Neurons upregulate PD-L1 via IFN/STAT1/IRF1 to alleviate damage by CD8+ T cells in cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is the most lethal complication of malaria, and survivors usually endure neurological sequelae. Notably, the cytotoxic effect of infiltrating Plasmodium-activated CD8+ T cells on cerebral microvasculature endothelial cells is a prominent feature of the experimental CM (ECM) model with blood-brain barrier disruption. However, the damage effect of CD8+ T cells infiltrating the brain parenchyma on neurons remains unclear. Based on the immunosuppressive effect of the PD-1/PD-L1 pathway on T cells, our previous study demonstrated that the systemic upregulation of PD-L1 to inhibit CD8+ T cell function could effectively alleviate the symptoms of ECM mice. However, it has not been reported whether neurons can suppress the pathogenic effect of CD8+ T cells through the PD-1/PD-L1 negative immunomodulatory pathway. As the important inflammatory factor of CM, interferons can induce the expression of PD-L1 via different molecular mechanisms according to the neuro-immune microenvironment. Therefore, this study aimed to investigate the direct interaction between CD8+ T cells and neurons, as well as the mechanism of neurons to alleviate the pathogenic effect of CD8+ T cells through up-regulating PD-L1 induced by IFNs. METHODS: Using the ECM model of C57BL/6J mice infected with Plasmodium berghei ANKA (PbA), morphological observations were conducted in vivo by electron microscope and IF staining. The interaction between the ECM CD8+ T cells (immune magnetic bead sorting from spleen of ECM mice) and primary cultured cortical neurons in vitro was observed by IF staining and time-lapse photography. RNA-seq was performed to analyze the signaling pathway of PD-L1 upregulation in neurons induced by IFNß or IFNγ, and verified through q-PCR, WB, IF staining, and flow cytometry both in vitro and in vivo using IFNAR or IFNGR gene knockout mice. The protective effect of adenovirus-mediated PD-L1 IgGFc fusion protein expression was verified in ECM mice with brain stereotaxic injection in vivo and in primary cultured neurons via viral infection in vitro. RESULTS: In vivo, ECM mice showed infiltration of activated CD8+ T cells and neuronal injury in the brain parenchyma. In vitro, ECM CD8+ T cells were in direct contact with neurons and induced axonal damage, as an active behavior. The PD-L1 protein level was elevated in neurons of ECM mice and in primary cultured neurons induced by IFNß, IFNγ, or ECM CD8+ T cells in vitro. Furthermore, the IFNß or IFNγ induced neuronal expression of PD-L1 was mediated by increasing STAT1/IRF1 pathway via IFN receptors. The increase of PD-L1 expression in neurons during PbA infection was weakened after deleting the IFNAR or IFNGR. Increased PD-L1 expression by adenovirus partially protected neurons from CD8+ T cell-mediated damage both in vitro and in vivo. CONCLUSION: Our study demonstrates that both type I and type II IFNs can induce neurons to upregulate PD-L1 via the STAT1/IRF1 pathway mediated by IFN receptors to protect against activated CD8+ T cell-mediated damage, providing a targeted pathway to alleviate neuroinflammation during ECM.

The benefits and risks of menopause hormone therapy for the cardiovascular system in postmenopausal women: a systematic review and meta-analysis.

