Structural basis of ketamine action on human NMDA receptors.

Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors1. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants2,3. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant4. Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.

Rapid Initiation of Antiretroviral Therapy with Coformulated Bictegravir, Emtricitabine, Tenofovir Alafenamide Versus Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in HIV-positive Men Who Have Sex with Men in China: Week 48 Results of the Multicenter, Randomized Clinical Trial.

BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with HIV-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400-mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among HIV-positive men who have sex with men (MSM). METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV(400-mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50 copies/ml) at 48 weeks per FDA Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression; and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (p < 0.001), respectively, discontinued treatment due to adverse effects, death, or loss to follow-up. The median increase of CD4 count was 181 and 223 cells/µL (p = 0.020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < 0.001). CONCLUSION: BIC/FTC/TAF was more efficacious and safer than EFV(400-mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.

Genetic characteristics of a novel HIV-1 recombinant lineage (CRF103_01B) and its prevalence in northern China.

During the routine surveillance of HIV-1 pretreatment drug resistance in Beijing, five men who have sex with men (MSM) and a woman were observed to get infected by newly identified CRF103_01B strain. To elucidate the genetic characteristics, the near full-length genome (NFLG) was obtained. Phylogenetic inference indicated that CRF103_01B NFLG was composed of six mosaic segments. Segments IV and V of CRF103_01B were located among the clusters subtype B and CRF01_AE (group 5), respectively. The CRF103_01B strain was deduced to originate from Beijing MSM population around 2002.3-2006.4 and continued to spread among MSM population at a low level, then to the general population via heterosexual contact in northern China. Molecular epidemiology surveillance of CRF103_01B should be reinforced.

Causal effect of PM1 on morbidity of cause-specific respiratory diseases based on a negative control exposure.

BACKGROUND: Extensive studies have linked PM2.5 and PM10 with respiratory diseases (RD). However, few is known about causal association between PM1 and morbidity of RD. We aimed to assess the causal effects of PM1 on cause-specific RD. METHODS: Hospital admission data were obtained for RD during 2014 and 2019 in Beijing, China. Negative control exposure and extreme gradient boosting with SHapley Additive exPlanation was used to explore the causality and contribution between PM1 and RD. Stratified analysis by gender, age, and season was conducted. RESULTS: A total of 1,183,591 admissions for RD were recorded. Per interquartile range (28 µg/m3) uptick in concentration of PM1 corresponded to a 3.08% [95% confidence interval (CI): 1.66%-4.52%] increment in morbidity of total RD. And that was 4.47% (95% CI: 2.46%-6.52%) and 0.15% (95% CI: 1.44%-1.78%), for COPD and asthma, respectively. Significantly positive causal associations were observed for PM1 with total RD and COPD. Females and the elderly had higher effects on total RD, COPD, and asthma only in the warm months (Z = 3.03, P = 0.002; Z = 4.01, P < 0.001; Z = 3.92, P < 0.001; Z = 2.11, P = 0.035; Z = 2.44, P = 0.015). Contribution of PM1 ranked first, second and second for total RD, COPD, and asthma among air pollutants. CONCLUSION: PM1 was causally associated with increased morbidity of total RD and COPD, but not causally associated with asthma. Females and the elderly were more vulnerable to PM1-associated effects on RD.

Long-term effects of PM2.5 components on hypertension: A national analysis in China.

