High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen.

High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen's ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.

Tat-CIRP Peptide Facilitates Frozen Wound Healing by Ameliorating Inflammation and Promoting Angiogenesis.

Background: Frostbite is a chemia resulting from cold-induced skin damage. The process of frostbite is often accompanied by inflammation, and the therapeutic strategies focusing on anti-inflammation are the main direction to data. Tat-CIRP is a 15 amino acid peptide containing HIV protein and cold-inducible RNA-binding protein (CIRP), which is believed to compete with endogenous CIRP for myeloid differentiation 2 (MD2) binding. This study aims to investigate the efficacy of Tat-CIRP in the treatment of frostbite. Methods: A mouse model of frostbite was established, and on the first day after frostbite occurrence, Tat-CIRP peptide was administered intravenously via the tail with a dosage interval of one day for a total of three doses. Frozen mouse skin sections were subjected to histological analysis, including hematoxylin-eosin (HE) staining, Masson staining, and immunohistochemical examination. Western blotting was performed to detect the expression level of Ki-67 in mouse skin tissue. Results: One day after frostbite, mice exhibited skin swelling and a solid appearance. From day 1 to 5 after frostbite, MD2 expression was significantly upregulated, while CIRP expression was downregulated. Compared to the frostbite group, mice treated with Tat-CIRP showed accelerated frostbite recovery, reduced levels of inflammatory factors and MD2. Furthermore, the expression of cell proliferation-associated protein Ki-67 and angiogenesis-related protein CD31 was upregulated. Conclusion: Tat-CIRP promotes frozen wound healing via inhibiting inflammation and promoting angiogenesis in frostbitten mice.

mHealth-Based Gamification Interventions Among Men Who Have Sex With Men in the HIV Prevention and Care Continuum: Systematic Review and Meta-Analysis.

Background: In the past few years, a burgeoning interest has emerged in applying gamification to promote desired health behaviors. However, little is known about the effectiveness of such applications in the HIV prevention and care continuum among men who have sex with men (MSM). Objective: This study aims to summarize and evaluate research on the effectiveness of gamification on the HIV prevention and care continuum, including HIV-testing promotion; condomless anal sex (CAS) reduction; and uptake of and adherence to pre-exposure prophylaxis (PrEP), postexposure prophylaxis (PEP), and antiretroviral therapy (ART). Methods: We comprehensively searched PubMed, Embase, the Cochrane Library, Web of Science, Scopus, and the Journal of Medical Internet Research and its sister journals for studies published in English and Chinese from inception to January 2024. Eligible studies were included when they used gamified interventions with an active or inactive control group and assessed at least one of the following outcomes: HIV testing; CAS; and uptake of and adherence to PrEP, PEP, and ART. During the meta-analysis, a random-effects model was applied. Two reviewers independently assessed the quality and risk of bias of each included study. Results: The systematic review identified 26 studies, including 10 randomized controlled trials (RCTs). The results indicated that gamified digital interventions had been applied to various HIV outcomes, such as HIV testing, CAS, PrEP uptake and adherence, PEP uptake, and ART adherence. Most of the studies were conducted in the United States (n=19, 73%). The most frequently used game component was gaining points, followed by challenges. The meta-analysis showed gamification interventions could reduce the number of CAS acts at the 3-month follow-up (n=2 RCTs; incidence rate ratio 0.62, 95% CI 0.44-0.88). The meta-analysis also suggested an effective but nonstatistically significant effect of PrEP adherence at the 3-month follow-up (n=3 RCTs; risk ratio 1.16, 95% CI 0.96-1.38) and 6-month follow-up (n=4 RCTs; risk ratio 1.28, 95% CI 0.89-1.84). Only 1 pilot RCT was designed to evaluate the effectiveness of a gamified app in promoting HIV testing and PrEP uptake. No RCT was conducted to evaluate the effect of the gamified digital intervention on PEP uptake and adherence, and ART initiation among MSM. Conclusions: Our findings suggest the short-term effect of gamified digital interventions on lowering the number of CAS acts in MSM. Further well-powered studies are still needed to evaluate the effect of the gamified digital intervention on HIV testing, PrEP uptake, PEP initiation and adherence, and ART initiation in MSM.

