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Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010–37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.

Increased CD4+GNLY+ T cells have been confirmed to be inversely associated with CD4+ T cell count in immunological non-responders (INRs), however, the underlying mechanisms are unknown. This study aimed to elucidate the characteristics of CD4+GNLY+ T cells and their relationship with immune restoration. Single-cell RNA sequencing, single-cell TCR sequencing, and flow cytometry were used to analyze the frequency, phenotypes, and function of CD4+GNLY+ T cells. Moreover, Enzyme linked immunosorbent assay was performed to detect plasma cytokines production in patients. CD4+GNLY+ T cells were found to be highly clonally expanded, characterized by higher levels of cytotoxicity, senescence, P24, and HIV-1 DNA than CD4+GNLY− T cells. Additionally, the frequency of CD4+GNLY+ T cells increased after ART, and further increased in INRs, and were positively associated with the antiretroviral therapy duration in INR. Furthermore, increased IL-15 levels in INRs positively correlated with the frequency and senescence of CD4+GNLY+ T cells, suggesting that CD4+GNLY+ T cells may provide new insights for understanding the poor immune reconstitution of INRs. In conclusion, increased, highly clonally expanded, and senescent CD4+GNLY+ T cells may contribute to poor immune reconstitution in HIV-1 infection.

The shape of nanochannels plays a crucial role in the ion selectivity and overall performance of reverse electrodialysis (RED) systems. However, current research on two-dimensional nanochannel shapes is largely limited to a few fixed asymmetric forms. This study explores the impact of randomly shaped nanochannels using dimensionless methods, controlling their randomness by varying their length and shape amplitude. The research systematically compares how alterations in the nanochannel length and shape amplitude influence various system performance parameters. Our findings indicate that increasing the nanochannel length can significantly enhance the system performance. While drastic changes in the nanochannel shape amplitude positively affect the system performance, the most significant improvements arise from the interplay between the nanochannel length and shape amplitude. This compounding effect creates a local optimum, resulting in peak system performance. Within the range of dimensionless lengths from 0 to 30, the system reaches its optimal performance at a dimensionless length of approximately 25. Additionally, we explored two other influencing factors: the nanochannel surface charge density and the concentration gradient of the solution across the nanochannel. Optimal performance is observed when the nanochannel has a high surface charge density and a low concentration gradient, particularly with random shapes. This study advances the theoretical understanding of RED systems in two-dimensional nanochannels, guiding research towards practical operational conditions.

An adaptive particle refinement (APR) algorithm has been developed for the smoothed particle hydrodynamics (SPH) method to augment the resolution of the region of interest to achieve high accuracy and simultaneously reduce the cost of computational resources. It is widely applied in the field of fluid-controlling problems involving large interface deformations, such as the two-phase flow and fluid–structure interaction because this algorithm can capture the interface with high accuracy. Nonetheless, existing APR algorithms widely encounter computational dispersion issues at the interface of regions of different particle resolutions. Moreover, traditional shifting algorithms applied in the APR processes also have difficulties in dealing with particles with different smooth lengths. In this work, an algorithm for fast particle generation was first developed based on the accelerated ray method, which accelerates the discretization of the flow field into particles. Then, a dynamic refinement/coarsening algorithm based on the APR algorithm is proposed to solve the computational dispersion problem that occurs at the refinement/coarsening interfaces. In addition, the shifting algorithm was improved in this work to ensure the particles are always well distributed during numerical calculations and, thus, can efficiently facilitate the adaptive particle refinement/coarsening processes. Comparative analysis indicates that the robust algorithms developed for the SPH method in this work can lead to more precise and reasonable flow fields compared with the conventional SPH adaptive methods.

The water entry of a torpedo is a complex nonlinear problem, involving transient impact, free surface deformation, droplet splashing, and fluid–structure coupling, which poses severe challenges to traditional mesh methods. The meshless smoothed particle hydrodynamics (SPH) method shows unique advantages in capturing the complex features of the water entry of the torpedo at different entry angles. However, it still suffers from some inherent shortcomings, such as low surface discretization accuracy, poor discretization flexibility, and low calculation efficiency. In this study, an improved adaptive SPH algorithm is proposed to investigate the water entry of the torpedo accurately and efficiently. This method integrates meshless point generation and adaptive techniques simultaneously. The numerical results demonstrate that when the torpedo vertically enters the water at different velocities, the induced impact loads acting on the head of the torpedo fluctuate significantly with two peak values in the initial stage and thereafter stabilize in a later stage. The impact load acting on the torpedo, the entry depth of the torpedo, the splash height of the droplets, and the size of the cavity generated around the torpedo increase with the increment in the entry velocity. When the torpedo enters the water at different entry angles under the same initial entry velocity, both the vertical and the horizontal movements of the torpedo are observed, which results in more complex variations in parameters along the x- and y-axes. The findings and the corresponding numerical method in this study can provide a certain basis for the future designs of the entry trajectory and the structural bearing capacity of torpedoes.

