Estimated Pulse Wave Velocity as a Novel Non-Invasive Biomarker for Metabolic Syndrome Among People Living with HIV.

Purpose: This study aims to investigate the relationship between estimated pulse wave velocity (ePWV) and metabolic syndrome (MetS) in people living with HIV (PLWH), proposing a novel and convenient predictor for early detection of MetS in PLWH. Patients and Methods: A total of 485 PLWH were enrolled. These participants were categorized into two groups based on the estimated pulse wave velocity (ePWV) level. Demographic and clinical data were collected to investigate the correlation between ePWV and MetS. Results: The cohort of 485 PLWH was categorized into high-ePWV and low-ePWV groups based on ePWV cutoff value of 10 m/s. We observed significant differences in components of MetS including triglycerides (TG, P < 0.05), HDL cholesterol (HDL-C, P < 0.01), systolic blood pressure (SBP, P < 0.001), diastolic blood pressure (DBP, P < 0.05), and fasting plasma glucose (FPG, P < 0.001) between the two groups. Furthermore, we employed receiver operating characteristic (ROC) curves to demonstrate the effectiveness of ePWV as a predictive indicator for MetS in PLWH (AUC = 0.739, P < 0.001). According to the ROC curve, the optimal cut-off value of ePWV was 7.4 m/s, and its sensitivity and specificity in diagnosing MetS in PLWH were 79.03% and 64.07%, respectively. Although the 7.4 m/s cutoff increased the false positive rate compared to the traditional cutoff, it significantly reduced the rate of missed diagnoses, effectively identifying 79.03% of PLWH with MetS. Conclusion: ePWV is a non-invasive and convenient novel biomarker with predictive capabilities for MetS in PLWH.

Short-term prediction of PM2.5 concentration by hybrid neural network based on sequence decomposition.

Accurate forecasting of PM2.5 concentrations serves as a critical tool for mitigating air pollution. This study introduces a novel hybrid prediction model, termed MIC-CEEMDAN-CNN-BiGRU, for short-term forecasting of PM2.5 concentrations using a 24-hour historical data window. Utilizing the Maximal Information Coefficient (MIC) for feature selection, the model integrates Complete Ensemble Empirical Mode Decomposition with Adaptive Noise (CEEMDAN), Convolutional Neural Network (CNN), and Bidirectional Recurrent Gated Neural Network (BiGRU) to optimize predictive accuracy. We used 2016 PM2.5 monitoring data from Beijing, China as the empirical basis of this study and compared the model with several deep learning frameworks. RNN, LSTM, GRU, and other hybrid models based on GRU, respectively. The experimental results show that the prediction results of the hybrid model proposed in this question are more accurate than those of other models, and the R2 of the hybrid model proposed in this paper improves the R2 by nearly 5 percentage points compared with that of the single model; reduces the MAE by nearly 5 percentage points; and reduces the RMSE by nearly 11 percentage points. The results show that the hybrid prediction model proposed in this study is more accurate than other models in predicting PM2.5.

Palladium-Catalyzed Intermolecular Dehydrogenative C-2 Pentenylation of Indoles with 2-Methyl-2-butene.

Five-carbon (C5) units are the fundamental building blocks that constitute a multitude of natural products. Herein we report an unprecedented unusual C5 functionalization of indole regioselectively at the C-2-position enabled by a (2-pyridyl)sulfonyl-directing palladium-catalyzed dehydrogenative strategy with a bulk chemical 2-methyl-2-butene as a C5 source. Compared to typical C5 functionalization using pentenyl alcohols, carbonates, borates, or halides as the C5 source, the protocol not only has a low cost advantage but also is of atom and step economy.

Association rule mining with a special rule coding and dynamic genetic algorithm for air quality impact factors in Beijing, China.

