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Abstract Background Natural killer (NK) cells play an important first-line role against tumour and viral infections and are regulated by inhibitory receptor expression. Among these inhibitory receptors, the expression, function, and mechanism of cluster of differentiation 47 (CD47) on NK cells during human immunodeficiency virus (HIV) infection remain unclear. Methods Fresh peripheral blood mononuclear cells (PBMCs) were collected from people living with HIV (PLWH) and HIV negative controls (NC) subjects. Soluble ligand expression levels of CD47 were measured using ELISA. HIV viral proteins or Toll-like receptor 7/8 (TLR7/8) agonist was used to investigate the mechanisms underlying the upregulation of CD47 expression. The effect of CD47 on NK cell activation, proliferation, and function were evaluated by flow cytometry. RNA-seq was used to identify downstream pathways for CD47 and its ligand interactions. A small molecule inhibitor was used to restore the inhibition of NK cell function by CD47 signalling. Results CD47 expression was highly upregulated on the NK cells from PLWH, which could be due to activation of the Toll-like receptor 7/8 (TLR7/8) pathway. Compared with NC subjects, PLWH subjects exhibited elevated levels of CD47 ligands, thrombospondin-1 (TSP1), and counter ligand signal regulatory protein-α (SIRPα). The TSP1–CD47 axis drives the suppression of interferon gamma (IFN-γ) production and the activation of the Janus kinase signal transducer and activator of transcription (JAK–STAT) pathway in NK cells. After treatment with a STAT3 inhibitor, the NK cells from PLWH showed significantly improved IFN-γ production. Conclusions The current data indicate that the binding of the inhibitory receptor CD47 to plasma TSP1 suppresses NK cell IFN-γ production by activating the JAK/STAT3 pathway during HIV infection. Our results suggest that CD47 and its related signalling pathways could be targets for improving NK cell function in people living with HIV.

Abstract Background The preference for glucose oxidative mode has crucial impacts on various physiological activities, including determining stem cell fate. External mechanical factors can play a decisive role in regulating critical metabolic enzymes and pathways of stem cells. Periodontal ligament stem cells (PDLSCs) are momentous effector cells that transform mechanical force into biological signals during the reconstruction of alveolar bone. However, mechanical stimuli-induced alteration of oxidative characteristics in PDLSCs and the underlying mechanisms have not been fully elucidated. Methods Herein, we examined the expression of LDH and COX4 by qRT-PCR, western blot, immunohistochemistry and immunofluorescence. We detected metabolites of lactic acid and reactive oxygen species for functional tests. We used tetramethylrhodamine methyl ester (TMRM) staining and a transmission electron microscope to clarify the mitochondrial status. After using western blot and immunofluorescence to clarify the change of DRP1, we further examined MFF, PINK1, and PARKIN by western blot. We used cyclosporin A (CsA) to confirm the regulation of mitophagy and ceased the stretching as a rescue experiment. Results Herein, we ascertained that mechanical force could increase the level of LDH and decrease the expression of COX4 in PDLSCs. Simultaneously, the yield of reactive oxygen species (ROS) in PDLSC reduced after stretching, while lactate acid augmented significantly. Furthermore, mitochondrial function in PDLSCs was negatively affected by impaired mitochondrial membrane potential (MMP) under mechanical force, and the augment of mitochondrial fission further induced PRKN-dependent mitophagy, which was confirmed by the rescue experiments via blocking mitophagy. As a reversible physiological stimulation, the anaerobic preference of PDLSCs altered by mechanical force could restore after the cessation of force stimulation. Conclusions Altogether, our study demonstrates that PDLSCs under mechanical force preferred anaerobic oxidation induced by the affected mitochondrial dynamics, especially mitophagy. Our findings support an association between mechanical stimulation and the oxidative profile of stem cells, which may shed light on the mechanical guidance of stem cell maintenance and commitment, and lay a molecular foundation for periodontal tissue regeneration. Graphical Abstract

