Amino Acid Substitution of the Membrane-Proximal External Region Alter Neutralization Sensitivity in a Chronic HIV-1 Clade B Infected Patient.

The membrane-proximal external region (MPER) represents a highly conserved region of the Human Immunodeficiency Virus (HIV) envelope glycoprotein (env) targeted by several broadly neutralizing antibodies (bnAbs). In this study, we employed single genome amplification to amplify 34 full-length env sequences from the 2005 plasma sample of CBJC504, a chronic HIV-1 clade B infected individual. We identified three amino acid changes (N671S, D674N, and K677R) in the MPER. A longitudinal analysis revealed that the proportion of env sequences with MPER mutations increased from 26.5% in 2005 to 56.0% in 2009, and the sequences with the same mutation clustered together. Nine functional pseudoviruses were generated from the 34 env sequences to examine the effect of these mutations on neutralizing activity. Pseudoviruses carrying N674 or R677 mutations demonstrate increased sensitivity to autologous plasma and monoclonal antibodies 2F5, 4E10, and 10E8. Reverse mutations were performed in env including N674, R677, D659, and S671/N677 mutations, to validate the impact of the mutations on neutralizing sensitivity. Neutralization assays indicated that the N671S mutation increased neutralization sensitivity to 2F5 and 10E8. The amino acid R at position 677 increased viral resistance to 10E8, whereas N enhanced viral resistance to 4E10 and 10E8. It has been proposed that critical amino acids in the extra-MPER and the number of potential N-like glycosylation sites (PNGSs) in the V1 loop may have an impact on neutralizing activity. Understanding the mutations and evolution of MPER in chronically infected patients with HIV-1 is crucial for the design and development of vaccines that trigger bnAbs against MPER.

Comparison of different sources of mesenchymal stem cells: focus on inflammatory bowel disease.

Inflammatory bowel disease (IBD) poses a significant challenge in modern medicine, with conventional treatments limited by efficacy and associated side effects, necessitating innovative therapeutic approaches. Mesenchymal stem cells (MSC) have emerged as promising candidates for IBD treatment due to their immunomodulatory properties and regenerative potential. This thesis aims to explore and compare various sources of MSC and evaluate their efficacy in treating IBD. This study comprehensively analyses MSC derived from multiple sources, including bone marrow, adipose tissue, umbilical cord, and other potential reservoirs. Core elements of this investigation include assessing differences in cell acquisition, immunomodulatory effects, and differentiation capabilities among these MSC sources, as well as comparing their clinical trial outcomes in IBD patients to their therapeutic efficacy in animal models. Through meticulous evaluation and comparative analysis, this thesis aims to elucidate disparities in the efficacy of different MSC sources for IBD treatment, thereby identifying the most promising therapeutic applications. The findings of this study are intended to advance our understanding of MSC biology and offer valuable insights for selecting the most effective MSC sources for personalized IBD therapy. Ultimately, this research endeavor will optimise therapeutic strategies for managing inflammatory bowel disease through the utilization of MSC.

Combined SET7/9 and CDK4 inhibition act synergistically against osteosarcoma.

Osteosarcoma is the most common malignant bone tumor. It has a poor prognosis because of a lack of therapeutic targets and strategies. The SET domain-containing lysine-specific methyltransferase, SET7/9, has various functions in different cancer types in tissue-type and signaling context-dependent manners. The role of SET7/9 in osteosarcoma cells is currently controversial and its potential as a therapeutic candidate in osteosarcoma is unknown. In the present study, SET7/9 inhibition or ablation suppressed osteosarcoma cell proliferation by causing G1 arrest. Mechanistically, SET7/9 inhibition disrupted the interaction between cyclin-dependent kinase 4 (CDK4) and cyclin D1, which affected CDK4-cyclin D1 complex function, leading to decreased phosphorylation of retinoblastoma protein. CDK4 was overexpressed in osteosarcoma tissues and was closely related to a poor prognosis in patients with osteosarcoma. We therefore hypothesized that SET7/9 inhibition might increase the sensitivity of osteosarcoma cells to CDK4 inhibitors, potentially decreasing the risk of adverse effects of CDK4 inhibitors. The combination of SET7/9 and CDK4 inhibition enabled dose reductions of both inhibitors and had a synergistic effect against osteosarcoma growth in vivo. Collectively, these findings indicate that SET7/9 plays an oncogenic role in osteosarcoma by regulating CDK4-cyclin D1 complex interaction and function. The combination of SET7/9 and CDK4 inhibition may thus provide a novel effective therapeutic strategy for osteosarcoma with no significant toxicity.