Unraveling the complex pathophysiology of white matter hemorrhage in intracerebral stroke: A single-cell RNA sequencing approach.

AIM: This study aims to elucidate the cellular dynamics and pathophysiology of white matter hemorrhage (WMH) in intracerebral hemorrhage (ICH). METHODS: Using varying doses of collagenase IV, a consistent rat ICH model characterized by pronounced WMH was established. Verification was achieved through behavioral assays, hematoma volume, and histological evaluations. Single-cell suspensions from the hemorrhaged region of the ipsilateral striatum on day three post-ICH were profiled using single-cell RNA sequencing (scRNA-seq). Gene Ontology (GO) and gene set variation analysis (GSVA) further interpreted the differentially expressed genes (DEGs). RESULTS: Following WMH induction, there was a notable increase in the percentage of myeloid cells and oligodendrocyte precursor cells (OPCs), alongside a reduction in the percentage of neurons, microglia, and oligodendrocytes (OLGs). Post-ICH WMH showed homeostatic microglia transitioning into pro-, anti-inflammatory, and proliferative states, influencing lipid metabolic pathways. Myeloid cells amplified chemokine expression, linked with ferroptosis pathways. Macrophages exhibited M1 and M2 phenotypes, and post-WMH, macrophages displayed a predominance of M2 phenotypes, characterized by their anti-inflammatory properties. A surge in OPC proliferation aligned with enhanced ribosomal signaling, suggesting potential reparative responses post-WMH. CONCLUSION: The study offers valuable insights into WMH's complex pathophysiology following ICH, highlighting the significance and utility of scRNA-seq in understanding the cellular dynamics and contributing to future cerebrovascular research.

Network pharmacology and gut microbiota insights: unraveling Shenling Baizhu powder's role in psoriasis treatment.

Background: Psoriasis, a chronic skin condition characterized by systemic inflammation and altered gut microbiota, has been a target of Traditional Chinese Medicine (TCM) for centuries. Shenling Baizhu Powder (SLBZP), a TCM formulation, holds promise for treating inflammatory diseases, but its specific role in psoriasis and impact on gut microbiota is not fully understood. Objective: This study aims to elucidate the mechanism of SLBZP in treating psoriasis, integrating component analysis, network pharmacology, and experimental validation in mice models. Methods: We commenced with a detailed component analysis of SLBZP using liquid chromatograph and mass spectrometer (LC-MS). Network pharmacology analysis was used to predict the potential action targets and pathways of SLBZP in psoriasis. An in vivo experiment was conducted with psoriasis mice models, treated with SLBZP. Therapeutic effects were assessed via symptomatology, histopathology, and immunohistochemical analysis. Gut microbiota composition was analyzed using 16S rRNA gene sequencing. Results: A total of 42 main components and quality markers were identified, primarily from licorice and ginseng, including flavonoids, saponins and other markers. PPI topology analysis showed that TNF, IL-6, IL-1ß, TP53 and JUN were the core DEPs. 168 signaling pathways including lipid and atherosclerosis, AGE-RAGE signaling pathway, IL-17 signaling pathway and Th17 cell differentiation were enriched by KEGG. SLBZP demonstrated significant therapeutic effects on psoriasis in mice, with alterations in skin pathology and biomarkers. Additionally, notable changes in gut microbiota composition were observed post-treatment, indicating a possible gut-skin axis involvement. Conclusion: This research has pinpointed lipid metabolism as a key pathway in the treatment of psoriasis with SLBZP. It explores how SLBZP's modulation of gut microbiota and lipid metabolism can alleviate psoriasis, suggesting that balancing gut microbiota may reduce inflammation mediators and offer therapeutic benefits. This underscores lipid metabolism modulation as a potential new strategy in psoriasis treatment.

The causal relationship between serum metabolites and the risk of psoriasis: a Mendelian randomization and meta-analysis study.