BACKGROUND: Evidence is less about the associations between fine particulate matter (PM2.5) components and hypertension. We aimed to examine the long-term effects of PM2.5 components on prevalence of hypertension, diastolic blood pressure (DBP) and systolic blood pressure (SBP). METHODS: We included participants between March 1, and July 31, 2021, from 13 provinces in China. Geocoded residential address was used for exposure assignment. Mixed-effect regression was used to assess 3-year average concentrations of PM2.5 and its components (black carbon, organic matter, nitrate, ammonium, and sulfate) on prevalence of hypertension, DBP and SBP with covariate-adjusted. SHapley Additive exPlanation was used to compare the contribution of PM2.5 components to hypertension, DBP, and SBP. Sex and age subgroup were also analyzed. RESULTS: We enrolled a total of 113,159 participants aged ≥18 years. Long-term exposure to PM2.5 and its components (black carbon, organic matter, nitrate, ammonium, and sulfate) had associations with prevalence of hypertension, with the Odds Ratios and 95% confidence interval (CI) of 1.06 (95%CI: 1.03-1.09), 1.07 (95%CI: 1.04-1.09), 1.07 (95%CI: 1.04-1.10), 1.05 (95%CI: 1.01-1.08), 1.03 (95%CI: 1.00-1.06), and 1.03 (95%CI: 1.00-1.04), respectively. Effects of that except for black carbon on DBP with per interquartile upticks of concentration were 0.23 (95%CI: 0.11-0.35), 0.17 (95%CI: 0.04-0.29), 0.35 (95%CI: 0.21-0.48), 0.40 (95%CI: 0.28-0.52), and 0.25 (95%CI: 0.13-0.26), respectively. Ammonium was associated with SBP, corresponding to an increase of 0.18 (95%CI: 0.01-0.35). Males had higher risks of DBP (Z = 2.54-6.08, P < 0.001). Older people were substantially more affected by PM2.5 and its components. Nitrate showed the highest contribution to hypertension, DBP and SBP compared with other components. CONCLUSIONS: Long-term exposure to PM2.5 and its components had adverse consequences on prevalence of hypertension, DBP and SBP, especially for males and older people. Nitrate contributed the highest to hypertension, DBP and SBP. Findings may have implications for pollution and hypertension control.

Role of microglia in HIV-1 infection.

The usage of antiretroviral treatment (ART) has considerably decreased the morbidity and mortality related to HIV-1 (human immunodeficiency virus type 1) infection. However, ART is ineffective in eradicating the virus from the persistent cell reservoirs (e.g., microglia), noticeably hindering the cure for HIV-1. Microglia participate in the progression of neuroinflammation, brain aging, and HIV-1-associated neurocognitive disorder (HAND). Some methods have currently been studied as fundamental strategies targeting microglia. The purpose of this study was to comprehend microglia biology and its functions in HIV-1 infection, as well as to look into potential therapeutic approaches targeting microglia.

Long-term effects of particulate matter on incident cardiovascular diseases in middle-aged and elder adults: The CHARLS cohort study.

BACKGROUND: Although there is evidence of long-term effects of particulate matter (PM) on cardiovascular diseases (CVD), researches about long-term effects of PM1 on CVD are limited. We aimed to examine the long-term effects and magnitude of PM, especially PM1, on incident CVD in China. METHODS: We included 6016 participants aged ≥ 45 years without CVD at baseline in 2011 from the China Health and Retirement Longitudinal Study. Personal PM (PM1, PM2.5, and PM10) concentrations were estimated using geocoded residential address. Generalized linear mixed models and SHapley Additive exPlanation were utilized to calculate the impacts and contributions of PM on CVD. Sensitivity analyses were used to check the robustness. RESULTS: After a follow up of 4-year, 481 (7.99 %) participants developed CVD. Per 10 µg/m3 uptick in 1-year average concentrations of PM1, PM2.5 and PM10 was associated with a 1.20 [95 % confidence interval (CI): 1.05-1.37], 1.13 (95 % CI: 1.11-1.15), and 1.10 (95 % CI: 1.06-1.13) fold risk of incident CVD, respectively. The 2-year average concentrations of PM1, PM2.5 and PM10 were associated with incident CVD, corresponding to a 1.03 (95 % CI: 0.96-1.10), 1.11 (95 % CI: 1.02-1.21), and 1.09 (95 % CI: 1.03-1.15) fold risk, respectively. The SHapley Additive exPlanation values of PM1, PM2.5, and PM10 were 0.170, 0.153, and 0.053, respectively, corresponding to the first, second, and fifth among all air pollutants. Effects of PM1, PM2.5 and PM10 on CVD remained statistically significant in two-pollutant models. The elderly, males, smokers and alcohol drinkers tended to have slightly higher effects, while the differences were not statistically significant (all P-values > 0.05) between subgroups. CONCLUSION: Long-term exposure to PM1, PM2.5, and PM10 was associated with an increased incidence of CVD. The smaller the particle size, the more important it was for incident CVD indicating that emphasis should be placed on small size of PM.