Bioequivalence Study of Tebipenem Pivoxil in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVE: Tebipenem pivoxil (TP) is a carbapenem and is applied against pneumonia, otitis media, and sinusitis. This study compared the pharmacokinetics (PK) and safety of a test (T) preparation and reference (R) preparation of TP in healthy Chinese adults. METHODS: This study was a single-center, randomized, open, single-dose (fasting/postprandial) oral administration, two-agent, two-sequence, two-cycle, crossover bioequivalence trial. A total of 60 participants were enrolled (24 fasting and 36 postprandial). All participants were randomly assigned to the TR sequence and RT sequence. Subsequently, they switched T sequences or R sequences 7 days later. PK blood samples were collected according to the protocol, plasma TP concentration was determined by liquid chromatography-mass spectrometry, main PK parameters were calculated based on a non-compartment model, and adverse events were recorded during the test. RESULTS: In the feeding arm, the geometric mean ratio of maximum concentration (Cmax) was 89.84% (90% confidence interval 84.33-95.70), the geometric mean ratio of area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration (AUC0-t) was 86.80% (83.62-90.10), and the geometric mean ratio of area under the plasma concentration-time curve from time 0 to infinity time of quantifiable concentration (AUC0-∞) was 86.90% (83.73-90.20), which were within the acceptable range of bioequivalence (80-125%). In the fasting arm, the geometric mean ratio of Cmax was 96.07% (89.62-102.99), the geometric mean ratio of AUC0-t was 93.09% (90.47-95.78), and the geometric mean ratio of AUC0-∞ was 93.09% (90.48-95.77), which was within the acceptable range of bioequivalence (80-125%). Hence, the T preparation and R preparation of TP had bioequivalence in the fasting arm and feeding arm of the clinical trial. In addition, all adverse events were mild, and no severe adverse events were noted. CONCLUSION: Preparations T and R of TP were bioequivalent in the fasting and postprandial groups in clinical trials, and TP was safe.

Real-time monitoring polymerization degree of organic photovoltaic materials toward no batch-to-batch variations in device performance.

Polymerization degree plays a vital role in material properties. Previous methodologies of molecular weight control generally cannot suppress or alleviate batch-to-batch variations in device performance, especially in polymer solar cells. Herein, we develop an in-situ photoluminescence system in tandem with a set of analysis and processing procedures to track and estimate the polymerization degree of organic photovoltaic materials. To support the development of this protocol, we introduce polymer acceptor PYT constructed by near-infrared Y-series small molecule acceptors via Stille polymerization, and shed light on the correlations between molecular weight, spectral parameters, and device efficiencies that enable the design of the optical setup and confirm its feasibility. The universality is verified in PYT derivatives with stereoregularity and fluoro-substitution as well as benzo[1,2-b:4,5-b']dithiophene-based polymers. Overall, our result provides a tool to tailor suitable conjugated oligomers applied to polymer solar cells and other organic electronics for industrial scalability and desired cost reduction.

Criteria for classification, nomenclature, and reference sequence selection for HIV sub-subtypes of CRF01_AE and CRF07_BC strains in China.

The available knowledge regarding classification, nomenclature, and reference sequence selection for the various sub-subtypes of circulating recombinant forms (CRFs) is inadequate to fulfill the growing demands of research focused on HIV prevention. We analyzed the spread of CRF01_AE and CRF07_BC strains, mainly in China, to complement and update the existing nomenclature and to propose a reference sequence selection criteria for sub-subtypes of CRFs.

Distinct genetic clusters in HIV-1 CRF01_AE-infected patients induced variable degrees of CD4+ T-cell loss.