Understanding air quality requires a comprehensive understanding of its various factors. Most of the association rule techniques focuses on high frequency terms, ignoring the potential importance of low- frequency terms and causing unnecessary storage space waste. Therefore, a dynamic genetic association rule mining algorithm is proposed in this paper, which combines the improved dynamic genetic algorithm with the association rule mining algorithm to realize the importance mining of low- frequency terms. Firstly, in the chromosome coding phase of genetic algorithm, an innovative multi-information coding strategy is proposed, which selectively stores similar values of different levels in one storage unit. It avoids storing all the values at once and facilitates efficient mining of valid rules later. Secondly, by weighting the evaluation indicators such as support, confidence and promotion in association rule mining, a new evaluation index is formed, avoiding the need to set a minimum threshold for high-interest rules. Finally, in order to improve the mining performance of the rules, the dynamic crossover rate and mutation rate are set to improve the search efficiency of the algorithm. In the experimental stage, this paper adopts the 2016 annual air quality data set of Beijing to verify the effectiveness of the unit point multi-information coding strategy in reducing the rule storage air, the effectiveness of mining the rules formed by the low frequency item set, and the effectiveness of combining the rule mining algorithm with the swarm intelligence optimization algorithm in terms of search time and convergence. In the experimental stage, this paper adopts the 2016 annual air quality data set of Beijing to verify the effectiveness of the above three aspects. The unit point multi-information coding strategy reduced the rule space storage consumption by 50%, the new evaluation index can mine more interesting rules whose interest level can be up to 90%, while mining the rules formed by the lower frequency terms, and in terms of search time, we reduced it about 20% compared with some meta-heuristic algorithms, while improving convergence.

LAIR1-mediated resistance of hepatocellular carcinoma cells to T cells through a GSK-3ß/ß-catenin/MYC/PD-L1 pathway.

BACKGROUND: An increasing number of studies have reported the involvement of oncogenes in the regulation of the immune system. LAIR1 is an immunosuppressive molecule and its role in immune-related diseases has been mainly reported. To date, it is unclear whether LAIR1 in tumor cells is involved in immune regulation. Therefore, the aim of this study was to investigate the role of LAIR1 in the immune microenvironment of hepatocellular carcinoma (HCC) to seek the novel therapeutic discoveries. METHODS: Tumor Immune Dysfunction and Exclusion database was used to predict the response of LAIR1 expression to immune checkpoint blockade. CD8+ T cells were co-cultured with HCC cells, and the killing efficiency of leukocytes on HCC cells was detected by flow cytometry. Flow cytometry was also used to detect the expression of inhibitory receptors. In addition, Western blot, immunofluorescence, and nucleus/cytoplasm fractionation experiments were performed to explore the molecular mechanisms by which LAIR1 created a suppressive tumor microenvironment. RESULTS: LAIR1 expression in HCC was associated with worse immune prognosis and T-cell dysfunction. HCC cells overexpressing LAIR1 co-cultured with CD8+ T cells induced exhaustion of latter. Mechanism studies indicated that LAIR1 in HCC cells up-regulated the phosphorylation of ß-catenin by inducing the phosphorylation of GSK-3ß, leading to the impairment of the expression and the nuclear localization signal of ß-catenin. Low ß-catenin expression and nuclear localization signal inhibited MYC-mediated PD-L1 expression. Therefore, PD-L1 up-regulated by LAIR1 caused the exhaustion of infiltrating CD8+ T cells in HCC, which aggravated the malignant progression of HCC. CONCLUSION: LAIR1 increased PD-L1 expression through the GSK-3ß/ß-catenin/MYC/PD-L1 pathway and promoted immune evasion of HCC cells. Targeted inhibition of LAIR1 helped to enhance the immune killing effect of CD8+ T cells in HCC.

Single-cell atlas reveals characteristic changes in intrahepatic HBV-specific leukocytes.

IMPORTANCE: Hepatitis B virus (HBV)-specific CD8+ T cells play a central role in the clearance of virus and HBV-related liver injury. Acute infection with HBV induces a vigorous, multifunctional CD8+ T cell response, whereas chronic one exhibits a weaker response. Our study elucidated HBV-specific T cell responses in terms of viral abundance rather than the timing of infection. We showed that in the premalignant stage, the degree of impaired T cell function was not synchronized with the viral surface antigen, which was attributed the liver's tolerance to the virus. However, after the development of hepatocellular carcinoma, T cell exhaustion was inevitable, and it was marked by the exhaustion of the signature transcription factor TOX.