Factors associated with human immunodeficiency virus-1 low-level viremia and its impact on virological and immunological outcomes: A retrospective cohort study in Beijing, China.

OBJECTIVES: We evaluated the impact of low-level viremia (LLV) on virological failure and immune reconstitution among people living with human immunodeficiency virus type 1 (HIV-1) treated with different antiretroviral regimens in Beijing, China. METHODS: Human immunodeficiency virus type 1-positive adults who were registered at an infectious disease hospital in Beijing between January 1, 2005 and January 1, 2020 were administered antiretroviral therapy (ART) and whose viral load and CD4 counts were monitored were included in this retrospective cohort study. Univariate and multivariate logistic regression analyses were performed to identify risk factors associated with LLV in patients on different ART regimens. Cox proportional hazard model was employed to analyze the virological suppression and immune reconstitution cumulative probability in patients with LLV during follow-up. RESULTS: A total of 10 124 HIV-1-infected participants was included. LLV occurred in 723 (8.2%), 204 (10.9%), 133 (8.6%), and 53 (14.4%) patients on first-line ART, second-line ART, third-line ART, and simplified regimens, respectively. Virological failure occurred in 514 (5.8%), 289 (15.5%), 86 (5.5%), and 34 (9.2%) patients on first-line ART, second-line ART, third-line ART, and simplified regimens, respectively. Earlier enrollment, lower baseline CD4 count, and higher baseline viral load were risk factors associated with LLV. LLV was related to increased hazards of virological failure compared to viral suppression of ≤50 copies/ml for those on first-line ART. CONCLUSIONS: The risk of virological failure and poor immune reconstitution increases when LLV occurs. Targeted viral load and CD4 count monitoring are recommended for people living with HIV-1 with LLV to improve health-related outcomes.

Effects of different integrase strand transfer inhibitors on body weight in patients with HIV/AIDS: a network meta-analysis.

BACKGROUND: Global antiretroviral therapy has entered a new era. Integrase strand transfer inhibitor (INSTI) has become the first choice in acquired immunodeficiency syndrome (AIDS) treatment. Because INSTI has high antiviral efficacy, rapid virus inhibition, and good tolerance. However, INSTIs may increase the risk of obesity. Each INSTI has its unique impact on weight gain in patients with human immunodeficiency virus (HIV)/AIDS. This study systematically assessed different INSTIs in causing significant weight gain in HIV/AIDS patients by integrating data from relevant literature. METHODS: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP), and Wanfang databases were searched to find studies on the influence of different INSTIs in weight gain. Data on weight change were extracted, and a network meta-analysis was performed. RESULTS: Eight studies reported weight changes in HIV/AIDS patients were included. Results of the network meta-analysis showed that the weight gain of HIV/AIDS patients treated with Dolutegravir (DTG) was significantly higher than that of Elvitegravir (EVG) [MD = 1.13, (0.18-2.07)]. The consistency test results showed no overall and local inconsistency, and no significant difference in the results of the direct and indirect comparison was detected (p > 0.05). The rank order of probability was DTG (79.2%) > Bictegravir (BIC) (77.9%) > Raltegravir (RAL) (33.2%) > EVG (9.7%), suggesting that DTG may be the INSTI drug that causes the most significant weight gain in HIV/AIDS patients. CONCLUSION: According to the data analysis, among the existing INSTIs, DTG may be the drug that causes the most significant weight gain in HIV/AIDS patients, followed by BIC.

Inhibition of enterovirus 71 replication and viral 3C protease by quercetin.