Abstract Background Given the rapid development of clinical immunology technologies, students majoring in laboratory medicine should master the technological principles and application of clinical laboratory immunology. However, many are required to take online courses due to COVID-19 restrictions, which highlights the need to revisit teaching strategies. Recently, various medical education courses (such as Biochemistry, Physiology, etc.) have implemented the flipped classroom (FC) and team-based learning (TBL) methods, resulting in more positive teaching evaluations. To promote the students' mastery of the difficult knowledge effectively during the online teaching work, we evaluated the performance of online FC-TBL in a clinical laboratory immunology course. Methods Sixty-two third-year students from two classes majoring in Laboratory Medicine were recruited and divided into two groups, including one group with traditional lecture-based learning teaching strategy (LBL group) and the other group with LBL or online FC combined with TBL teaching strategy (FC-TBL group). We selected three chapters to conduct FC-TBL teaching in class. All participants took in-class quizzes and final examinations that targeted the same knowledge points. Finally, all participants completed anonymous questionnaires asking for their perceptions of the respective teaching models. In addition, we conducted a survey of teaching suggestions by a FC-TBL class of students majoring in Laboratory Medicine. Results The FC-TBL group (vs LBL group) had significantly higher scores on the in-class quizzes and final examinations, and also reported high satisfaction with the FC-TBL model. These findings indicate that FC-TBL is suitable for clinical laboratory immunology, as the participants quickly gained essential knowledge. Specifically, FC-TBL helped to “increase learning motivation,” “promote self-directed learning skills,” “extend more related knowledge,” “enhance problem-solving abilities,” “enhance clinical reasoning abilities,” and “enhance communication skills.” For participants’ suggestions, 48.38% (15/31) students held positive attitude to FC-TBL teaching strategy compared to 25.81% (8/31) students who considered FC-TBL teaching strategy still needs continuous improvement, and 25.81% (8/31) students reported that they believed FC-TBL teaching strategy was perfect and no further suggestions. Conclusions Online FC-TBL effectively enhanced learning activity among students of a clinical laboratory immunology course. This is particularly useful in the COVID-19 context.

Cryptococcal meningoencephalitis (CM) is emerging as an infection in HIV/AIDS patients shifted from primarily ART­naive to ART-experienced individuals, as well as patients with COVID-19 and immunocompetent hosts. This fungal infection is mainly caused by the opportunistic human pathogen Cryptococcus neoformans. Brain or central nervous system (CNS) dissemination is the deadliest process for this disease; however, mechanisms underlying this process have yet to be elucidated. Moreover, illustrations of clinically relevant responses in cryptococcosis are currently limited due to the low availability of clinical samples. In this study, to explore the clinically relevant responses during C. neoformans infection, macaque and mouse infection models were employed and miRNA-mRNA transcriptomes were performed and combined, which revealed cytoskeleton, a major feature of HIV/AIDS patients, was a centric pathway regulated in both infection models. Notably, assays of clinical immune cells confirmed an enhanced macrophage “Trojan Horse” in patients with HIV/AIDS, which could be shut down by cytoskeleton inhibitors. Furthermore, myocilin, encoded by MYOC, was found to be a novel enhancer for the macrophage “Trojan Horse,” and an enhanced fungal burden was achieved in the brains of MYOC-transgenic mice. Taken together, the findings from this study reveal fundamental roles of the cytoskeleton and MYOC in fungal CNS dissemination, which not only helps to understand the high prevalence of CM in HIV/AIDS but also facilitates the development of novel therapeutics for meningoencephalitis caused by C. neoformans and other pathogenic microorganisms.

Vegetation is the most vulnerable component of terrestrial ecosystems to climate change. In recent decades, there has been a significant warming and humidification trend in the Tibetan Plateau. It is crucial to study and analyze the impact of these changes on the ecosystem and their future trends for protecting the Tibetan Plateau’s ecosystem. This study collected and analyzed climate (temperature, precipitation) data and vegetation index data (the normalized difference vegetation index (NDVI) and the leaf area index (LAI)), as well as data from significance tests combined with Mann–Kendall tests and Sen’s slope estimation. The effects of temperature and precipitation factors on vegetation indices were revealed, leading to a multiple regression model predicting NDVI and LAI value changes under climate change from 2021 to 2100. The results indicate a general increase in temperature and precipitation levels across the Tibetan Plateau between 2000 and 2020. The climate experienced a clear pattern of warming and moist conditions, with the southeast region experiencing warmer and wetter conditions, and the northwest region experiencing drier and colder conditions. The trends of the LAI and NDVI values of the Tibetan Plateau indicated a general increase, with a gradual decline from the southeast to the northwest. Precipitation and temperature were differentially correlated with the NDVI and LAI values across various regions of the plateau. Between 2021 and 2100, the Tibetan Plateau is expected to experience year-on-year increases in both precipitation and temperature levels. However, the increase in precipitation was found to be less significant than that of the climate and, comparatively, smoother. There is a certain correlation between the NDVI and LAI values, and the changes in temperature and precipitation. The variations of both are more influenced by temperature than precipitation, with an overall increasing trend observed over the years, which is also quite evident. This study could serve as a scientific foundation and a point of reference for monitoring vegetation changes over a long period of time on the plateau, as well as for the planning and execution of ecological development in the Tibetan Plateau.