CRF01_AE strains have been shown to form multiple transmission clusters in China, and some clusters have disparate pathogenicity in Chinese men who have sex with men. This study focused on other CRF01_AE clusters prevalent in heterosexual populations. The CD4+ T-cell counts from both cross-section data in National HIV Molecular Epidemiology Survey and seropositive cohort data were used to evaluate the pathogenicity of the CRF01_AE clusters and other HIV-1 sub-types. Their mechanisms of pathogenicity were evaluated by co-receptor tropisms, predicted by genotyping and confirmed with virus isolate phenotyping, as well as inflammation parameters. Our research elucidated that individuals infected with CRF01_AE clusters 1 and 2 exhibited significantly lower baseline CD4+ T-cell counts and greater CD4+ T-cell loss in cohort follow-up, compared with other HIV-1 sub-types and CRF01_AE clusters. The increased pathogenesis of cluster 1 or 2 was associated with higher CXCR4 tropisms, higher inflammation/immune activation, and increased pyroptosis. The protein structure modeling analysis revealed that the envelope V3 loop of clusters 1 and 2 viruses is favorable for CXCR4 co-receptor usage. Imbedded with the most mutating reverse transcriptase, HIV-1 is one of the most variable viruses. CRF01_AE clusters 1 and 2 have been found to have evolved into more virulent strains in regions with predominant heterosexual infections. The virulent strains increased the pressure for early diagnosis and treatment in HIV patients. To save more lives, HIV-1 surveillance systems should be upgraded from serology and genotyping to phenotyping, which could support precision interventions for those infected by virulent viruses. IMPORTANCE: Retroviruses swiftly adapt, employing error-prone enzymes for genetic and phenotypic evolution, optimizing survival strategies, and enhancing virulence levels. HIV-1 CRF01_AE has persistently undergone adaptive selection, and cluster 1 and 2 infections display lower counts and fast loss of CD4+ T cells than other HIV-1 sub-types and CRF01_AE clusters. Its mechanisms are associated with increased CXCR4 tropism due to an envelope structure change favoring a tropism shift from CCR5 to CXCR4, thereby shaping viral phenotype features and impacting pathogenicity. This underscores the significance of consistently monitoring HIV-1 genetic evolution and phenotypic transfer to see whether selection bias across risk groups alters the delicate balance of transmissible versus toxic trade-offs, since virulent strains such as CRF01_AE clusters 1 and 2 could seriously compromise the efficacy of antiviral treatment. Only through such early warning and diagnostic services can precise antiviral treatments be administered to those infected with more virulent HIV-1 strains.

Special Staining and Protein Expression of VEGF/EGFR and P53/NF-κB in Cryptorchid Tissue of Erhualian Pigs.

Erhualian pigs exhibit one of the highest reproductive rates globally, and cryptorchidism is a crucial factor affecting reproductive abilities of boars. This investigation focused on cryptorchid tissues from Erhualian pigs, where the histological structure of cryptorchidism was observed using specialized staining. In addition, protein expression of P53/NF-κB in cryptorchid tissues was assessed using Western blot and immunohistochemistry. In comparison to normal Erhualian testes, Masson's trichrome staining indicated a reduction in collagen fibers in the connective tissue and around the basal membrane of the seminiferous tubules in cryptorchid testes. Moreover, collagen fiber distribution was observed to be disordered. Verhoeff Van Gieson (EVG) and argyrophilic staining demonstrated brownish-black granular nucleoli organized regions in mesenchymal cells and germ cells. When compared to normal testicles, the convoluted seminiferous tubules of cryptorchids exhibited a significantly reduced number and diameter (p < 0.01). Notably, VEGF/EGFR and P53/NF-κB expression in cryptorchidism significantly differed from that in normal testes. In particular, the expression of VEGF and P53 in cryptorchid tissues was significantly higher than that in normal testes tissues, whereas the expression of EGFR in cryptorchid tissues was significantly lower than that in normal testes tissues (all p < 0.01). NF-κB expressed no difference in both conditions. The expressions of VEGF and NF-κB were observed in the cytoplasm of testicular Leydig cells and spermatogenic cells, but they were weak in the nucleus. EGFR and P53 were more positively expressed in the cytoplasm of these cells, with no positive expression in the nucleus. Conclusion: There were changes in the tissue morphology and structure of the cryptorchid testis, coupled with abnormally high expression of VEGF and P53 proteins in Erhualian pigs. We speculate that this may be an important limiting factor to fecundity during cryptorchidism.

DNase aggravates intestinal microvascular injury in IBD patients by releasing NET-related proteins.