BACKGROUND: Enterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease (HFMD), which is sometimes associated with severe central nervous system disease in children. There is currently no specific medication for EV71 infection. Quercetin, one of the most widely distributed flavonoids in plants, has been demonstrated to inhibit various viral infections. However, investigation of the anti-EV71 mechanism has not been reported to date. METHODS: The anti-EV71 activity of quercetin was evaluated by phenotype screening, determining the cytopathic effect (CPE) and EV71-induced cells apoptosis. The effects on EV71 replication were evaluated further by determining virus yield, viral RNA synthesis and protein expression, respectively. The mechanism of action against EV71 was determined from the effective stage and time-of-addition assays. The possible inhibitory functions of quercetin via viral 2Apro, 3Cpro or 3Dpol were tested. The interaction between EV71 3Cpro and quercetin was predicted and calculated by molecular docking. RESULTS: Quercetin inhibited EV71-mediated cytopathogenic effects, reduced EV71 progeny yields, and prevented EV71-induced apoptosis with low cytotoxicity. Investigation of the underlying mechanism of action revealed that quercetin exhibited a preventive effect against EV71 infection and inhibited viral adsorption. Moreover, quercetin mediated its powerful therapeutic effects primarily by blocking the early post-attachment stage of viral infection. Further experiments demonstrated that quercetin potently inhibited the activity of the EV71 protease, 3Cpro, blocking viral replication, but not the activity of the protease, 2Apro, or the RNA polymerase, 3Dpol. Modeling of the molecular binding of the 3Cpro-quercetin complex revealed that quercetin was predicted to insert into the substrate-binding pocket of EV71 3Cpro, blocking substrate recognition and thereby inhibiting EV71 3Cpro activity. CONCLUSIONS: Quercetin can effectively prevent EV71-induced cell injury with low toxicity to host cells. Quercetin may act in more than one way to deter viral infection, exhibiting some preventive and a powerful therapeutic effect against EV71. Further, quercetin potently inhibits EV71 3Cpro activity, thereby blocking EV71 replication.

Evaluation of Stability, Inactivation, and Disinfection Effectiveness of Mpox Virus.

BACKGROUND: Mpox virus (MPXV) infections have increased in many countries since May 2022, increasing demand for diagnostic tests and research on the virus. To ensure personnel safety, appropriate and reliable measures are needed to disinfect and inactivate infectious samples; Methods: We evaluated the stability of infectious MPXV cultures stored at different temperatures and through freeze-thaw cycles. Heat physical treatment (56 °C, 70 °C, 95 °C), chemical treatment (beta-propiolactone (BPL)) and two commercialized disinfectants (Micro-Chem Plus (MCP) and ethanol) were tested against infectious MPXV cultures; Results: The results indicated that MPXV stability increases with lower temperatures. The MPXV titer was stable within three freeze-thaw cycles and only decreased by 1.04 log10 (lg) 50% cell culture infective dose (CCID50) per milliliter (12.44%) after twelve cycles. MPXV could be effectively inactivated at 56 °C for 40 min, 70 °C for 10 min, and 95 °C for 5 min. For BPL inactivation, a 1:1000 volume ratio (BPL:virus) could also effectively inactivate MPXV. A total of 2% or 5% MCP and 75% ethanol treated with MPXV for at least 1 min could reduce >4.25 lg; Conclusions: MPXV shows high stability to temperature and freeze-thaw. Heat and BPL treatments are effective for the inactivation of MPXV, while MCP and ethanol are effective for disinfection, which could help laboratory staff operate the MPXV under safer conditions and improve operational protocols.

NMDA receptors as therapeutic targets for depression treatment: Evidence from clinical to basic research.