The ectonucleotidases CD38 and CD39 have a critical regulatory effect on tumors and viral infections via the adenosine axis. Natural killer (NK) cells produce cytokines, induce cytotoxic responses against viral infection, and acquire immunoregulatory properties. However, the roles of CD38 and CD39 expressed NK cells in HIV disease require elucidation. Our study showed that the proportions of CD38+CD39+ NK cells in HIV-infected individuals were positively associated with HIV viral loads and negatively associated with the CD4+ T cell count. Furthermore, CD38+CD39+ NK cells expressed additional inhibitory receptors, TIM-3 and LAG-3, and produced more TGF-β. Moreover, autologous NK cells suppressed the proliferation of CD8+ T and CD4+ T cells of HIV-infected individuals, and inhibiting CD38 and CD39 on NK cells restored CD8+ T and CD4+ T cell proliferation in vitro. In conclusion, these data support a critical role for CD38 and CD39 on NK cells in HIV infection and targeting CD38 and CD39 on NK cells may be a potential therapeutic strategy against HIV infection.

Natural killer (NK) cells are crucial for immune responses to viral infections. CD160 is an important NK cell activating receptor, with unknown function in HIV infection. Here, we found that CD160 expression was reduced on NK cells from HIV-infected individuals and its expression was negatively correlated with HIV disease progression. Further, GLUT1 expression and glucose uptake were higher in CD160+ NK cells, and the results of RNA-seq and flow cytometry demonstrated that CD160 positively regulated glucose metabolism through the PI3K/AKT/mTOR/s6k signaling pathway, thereby enhancing NK cell function. Moreover, we determined that reduced CD160 expression on NK cells could be attributed to the higher plasma levels of TGF-β1 in HIV-infected individuals. Overall, these results highlight the vital role of CD160 in HIV disease progression and regulation of glucose metabolism, indicating a potential target for HIV immunotherapy.

Summary: HIV-1 infects blood CD4 T cells through the use of CD4 and CXCR4 or CCR5 receptors, which can be targeted through blocking viral binding to CD4/CXCR4/CCR5 or virus-cell fusion. Here we describe a novel mechanism by which HIV-1 nuclear entry can also be blocked through targeting a non-entry receptor, CD2. Cluster of differentiation 2 (CD2) is an adhesion molecule highly expressed on human blood CD4, particularly, memory CD4 T cells. We found that CD2 ligation with its cell-free ligand LFA-3 or anti-CD2 antibodies rendered blood resting CD4 T cells highly resistant to HIV-1 infection. We further demonstrate that mechanistically, CD2 binding initiates competitive signaling leading to cofilin activation and localized actin polymerization around CD2, which spatially inhibits HIV-1-initiated local actin polymerization needed for viral nuclear migration. Our study identifies CD2 as a novel target to block HIV-1 infection of blood resting T cells.

BACKGROUND: Rapid on-site triage is critical after mass-casualty incidents (MCIs) and other mass injury events. Unmanned aerial vehicles (UAVs) have been used in MCIs to search and rescue wounded individuals, but they mainly depend on the UAV operator's experience. We used UAVs and artificial intelligence (AI) to provide a new technique for the triage of MCIs and more efficient solutions for emergency rescue. METHODS: This was a preliminary experimental study. We developed an intelligent triage system based on two AI algorithms, namely OpenPose and YOLO. Volunteers were recruited to simulate the MCI scene and triage, combined with UAV and Fifth Generation (5G) Mobile Communication Technology real-time transmission technique, to achieve triage in the simulated MCI scene. RESULTS: Seven postures were designed and recognized to achieve brief but meaningful triage in MCIs. Eight volunteers participated in the MCI simulation scenario. The results of simulation scenarios showed that the proposed method was feasible in tasks of triage for MCIs. CONCLUSION: The proposed technique may provide an alternative technique for the triage of MCIs and is an innovative method in emergency rescue. [ABSTRACT FROM AUTHOR]

The ectonucleotidases CD38 and CD39 have a critical regulatory effect on tumors and viral infections via the adenosine axis. Natural killer (NK) cells produce cytokines, induce cytotoxic responses against viral infection, and acquire immunoregulatory properties. However, the roles of CD38 and CD39 expressed NK cells in HIV disease require elucidation. Our study showed that the proportions of CD38+CD39+ NK cells in HIV-infected individuals were positively associated with HIV viral loads and negatively associated with the CD4+ T cell count. Furthermore, CD38+CD39+ NK cells expressed additional inhibitory receptors, TIM-3 and LAG-3, and produced more TGF-β. Moreover, autologous NK cells suppressed the proliferation of CD8+ T and CD4+ T cells of HIV-infected individuals, and inhibiting CD38 and CD39 on NK cells restored CD8+ T and CD4+ T cell proliferation in vitro. In conclusion, these data support a critical role for CD38 and CD39 on NK cells in HIV infection and targeting CD38 and CD39 on NK cells may be a potential therapeutic strategy against HIV infection. [ABSTRACT FROM AUTHOR]