Neutrophils accumulate in the inflammatory mucosa of patients with inflammatory bowel disease (IBD), and excessive release of NETs (neutrophil extracellular traps may be one of the important factors that cause IBD progression. However, the specific mechanism underlying vascular injury caused by NETs remains unclear. Immunofluorescence, ELISA, and flow cytometry were used in this study to detect the expression of NETs and DNase in the tissue and peripheral blood samples of patients with IBD. DSS mouse model was used to detect colon injury and vascular permeability. We found that NETs and DNase levels increased in the colon of patients with IBD. We found an increase in the activity of NET-related MPO released by DNase. DNase released NET-related proteins and damaged vascular endothelial cells in vitro. In DSS mouse model, the synchronous increase of DNase and NETs in the colon leads to an increase in vascular injury markers (CD44, sTM). DNase aggravated colon injury and increased vascular permeability in vivo, which was inhibited by gentamicin sulfate (GS). GS does not reduce the expression of DNase, but rather reduces the release of NET-related proteins to protect vascular endothelium by inhibiting DNase activity. MPO and histones synergistically damaged the vascular endothelium, and vascular injury can be improved by their active inhibitors. We further found that H2 O2 is an important substrate for MPO induced vascular damage. In conclusion, in IBD, DNase, and NET levels increased synchronously in the lesion area and released NET-related proteins to damage the vascular endothelium. Therefore, targeting DNase may be beneficial for the treatment of IBD.

Processability Considerations for Next-Generation Organic Photovoltaic Materials.

The evolution of organic semiconductors for organic photovoltaics (OPVs) has resulted in unforeseen outcomes. This has provided substitute choices of photoactive layer materials, which effectively convert sunlight into electricity. Recently developed OPV materials have narrowed down the gaps in efficiency, stability, and cost in devices. Records now show power conversion efficiency in single-junction devices closing to 20%. Despite this, there is still a gap between the currently developed OPV materials and those that meet the requirements of practical applications, especially the solution processability issue widely concerned in the field of OPVs. Based on the general rule that structure determines properties, methodologies to enhance the processability of OPV materials are reviewed and explored from the perspective of material design and views on the further development of processable OPV materials are presented. Considering the current dilemma that the existing evaluation indicators cannot reflect the industrial processability of OPV materials, a more complete set of key performance indicators are proposed for their processability considerations. The purpose of this perspective is to raise awareness of the boundary conditions that exist in industrial OPV manufacturing and to provide guidance for academic research that aspires to contribute to technological advancements.

HIV transmission and associated factors under the scale-up of HIV antiretroviral therapy: a population-based longitudinal molecular network study.

OBJECTIVES: To evaluate the prevention efficacy of scaling up HIV/AIDS antiretroviral therapy (ART) on HIV transmission at the population level and determine associated factors of HIV secondary transmission. METHODS: We used HIV longitudinal molecular networks to assess the genetic linkage between baseline and newly diagnosed cases. A generalized estimating equation was applied to determine the associations between demographic, clinical characteristics and HIV transmission. RESULTS: Patients on ART had a 32% lower risk of HIV transmission than those not on ART. A 36% reduction in risk was also seen if ART-patients maintained their HIV viral load lower than 50 copies/mL. A 71% lower risk occurred when patients sustained ART for at least 3 years and kept HIV viral load less than 50 copies/mL. Patients who discontinued ART had a similar HIV transmission risk as those not on ART. Patients who were older, male, non-Han, not single, retired, infected via a heterosexual route of transmission and those who possessed higher CD4 counts had a higher risk of HIV transmission. HIV-1 subtype of CRF01_AE was less transmissible than other subtypes. CONCLUSIONS: The efficacy of ART in a real-world setting was supported by this longitudinal molecular network study. Promoting adherence to ART is crucial to reduce HIV transmission.

Epithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling.

Dysregulation of IL-17A is closely associated with airway inflammation and remodeling in severe asthma. However, the molecular mechanisms by which IL-17A is regulated remain unclear. Here we identify epithelial sirtuin 6 (SIRT6) as an epigenetic regulator that governs IL-17A pathogenicity in severe asthma. Mice with airway epithelial cell-specific deletion of Sirt6 are protected against allergen-induced airway inflammation and remodeling via inhibiting IL-17A-mediated inflammatory chemokines and mesenchymal reprogramming. Mechanistically, SIRT6 directly interacts with RORγt and mediates RORγt deacetylation at lysine 192 via its PPXY motifs. SIRT6 promotes RORγt recruitment to the IL-17A gene promoter and enhances its transcription. In severe asthma patients, high expression of SIRT6 positively correlates with airway remodeling and disease severity. SIRT6 inhibitor (OSS_128167) treatment significantly attenuates airway inflammation and remodeling in mice. Collectively, these results uncover a function for SIRT6 in regulating IL-17A pathogenicity in severe asthma, implicating SIRT6 as a potential therapeutic target for severe asthma.