BACKGROUND: Menopause hormone therapy (MHT), as an effective method to alleviate the menopause-related symptoms of women, its benefits, risks, and potential influencing factors for the cardiovascular system of postmenopausal women are not very clear. OBJECTIVES: To evaluate cardiovascular benefits and risks of MHT in postmenopausal women, and analyze the underlying factors that affect both. SEARCH STRATEGY: The EMBASE, MEDLINE, and CENTRAL databases were searched from 1975 to July 2022. SELECTION CRITERIA: Randomized Clinical Trials (RCTs) that met pre-specified inclusion criteria were included. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data independently. A meta-analysis of random effects was used to analyze data. MAIN RESULTS: This systematic review identified 33 RCTs using MHT involving 44,639 postmenopausal women with a mean age of 60.3 (range 48 to 72 years). There was no significant difference between MHT and placebo (or no treatment) in all-cause death (RR = 0.96, 95%CI 0.85 to 1.09, I2 = 14%) and cardiovascular events (RR = 0.97, 95%CI 0.82 to 1.14, I2 = 38%) in the overall population of postmenopausal women. However, MHT would increase the risk of stroke (RR = 1.23, 95%CI 1.08 to 1.41,I2 = 0%) and venous thromboembolism (RR = 1.86, 95%CI 1.39 to 2.50, I2 = 24%). Compared with placebo, MHT could improve flow-mediated arterial dilation (FMD) (SMD = 1.46, 95%CI 0.86 to 2.07, I2 = 90%), but it did not improve nitroglycerin-mediated arterial dilation (NMD) (SMD = 0.27, 95%CI - 0.08 to 0.62, I2 = 76%). Compared with women started MHT more than 10 years after menopause, women started MHT within 10 years after menopause had lower frequency of all-cause death (P = 0.02) and cardiovascular events (P = 0.002), and more significant improvement in FMD (P = 0.0003). Compared to mono-estrogen therapy, the combination therapy of estrogen and progesterone would not alter the outcomes of endpoint event. (all-cause death P = 0.52, cardiovascular events P = 0.90, stroke P = 0.85, venous thromboembolism P = 0.33, FMD P = 0.46, NMD P = 0.27). CONCLUSIONS: MHT improves flow-mediated arterial dilation (FMD) but fails to lower the risk of all-cause death and cardiovascular events, and increases the risk of stroke and venous thrombosis in postmenopausal women. Early acceptance of MHT not only reduces the risk of all-cause death and cardiovascular events but also further improves FMD, although the risk of stroke and venous thrombosis is not reduced. There is no difference in the outcome of cardiovascular system endpoints between mono-estrogen therapy and combination therapy of estrogen and progesterone.

Sustainable, Insoluble, and Photonic Cellulose Nanocrystal Patches for Calcium Ion Sensing in Sweat.

Self-assembly of cellulose nanocrystals (CNCs) is invaluable for the development of sustainable optics and photonics. However, the functional failure of CNC-derived materials in humid or liquid environments inevitably impairs their development in biomedicine, membrane separation, environmental monitoring, and wearable devices. Here, a facile and robust method to fabricate insoluble hydrogels in a self-assembled CNC-polyvinyl alcohol (PVA) system is reported. Due to the reconstruction of inter- or intra-molecular hydrogen bond interactions, thermal dehydration makes an optimized CNC/PVA photonic film form a stable hydrogel network in an aqueous solution rather than dissolve. Notably, the resulting hydrogel exhibits superb mechanical performance (stress up to 3.3 Mpa and tough up to 0.73 MJ m-3 ) and reversible conversion between dry and wet states, enabling it convenient for specific functionalization. Sodium alginate (SA) can be adsorbed into the CNC photonic structure by swelling dry CNC/PVA film in a SA solution. The prepared hydrogel showcases the comprehensive properties of freezing resistance (-20°C), strong adhesion, satisfactory biocompatibility, and highly sensitive and selective Ca2+ sensing. The material could act as a portable wearable patch on the skin for the continuous analysis of calcium trends during different physical exercises, facilitating their development in precision nutrition and health monitoring.

The over-expression of miRNA-206 in peripheral blood of patients with burning mouth syndrome and its relationship with anxiety and depression.

BACKGROUND: Burning mouth syndrome (BMS) is characterised by persisting burning pain of the oral mucosa, and its etiopathogenesis remains poorly understood. OBJECTIVES: Our study aimed to detect the expression of miRNA-206 in the blood and clarify the relationship among miRNA-206, pain, anxiety and depression of BMS patients. METHODS: Thirty patients with BMS and 30 healthy individuals were enrolled in the experimental and control groups, respectively. Data on medical history and clinical oral examination for all participants were collected. Simultaneously, scores of Visual Analogous Scale (VAS), Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were administered. The expression level of miRNA-206 in plasma were determined by RT-(q)PCR. Finally, the relationship of miRNA-206 expression with the VAS score, SAS score, and SDS score was analysed. Chi-square test and t-test were used for statistical analysis of the data, and p < .05 was considered statistically significant. RESULTS: The majority of the patients with BMS identified the tongue as the main pain area, and showed dry mouth and poor sleep quality. The SAS and SDS scores of patients with BMS were higher than those of healthy controls (p < .05) and were positively correlated with VAS pain score. In addition, miRNA-206 expression was higher in patients with BMS than in healthy individuals (p < .05), and was positively correlated with the VAS and SDS scores (p < .05). CONCLUSIONS: Patients with BMS suffer from pain and tend to be more anxious and depressed than healthy controls. miRNA-206 expression in the peripheral blood of patients with BMS is positively correlated with pain and depression, which may be involved in the pathogenesis of BMS.