Objective: To explore the influence of serum metabolites on the risk of psoriasis. Methods: In the initial stage, we applied Mendelian randomization to evaluate the association between 1,400 serum metabolites and the risk of psoriasis. Causal effects were primarily assessed through the Inverse-Variance Weighted method and Wald Ratio's odds ratios, and 95% confidence intervals. False Discovery Rate was used for multiple comparison corrections. Sensitivity analyses were conducted using Cochran's Q Test, MR-PRESSO. MR-Steiger Test was employed to check for reverse causality. In the validation stage, we sought other sources of psoriasis GWAS data to verify the initial results and used meta-analysis to combine the effect sizes to obtain robust causal relationships. In addition, we also conducted metabolic pathway enrichment analysis on known metabolites that have a causal relationship with the risk of psoriasis in both stages. Results: In the initial stage, we identified 112 metabolites causally associated with psoriasis, including 32 metabolite ratios and 80 metabolites (69 known and 11 unknown). In the validation stage, 24 metabolites (16 known, 1 unknown, and 7 metabolite ratios) were confirmed to have a causal relationship with psoriasis onset. Meta-analysis results showed that the overall effect of combined metabolites was consistent with the main analysis in direction and robust in the causal relationship with psoriasis onset. Of the 16 known metabolites, most were attributed to lipid metabolism, with 5 as risk factors and 8 as protective factors for psoriasis. Peptidic metabolite Gamma-glutamylvaline levels had a negative causal relationship with psoriasis, while exogenous metabolite Catechol sulfate levels and amino acid 3-methylglutaconate levels had a positive causal relationship with the disease onset. The metabolites associated with psoriasis risk in the two stages are mainly enriched in the following metabolic pathways: Glutathione metabolism, Alpha Linolenic Acid and Linoleic Acid Metabolism, Biosynthesis of unsaturated fatty acids, Arachidonic acid metabolism, Glycerophospholipid metabolism. Conclusion: Circulating metabolites may have a potential causal relationship with psoriasis risk, and targeting specific metabolites may benefit psoriasis diagnosis, disease assessment, and treatment.

A bibliometrics study on the status quo and hot topics of pathogenesis of psoriasis based on Web of Science.

BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory skin disease. Great progress has been made in the pathogenesis of psoriasis in recent years, but there is no bibliometric study on the pathogenesis of psoriasis. The purpose of this study was to use bibliometrics method to analyze the research overview and hot spots of pathogenesis of psoriasis in recent 10 years, so as to further understand the development trend and frontier of this field. METHODS: The core literatures on the pathogenesis of psoriasis were searched in the Web of Science database, and analyzed by VOSviewer, CiteSpace, and Bibliometrix in terms of the annual publication volume, country, institution, author, journal, keywords, and so on. RESULTS: A total of 3570 literatures were included. China and the United States were the main research countries in this field, and Rockefeller University was the main research institution. Krueger JG, the author, had the highest number of publications and the greatest influence, and Boehncke (2015) was the most cited local literature. J INVEST DERMATOL takes the top spot in terms of the number of Dermatol articles and citation frequency. The main research hotspots in the pathogenesis of psoriasis are as follows: (1) The interaction between innate and adaptive immunity and the related inflammatory loop dominated by Th17 cells and IL-23/IL-17 axis are still the key mechanisms of psoriasis; (2) molecular genetic studies represented by Long Non-Coding RNA (LncRNA); (3) integrated research of multi-omics techniques represented by gut microbiota; and (4) Exploring the comorbidity mechanism of psoriasis represented by Metabolic Syndrome (MetS). CONCLUSION: This study is a summary of the current research status and hot trend of the pathogenesis of psoriasis, which will provide some reference for the scholars studying the pathogenesis of psoriasis.

The key aroma components of steamed green tea decoded by sensomics and their changes under different withering degree.

Steamed green tea has a long history and unique aroma, but little is known about its key aroma components. In this study, 173 volatiles in steamed green tea were identified using solvent-assisted flavor evaporation and headspace-solid phase microextraction plus two chromatographic columns of different polarities. Aroma extract dilution analysis revealed 48 highly aroma-active compounds with flavor dilution factors 64-1024. Internal standards were used to calculate odorant active value (OAV), and 11 OAV > 1 key aroma compounds were determined. Omission test identified eight substances, including dimethyl sulfide, (E)-ß-ionone, cis-jasmone, linalool, nonanal, heptanal, isovaleraldehyde and (Z)-3-hexenol, as the key aroma active compounds of steamed green tea. With the increase of withering degree, the content of these substances increased first and then decreased except for heptanal and cis-jasmone. Moreover, the water content of 62 % was suggested to be an appropriate withering degree during the processing of steamed green tea.