Distribution pattern, molecular transmission networks, and phylodynamic of hepatitis C virus in China.

In China, few molecular epidemiological data on hepatitis C virus (HCV) are available and all previous studies were limited by small sample sizes or specific population characteristics. Here, we report characterization of the epidemic history and transmission dynamics of HCV strains in China. We included HCV sequences of individuals belonging to three HCV surveillance programs: 1) patients diagnosed with HIV infection at the Beijing HIV laboratory network, most of whom were people who inject drugs and former paid blood donors, 2) men who have sex with men, and 3) the general population. We also used publicly available HCV sequences sampled in China in our study. In total, we obtained 1,603 Ns5b and 865 C/E2 sequences from 1,811 individuals. The most common HCV strains were subtypes 1b (29.1%), 3b (25.5%) and 3a (15.1%). In transmission network analysis, factors independently associated with clustering included the region (OR: 0.37, 95% CI: 0.19-0.71), infection subtype (OR: 0.23, 95% CI: 0.1-0.52), and sampling period (OR: 0.43, 95% CI: 0.27-0.68). The history of the major HCV subtypes was complex, which coincided with some important sociomedical events in China. Of note, five of eight HCV subtype (1a, 1b, 2a, 3a, and 3b), which constituted 81.8% HCV strains genotyped in our study, showed a tendency towards decline in the effective population size during the past decade until present, which is a good omen for the goal of eliminating HCV by 2030 in China.

Characterization of HIV-1 CRF02_AG/A3/G unique recombinant forms identified among children in Larkana, Pakistan.

Co-circulation of different human immunodeficiency virus type 1 HIV-1 subtypes among infected populations can lead to the generation of new recombinants. In Pakistan, subtype A1 and CRF02_AG are the dominant strains circulating among key populations. The high prevalence of new HIV infections among the key populations highlights the possibility of recombination between the dominant strains, which can lead to the generation of new recombinants. Here, we identified a recombinant cluster composed of CRF02_AG, sub-subtype A3, and subtype G among HIV-infected children in Larkana. For the study, 10 retrospectively collected samples, with recombination signals in the pol gene, were used to perform a near full-length genome NFLG sequencing. Of the 10 samples, NFLG was successfully sequenced from seven samples. Phylogenetic analysis of the seven NFLGs showed that all recombinants formed a distinct monophyletic cluster and were distinct from known HIV-1 circulating recombinant forms CRFs. Recombination analyses showed that all seven NFLGs shared a similar recombinant structure consisting of CRF02_AG, sub-subtype A3, and subtype G, with a sub-subtype A3 fragment inserted into pol and vif regions spanning from (HXB2: 4218-5518), and a subtype G fragment inserted into vpu, rev, tat and env regions spanning from (HXB2: 5957-8250) of the CRF02_AG backbone. The identification of unique recombinant forms may indicate the presence and transmission of several co-circulating lineages in Larkana, giving rise to newer CRFs. This study also highlights the importance of continuous molecular surveillance to fully understand HIV-1 genetic diversity in Pakistan, particularly in Larkana, which is the epicenter of HIV outbreaks.

Pretreatment HIV Drug Resistance and the Molecular Transmission Network Among HIV-Positive Individuals in China in 2022: Multicenter Observational Study.