Research trends and hotspots of recurrent pregnancy loss with thrombophilia: a bibliometric analysis.

BACKGROUND: Thrombophilia is a group of disorders that result in a blood hypercoagulable state and induce thrombosis, which was found widely existed in recurrent pregnancy loss (RPL). More and more research about thrombophilia has been conducted but the association between thrombophilia and RPL remains uncertain. Thus, it's necessary to combine relevant literature to find the research hotspots and analyze the internal link between different study points, and then predict the development trend in RPL with thrombophilia. METHODS: Relevant articles between 1970 and 2022 were obtained from the Web of Science (WoS) database. Software VOSviewer and CiteSpace were used to perform the analysis and conduct visualization of scientific productivity and emerging trends. RESULTS: Seven hundred twenty-five articles published in recent 30 years by 3205 authors from 1139 organizations and 68 countries were analyzed. 37authors, 38 countries, and 53 organizations published papers ≥5. The United States was the most productive country and Univ Amsterdam was the most productive institution. Journal thrombosis and haemostasis had the most total citations. In keyword and clusters, factor-v-Leiden, inherited thrombophilia, activated protein-c, low-dose aspirin, molecular-weigh heparin, polymorphism had high-frequency focus on its etiology, diagnostics, and therapeutics. The strongest keyword bursts showed the research hotspots changed over time. CONCLUSIONS: There could be differences in the clinical relevance of different type of thrombophilia, as well as single and multiple thrombophilic factors. Anticoagulation and immunotherapy are currently the main treatment options. More clinical trials and basic research are expected and we should attach more attention to the whole management of in-vitro fertilization in the future.

Oral innate immunity in HIV infection in HAART era.

Oral innate immunity, an important component in host defense and immune surveillance in the oral cavity, plays a crucial role in the regulation of oral health. As part of the innate immune system, epithelial cells lining oral mucosal surfaces not only provide a physical barrier but also produce different antimicrobial peptides, including human ß-defensins (hBDs), secretory leukocyte protease inhibitor (SLPI), and various cytokines. These innate immune mediators help in maintaining oral homeostasis. When they are impaired either by local or systemic causes, various oral infections and malignancies may be developed. Human immunodeficiency virus (HIV) infection and other co-infections appear to have both direct and indirect effects on systemic and local innate immunity leading to the development of oral opportunistic infections and malignancies. Highly active antiretroviral therapy (HAART), the standard treatment of HIV infection, contributed to a global reduction of HIV-associated oral lesions. However, prolonged use of HAART may lead to adverse effects on the oral innate immunity resulting in the relapse of oral lesions. This review article focused on the roles of oral innate immunity in HIV infection in HAART era. The following five key questions were addressed: (i) What are the roles of oral innate immunity in health and disease?, (ii) What are the effects of HIV infection on oral innate immunity?, (iii) What are the roles of oral innate immunity against other co-infections?, (iv) What are the effects of HAART on oral innate immunity?, and (v) Is oral innate immunity enhanced by HAART?

Analysis of the immune response of a new malaria vaccine based on the modification of cryptic epitopes.

Malaria is a severe, life-threatening infectious disease that endangers human health. However, there are no vaccines or immune strategy of vaccines succeeding in both erythrocytic and pre-erythrocytic stage. During the liver stage of the Plasmodium life cycle, sporozoites invade the host liver cells. The sporozoites, then, induce a cellular immune response via the major histocompatibility complex (MHC) molecules on their surfaces. The cytotoxic T lymphocytes (CTLs) then recognize the corresponding antigen-MHC complex on the surfaces of these infected liver cells and kill them. However, dominant epitopes with high MHC affinity are prone to mutation due to immune selection pressure. CTLs evoked by the original dominant epitopes cannot recognize the mutated epitopes, leading to immune evasion. In this study, we have modified the cryptic epitopes of different antigens in the sporozoite and liver stages of Plasmodium falciparum to increase their immunogenicity without changing T cell antigen receptor (TCR)-peptide binding specificity. In addition, we have also added an important erythrocytic phase protective antigen, named apical membrane antigen 1 (AMA-1), to this process with the goal of constructing a complex multi-stage, multi-epitope recombinant DNA vaccine against P. falciparum. The vaccine was tested in HHD-2 mice. The method involved multiple stages of the P. falciparum life cycle as well as elucidation both humoral and cellular immunity. The conclusion drawn from the study was that the vaccine might provide an important theoretical and practical basis for generating effective preventative or therapeutic vaccine against P. falciparum.

