pol gene by nested RT-PCR. The amplified products were sequenced. After editing and modification, all sequences were characterized for preliminary subtyping by genotyping and confirmed with phylogenetic tree constructed by MEGA 5.03 software. The recombinant identification of 2 unknown recombinant strains was determined by RIP and jpHMM at GOBICS. RESULTS: Among 152 patients, 137 full-length pol genes were successfully amplified and 127 HIV-1 subtypes were identified. The distribution and proportion of subtypes was summarized as the following 71 cases of CRF01_AE, accounting for 55.9% (71/127), 38 CRF08_BC, 29.9% (38/127), 13 CRF07_BC, 10.2% (13/127), and 3 B (B'), 2.4% (3/127), 2 unknown recombinant strains, 1.6% (2/127). In 11 cites of Guangxi Autonomous Region, subtype CRF01_AE was the dominant strain. Among heterosexual transmitted patients and drug abusers, the proportions of subtype CRF01_AE were 67.4% (58/86) and 34.1% (14/41), respectively. There was a significance different in the distribution of CRF01_AE in different routes of transmission (χ(2)=15.07, P<0.001). In age 21- 35, age 36- 60 and age>60 groups, the proportions of CRF01_AE was 43.6% (17/39), 57.6% (38/66), 77.3% (17/22), and CRF08_BC was 43.6% (17/39), 28.8% (19/66), 9.1% (2/22), respectively, the difference in proportions was significant(χ(2)=8.48, P= 0.014). The patterns of two unknown recombinant strains were found to be CRF01_AE/B (B') and CRF01_AE/C/B(B'), respectively. CONCLUSION: CRF01_AE was the dominant HIV-1 subtype in Guangxi Autonomous Region from 2010 to 2012, with heterosexual transmission as its main spreading route. The two unknown recombinant strains in Guangxi Autonomous Region were reconstructed by subtype CRF01_AE and CRF_BC.

[The efficacy of antiviral therapy and drug resistance analysis among HIV/AIDS patients with heroin addiction in Guangxi Zhuang Autonomous Region].

OBJECTIVE: To investigate the impact of heroin for antiviral treatment, drug resistance, mutation types and frequency in HIV/AIDS patients in Guangxi Zhuang Autonomous Region. METHODS: HIV/AIDS patients were recruited in Methadone Maintenance Treatment Clinics, HIV/AIDS Clinic and HIV Voluntary Counseling and Testing Center Liuzhou and Baise city from April 2008 to October 2009. The patients were grouped by the situation of antiviral treatment and use of heroin. A total of 435 HIV/AIDS patients were recruited, among which 108 cases in antiviral treatment and heroin group, 93 cases in antiviral treatment and never using drug group, 105 cases in no antiviral treatment and using heroin group, 129 cases in no antiviral treatment and never using drug group. The effect of antiviral treatment was evaluated by questionnaire survey, viral load measurement and CD4(+) T lymphocyte count. HIV-1 RNA from plasma was extracted, and then the pol genes were amplified and sequenced. The sequences were analyzed for HIV-1 genotype drug-resistance. RESULTS: For the patients who received antiviral treatment, the viral load in heroin group was higher than that in never using drug group (lg (2.61 ± 1.24) vs lg (2.08 ± 0.80), t = 3.54, P < 0.05) , and the percentage of viral load lower than 1 000 copies/ml in heroin group was significantly less than that in never using drug group (63.9% vs 86.0%,χ(2) = 12.76, P < 0.05). For the patients who received antiviral treatment, the difference has no significance in CD4(+) T lymphocyte count between heroin group and never using drug group ((337.92 ± 181.66) vs (326.14 ± 254.98), t = 0.38, P = 0.703). For the patients who didn't receive antiviral treatment, the difference also has no significance in CD4(+) T lymphocyte count between heroin group and never using drug group ((373.73 ± 155.97) vs (337.53 ± 209.26), t = 1.47, P = 0.143). For the patients who received antiviral treatment, there was no difference in the percentage of the CD4(+) T lymphocyte count more than 350/ml between heroin group and never using drug group (48.1% vs 43.0%, χ(2) = 0.53, P = 0.466). 319 HIV-1 pol gene sequences were obtained. Among the patients who received antiviral treatment, the mutation frequency of M184V/I, T215Y/F, L210W and T69N/S in heroin abuser group were significantly higher than that in never using drug group (14.9% (11/74) vs 4.4% (3/68), 12.2% (9/74) vs 1.5% (1/68), 12.2% (9/74) vs 1.5% (1/68) and 10.8% (8/74) vs 1.5% (1/68) respectively) (P < 0.05). CONCLUSION: Using heroin may promote HIV replication, reducing the virological response to antiviral treatment and increasing the frequencies of drug resistance loci among HIV/AIDS patients.Heroin rehabilitation may benefit from the antiviral treatment and obtain better antiviral effect.

Exploring the Mechanisms of Traditional Chinese Herbal Therapy in Gastric Cancer: A Comprehensive Network Pharmacology Study of the Tiao-Yuan-Tong-Wei decoction.