Abstract Background Hypertriglyceridemia is associated with subclinical atherosclerosis and vascular inflammation even when low-density lipoprotein cholesterol levels are normal. However, few cohort studies on hypertriglyceridemia have been conducted in males with higher susceptibility to human immunodeficiency virus (HIV)-related deterioration of arterial structure and function. Our objective was to investigate the incidence of hypertriglyceridemia during treatment with combination antiretroviral therapy (cART) in males with HIV and explore its related risk factors. Methods In this retrospective study, we included 309 males living with HIV (median age 31 years [interquartile range 26–42.5]) who initiated cART treatment in our hospital from January 2013 to December 2018. We collected follow-up data on serum triglycerides and other related information as of June 31, 2021. A Cox proportional hazards regression model was used to analyze the related risk factors. Results In 666.7 person-years, hypertriglyceridemia occurred in 140 patients (triglyceride ≥2.3 mmol/L [200 mg/dL]), and the incidence rate was 21.0 per 100 person-years (Patients who took the lamivudine [3TC] + tenofovir disoproxil fumarate [TDF] + efavirenz [EFV] regimen accounted for 77.0% of the total patients.). Multiple Cox regression analysis showed that baseline CD4/CD8 ratio

Fish-like robots have been widely used in intelligent surveillance and investigation because of their high swimming efficiency and low traveling noise. Numerical simulations are usually selected to simulate the movement modes and hydrodynamic characteristics of fish-like robots during design and manufacture. However, the body-fitted grid method traditionally utilized in numerical simulations often has difficulty dealing with moving solid boundaries. In this work, the immersed boundary method, superior in handling the moving boundary conditions, is employed to simulate the movement of a fish-like robot swimming in high Reynolds number flows in combination with the RANS turbulence model. The numerical method is first validated using a fluid flowing over a square block, and the corresponding results are in good agreement with the ones reported in reference. Then, the swing of the fish-like robot under three different Reynolds numbers is studied. The lift coefficient and the drag coefficient of the fish-like robot decrease with increasing the Reynolds number. This paper provides remarkable support for future designs and applications of fish-like robots.

In this paper, an opposing jet is applied to the space shuttle arc leading edge and the lifting body cone leading edge in the hypersonic condition of the rarefied flow field. The DSMC numerical algorithm is used to simulate and analyze the underlying working physics of the opposing jet. The results provide a reference for designing hypersonic vehicles in near space that reduce drag and protect against heat.

Syphilis is an important health problem worldwide; however, few studies have probed the impact of syphilitic infection on T cell turnover. The mechanisms behind the frequency of T cell subset changes and the associations between these subsets during syphilitic infection remain unclear. Herein, we used a cell-staining method and flow cytometry to explore changes in T cell subpopulations and potential contribution of apoptosis and pyroptosis that triggered therein. We investigated caspase-1-mediated pyroptosis and caspase-3-mediated apoptosis of CD4 + and CD8 + T cells, the major effector lymphocytes with pivotal roles in the pathogenesis of infectious diseases. We found that the levels of caspase-1 and caspase-3 increased in both the circulation and intracellularly in CD4 + and CD8 + T cells. Caspase-1 showed a continual increase from early latent stage infection through to phase 2 disease, whereas caspase-3 increased through to phase 1 disease but declined during phase 2. In addition, serum levels and intracellular expression of caspase-1 and caspase-3 were positively correlated. Overall, this study increases our understanding of how syphilitic infection influences CD4 + and CD8 + T-cell turnover, which may help with designing novel and effective strategies to control syphilis infection and prevent its transmission.

Sensitive assays for HIV-1 neutralizing antibody detection are urgently needed for vaccine immunogen optimization and identification of protective immune response levels. In this study, we developed an easy-to-use HIV-1 pseudovirus neutralization assay based on a human CD4+ lymphoblastoid cell line A3R5 by employing a high efficient pseudovirus production system. Optimal conditions for cell counts, infection time, virus dose and concentration of DEAE-dextran were tested and identified. For T-cell line-adapted tier 1 virus strains, significantly higher inhibitory efficiency was observed for both monoclonal neutralizing antibody (4 fold) and plasma (2 fold) samples in A3R5 than those in TZM-bl assay. For circulating tier 2 strains, the A3R5 pseudovirus assay showed even much higher sensitivity for both neutralizing antibody (10 fold) and plasma (9 fold) samples. When sequential neutralizing antibody seroconverting samples were tested in both A3R5 and TZM-bl assays, the seroconverting points could be detected earlier for tier 1 (15.7 weeks) and tier 2 (68.3 weeks) strains in A3R5 assay respectively. The high sensitive pseudovirus assay using more physiological target cells could serve as an alternative to the TZM-bl assay for evaluation of vaccine-induced neutralizing antibodies and identification of the correlates of protection.