SUMOylation inhibitors activate anti-tumor immunity by reshaping the immune microenvironment in a preclinical model of hepatocellular carcinoma.

PURPOSE: High levels of heterogeneity and immunosuppression characterize the HCC immune microenvironment (TME). Unfortunately, the majority of hepatocellular carcinoma (HCC) patients do not benefit from immune checkpoint inhibitors (ICIs) therapy. New small molecule therapies for the treatment of HCC are the goal of our research. METHODS: SUMOylation inhibitors (TAK-981 and ML-792) were evaluated for the treatment of preclinical mouse HCC models (including subcutaneous and orthotopic HCC models). We profile immune cell subsets from tumor samples after SUMOylation inhibitors treatment using single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), flow cytometry, and multiple immunofluorescences (mIF). RESULTS: We discover that SUMOylation is higher in HCC patient samples compared to normal liver tissue. TAK-981 and ML-792 decrease SUMOylation at nanomolar levels in HCC cells and also successfully reduced the tumor burden. Analysis combining scRNA-seq and CyTOF demonstrate that treatment with SUMOylation inhibitors reduces the exhausted CD8+T (Tex) cells while enhancing the cytotoxic NK cells, M1 macrophages and cytotoxic T lymphocytes (CTL) in preclinical mouse HCC model. Furthermore, SUMOylation inhibitors have the potential to activate innate immune signals from CD8+T, NK and macrophages while promoting TNFα and IL-17 secretion. Most notably, SUMOylation inhibitors can directly alter the TME by adjusting the abundance of intestinal microbiota, thereby restoring anti-tumor immunity in HCC models. CONCLUSIONS: This preclinical study suggests that SUMO signaling inhibitors may be beneficial for the treatment of HCC.

Microbial fortification of pharmacological metabolites in medicinal plants.

Medicinal plants are rich in secondary metabolites with beneficial pharmacological effects. The production of plant secondary metabolites is subjected to the influences by environmental factors including the plant-associated microbiome, which is crucial to the host's fitness and survival. As a result, research interests are increasing in exploiting microbial capacities for enhancing plant production of pharmacological metabolites. A growing body of recent research provides accumulating evidence in support of developing microbe-based tools for achieving this objective. This mini review presents brief summaries of recent studies on medicinal plants that demonstrate microbe-augmented production of pharmacological terpenoids, polyphenols, and alkaloids, followed by discussions on some key questions beyond the promising observations. Explicit molecular insights into the underlying mechanisms will enhance microbial applications for metabolic fortification in medicinal plants.

A modified immune cell infiltration score achieves ideal stratification for CD8+ T cell efficacy and immunotherapy benefit in hepatocellular carcinoma.

Immunotherapy, which aims to enhance the function of T cells, has emerged as a novel therapeutic approach for hepatocellular carcinoma (HCC). Nevertheless, the clinical utility of using flow cytometry to assess immune cell infiltration (ICI) is hindered by its cumbersome procedures, prompting the need for more accessible methods. Here, we acquired gene expression profiles and survival data of HCC from TCGA and GSE10186 datasets. The patients were categorized into two clusters of ICI, and a set of 11 characteristic genes responsible for the differentiation performance of these ICI clusters were identified. Subsequently, we successfully developed a modified ICI score (mICIS) by utilizing the expression levels of these genes. The efficacy of our mICIS was confirmed via mass cytometry, flow cytometry, and immunohistochemistry. Our research indicated that the favorable overall survival (OS) rate could be attributed to the improved function of anti-tumor leukocytes rather than their infiltration. Furthermore, we observed that the low score group exhibited lower expression levels of T-cell exhaustion-associated genes, which was confirmed in both HCC tissues from patients and mice, which demonstrated that the benefits of the low scores were due to enhanced active/cytotoxic CD8+ T cells and reduced exhausted CD8+ T cells. Additionally, our mICIS stratified the benefits derived from immunotherapies. Lastly, we observed a misalignment between CD8+ T-cell infiltration and function in HCC. In summary, our mICIS demonstrated proficiency in assessing the OS rate of HCC and offering significant stratified data pertaining to distinct responses to immunotherapy.