Study on color, aroma, and taste formation mechanism of large-leaf yellow tea during an innovative manufacturing process.

This study used samples processed with an innovative manufacturing process to explore the dynamic changes of large-leaf yellow tea (LYT) in color, aroma, and taste substances, and the quality components were most significantly affected in the stages of first pile-yellowing (FP) and over-fired drying (TD). In this process, the moisture and temperature conditions caused chlorophyll degradation, Maillard reactions, caramelization reactions, and isomerization of phenolic substances, forming the quality of LYT. Specifically, chlorophyll degradation favored the formation of color quality; the taste quality was determined by the content of soluble sugars, amino acids, catechins, etc.; the aroma quality was dependent on the content changes of alcohols and aldehydes, as well as the increase of sweet and roasting aroma substances in the third drying stage. Additionally, twelve key aroma components, including linalool, (E)-ß-ionone, 2,3-diethyl-5-methyl-pyrazine, etc., were identified as contributors to revealing LYT rice crust-like and sweet aroma formation mechanism.

Heterogeneous Structures Consisting of Rod-like ZnO Interspersed with Ce2S3 Nanoparticles for Photo-Sensitive Supercapacitors with Enhanced Capacitive Performance.

Photosensitive supercapacitors incorporate light-sensitive materials on capacitive electrodes, enabling solar energy conversion and storage in one device. In this study, heterogeneous structures of rod-shaped ZnO decorated with Ce2S3 nanoparticles on nickel foam (ZnO@Ce2S3/NF) are synthesized using a two-step hydrothermal method as photosensitive supercapacitor electrodes for capacitance enhancement under visible light. The formation of ZnO@Ce2S3 heterogeneous structures is confirmed using various structural characterization techniques. The area-specific capacitance of the ZnO@Ce2S3/NF composite electrode increased from 1738.1 to 1844.0 mF cm-2 after illumination under a current density of 5 mA cm-2, which is 2.4 and 2.8 times higher than that of ZnO and Ce2S3 electrodes under similar conditions, respectively, indicating the remarkable light-induced capacitance enhancement performance. The ZnO@Ce2S3/NF electrode also exhibits a higher photocurrent and photovoltage than the two single electrodes, demonstrating its excellent photosensitivity. The improved capacitance performance and photosensitivity under illumination are attributed to the well-constructed energy-level structure, which stimulates the flow of photogenerated electrons from the outer circuit and the involvement of photogenerated holes in the resulting surface-controlled capacitance. In addition, the assembled ZnO@Ce2S3/NF-based hybrid supercapacitor exhibits a great energy density of 145.0 mWh cm-2 under illumination. This study provides a novel strategy for the development of high-performance solar energy conversion/storage devices.

Mechanism of aroma enhancement methods in accelerating Congou black tea acidification subjected to room temperature storage.

Acidification of aroma-enhanced black tea during storage was studied. UPLC-Q-TOF/MS (Ultra Performance Liquid Chromatography and Quadrupole-Time of Flight Mass Spectrometer) and HPLC (High-Performance Liquid Chromatography) analysis of non-volatile substances and organic acids revealed a decrease of soluble sugars and amino acids in aroma-enhanced black tea, while an increase in organic acids such as oxalic acid, malic acid and quinic acid. Further in vitro experiments indicated that the acidification of aroma-enhanced tea during storage can be attributed to decomposition of sugars and amino acids by heating, oxidation of aromatic aldehydes. Meanwhile, the amino acids, catechins, soluble sugars and flavonoids that constitute the taste of black tea are further reduced, changing the taste composition of tea infusion and further increasing its acidity. This study revealed the reasons for black tea acidification during aroma enhancement and storage and provided a theoretical basis for improving black tea quality.

Hypobaric hypoxia induces iron mobilization from liver and spleen and increases serum iron via activation of ghrelin/GHSR1a/MAPK signalling pathway in mice.