Over 95% of CD4 cell death occurs by Caspase-1-mediated pyroptosis during HIV infection. Caspase-3-mediated apoptosis accounts for the death in a small proportion of infected CD4 cells. To date, there have been no reports on the dynamics of Caspase-1 and Caspase-3 and their relationship with disease progression in acute HIV-1 infection. In this study, two distinct HIV-1 patient groups were enrolled. The CD4High group maintained a CD4 level above 450 cells/μl while CD4 levels in the CD4Low group dropped below 250 cells/μl within 2 years after infection. Blood samples were collected at 1, 2, 3, 4, 6, 12 and 24 months after HIV infection. Plasma Caspase-1 and Caspase-3 levels in the two patients groups were determined by a single-step ELISA using commercially available monoclonal antibodies. The results showed that Caspase-1 and Caspase-3 levels in the CD4High group increased rapidly and then decreased within a short time during early HIV-1 infection. In contrast, Caspase-1 and Caspase-3 levels in the CD4Low group were obviously increased after 1 year of HIV-1 infection.

BACKGROUND: Epidemics of HFMD are elevated every year globally, especially in mainland China. The disease now presents as an increasing threat to public health worldwide. METHODS: Five hundred and seventy-one EV71-infected HFMD patients in Beijing You'an Hospital were grouped by disease severity: Mild (no severe complication) (n=221), and Severe group (complicated with brainstem encephalitis (BE), and/or pulmonary edema (PE) (n=350)). Clinical and laboratory findings and levels of 7 serum cytokines were analyzed. RESULTS: Univariate analysis showed that (RR)>26/min (p8.3 mmol/L (p=0.008), CL1.2 × 10(9)/L (p=0.040) were associated with severe cases. Results of multivariate analysis indicated five independent risk factors (RR>26/min (p8.3 mmol/L (p=0.011), LYM>40% (p=0.010), and ALT>40 U/L (p=0.045)). In addition to single-factor analysis, we further analyzed the use of different combinations of risk factors. "GLU>8.3 and CL26" (confidence ration (CR)=100%) is the top indicator, followed by "ALT>40 and LYM>40% and RR>26 and Age

BACKGROUND: Early diagnosis is vital to HIV control. γδ T cells play critical roles in viral infections, but their activation in acute HIV infected patients and follow up to 18 months has not been described. METHODS: Changes in γδ T cells, including subsets, function and activation, in treated and untreated acutely HIV-infected patients (n = 79) were compared by cytotoxicity assay and flow cytometry with healthy controls (n = 21) at month 0, 6, 12 and 18. RESULTS: In acutely HIV-infected patients, Vδ1 cell proportion was elevated (P = 0.027) with Vδ2 population reduced (P = 0.002). Effector and central memory γδ T cell factions were decreased (P = 0.006 and P = 0.001, respectively), while proportion of terminal γδ T cells increased (P = 0.002). γδ T cell cytotoxicity was compromised over time. Fraction of IL-17-producing cells increased (P = 0.008), and IFN-γ-producing cells were unaffected (P = 0.115). Elevation of a microbial translocation marker, sCD14, was associated with γδ T cell activation (P = 0.001), which increased in a time-dependent manner, correlating with CD4/CD8 T cell activation set-points and CD4 counts. Antiretroviral therapy did not affect these changes. CONCLUSIONS: γδ T cell subpopulation and functions change significantly in acute HIV infection and over time. Early γδ T cell activation was associated with CD4/CD8 T cell activation set-points, which predict AIDS progression. Therefore, γδ T cell activation represents a potential surrogate marker of AIDS progression.

BACKGROUND: Active tuberculosis infection represents a very common and significant threat to HIV-infected patients. But measures to accurately detect it are limited. OBJECTIVE: To compare and analyze the diagnostic efficacy of T-SPOT.TB alone and in combination with TST in HIV-infected patients in China. METHOD: TST (tuberculin skin test) and T-SPOT.TB were performed on 131 HIV-infected patients admitted in Beijing You'an Hospital and Beijing Ditan Hospital between Oct, 2010 and Jul, 2012, who were initially diagnosed as suspected ATB (active TB). The patients were further categorized into ATB and Not ATB based on clinical and cultural evidences. The performance of TST and T-SPOT.TB were analyzed and compared. RESULTS: The sensitivity and specificity of T-SPOT.TB were 41.3% and 94.6%, respectively, both higher than TST (12.9% and 91.8%). By combining T-SPOT.TB and TST, the sensitivity did not increase, but specificity was elevated to 100%. TST, T-SPOT.TB and their combinations all performed better in patients with extra-pulmonary diseases than with pulmonary disorders. False-positive T-SPOT.TB results were found to be associated with history of prior TB. In addition, concomitant bacterial infections and low CD4 counts were associated with increased ATB risk. CONCLUSIONS: T-SPOT.TB is superior in screening ATB in HIV-infected patients in China over traditional TST. Additional TST would help to confirm a positive T-SPOT.TB result. Both tests work better for patients with extra-pulmonary conditions.