Black Phosphorus for Photonic Integrated Circuits.

Black phosphorus gives several advantages and complementarities over other two-dimensional materials. It has drawn extensive interest owing to its relatively high carrier mobility, wide tunable bandgap, and in-plane anisotropy in recent years. This manuscript briefly reviews the structure and physical properties of black phosphorus and targets on black phosphorus for photonic integrated circuits. Some of the applications are discussed including photodetection, optical modulation, light emission, and polarization conversion. Corresponding recent progresses, associated challenges, and future potentials are covered.

2,5-dimethylcelecoxib alleviated NK and T-cell exhaustion in hepatocellular carcinoma via the gastrointestinal microbiota-AMPK-mTOR axis.

BACKGROUND: 2,5-dimethylcelecoxib (DMC), a derivative of celecoxib, is an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Our previous studies have demonstrated that DMC inhibits the expression of programmed death-ligand 1 on hepatocellular carcinoma (HCC) cells to prevent tumor progression. However, the effect and mechanism of DMC on HCC infiltrating immune cells remain unclear. METHODS: In this study, single-cell-based high-dimensional mass cytometry was performed on the tumor microenvironment of HCC mice treated with DMC, celecoxib and MK-886 (a known mPGES-1 inhibitor). Moreover, 16S ribosomal RNA sequencing was employed to analyze how DMC improved the tumor microenvironment of HCC by remodeling the gastrointestinal microflora. RESULTS: We found that (1) DMC significantly inhibited the growth of HCC and improved the prognosis of the mice, and this depended on the stronger antitumor activity of natural killer (NK) and T cells; (2) compared with celecoxib and MK-886, DMC significantly enhanced the cytotoxic and stem-like potential, and inhibited exhaustion of NK and T cells; (3) mechanistically, DMC inhibited the expression of programmed cell death protein-1 and upregulated interferon-γ expression of NK and T cells via the gastrointestinal microbiota (Bacteroides acidifaciens, Odoribacter laneus, and Odoribacter splanchnicus)-AMPK-mTOR axis. CONCLUSIONS: Our study uncovers the role of DMC in improving the tumor microenvironment of HCC, which not only enriches the relationship between the mPGES-1/prostaglandin E2 pathway and the antitumor function of NK and T cells, but also provide an important strategic reference for multitarget or combined immunotherapy of HCC.Cite Now.

The advantages of penehyclidine hydrochloride over atropine in acute organophosphorus pesticide poisoning: A meta-analysis.

Background: Penehyclidine hydrochloride (PHC) has been used for many years as an anticholinergic drug for the treatment of acute organophosphorus pesticide poisoning (AOPP). The purpose of this meta-analysis was to explore whether PHC has advantages over atropine in the use of anticholinergic drugs in AOPP. Methods: We searched Scopus, Embase, Cochrane, PubMed, ProQuest, Ovid, Web of Science, China Science and Technology Journal Database (VIP), Duxiu, Chinese Biomedical literature (CBM), WanFang, and Chinese National Knowledge Infrastructure (CNKI), from inception to March 2022. After all qualified randomized controlled trials (RCTs) were included, we conducted quality evaluation, data extraction, and statistical analysis. Statistics using risk ratios (RR), weighted mean difference (WMD), and standard mean difference (SMD). Results: Our meta-analysis included 20,797 subjects from 240 studies across 242 different hospitals in China. Compared with the atropine group, the PHC group showed decreased mortality rate (RR=0.20, 95% confidence intervals [CI]: 0.16-0.25, P <0.001), hospitalization time (WMD=-3.89, 95% CI: -4.37 to -3.41, P <0.001), overall incidence rate of complications (RR=0.35, 95% CI: 0.28-0.43, P <0.001), overall incidence of adverse reactions (RR=0.19, 95% CI: 0.17-0.22, P <0.001), total symptom disappearance time (SMD=-2.13, 95% CI: -2.35 to -1.90, P <0.001), time for cholinesterase activity to return to normal value 50-60% (SMD=-1.87, 95% CI: -2.03 to -1.70, P <0.001), coma time (WMD=-5.57, 95% CI: -7.20 to -3.95, P <0.001), and mechanical ventilation time (WMD=-2.16, 95% CI: -2.79 to -1.53, P <0.001). Conclusion: PHC has several advantages over atropine as an anticholinergic drug in AOPP.