Ketamine, functioning as a channel blocker of the excitatory glutamate-gated N-methyl-d-aspartate (NMDA) receptors, displays compelling fast-acting and sustained antidepressant effects for treatment-resistant depression. Over the past decades, clinical and preclinical studies have implied that the pathology of depression is associated with dysfunction of glutamatergic transmission. In particular, the discovery of antidepressant agents modulating NMDA receptor function has prompted breakthroughs for depression treatment compared with conventional antidepressants targeting the monoaminergic system. In this review, we first summarized the signalling pathway of the ketamine-mediated antidepressant effects, based on the glutamate hypothesis of depression. Second, we reviewed the hypotheses of the synaptic mechanism and network of ketamine antidepressant effects within different brain areas and distinct subcellular localizations, including NMDA receptor antagonism on GABAergic interneurons, extrasynaptic and synaptic NMDA receptor-mediated antagonism, and ketamine blocking bursting activities in the lateral habenula. Third, we reviewed the different roles of NMDA receptor subunits in ketamine-mediated cognitive and psychiatric behaviours in genetically-manipulated rodent models. Finally, we summarized the structural basis of NMDA receptor channel blockers and discussed NMDA receptor modulators that have been reported to exert potential antidepressant effects in animal models or in clinical trials. Integrating the cutting-edge technologies of cryo-EM and artificial intelligence-based drug design (AIDD), we expect that the next generation of first-in-class rapid antidepressants targeting NMDA receptors would be an emerging direction for depression therapeutics. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

Association Between Long-Term Exposure to Fine Particulate Matter Constituents and Progression of Cerebral Blood Flow Velocity in Beijing: Modifying Effect of Greenness.

Few studies have explored the effects of fine particulate matter (PM2.5) and its constituents on the progression of cerebral blood flow velocity (BFV) and the potential modifying role of greenness. In this study, we investigated the association of PM2.5 and its constituents, including sulfate (SO4 2-), nitrate (NO3 -), ammonium (NH4 +), organic matter (OM), and black carbon (BC), with the progression of BFV in the middle cerebral artery. Participants from the Beijing Health Management Cohort who underwent at least two transcranial Doppler sonography examinations during 2015-2020 were recruited. BFV change and BFV change rate were used to define the progression of cerebral BFV. Linear mixed effects models were employed to analyze the data, and the weighted quantile sum regression assessed the contribution of PM2.5 constituents. Additionally, greenness was examined as a modifier. Among the examined constituents, OM exhibited the strongest association with BFV progression. An interquartile range increase in PM2.5 and OM exposure concentrations was associated with a decrease of -16.519 cm/s (95% CI: -17.837, -15.201) and -15.403 cm/s (95% CI: -16.681, -14.126) in BFV change, and -10.369 cm/s/year (95% CI: -11.387, -9.352) and -9.615 cm/s/year (95% CI: -10.599, -8.632) in BFV change rate, respectively. Furthermore, stronger associations between PM2.5 and BFV progression were observed in individuals working in areas with lower greenness, those aged under 45 years, and females. In conclusion, reducing PM2.5 levels in the air, particularly the OM constituent, and enhancing greenness could potentially contribute to the protection of cerebrovascular health.

Role of Proviral HIV-1 DNA Genotyping for People Living with HIV (PLWH) Who Had Low-Level Viremia While Receiving Antiretroviral Therapy.

Objective: To analyze the antiretroviral resistance in people living with HIV (PLWH) who developed low-level viremia (LLV) during antiretroviral therapy (ART) via sequencing of their HIV-1 proviral DNA and RNA and comparisons of their proviral DNA genotyping data with their past and synchronous RNA genotyping data. Patients and Methods: PLWH with LLV while receiving ART for 6 months or longer from January 2020 to September 2021 were included. HIV-1 proviral DNA and RNA were extracted from white-blood cells and concentrated plasma by ultracentrifugation, respectively, and HIV-1 pol gene fragments were amplified and sequenced. The concordance in the detection of resistance-associated mutations (RAMs) were examined between proviral DNA vs past RNA genotyping and proviral DNA vs synchronous RNA genotyping. Results: Of the 150 PLWH with LLV, 117 proviral DNA pol sequences detected in 105 PLWH were successfully amplified and RAMs were present in 27.6% and the rate of RAMs conferring low-level or greater resistance to antiretrovirals examined was 17.1%. Fifty-six and 57 PLWH had results of past and synchronous RNA genotyping, respectively, for comparisons with those of proviral DNA genotyping; and the concordance rates were 76.8% and 75.4%, respectively. However, proviral DNA genotyping lost than gained partial information on antiretroviral resistance compared with past or synchronous RNA genotyping. Conclusion: We found that the concordance between proviral DNA and past and synchronous RNA genotyping was moderate. Proviral DNA genotyping lost than gained more information on antiretroviral resistance compared with past or synchronous RNA genotyping. To optimize ART in PLWH with LLV, antiretroviral resistance profile should be interpreted in combination with proviral DNA and RNA genotyping and a comprehensive review of previous treatment history.