Dynamics of T-cell subsets and their relationship with oral and systemic opportunistic infections in HIV/AIDS patients during the first year of HAART in Guangxi, China.

To analyze the dynamic changes in Th1, Th2, Tc1, and Tc2 of HIV/AIDS patients during the first year of highly active antiretroviral therapy (HAART) and to explore their relationship with oral and systemic opportunistic infections, a cohort study was carried out among HIV/AIDS patients in Guangxi, China. Ninety HIV/AIDS patients and 30 healthy controls (HC) were included. The enrolled HIV/AIDS patients were examined at baseline and after 3, 6, and 12 months of HAART. On each visit, oral and systemic opportunistic infections were recorded, oral Candida load and plasma viral load (VL) were counted, differential T-cell counts and flow cytometric analysis of T-cell subsets were performed. During the first year of HAART, the total number of opportunistic infections decreased steadily with the change in oral candidiasis (OC) most representatively. A significant Th1→Th2 switch (Th1/Th2 ratio 0.23 ± 0.12, HC 1.45 ± 0.38) and slight Tc1→Tc2 shift (Tc1/Tc2 ratio 0.93 ± 0.29, HC 1.13 ± 0.33) were found at baseline, and both received slow mitigation after HAART. LgCFU and clinical OC were correlated positively with both LgVL and clinical stage (P < 0.05) at baseline. LgCFU was also correlated positively with clinical stage at all four time points (P < 0.05). In multiple factor analysis, Th1 was confirmed to be correlated negatively with LgVL (Std.B = -0.295, P = 0.025) and LgCFU (Std.B = -0.227, P < 0.001) at baseline. After HAART, LgCFU and clinical stage were only correlated negatively with CD4 when all factors were included. These results suggest that oral candidiasis and oral Candida load could be useful clinical markers in the evaluation of HIV/AIDS patients. Th1 may play an important role against oral and systemic opportunistic infections. Tc1 and Tc2 both showed positive roles in the control of viremia without HAART. J. Med. Virol. 87:1158-1167, 2015. © 2015 Wiley Periodicals, Inc.

Combining Fourier and lagged k-nearest neighbor imputation for biomedical time series data.

Most clinical and biomedical data contain missing values. A patient's record may be split across multiple institutions, devices may fail, and sensors may not be worn at all times. While these missing values are often ignored, this can lead to bias and error when the data are mined. Further, the data are not simply missing at random. Instead the measurement of a variable such as blood glucose may depend on its prior values as well as that of other variables. These dependencies exist across time as well, but current methods have yet to incorporate these temporal relationships as well as multiple types of missingness. To address this, we propose an imputation method (FLk-NN) that incorporates time lagged correlations both within and across variables by combining two imputation methods, based on an extension to k-NN and the Fourier transform. This enables imputation of missing values even when all data at a time point is missing and when there are different types of missingness both within and across variables. In comparison to other approaches on three biological datasets (simulated and actual Type 1 diabetes datasets, and multi-modality neurological ICU monitoring) the proposed method has the highest imputation accuracy. This was true for up to half the data being missing and when consecutive missing values are a significant fraction of the overall time series length.

Computational prediction of protein interactions related to the invasion of erythrocytes by malarial parasites.