Protective antibodies play a critical role in an effective HIV vaccine; however, eliciting antibodies to block infection by viruses from diverse genetic subtypes remains a major challenge. As the world's most populous country, China has been under the threat of at least three major subtypes of circulating HIV-1 viruses. Understanding the cross reactivity and specificities of serum antibody responses that mediate broad neutralization of the virus in HIV-1 infected Chinese patients will provide valuable information for the design of vaccines to prevent HIV-1 transmission in China. Sera from a cohort of homosexual men, who have been managed by a major HIV clinical center in Beijing, China, were analyzed for cross-sectional neutralizing activities against pseudotyped viruses expressing Env antigens of the major subtype viruses (AE, BC and B subtypes) circulating in China. Neutralizing activities in infected patients' blood were most capable of neutralizing viruses in the homologous subtype; however, a subset of blood samples was able to achieve broad neutralizing activities across different subtypes. Such cross neutralizing activity took 1-2 years to develop and CD4 binding site antibodies were critical components in these blood samples. Our study confirmed the presence of broadly neutralizing sera in China's HIV-1 patient population. Understanding the specificity and breadth of these neutralizing activities can guide efforts for the development of HIV vaccines against major HIV-1 viruses in China.

It has been emphasized that chronic generalized immune dysfunction is the leading event in the pathogenesis of HIV infection, in which the contribution of dendritic cells (DCs) and regulatory T cells (Tregs) should not be underestimated. In current study, we assessed the longitudinal changes of peripheral blood DC subsets and Tregs in chronically asymptomatic treatment-naive HIV-1-infected patients during 60 weeks of antiretroviral therapy (ART), and compared with those in healthy controls and long term non-progressors (LTNPs). Blood samples were collected at week 0, 4, 12, 24, 48 and 60 of treatment to measure the counts of DC subsets and Tregs by flow cytometry and IFN-a plasma levels by ELISA. The counts of myeloid dendritic cells (mDCs) increased during ART, reaching similar levels to healthy controls at week 60 post ART but still lower than those of LTNPs. In HIV-1-infected patients, the mDCs counts were directly correlated with CD4 counts during ART. Changes in mDCs at week 8 were positively correlated with the changes in CD4 counts at week 60 post ART. However, the counts and function of plasmacytoid dendritic cells (pDCs) remained relatively stable during ART, and similar to those in healthy controls and LTNPs. The percentage of Tregs increased before ART and normalized after ART. Importantly, we found pDCs counts were associated with percentage of Tregs during ART, which may help in understanding of the role of these cells in HIV infection.

BACKGROUND: Despite prolonged treatment with highly active antiretroviral therapy (HAART), the infectious HIV-1 continues to replicate and resides latently in the resting memory CD4+ T lymphocytes, which blocks the eradication of HIV-1. The viral persistence of HIV-1 is mainly caused by its proviral DNA being either linear nonintegrated, circular nonintegrated, or integrated. Previous reports have largely focused on the dynamics of HIV-1 DNA from the samples collected with relatively long time intervals during the process of disease and HAART treatment, which may have missed the intricate changes during the intervals in early treatment. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the dynamics of HIV-1 DNA in patients during the early phase of HARRT treatment. Using optimized real time PCR, we observed significant changes in 2-LTR during the first 12-week of treatment, while total and integrated HIV-1 DNA remained stable. The doubling time and half-life of 2-LTR were not correlated with the baseline and the rate of changes in plasma viral load and various CD4+ T-cell populations. Longitudinal analyses on 2-LTR sequences and plasma lipopolysaccharide (LPS) levels did not reveal any significant changes in the same treatment period. CONCLUSIONS/SIGNIFICANCE: Our study revealed the rapid changes in 2-LTR concentration in a relatively large number of patients during the early HAART treatment. The rapid changes indicate the rapid infusion and clearance of cells bearing 2-LTR in the peripheral blood. Those changes are not expected to be caused by the blocking of viral integration, as our study did not include the integrase inhibitor raltegravir. Our study helps better understand the dynamics of HIV-DNA and its potential role as a biomarker for the diseases and for the treatment efficacy of HAART.