TGF-ß-p-STAT1-LAIR2 axis has a "self-rescue" role for exhausted CD8+ T cells in hepatocellular carcinoma.

BACKGROUND: TGF-ß is related to the function of T cells in the tumor microenvironment. However, the characteristics of TGF-ß affecting the function of CD8+ T cells in hepatocellular carcinoma (HCC) have not been clearly resolved. METHODS: In this study, flow cytometry, mass cytometry, immunohistochemistry, RNA-seq, single-cell RNA-seq, assay for transposase-accessible chromatin with high throughput sequencing, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were used to study the regulatory effect and molecular mechanism of TGF-ß on HCC infiltrating CD8+ T cells. RESULTS: Here, we demonstrated that the overall effect of TGF-ß on CD8+ T cells in HCC was to activate p-p38 to induce exhaustion, but it also initiated cell-intrinsic resistance mechanisms: 1) TGF-ß upregulated the levels of p-STAT1 (S727) and promoted LAIR2 secretion; 2) the TGF-ß-p-STAT1-LAIR2 axis relieved CD8+ T cells from exhaustion, which we called "self-rescue"; 3) this "self-rescue" behavior showed time and dose limitations on TGF-ß stimulation, which was easily masked by stronger inhibitory signals; 4) the function of CD8+ T cells was improved by using TAK-981 to amplify "self-rescue" signal. CONCLUSION: Our study describes a "self-rescue" mechanism of CD8+ T cells in HCC against exhaustion and the good effects from amplifying this signal.

SUMOylated IL-33 in the nucleus stabilizes the transcription factor IRF1 in hepatocellular carcinoma cells to promote immune escape.

Interleukin-33 (IL-33) functions both as a secreted cytokine and as a nuclear factor, with pleiotropic roles in cancer and immunity. Here, we explored its role in hepatocellular carcinoma (HCC) and identified that a posttranslational modification altered its nuclear activity and promoted immune escape for HCC. IL-33 abundance was overall decreased but more frequently localized to the nucleus in patient HCC tissues than in normal liver tissues. In human and mouse HCC cells in culture and in vivo, IL-33 overexpression inhibited proliferation and repressed the abundance of programmed death ligand 1 (PD-L1) at the transcriptional level by promoting the ubiquitin-dependent degradation of interferon regulatory factor 1 (IRF1). However, this interaction was disrupted by SUMOylation of IL-33 at Lys54 mediated by the E3 ligase RanBP2. IL-33 SUMOylation correlated with its nuclear localization in HCC cells and tumors. An increase in SUMOylated IL-33 in HCC cells in cocultures and in vivo stabilized IRF1 and increased PD-L1 abundance and chemokine IL-8 secretion, which prevented the activation of cytotoxic T cells and promoted the M2 polarization of macrophages, respectively. Mutating the SUMOylation site in IL-33 reversed these effects and suppressed tumor growth. These findings indicate that SUMOylation of nuclear IL-33 in HCC cells impairs antitumor immunity.

XPO1 intensifies sorafenib resistance by stabilizing acetylation of NPM1 and enhancing epithelial-mesenchymal transition in hepatocellular carcinoma.