BACKGROUND: The invasion of red blood cells (RBCs) by malarial parasites is an essential step in the life cycle of Plasmodium falciparum. Human-parasite surface protein interactions play a critical role in this process. Although several interactions between human and parasite proteins have been discovered, the mechanism related to invasion remains poorly understood because numerous human-parasite protein interactions have not yet been identified. High-throughput screening experiments are not feasible for malarial parasites due to difficulty in expressing the parasite proteins. Here, we performed computational prediction of the PPIs involved in malaria parasite invasion to elucidate the mechanism by which invasion occurs. RESULTS: In this study, an expectation maximization algorithm was used to estimate the probabilities of domain-domain interactions (DDIs). Estimates of DDI probabilities were then used to infer PPI probabilities. We found that our prediction performance was better than that based on the information of D. melanogaster alone when information related to the six species was used. Prediction performance was assessed using protein interaction data from S. cerevisiae, indicating that the predicted results were reliable. We then used the estimates of DDI probabilities to infer interactions between 490 parasite and 3,787 human membrane proteins. A small-scale dataset was used to illustrate the usability of our method in predicting interactions between human and parasite proteins. The positive predictive value (PPV) was lower than that observed in S. cerevisiae. We integrated gene expression data to improve prediction accuracy and to reduce false positives. We identified 80 membrane proteins highly expressed in the schizont stage by fast Fourier transform method. Approximately 221 erythrocyte membrane proteins were identified using published mass spectral datasets. A network consisting of 205 interactions was predicted. Results of network analysis suggest that SNARE proteins of parasites and APP of humans may function in the invasion of RBCs by parasites. CONCLUSIONS: We predicted a small-scale PPI network that may be involved in parasite invasion of RBCs by integrating DDI information and expression profiles. Experimental studies should be conducted to validate the predicted interactions. The predicted PPIs help elucidate the mechanism of parasite invasion and provide directions for future experimental investigations.

Dynamic changes of Th1/Th2/Th17 cytokines and hBD-2/3 in erosive oral lichen planus patients saliva before and after prednisone acetate treatment.

Objective: This study aimed to investigate the expression of T helper 1 (Th1)/Th2/Th17- related cytokines and human beta defensins 2 and 3 (hBD-2 and -3) in the saliva of patients with erosive oral lichen planus (EOLP) and to explore their role in the pathogenesis of EOLP and the effects of glucocorticoids on EOLP. Methods: A total of 30 patients with EOLP and 20 age- and sex-matched healthy individuals were included in this study. The patients were treated with prednisone at a dose of 0.4 mg/(kg·d) for 1 week and examined before and after treatment. Unstimulated whole saliva samples were collected to determine the levels of cytokines (interleukin 1 beta [IL-1ß], tumour necrosis factor alpha [TNF]-α, interferon gamma [IFN-γ], IL-4, IL-6, IL-10 and IL-17) by cytometric bead array and those of hBD-2 and -3 b y enzyme-linked immunosorbent assay. In addition, oral rinse samples were collected to detect Candida load. Results: The levels of salivary IL-1ß, IL-6, hBD-2 and hBD-3 were higher and the IFN-γ/IL-4 and IL-1ß/IL-6 ratios were lower in patients with EOLP than in healthy individuals. In patients with EOLP, hBD-2 levels were positively correlated with IFN-γ levels and negatively correlated with IL-17 levels, whereas hBD-3 levels were negatively correlated with IL-17 and IL-10 levels. In addition, the prevalence of EOLP was positively correlated with IL-6 levels and negatively correlated with the IFN-γ/IL-4 ratio. The levels of IL-1ß, TNF-α, IFN-γ, IL-6, hBD-2 and hBD-3 and the IFN-γ/IL-4 ratio decreased after treatment with prednisone for 1 week. The levels of IL-6, hBD-2 and hBD-3 were significantly higher in EOLP patients than in healthy individuals; while TNF-α levels and the IFN-γ/IL-4 ratio were significantly lower in EOLP patients than in healthy individuals. Furthermore, the oral counts of Candida spp. (colony forming unit [CFU]) were negatively correlated with TNF-α levels. Numerical Rating Scale(NRS) and Sign scores decreased in EOLP patients after treatment. Approximately 80 % of patients were effectively treated. Salivary TNF-α levels were significantly higher in the treatment-ineffective group than in the treatment-effective group before treatment with prednisone, and differences in salivary IL-6 levels before and after treatment were significantly higher in the treatment-effective group than in the treatment-ineffective group. Conclusions: High expression of IL-1ß, IL-6, hBD-2 and Th1/Th2 imbalance in saliva may be associated with the pathogenesis of EOLP. IFN-γ/IL-4 balance may serve as a protective factor for EOLP. Glucocorticoids significantly alleviate the symptoms of EOLP and inhibit the expression of Th1/Th2 cytokines.

CD8+ T cell infiltration and proliferation in the brainstem during experimental cerebral malaria.