The use of herbal medicine as an adjuvant therapy in the management of gastric cancer has yielded encouraging outcomes, notably in enhancing overall survival rates and extending periods of disease remission. Additionally, herbal medicines have demonstrated potential anti-metastatic effects in gastric cancer. Despite these promising findings, there remains a significant gap in our understanding regarding the precise pharmacological mechanisms, the identification of specific herbal compounds, and their safety and efficacy profiles in the context of gastric cancer therapy. In addressing this knowledge deficit, the present study proposes a comprehensive exploratory analysis of the Tiao-Yuan-Tong-Wei decoction (TYTW), utilizing an integrative approach combining system pharmacology and molecular docking techniques. This investigation aims to elucidate the pharmacological actions of TYTW in gastric pathologies. It is hypothesized that the therapeutic efficacy of TYTW in counteracting gastric diseases stems from its ability to modulate key signaling pathways, thereby influencing PIK3CA activity and exerting anti-inflammatory effects. This modulation is observed predominantly in pathways such as PI3K/AKT, MAPK, and those directly associated with gastric cancer. Furthermore, the study explores how TYTW's metabolites (agrimoniin, baicalin, corosolic acid, and luteolin) interact with molecular targets like AKT1, CASP3, ESR1, IL6, PIK3CA, and PTGS2, and their subsequent impact on these critical pathways and biological processes. Therefore, this study represents preliminary research on the anticancer molecular mechanism of TYTW by performing network pharmacology and providing theoretical evidence for further experimental investigations.

Blood Lead Mediates the Relationship between Biological Aging and Hypertension: Based on the NHANES Database.

Hypertension remains a major global public health crisis due to various contributing factors, such as age and environmental exposures. This study delves into exploring the intricate association between biological aging, blood lead levels, and hypertension, along with examining the mediating role of blood lead levels in the relationship between biological aging and hypertension. We analyzed data from two cycles of the NHANES, encompassing 4473 individuals aged 18 years and older. Our findings indicate that biological aging potentially escalates the risk of hypertension and the incidences of systolic blood pressure (SBP) and diastolic blood pressure (DBP) abnormalities. Utilizing weighted quantile sum (WQS) and quantile g-computation (QGC) model analyses, we observed that exposure to heavy metal mixtures, particularly lead, may elevate the likelihood of hypertension, SBP, and DBP abnormalities. Further mediation analysis revealed that lead significantly mediated the relationship between biological aging and hypertension and between biological aging and SBP abnormalities, accounting for 64% (95% CI, 49% to 89%) and 64% (95% CI, 44% to 88%) of the effects, respectively. These outcomes emphasize the criticality of implementing environmental health measures.

Prognostic value of sarcopenic visceral obesity in hepatocellular carcinoma treated with TACE.

Although Transartial chemoembolization (TACE) is one of the recommended treatments for hepatocellular carcinoma (HCC), there is always a dispute on the selection of the best beneficiary for treatment. We studied the prognostic value of nutritional markers, obesity, visceral obesity and sarcopenia on survival outcomes under single and different combinations. In a retrospective cohort of 235 patients with HCC at different stages, more accurate comprehensive prognostic factors were obtained by combining and comparing the multifactor hazard ratios (HR) of various parameters, including skeletal muscle index (SMI) and visceral fat index (VFI) obtained by computer tomography, laboratory index albumin-to-globulin (A/G) ratio, anthropometric body mass index (BMI) and other parameters. The study cohort was dominated by men (73.6%), with a median age of 54 years. According to the survival outcome of HCC patients, we obtained the ideal sex cutoff value of VFI: ≥40.54 cm 2 /m 2 for males (the receiver operating characteristic curve [ROC] = 0.764, P  < .001) and ≥ 43.19 cm 2 /m 2 for females (ROC = 0.718, P  < .05). According to the results of multifactor analysis, sarcopenic visceral obesity (HR = 8.35, 95% confidence intervals [CI] = [4.96, 14.05], P  < .001) is more effective than any single or combined prognosis assessment, including sarcopenic dystrophy (HR = 2.70, 95% CI = [1.85, 3.95], P  < .001), sarcopenic obesity (HR = 5.23, 95% CI = [3.41, 8.02], P  < .001), sarcopenia (HR = 5.74, 95% CI = [3.61, 9.11], P  < .001) and visceral obesity (HR = 3.44, 95% CI = [2.24, 5.27], P  < .001). Sarcopenic visceral obesity, defined by SMI and VFI, is a more objective and accurate prognostic indicator of HCC.

3D-printed gelatin/sodium alginate/58S bioactive glass scaffolds promote osteogenesis in vitro and in vivo.

Three-dimensional (3D)-printed scaffolds are a new strategy to fabricate biomaterials for treating bone defects. Here, using a 3D-printing technique, we fabricated scaffolds consisting of gelatin (Gel), sodium alginate (SA), and 58S bioactive glass (58S BG). To evaluate mechanical properties and biocompatibility of Gel/SA/58S BG scaffolds, the degradation test, compressive strength test, and cytotoxicity test were performed. The effect of the scaffolds on cell proliferation in vitro was determined by 4',6-diamidino-2-phenylindole (DAPI) staining. To evaluate osteoinductive properties, rBMSCs were cultured on the scaffolds for 7, 14, and 21 days and the expression of osteogenesis-related genes was analyzed using qRT-PCR. To examine the bone healing properties of Gel/SA/58S BG scaffolds in vivo, we used a rat mandibular critical-size defect bone model. The scaffolds were implanted into the defect area of rat mandible and bone regeneration and new tissue formation were assessed using microcomputed tomography (microCT) and hematoxylin and eosin (H&E) staining. The results showed that Gel/SA/58S BG scaffolds had appropriate mechanical strength as a filling material for bone defects. Furthermore, the scaffolds could be compressed within certain limits and then could recover their shape. The extract of the Gel/SA/58S BG scaffold showed no cytotoxicity. In vitro, the expression levels of Bmp2, Runx2, and OCN were increased in rBMSCs cultured on the scaffolds. In vivo, microCT and H&E staining demonstrated that scaffolds induced the formation of new bone at the mandibular defect area. These results indicated that Gel/SA/58S BG scaffolds have excellent mechanical characteristics, biocompatibility, and osteoinductive properties, suggesting that it could be a promising biomaterial for the repair of bone defects.