Emerging studies have suggested that exportin-1 (XPO1) plays a pivotal role in hepatocellular carcinoma (HCC). However, the underlying mechanism of XPO1 in HCC sorafenib resistance remains enigmatic. The expression of XPO1 in HCC tumor tissues and sorafenib-resistant (SR) cells were analyzed by bioinformatics analysis, immunohistochemistry (IHC) and Western blotting. The interaction mechanism between XPO1 and Nucleophosmin (NPM1) was investigated by immunoprecipitation (IP), Mass-spectrometric (MS) analysis, immunofluorescence colocalization, CRISPR/CAS9 technology and RNA-seq. Analyses were also conducted on KPT-8602 and sorafenib's combined therapeutic effect. Our findings unraveled that the XPO1 overexpression was observed in HCC, and correlated with poorer survival. Knockdown of XPO1 inhibited the migration and proliferation of HCC cells, and also reduced the resistance of HCC cells to sorafenib. Mechanistically, XPO1 interacted with the C-terminus of NPM1 and mediated the acetylation of NPM1 at lysine 54 to maintain sorafenib resistance. XPO1 was bound to Vimentin, resulting in the epithelial-mesenchymal transition (EMT) progression in sorafenib-resistant cells. KPT-8602 in combination with sorafenib suppressed the tumor growth. These results highlighted the therapeutic value of targeting XPO1 in overcoming sorafenib resistance. The combinational treatment of KPT-8602 and sorafenib might be an improved therapeutic option.

SRY-box transcription factor 9 modulates Müller cell gliosis in diabetic retinopathy by upregulating TXNIP transcription.

Diabetic retinopathy (DR), a common complication of diabetes, involves excessive proliferation and inflammation of Muller cells and ultimately leads to vision loss and blindness. SRY-box transcription factor 9 (SOX9) has been reported to be highly expressed in Müller cells in light-induced retinal damage rats, but the functional role of SOX9 in DR remains unclear. To explore this issue, the DR rat model was successfully constructed via injection with streptozotocin (65 mg/kg) and the retinal thicknesses and blood glucose levels were evaluated. Müller cells were treated with 25 mmol/l glucose to create a cell model in vitro. The results indicated that SOX9 expression was significantly increased in DR rat retinas and in Müller cells stimulated with a high glucose (HG) concentration. HG treatment promoted the proliferation and migration capabilities of Müller cells, whereas SOX9 knockdown reversed those behaviors. Moreover, SOX9 knockdown provided protection against an HG-induced inflammatory response, as evidenced by reduced tumor necrosis factor-α, IL-1ß, and IL-6 levels in serum and decreased NLRP3 inflammasome activation. Notably, SOX9 acted as a transcription factor that positively regulated thioredoxin-interacting protein (TXNIP), a positive regulator of Müller cells gliosis under HG conditions. A dual-luciferase assay demonstrated that SOX9 could enhance TXNIP expression at the transcriptional level through binding to the promoter of TXNIP. Moreover, TXNIP overexpression restored the effects caused by SOX9 silencing. In conclusion, these findings demonstrate that SOX9 may accelerate the progression of DR by promoting glial cell proliferation, metastasis, and inflammation, which involves the transcriptional regulation of TXNIP, providing new theoretical fundamentals for DR therapy.

Targeted inhibition of RBPJ transcription complex alleviates the exhaustion of CD8+ T cells in hepatocellular carcinoma.

Impaired function of CD8+ T cells in hepatocellular carcinoma (HCC) is an important reason for acquired resistance. Compared with single-target inhibitors, small-molecule compounds that could both inhibit tumor cells and alleviate T cell exhaustion are more promising to reduce resistance. In this study, we screened immunosuppressive targets in HCC by combining cancer-immunity cycle score with weighted gene co-expression network and system analysis. Through in vitro and in vivo validation experiments, we found that one of the screened molecules, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), was negatively correlated with CD8+ T cell mediated killing function. More importantly, its transcription complex inhibitor RIN1 not only inhibited the malignant biological behaviors of HCC cells by inhibiting mTOR pathway, but also reduced the expression of PD-L1 and L-kynurenine synthesis in HCC cells, thus alleviating T cell exhaustion. Meanwhile, the combination of RIN1 and anti-PD-1/PD-L1 antibodies could further activate CD8+ T cells. In short, RBPJ is an important factor regulating the function of T cells. Target inhibition of RBPJ transcription complex by small molecule compound may be a new strategy for immunotherapy of HCC.