Hypobaric hypoxia (HH) exposure affects appetite and serum iron levels in both humans and animals. Thus, whether appetite-regulating ghrelin is involved in iron regulation under HH needs to be elucidated. In vivo, C57BL/6J mice were placed in a hypobaric chamber to establish a 6000-m-high altitude exposure animal model. In vitro, mouse primary hepatocytes and peritoneal macrophages were exposed to hypoxia (1% O2) to examine the effects of ghrelin on iron-regulating proteins. HH obviously reduced the body weight of mice and significantly increased the levels of erythrocytes, and also significantly enhanced the levels of serum iron and plasma ghrelin. However, iron content in the liver and spleen was decreased, while ferroportin (Fpn) expression was increased. Moreover, ghrelin significantly induced Fpn and pERK expression in both hepatocytes and macrophages under hypoxia, which were reversed by pretreatment with growth hormone secretagogue receptor 1a (GHSR1a) antagonist or pERK inhibitor. Our findings indicated that HH leads to decreased appetite and insufficient dietary intake, which may negatively regulate the levels of ghrelin. Furthermore, GHSR1a/ERK signalling pathway is further activated to upregulate the expression of Fpn, and then promoting iron mobilization both in the liver/hepatocytes and spleen/macrophages in mice. Thus, these results revealed that ghrelin may be a potential iron regulatory hormone, and raised the possibility of ghrelin as a promising therapeutic target against iron disorders under HH.

Characterizing and Decoding the Effects of Different Fermentation Levels on Key Aroma Substances of Congou Black Tea by Sensomics.

Fermentation is the key technology for black tea aroma formation. The key aroma substances of black tea at different fermentation stages (unfermented (WDY), underfermented (F1H), fully fermented (F4H), and overfermented (F8H)) were characterized by the methodology of Sensomics. Aroma extract dilution analysis was performed on volatile fractions extracted by using solvent-assisted flavor evaporation and solid-phase microextraction, yielding 93 odor-active areas. Internal standard method plus stable isotope dilution analysis was used for quantitative analysis. The omission experiment identified 23 aroma substances. Further reduction and addition experiments revealed phenylacetaldehyde, (E,E)-2,4-heptadienal, geraniol, linalool, ß-damascenone, 2-methylbutyraldehyde, dimethyl sulfide, and isovaleraldehyde with odor activity values (OAV) > 100 as the characteristic aroma components of F4H and also as the main contributors to aroma differences between different fermentation degrees. The green odor of (E,E)-2,4-heptadienal was highlighted in WDY and F1H relative to that in F4H due to the lower contribution of phenylacetaldehyde and ß-damascenone in the former two samples. Additionally, excessive OAV increase of fatty aldehydes in F8H masked its similar floral and fruity aroma.

Exosomal EIF5A derived from Lewis lung carcinoma induced adipocyte wasting in cancer cachexia.

Cancer cachexia is a systemic inflammation-driven syndrome, characterized by muscle atrophy and adipose tissue wasting, with progressive weight loss leading to serious impairment of physiological function. Extracellular vesicles (EVs) derived from cancer cells play a significant role in adipocyte lipolysis, yet the mechanism remain uneclucidated. In this study, EVs derived from Lewis lung carcinoma (LLC) cells were extracted and characterized. 3T3-L1 and HIB1B adipocytes were cultured with conditioned medium or EVs from LLC, and LLC cells were used to establish a cancer cachexia mouse model. EVs derived from LLC cells were taken up by 3T3-L1 and HIB1B adipocytes, and derived exosomal EIF5A protein-induced lipolysis of adipocytes. High level of EIF5A was expressed in EVs from LLC cells, exosomal EIF5A is linked to lipid metabolism. Elevated expression of EIF5A is associated with shorter overall survival in lung cancer patients. Western blots, glycerol release and Oil red O staining assays were used to evaluate lipolysis of adipocytes. The reduction of lipolysis in 3T3-L1 and HIB1B adipocytes is achieved through silencing EIF5A or treating with pharmacologic inhibitor GC7 in vitro, and suppressing the expression of EIF5A in LLC cells by infected with shRNA or GC7 treatment partly alleviated white and brown adipose tissue lipolysis in vivo. Mechanistically, EIF5A directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA to promote its translation and then activates cAMP response element binding protein (CREB) signaling pathway to induce lipolysis. This study demonstrates that exosomal EIF5A from LLC cells, with hypusinated EIF5A, has a lipolytic effect on adipocyte and adipose tissues in cancer cachexia model. Exosomal EIF5A could be involved in lipolysis and these findings indicate that a novel regulator and potential target for cachexia treatment.