INTRODUCTION: Cerebral malaria (CM) is a lethal neuroinflammatory disease caused by Plasmodium infection. Immune cells and brain parenchyma cells contribute to the pathogenesis of CM. However, a systematic examination of the changes that occur in the brain parenchyma region during CM at the single-cell resolution is still poorly studied. AIMS: To explore cell composition and CD8+ T cell infiltration, single-cell RNA sequencing (scRNA-seq) was performed on the brainstems of healthy and experimental cerebral malaria (ECM) mice. Then CD8+ T cell infiltration was confirmed by flow cytometry and immunofluorescence assays. Subsequently, the characteristics of the brain-infiltrated CD8+ T cells were analyzed. Finally, the interactions between parenchyma cells and brain-infiltrated CD8+ T cells were studied with an astrocytes-CD8+ T cell cocultured model. RESULTS: The brainstem is the most severely damaged site during ECM. ScRNA-seq revealed a large number of CD8+ T cells infiltrating into the brainstem in ECM mice. Brain-infiltrated CD8+ T cells were highly activated according to scRNA-seq, immunofluorescence, and flow cytometry assays. Further analysis found a subset of ki-67+ CD8+ T cells that have a higher transcriptional level of genes related to T cell function, activation, and proliferation, suggesting that they were exposed to specific antigens presented by brain parenchyma cells. Brain-infiltrated CD8+ T cells were the only prominent source of IFN-γ in this single-cell analysis. Astrocytes, which have a high interferon response, act as cross-presenting cells to recruit and re-activate brain-infiltrated CD8+ T cells. We also found that brain-infiltrated CD8+ T cells were highly expressed immune checkpoint molecule PD-1, while parenchyma cells showed up-regulation of PD-L1 after infection. CONCLUSIONS: These findings reveal a novel interaction between brain-infiltrated CD8+ T cells and parenchyma cells in the ECM brainstem, suggesting that the PD-1/PD-L1 signal pathway is a promising adjunctive therapeutic strategy for ECM targeting over-activated CD8+ T cells.

Decoding connections in the European population: serum uric acid, sex hormone-binding globulin, total testosterone, estradiol, and female infertility - advanced bidirectional and mediative Mendelian randomization.

Background: Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain. Objective: This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations. Methods: We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality. Results: We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (ß=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (ß=-0.127), showed an indirect effect on infertility mediated by SUA (ß=-0.0187; 95% CI, -0.041 to -0.003; P=0.046). Conclusion: Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms.

Causal pathways in preeclampsia: a Mendelian randomization study in European populations.

Purpose: Our study utilizes Mendelian Randomization (MR) to explore the causal relationships between a range of risk factors and preeclampsia, a major contributor to maternal and perinatal morbidity and mortality. Methods: Employing the Inverse Variance Weighting (IVW) approach, we conducted a comprehensive multi-exposure MR study analyzing genetic variants linked to 25 risk factors including metabolic disorders, circulating lipid levels, immune and inflammatory responses, lifestyle choices, and bone metabolism. We applied rigorous statistical techniques such as sensitivity analyses, Cochran's Q test, MR Egger regression, funnel plots, and leave-one-out sensitivity analysis to address potential biases like pleiotropy and population stratification. Results: Our analysis included 267,242 individuals, focusing on European ancestries and involving 2,355 patients with preeclampsia. We identified strong genetic associations linking increased preeclampsia risk with factors such as hyperthyroidism, BMI, type 2 diabetes, and elevated serum uric acid levels. Conversely, no significant causal links were found with gestational diabetes, total cholesterol, sleep duration, and bone mineral density, suggesting areas for further investigation. A notable finding was the causal relationship between systemic lupus erythematosus and increased preeclampsia risk, highlighting the significant role of immune and inflammatory responses. Conclusion: This extensive MR study sheds light on the complex etiology of preeclampsia, underscoring the causal impact of specific metabolic, lipid, immune, lifestyle, and bone metabolism factors. Our findings advocate for a multidimensional approach to better understand and manage preeclampsia, paving the way for future research to develop targeted preventive and therapeutic strategies.

Intense Left-handed Circularly Polarized Luminescence in Chiral Nematic Hydroxypropyl Cellulose Composite Films.