BACKGROUND: Emerging HIV drug resistance caused by increased usage of antiretroviral drugs (ARV) could jeopardize the success of standardized HIV management protocols in resource-limited settings. OBJECTIVE: We aimed to characterize pretreatment HIV drug resistance (PDR) among HIV-positive individuals and risk factors in China in 2022. METHODS: This cross-sectional study was conducted using 2-stage systematic sampling according to the World Health Organization's surveillance guidelines in 8 provincial-level administrative divisions in 2022. Demographic information and plasma samples were obtained from study participants. PDR was analyzed using the Stanford HIV drug resistance database, and the Tamura-Nei 93 model in HIV-TRACE was used to calculate pairwise matches with a genetic distance of 0.01 substitutions per site. Logistic regression was used to identify and estimate factors associated with PDR. RESULTS: PDR testing was conducted on 2568 participants in 2022. Of the participants, 34.8% (n=893) were aged 30-49 years, 81.4% (n=2091) were male, and 3.2% (n=81) had prior ARV exposure. The prevalence of PDR to protease and reverse transcriptase regions, nonnucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors were 7.4% (n=190), 6.3% (n=163), 1.2% (n=32), and 0.2% (n=5), respectively. Yunnan, Jilin, and Zhejiang had much higher PDR incidence than did Sichuan. The prevalence of nonnucleoside reverse transcriptase inhibitor-related drug resistance was 6.1% (n=157) for efavirenz and 6.3% (n=163) for nevirapine. Multivariable logistic regression models indicated that participants who had prior ARV exposure (odds ratio [OR] 7.45, 95% CI 4.50-12.34) and the CRF55_01B HIV subtype (OR 2.61, 95% CI 1.41-4.83) were significantly associated with PDR. Among 618 (24.2%) sequences (nodes) associated with 253 molecular transmission clusters (size range 2-13), drug resistance mutation sites included K103, E138, V179, P225, V106, V108, L210, T215, P225, K238, and A98. CONCLUSIONS: The overall prevalence of PDR in China in 2022 was modest. Targeted genotypic PDR testing and medication compliance interventions must be urgently expanded to address PDR among newly diagnosed people living with HIV in China.

Outcomes of prophylactic lauromacrogol injection versus non-injection in patients with endogenous cesarean scar pregnancy treated by hysteroscopic surgery: a retrospective cohort study.

BACKGROUND: This study aimed to investigate the efficacy of hysteroscopic surgery for endogenous cesarean scar pregnancy (CSP) and the value of prophylactic ultrasound-guided local injection of lauromacrogol. METHODS: This retrospective study included 131 patients diagnosed with endogenous CSP who underwent hysteroscopic surgery at the Hangzhou Fuyang Women and Children Hospital between January 2018 and May 2022. Lauromacrogol (10-20 mL) was administered within 24 h preoperatively using an ultrasound-guided vaginal injection to 78 patients (L group) versus not administered to 53 patients (non-L group). Their clinical data and outcomes were analyzed. RESULTS: Mean gestational age, gestational mass size, and uterine scar thickness and median preoperative blood ß-human chorionic gonadotropin levels of the non-L versus L groups were 46.26 versus 45.01 days, 2.05 versus 2.39 cm, 0.35 versus 0.32 cm, and 19850.0 versus 26790.0 U/L, respectively (P > 0.05 for each). The non-L and L groups had similar success rates (98.1% vs. 98.7%, P = 1.0). Complications related to lauromacrogol administration, including abdominal pain, massive bleeding, and bradycardia, were experienced by 46.2% (36/78; P < 0.001) of L group patients. The non-L had a significantly shorter mean hospital stay (4.85 ± 1.12 vs 5.44 ± 1.08 days) and lower total cost (6148.75 ± 1028.71 vs 9016.61 ± 1181.19) (P < 0.01). CONCLUSIONS: Hysteroscopic surgery is effective and safe for patients with endogenous CSP. Prophylactic lauromacrogol injection increases the incidence of complications and costs. Direct hysteroscopic surgery can reduce pain and financial burden in patients with endogenous CSP and save medical resources for other patients.

VCAM-1 Promotes Angiogenesis of Bone Marrow Mesenchymal Stem Cells Derived from Patients with Trauma-Induced Osteonecrosis of the Femoral Head by Regulating the Apelin/CCN2 Pathway.

Trauma-induced osteonecrosis of the femoral head (TI-ONFH) is a pathological process in which the destruction of blood vessels supplying blood to the femoral head causes the death of bone tissue cells. Vascular cell adhesion molecule 1 (VCAM-1) has been shown to have potent proangiogenic activity, but the role in angiogenesis of TI-ONFH is unclear. In this work, we discovered that VCAM-1 was significantly downregulated in the bone marrow mesenchymal stem cells (BMSCs) derived from patients with TI-ONFH. Subsequently, we constructed BMSCs overexpressing VCAM-1 using a lentiviral vector. VCAM-1 enhances the migration and angiogenesis of BMSCs. We further performed mRNA transcriptome sequencing to explore the mechanisms by which VCAM-1 promotes angiogenesis. Gene ontology biological process enrichment analysis demonstrated that upregulated differentially expressed genes (DEGs) were related to blood vessel development. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that upregulated DEGs were engaged in the Apelin signaling pathway. Apelin-13 is the endogenous ligand of the APJ receptor and activates this G protein-coupled receptor. Treatment with Apelin-13 activated the Apelin signaling pathway and suppressed the expression of cellular communication network factor 2 in BMSCs. Furthermore, Apelin-13 also inhibits the migration and angiogenesis of VCAM-1-BMSCs. In summary, VCAM-1 plays an important role in vascular microcirculation disorders of TI-ONFH, which provides a new direction for the molecular mechanism and treatment of TI-ONFH.