A predictive model for hyperuricemia among type 2 diabetes mellitus patients in Urumqi, China.

BACKGROUND: Patients with type 2 diabetes Mellitus (T2DM) are more likely to suffer from a higher uric acid level in blood-hyperuricemia (HUA). There are no conclusive studies done to predict HUA among T2DM patients. Therefore, this study aims to explore the risk factors of HUA among T2DM patients and finally suggest a model to help with its prediction. METHOD: In this retrospective research, all the date were collected between March 2017 and October 2019 in the Medical Laboratory Center of the First Affiliated Hospital of Xinjiang Medical University. The information included sociodemographic factors, blood routine index, thyroid function indicators and serum biochemical markers. The least absolute shrinkage and selection operator (LASSO) and multivariate binary logistic regression were performed to screen the risk factors of HUA among T2DM patients in blood tests, and the nomogram was used to perform and visualise the predictive model. The receiver operator characteristic (ROC) curve, internal validation, and clinical decision curve analysis (DCA) were applied to evaluate the prediction performance of the model. RESULTS: We total collected the clinical date of 841 T2DM patients, whose age vary from 19-86. In this study, the overall prevalence of HUA in T2DM patients was 12.6%. According to the result of LASSO-logistic regression analysis, sex, ethnicity, serum albumin (ALB), serum cystatin C (CysC), serum inorganic phosphorus (IPHOS), alkaline phosphatase (ALP), serum bicarbonate (CO2) and high-density lipoprotein (HDLC) were included in the HUA risk prediction model. The nomogram confirmed that the prediction model fits well (χ2 = 5.4952, P = 0.704) and the calibration curve indicates the model had a good calibration. ROC analysis indicates that the predictive model shows the best discrimination ability (AUC = 0.827; 95% CI: 0.78-0.874) whose specificity is 0.885, and sensitivity is 0.602. CONCLUSION: Our study reveals that there were 8 variables that can be considered as independent risk factors for HUA among T2DM patients. In light of our findings, a predictive model was developed and clinical advice was given on its use.

Using HIV Risk Self-Assessment Tools to Increase HIV Testing in Men Who Have Sex With Men in Beijing, China: App-Based Randomized Controlled Trial.

BACKGROUND: Men who have sex with men (MSM) in China hold a low-risk perception of acquiring HIV. This has resulted in an inadequate HIV testing rate. OBJECTIVE: This study aims to investigate whether administering HIV risk self-assessments with tailored feedback on a gay geosocial networking (GSN) app could improve HIV testing rates and reduce sexual risk behaviors in Chinese MSM. METHODS: We recruited MSM from Beijing, China, who used the GSN platform Blued in October 2017 in this 12-month double-blinded randomized controlled trial. From October 2017 to September 2018, eligible participants were randomly assigned to use a self-reported HIV risk assessment tool that provided tailored feedback according to transmission risk (group 1), access to the same HIV risk assessment without feedback (group 2), or government-recommended HIV education materials (control). All interventions were remotely delivered through the mobile phone-based app Blued, and participants were followed up at 1, 3, 6, and 12 months from baseline. The number of HIV tests over the 12-month study was the primary outcome and was assessed using an intention-to-treat analysis with an incident rate ratio (IRR). Unprotected anal intercourse (UAI) over 6 months was assessed by a modified intention-to-treat analysis and was the secondary outcome. All statistical analyses were conducted in SAS 9.3 (SAS Institute, Inc.), and a P value <.05 was considered statistically significant. RESULTS: In total, 9280 MSM were recruited from baseline and were randomly assigned to group 1 (n=3028), group 2 (n=3065), or controls (n=3187). After follow-up, 1034 (34.1%), 993 (32.4%), and 1103 (34.6%) remained in each group, respectively. Over 12 months, group 1 took 391 tests (mean of 2.51 tests per person), group 2 took 352 tests (mean of 2.01 tests per person), and controls took 295 tests (mean of 1.72 tests per person). Group 1 had significantly more HIV testing than the control group (IRR 1.32, 95% CI 1.09-4.58; P=.01), while group 2 did not differ significantly from the controls (IRR 1.06, 95% CI 0.86-1.30; P=.60). The proportion of UAI was not statistically different among different groups, but all 3 groups had UAI, which declined from baseline. CONCLUSIONS: Repeated HIV risk assessments coupled with tailored feedback through GSN apps improved HIV testing. Such interventions should be considered a simple way of improving HIV testing among MSM in China and increasing awareness of HIV status. TRIAL REGISTRATION: ClinicalTrials.gov NCT03320239; https://clinicaltrials.gov/study/NCT03320239.