Integrating optically active components into chiral photonic cellulose to fabricate circularly polarized luminescent materials has transformative potential in disease detection, asymmetric reactions, and anticounterfeiting techniques. However, the lack of cellulose-based left-handed circularly polarized light (L-CPL) emissions hampers the progress of these chiral functionalizations. Here, this work proposes an unprecedented strategy: incorporating a chiral nematic organization of hydroxypropyl cellulose with robust aggregation-induced emission luminogens to generate intense L-CPL emission. By utilizing N,N-dimethylformamide as a good solvent for fluorescent components and cellulose matrices, this work produces a right-handed chiral nematic structure film with a uniform appearance in reflective and fluorescent states. Remarkably, this system integrates a high asymmetric factor (0.51) and an impressive emission quantum yield (55.8%) into one fascinating composite. More meaningfully, this approach is versatile, allowing for the incorporation of luminogen derivatives emitting multicolored L-CPL. These chiral fluorescent films possess exceptional mechanical flexibility (toughness up to 0.9 MJ m-3) and structural stability even under harsh environmental exposures, making them promising for the fabrication of various products. Additionally, these films can be cast on the fabrics to reveal multilevel and durable anticounterfeiting capabilities or used as a chiral light source to induce enantioselective photopolymerization, thereby offering significant potential for diverse practical applications.

NLRX1: a key regulator in mitochondrial respiration and colorectal cancer progression.

Colorectal cancer (CRC) is a prevalent and aggressive malignancy with high mortality rates and significant risks to human well-being. Population-wide screening for tumor suppressor genes and oncogenes shows promise for reducing the incidence and fatality of CRC. Recent studies have suggested that NLRX1, an innate immunity suppressor, may play a role in regulating chronic inflammation and tumorigenesis. However, further investigation is needed to understand the specific role of NLRX1 in CRC. To evaluate the impact of NLRX1 on migration, invasion, and metastasis, two human colon cancer cell lines were studied in vitro. Additionally, a knockout mouse tumor-bearing model was used to validate the inhibitory effect of NLRX1 on tumor emergence and progression. The Seahorse XF96 technology was employed to assess mitochondrial function and glycolysis in colorectal cancer cells overexpressing NLRX1. Moreover, public databases were consulted to analyze gene and protein expression levels of NLRX1. Finally, the results were validated using a series of CRC patient samples. Our findings demonstrate that downregulation of NLRX1 enhances proliferation, colony formation, and tumor-forming capacity in HCT116 and LoVo cells. Conversely, overexpression of NLRX1 negatively impacts basal respiration and mitochondrial ATP-linked respiration in both cell lines, resulting in a notable decrease in maximal respiration during the standard mitochondrial stress test. Furthermore, analysis of data from the TCGA database reveals a significant reduction in NLRX1 expression in colon and rectal cancer tissues compared to normal tissues. This result was validated using clinical samples, where immunohistochemistry staining and western blotting demonstrated a notable reduction in NLRX1 protein levels in CRC compared to adjacent normal tissues. The decreased expression of NLRX1 may serve as a significant prognostic indicator and diagnostic biomarker for CRC patients.

The efficacy and safety of Bazi Bushen Capsule in treating premature aging: A randomized, double blind, multicenter, placebo-controlled clinical trial.

PURPOSE: It is unclear whether traditional Chinese patent medicines can resist premature aging. This prospective study investigated the effects of Bazi Bushen Capsule (BZBS) which is a traditional Chinese patent medicine for tonifying the kidney essence on premature senility symptoms and quality of life, telomerase activity and telomere length. STUDY DESIGN AND METHODS: It was a parallel, multicenter, double-blind, randomized, and placebo-controlled trial. Subjects (n = 530) aged 30-78 years were randomized to receive BZBS or placebo capsules 12 weeks. The primary outcome was the clinical feature of change in kidney deficiency for aging evaluation scale (CFCKD-AES) and tilburg frailty indicator (TFI). The secondary outcomes were SF-36, serum sex hormone level, five times sit-to-stand time (FTSST), 6MWT, motor function test-grip strength, balance test, walking speed, muscle mass measurement, telomerase and telomere length. RESULTS: After 12 weeks of treatment, the CFCKD-AES and TFI scores in the BZBS group decreased by 13.79 and 1.50 respectively (6.42 and 0.58 in the placebo group, respectively); The SF-36 in the BZBS group increased by 98.38 (23.79 in the placebo group). The FTSST, motor function test grip strength, balance test, walking speed, and muscle mass in the elderly subgroup were all improved in the BZBS group. The telomerase content in the BZBS group increased by 150.04 ng/ml compared to the placebo group. The fever led one patient in the placebo group to discontinue the trial. One patient in the placebo group withdrew from the trial due to pregnancy. None of the serious AEs led to treatment discontinuation, and 3 AEs (1.14%) were assessed as related to BZBS by the primary investigator. CONCLUSIONS: BZBS can improve premature aging symptoms, frailty scores, and quality of life, as well as improve FTSST, motor function: grip strength, balance test, walking speed, and muscle mass in elderly subgroups of patients, and enhance telomerase activity, but it is not significantly associated with increasing telomere length which is important for healthy aging. TRIAL REGISTRY: https://www.chictr.org.cn/showproj.html?proj=166181.