Identification of specific and shared epitopes at the extreme N-terminal VP1 of Coxsackievirus A4, A2 and A5 by monoclonal antibodies.

Hand, foot and mouth disease (HFMD) is caused by a variety of serotypes in species A of the Enterovirus genus, including recently re-emerged Coxsackievirus A2 (CV-A2), CV-A4 and CV-A5. For development of diagnostic reagents, for surveillance, and the development of multivalent vaccines against HFMD, the antigenicity of HFMD-associated enteroviruses warrants investigation. The purified virions of CV-A4 were inoculated into Balb/c mice and hybridomas were obtained secreting monoclonal antibodies (mAbs) directed against CV-A4 and cross-reacting with other closely related species A enteroviruses. The mAbs were characterized by ELISA, Western blotting and in vitro neutralizing assays. The majority of mAbs was non-neutralizing, with only 2% of the mAbs neutralizing CV-A4 specifically. Most of mAbs bound to linear VP1 epitopes of CV-A4. Interestingly, four types of mAbs were obtained which bound specifically to CV-A4 or were broadly to CV-A4/-A2, CV-A4/-A5 and CV-A4/-A2/-A5, respectively. Mapping with overlapping or single-amino-acid mutant peptides revealed that the four types of mAbs all bound to the first 15 amino acids at the N-terminus of the VP1. This region of picornaviruses is functionally important as it is involved in uncoating and releasing of viral RNA into the cytosol. The binding footprints of four type mAbs are composed of conserved and variable residues and are different from each other. The newly discovered broadly cross-reactive mAbs reflect the high homology of CV-A4/ CV-A2/CV-A5. The results also demonstrate that it is possible and beneficial to develop the diagnostic reagents to detect rapidly the main pathogens of enteroviruses associated with HFMD cause by CV-A4/CV-A2/CV-A5.

The immunogenicity of Alum+CpG adjuvant SARS-CoV-2 inactivated vaccine in mice.

The ongoing evolution and emergence of SARS-CoV-2 variants have raised concerns regarding the efficacy of existing vaccines and therapeutic agents. This study aimed to investigate the immunogenicity of an aluminum hydroxide (Alum) and CpG adjuvanted inactivated vaccine (IAV) candidate against SARS-CoV-2 in mice. A comparison was made between the immune response of mice vaccinated with the Alum+CpG adjuvant IAV and those vaccinated with the Alum adjuvant IAV. Mice immunized with Alum+CpG adjuvant IAV demonstrated high antibody titers and a durable humoral immune response, as well as a Th1-type cellular immune response. Notably, compared to Alum alone vaccine, the Alum+CpG adjuvant IAV induced significantly higher proportions of GC B cells in the splenocytes of immunized mice. Importantly, the changes in inflammatory cytokine levels in the sera of mice vaccinated with the Alum+CpG adjuvant IAV followed a similar trend to that of the Alum adjuvant IAV, which had been proven safe in clinical trials. Overall, our results demonstrate that Alum+CpG adjuvant has the potential to serve as a novel adjuvant, thereby providing valuable insights into the development of vaccine formulations.

The assessment on cross immunity with smallpox virus and antiviral drug sensitivity of the isolated mpox virus strain WIBP-MPXV-001 in China.