Analysis of the potential pyroptosis mechanism in psoriasis and experimental validation of NLRP3 in vitro and in vivo.

Pyroptosis provides new perspectives on the mechanisms underlying psoriasis and the development of new treatment strategies. Here, we aimed to identify pyroptosis-related genes (PRGs) involved in the pathogenesis and progression of psoriasis. Based on the inclusion/exclusion criteria, three gene datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differential gene expression, weighted gene co-expression network analysis (WGCNA), and functional enrichment analyses were performed to identify candidate PRGs for psoriasis. Least absolute shrinkage and selection operator (LASSO) regression was used to identify hub genes, and receiver operating characteristic (ROC) curves were used to determine the clinical value of the hub genes. Imiquimod-inducedpsoriasis-like mice and lipopolysaccharide (LPS)-induced RAW 264.7 cells were employed to verify the pro-inflammatory factors that may drive changes in pyroptosis. In total, 159 skin samples were analysed, and a total of 21 common targets were obtained by crossing PRGs with all the differentially expressed genes (DEGs) in different disease states. 11 genes were identified via LASSO screening. Similarly, the last six PRGs biomarkers and the green module genes were screened. All hub genes with an area under the ROC curve > 0.5 were intersected, and NLRP3 was identified. NLRP3 expression was elevated in imiquimod-induced psoriatic lesions in mice and LPS-stimulated RAW 264.7 cells. The mice exhibited reduced psoriasis area and severity index scores, hyperproliferation, and inflammation after treatment with MCC950 (a specific inhibitor of NLRP3). MCC950 decreased IL-1ß, IL-6, and TNF-α mRNA expression, and NLRP3 and p-p65 protein levels in LPS-stimulated RAW 264.7 cells. Our study indicates that NLRP3 may be a promising therapeutic target for the treatment of psoriasis.

CX3CL1/CX3CR1 signal mediates M1-type microglia and accelerates high-altitude-induced forgetting.

Introduction: Hypoxia-induced neuronal damage is the primary cause of cognitive impairment induced by high-altitude exposure. Microglia play a crucial regulatory role in the central nervous system (CNS) homeostasis and synaptic plasticity. M1-type polarized microglia are suspected to be responsible for CNS injury under hypoxic conditions, but the exact molecular mechanism is still unelucidated. Methods: CX3CR1 knock out and wide type mice were exposed to a simulated plateau at 7000 m for 48 h to construct the model of hypobaric hypoxia-induced memory impairment. The memory impairment of mice was assessed by Morris water maze. The dendritic spine density in the hippocampus was examined by Golgi staining. The synapses in the CA1 region and the number of neurons in the DG region were examined by immunofluorescence staining. The synapses in microglia activation and phagocytosis were examined by immunofluorescence. The levels of CX3CL1/CX3CR1 and their downstream proteins were detected. CX3CR1 knockout primary microglia were treated with CX3CL1 combined with 1% O2. The levels of proteins related to microglial polarization, the uptake of synaptosome and phagocytotic ability of microglia were detected. Results: In this study, mice exposed to a simulated 7000 m altitude for 48 h developed significant amnesia for recent memories, but no significant change in their anxiety levels was observed. Hypobaric hypoxia exposure (7000 m altitude above sea level for 48 h) resulted in synapse loss in the CA1 region of the hippocampus, but no significant changes occurred in the total number of neurons. Meanwhile, microglia activation, increased phagocytosis of synapses by microglia, and CX3CL1/CX3CR1 signal activation were observed under hypobaric hypoxic exposure. Further, we found that after hypobaric hypoxia exposure, CX3CR1-deficient mice showed less amnesia, less synaptic loss in the CA1 region, and less increase in M1 microglia, compared to their wildtype siblings. CX3CR1-deficient microglia did not exhibit M1-type polarization in response to either hypoxia or CX3CL1 induction. Both hypoxia and CX3CL1 induced the phagocytosis of synapses by microglia through the upregulation of microglial phagocytosis. Discussion: The current study demonstrates that CX3CL1/CX3CR1 signal mediates the M1-type polarization of microglia under high-altitude exposure and upregulates microglial phagocytosis, which increases the phagocytosis of synapses in the CA1 region of the hippocampus, causing synaptic loss and inducing forgetting.