Immune responses induced in HHD mice by multiepitope HIV vaccine based on cryptic epitope modification.

CD8+ T cells play an important role in early HIV infection. However, HIV has the capacity to avoid specific CTL responses due to a high rate of mutation under selection pressure. Although the HIV proteins, gag and pol, are relatively conserved, these sequences generate low-affinity MHC-associated epitopes that are poorly immunogenic. Here, we applied an approach that enhanced the immunogenicity of low-affinity HLA-A2.1-binding peptides. The first position with tyrosine (P1Y) substitution enhanced the affinity of HLA-A2.1-associated peptides without altering their antigenic specificity. More importantly, P1Y variants efficiently stimulated in vivo native peptide-specific CTL that also recognized the corresponding naturally processed epitope. The potential to generate CTL against any low-affinity HLA-A2.1-associated peptide provides us with the necessary technique for identification of virus cryptic epitopes for development of peptide-based immunotherapy. Therefore, identification and modification of the cryptic epitopes of gal and pol provides promising candidates for HIV immunotherapy dependent upon efficient presentation by virus cells. Furthermore, this may be a breakthrough that overcomes the obstacle of immune escape caused by high rates of mutation. In this study, bioinformatics analysis was used to predict six low-affinity cryptic HIV gag and pol epitopes presented by HLA-A*0201. A HIV compound multi-CTL epitope gene was constructed comprising the gene encoding the modified cryptic epitope and the HIV p24 antigen, which induced a strong CD8+ T cell immune response regardless of the mutation. This approach represents a novel strategy for the development of safe and effective HIV prophylactic and therapeutic vaccines.

Integrated Transcriptomics and Metabolomics Analyses Provide Insights into Qingke in Response to Cold Stress.

The survival and productivity of qingke in high altitude (>4300 m, average yearly temperature <0 °C) of the Tibetan Plateau are significantly impacted by low-temperature stress. Uncovering the mechanisms underlying low-temperature stress response in cold-tolerant qingke varieties is crucial for qingke breeding. Herein, we conducted a comprehensive transcriptomic and metabolomic analysis on cold-sensitive (ZQ) and cold-tolerant (XL) qingke varieties under chilling and freezing treatments and identified lipid metabolism pathways as enriched in response to freezing treatment. Additionally, a significant positive correlation was observed between the expression of C-repeat (CRT) binding factor 10A (HvCBF10A) and Gly-Asp-Ser-Leu-motif lipase (HvGDSL) and the accumulation of multiple lipids. Functional analysis confirmed that HvCBF10A directly binds to HvGDSL, and silencing HvCBF10A resulted in a significant decrease in both HvGDSL and lipid levels, consequently impairing the cold tolerance. Overall, HvCBF10A and HvGDSL are functional units in actively regulating lipid metabolism to enhance freezing stress tolerance in qingke.

Amer: A New Attribute-Missing Network Embedding Approach.

Network embedding which aims to learn a low dimensional representation of nodes is a powerful technique for network analysis. While network embedding for networks with complete attributes has been widely investigated, in many real-world applications the attributes of partial nodes are unobserved (i.e., missing) due to privacy concern or resource limit. Very recently, several network embedding methods have been proposed for attribute-missing networks. They first complete the missing attributes and then use the complemented network to learn network embedding. The parameters of these two processes cannot be adjusted by each other, resulting in compromised results. To address this problem, we propose a unified model in which the process of completing missing attributes and the process of learning embedding are not separated but closely intertwined. Being specific, completing missing attributes is under the guidance of learning network representation via mutual information maximization, and the complemented attributes directly enter network representation module which will generate further feedback for completing missing attributes. We further impose attribute-structure relationship constraint for completing missing attributes by designing a new generative adversarial networks (GANs) model. To the best of our knowledge, this is the first unified model for attribute-missing network embedding. Empirical results on real-world datasets show the superiority of our new method over other state-of-the-art methods on four network analysis tasks, including node classification, node clustering, link prediction, and network visualization.