Immunity Induced by Inactivated SARS-CoV-2 Vaccine: Breadth, Durability, Potency, and Specificity in a Healthcare Worker Cohort.

Vaccination has proven to be highly effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the long-term immunogenicity and the functional preserved immune responses of vaccines are needed to inform evolving evidence-based guidelines for boosting schedules. We enrolled 205 healthcare workers into a cohort study; all had received three doses of BBIBP-CorV (China Sinopharm Bio-Beijing Company, Beijing, China) inactivated vaccine. We assessed SARS-CoV-2 specific binding antibodies, neutralizing antibodies, and peripheral T and B cell responses. We demonstrated that more robust antibody responses to SARS-CoV-2 were elicited by booster immunization compared with primary vaccination. Neutralizing antibody titers to SARS-CoV-2 Omicron BA.1 were also efficiently elevated post-homologous vaccine booster despite being in a lower titer compared with the prototype stain. In addition to S-specific humoral and cellular immunity, BBIBP-CorV also induced N-specific antibody and effector T cell responses. The third-dose vaccination led to further expansion of critical polyfunctional T cell responses, likely an essential element for vaccine protection. In particular, a functional role for Tfh cell subsets in immunity was suggested by the correlation between both CD4+ Tfh and CD8+ Tfh with total antibody, IgG, B cell responses, and neutralizing antibodies. Our study details the humoral and cellular responses generated by the BBIBP-CorV booster vaccination in a seven-month follow-up study. There is a clear immunologic boosting value of homologous inactivated SARS-CoV-2 vaccine boosters, a consideration for future vaccine strategies.

Pharmacokinetics and Drug-Drug Interaction of Allisartan Isoproxil and Indapamide Sustained-Release Formulation.

Allisartan isoproxil (AI) is an angiotensin II type 1 receptor blocker and be converted into the active substance EXP3174 in vivo. We evaluated the drug-drug interactions of AI and an indapamide sustained-release (Ind SR) preparation, as well as the pharmacokinetic characteristics and safety of AI and Ind SR in healthy subjects. The trial was set up in 6 sequences and 3 cycles, and each cycle contained a 7-day washout period. Subjects received 3 different trial drugs (A, AI; B, Ind SR; C, AI + Ind SR) during 3 different cycles. Twenty-four subjects were enrolled in the clinical trial. Of these, 22 completed the study, 2 subjects dropped out due to adverse events (AEs). For subjects given AI alone or combined with Ind SR, the pharmacogenetic parameters Cmax and the geometric mean ratio of steady state (combined/single) of EXP3174 was 130%. The geometric mean ratio of area under the concentration-time curve over the dosing interval at steady state (combined/single use) was 144.5%. Therefore, the combination of Ind SR had an impact on the pharmacokinetics of AI. Then, the results indicated that the AI combination had no effect on the pharmacokinetics of Ind SR. Serious AEs did not occur. The AEs in this clinical trial were the same as those for AI and Ind SR. Combined administration resulted in 2 cases (2 subjects) of Grade 3 hypotension and 1 case of Grade 3 hypotension with AI alone. Considering that this trial included healthy volunteers, the risk of hypotension was expected to be manageable.

The spectrum of opportunistic infections and malignancies among women on antiretroviral therapy in Ethiopia.

ABBREVIATIONS: AIDS: acquired immune deficiency syndrome; CI: confidence interval; EPHI: Ethiopian Public Health Institute; HAART: highly active antiretroviral therapy; HIV: human immunodeficiency virus; HR: hazard ratio; Mg/dl: milligram per deciliter; TB: tuberculosis; PCP: pneumocystis carinii pneumonia; ZJU: Zhejiang University.