Neuroinflammation aggravated by traumatic brain injury at high altitude is reversed by L-serine via NFAT1-mediated microglial polarization.

Traumatic brain injury (TBI) is one of the main causes of disability and death, especially in plateau areas, where the degree of injury is often more serious than in plain areas. It is likely that high altitude (HA) aggravates neuroinflammation; however, prior studies are limited. This study was designed to evaluate the effects of HA on the degree of TBI and the neuroprotective effects and underlying mechanisms of L-serine against TBI at HA (HA-TBI). In in vivo experiments, wild-type mice and mice with Nfat1 (Nfat1-/- ) deficiency in the C57BL/6 background were kept in a hypobaric chamber for 3 days under simulated conditions of 4,000 m, 6,000 m and 8,000 m above sea level. After leaving the chamber, the standardized TBI model was established immediately. Mice were then intraperitoneally injected with L-serine (342 mg.kg-1) 2 h after TBI and then daily for 5 days. Behavioral tests and histological analysis were assessed at different time points post TBI induction. In vitro, we applied primary cultured microglia for hypoxia treatment (1% O2 for 24 h). The major findings include the following: (1) with increasing altitude, the neurological function of TBI mice decreased, and the damage to cerebral gray matter and white matter became more significant, (2) L-serine significantly improved the sensorimotor function of mice, reversed the increase in brain lesion volume, and promoted the renovation of brain tissue after HA-TBI, (3) L-serine significantly decreased the activation of microglia and promoted microglia polarization toward the protective M2 phenotype both in vivo and in vitro, (4) L-serine significantly suppressed the expression of NFAT1 in mice after HA-TBI and inhibited NFAT1 expression in primary microglia after hypoxia, and (5) knockout of Nfat1 inhibited the inflammatory reaction caused by excessive activation of microglia, and L-serine lost its neuroprotective effect in Nfat1 knockout mice. The present study suggests that HA aggravates brain damage after TBI and that the damage also increases with increasing altitude. As an endogenous amino acid, L-serine may be a neuroprotective agent against HA-TBI, and suppression of NFAT1 in microglia is a potential therapy for neuroinflammation in the future.

hUMSCs Restore Uterine Function by Inhibiting Endometrial Fibrosis via Regulation of the MMP-9/TIMP-1 Ratio in CDDP-Induced Injury Rats.

The fertility of females of childbearing age who are cured of cancer by chemotherapy is gradually declining globally. As a broad-spectrum chemotherapy drug in clinic, the damage of cisplatin (CDDP) to female reproductive function cannot be ignored. At present, the study of CDDP damage to the uterus is not sufficient, and the exact mechanism needs to be further explored. Therefore, we conducted this research to determine whether uterine injury in CDDP-induced injury rats might be improved by human umbilical cord mesenchymal stem cells (hUMSCs) and to further explore the precise mechanism. The rat model of CDDP-induced injury was established by intraperitoneal injection of CDDP, and hUMSCs were injected into the tail vein 7 days later. In vivo, uterine function in CDDP-induced injury rats was affected after hUMSC transplantation. In vitro, the specific mechanism was further explored from the cell and protein levels. Overall, the specific reason of CDDP-induced uterine dysfunction in rats was endometrial fibrosis, which was significantly improved after hUMSC transplantation. Further investigation of the mechanism found that hUMSCs could regulate the ratio of matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) in endometrial stromal cells (EnSCs) after CDDP injury.