Since May 2022, human mpox cases have increased unexpectedly in non-endemic countries. The first imported case of human mpox in Hong Kong was reported in September 2022. Here we report the isolation and identification of MPXV from the vesicle swabs of this patient. In this research, the vesicle swabs were inoculated in Vero and Vero E6 cells. In addition to observing cytopathic effects (CPEs) in Vero or Vero E6 cells, the isolated virus was identified as mpox virus (MPXV) using quantitative Real-Time PCR (RT-PCR), transmission electron microscopy, and high-throughput sequencing. The experiment also assessed the cross-protective efficacy of sera from the smallpox vaccinated population and preliminarily assessed the inhibitory effect of anti-smallpox virus drugs against MPXV. CPEs can be observed on Vero E6 cells at 24 h and Vero cells at 48 h. The virus particles could be observed by transmission electron microscope, showing typical orthopoxvirus morphology. In addition, F3L and ATI genes which from MPXV A39R, B2R, HA genes which from orthopoxvirus were confirmed by conventional PCR and Sanger sequencing. The next generation sequencing (NGS) suggests that the MPXV strain belongs to B.1 branch of the West African linage, and has a high identity with the sequence of the 2022 ongoing outbreak. PRNT50 results showed that 26.7% of sera from individuals born before 1981 who had been immunized with smallpox were positive, but no MPXV-neutralizing antibodies were found in sera from individuals born later. All four anti-smallpox virus drugs evaluated demonstrated inhibition of mpox virus.

Causal Associations of Air Pollution With Cardiovascular Disease and Respiratory Diseases Among Elder Diabetic Patients.

Extensive researches have linked air pollutants with cardiovascular disease (CVD) and respiratory diseases (RD), however, there is limited evidence on causal effects of air pollutants on morbidity of CVD or RD with comorbidities, particularly diabetes mellitus in elder patients. We included hospital admissions for CVD or RD among elder (≥65 years) diabetic patients between 2014 and 2019 in Beijing. A time-stratified case-crossover design based on negative-control exposure was used to assess causal associations of short-term exposure to air pollutants with CVD and RD among diabetic patients with the maximum lag of 7 days. A random forest regression model was used to calculate the contribution magnitude of air pollutants. A total of 493,046 hospital admissions were recorded. Per 10 µg/m3 uptick in PM1, PM2.5, PM10, SO2, NO2, O3, and 1 mg/m3 in CO was associated with 0.29 (0.05, 0.53), 0.14 (0.02, 0.26), 0.06 (0.00, 0.12), 0.36 (0.01, 0.70), 0.21 (0.02, 0.40), -0.08 (-0.25, 0.09), and 4.59 (0.56, 8.61) causal effect estimator for admission of CVD among diabetic patients, corresponding to 0.12 (0.05, 0.18), 0.09 (0.05, 0.13), 0.05, 0.23 (0.06, 0.41), 0.10 (0.02, 0.19), -0.04 (-0.06, -0.01), and 3.91(1.81, 6.01) causal effect estimator for RD among diabetic patients. The effect of gaseous pollutants was higher than particulate pollutants in random forest model. Short-term exposure to air pollution was causally associated with increased admission of CVD and RD among elder diabetic patients. Gaseous pollutants had a greater contribution to CVD and RD among elder diabetic patients.

Insights into the HIV-1 Latent Reservoir and Strategies to Cure HIV-1 Infection.

Since the first discovery of human immunodeficiency virus 1 (HIV-1) in 1983, the targeted treatment, antiretroviral therapy (ART), has effectively limited the detected plasma viremia below a very low level and the technique has been improved rapidly. However, due to the persistence of the latent reservoir of replication-competent HIV-1 in patients treated with ART, a sudden withdrawal of the drug inevitably results in HIV viral rebound and HIV progression. Therefore, more understanding of the HIV-1 latent reservoir (LR) is the priority before developing a cure that thoroughly eliminates the reservoir. HIV-1 spreads through both the release of cell-free particles and by cell-to-cell transmission. Mounting evidence indicates that cell-to-cell transmission is more efficient than cell-free transmission of particles and likely influences the pathogenesis of HIV-1 infection. This mode of viral transmission also influences the generation and maintenance of the latent reservoir, which represents the main obstacle for curing the infection. In this review, the definition, establishment, and maintenance of the HIV-1 LR, along with the state-of-the-art quantitative approaches that directly quantify HIV-1 intact proviruses, are elucidated. Strategies to cure HIV infection are highlighted. This review will renew hope for a better and more thorough cure of HIV infection for mankind and encourage more clinical trials to achieve ART-free HIV remission.