Association of HMGCR inhibition with rheumatoid arthritis: a Mendelian randomization and colocalization study.

Objective: The objective of this study was to investigate the association between hydroxymethylglutaryl coenzyme A reductase (HMGCR) inhibition and rheumatoid arthritis (RA) using drug-target Mendelian randomization (MR) and genetic colocalization analyses. Methods: Two sets of genetic instruments were employed to proxy HMGCR inhibitors: expression quantitative trait loci (eQTLs) of target genes from the eQTLGen Consortium and genetic variants associated with low-density lipoprotein cholesterol (LDL-C) levels with HMGCR locus from open genome-wide association studies (GWAS). Positive control analyses were conducted on type 2 diabetes and coronary heart disease, and multiple sensitivity analyses were performed. Results: Genetically proxied expression of eQTL was associated with a lower risk of RA (OR=0.996, 95% CI =0.992-0.999, p= 0.032). Similarly, hydroxymethylglutaryl coenzyme A reductase (HMGCR)-mediated low-density lipoprotein cholesterol was negatively associated with risk of RA (OR=0.995, 95% CI =0.991-0.998, p= 0.007) in the inverse variance weighted (IVW) method. Colocalization analysis suggested a 74.6% posterior probability of sharing a causal variant within the SNPs locus (PH4 = 74.6%). A causal relationship also existed between HMGCR-mediated LDL and RA risk factors. The results were also confirmed by multiple sensitivity analyses. The results in positive control were consistent with the previous study. Conclusion: Our study suggested that HMGCR inhibition was associated with an increased risk of RA while also highlighting an increased risk of current smoking and obesity. These findings contribute to a growing body of evidence regarding the adverse effects of HMGCR inhibition on RA risk, calling for further research on alternative approaches using HMGCR inhibitors in RA management.

Mendelian Randomization Study of Lipid Metabolites Reveals Causal Associations with Heel Bone Mineral Density.

BACKGROUND: Osteoporosis, which is a bone disease, is characterized by low bone mineral density and an increased risk of fractures. The heel bone mineral density is often used as a representative measure of overall bone mineral density. Lipid metabolism, which includes processes such as fatty acid metabolism, glycerol metabolism, inositol metabolism, bile acid metabolism, carnitine metabolism, ketone body metabolism, sterol and steroid metabolism, etc., may have an impact on changes in bone mineral density. While some studies have reported correlations between lipid metabolism and heel bone mineral density, the overall causal relationship between metabolites and heel bone mineral density remains unclear. OBJECTIVE: to investigate the causal relationship between lipid metabolites and heel bone mineral density using two-sample Mendelian randomization analysis. METHODS: Summary-level data from large-scale genome-wide association studies were extracted to identify genetic variants linked to lipid metabolite levels. These genetic variants were subsequently employed as instrumental variables in Mendelian randomization analysis to estimate the causal effects of each lipid metabolite on heel bone mineral density. Furthermore, metabolites that could potentially be influenced by causal relationships with bone mineral density were extracted from the KEGG and WikiPathways databases. The causal associations between these downstream metabolites and heel bone mineral density were then examined. Lastly, a sensitivity analysis was conducted to evaluate the robustness of the results and address potential sources of bias. RESULTS: A total of 130 lipid metabolites were analyzed, and it was found that acetylcarnitine, propionylcarnitine, hexadecanedioate, tetradecanedioate, myo-inositol, 1-arachidonoylglycerophosphorine, 1-linoleoylglycerophoethanolamine, and epiandrosterone sulfate had a causal relationship with heel bone mineral density (p < 0.05). Furthermore, our findings also indicate an absence of causal association between the downstream metabolites associated with the aforementioned metabolites identified in the KEGG and WikiPathways databases and heel bone mineral density. CONCLUSION: This work supports the hypothesis that lipid metabolites have an impact on bone health through demonstrating a causal relationship between specific lipid metabolites and heel bone mineral density. This study has significant implications for the development of new strategies to osteoporosis prevention and treatment.

NiCo layered double hydroxides/NiFe layered double hydroxides composite (NiCo-LDH/NiFe-LDH) towards efficient oxygen evolution in different water matrices.

Engineering robust non-noble metal electrocatalysts towards efficient impure water (e.g., seawater, wastewater) oxidation is a prospective approach to achieve carbon neutrality via accelerating green hydrogen energy development. Herein, a NiCo layered double hydroxides (LDH)/NiFe LDH composite (NiCo-LDH/NiFe-LDH) was developed for oxygen evolution reaction (OER) via a hydrothermal process-electrodeposition method. The optimal NiCo-LDH/NiFe-LDH-30 composite only needed an overpotential (η) of 240 mV to drive 100 mA/cm2 in alkalized freshwater, with a low Tafel slope of 16.6 mV/dec and good stability for over 90 h. Further analyses suggested that the strong interface interaction between NiCo-LDH and NiFe-LDH accelerated the oxygen gas bubble evolution and boosted interfacial charge transfer, and the formed built-in electric field and higher oxidation state species (metal oxyhydroxides) contributed to the high intrinsic catalytic activity. The NiCo-LDH/NiFe-LDH-30 composite also held excellent OER activities in different impure water environments, including alkaline 0.5 M NaCl solution (η100 = 333 mV), alkaline lake water (η100 = 345 mV), and alkaline wastewater treatment plant (WWTP) effluent (η100 = 320 mV). More importantly, the potential effects of Cl- and CO32- in impure water were revealed during the OER process. This work elaborates on the role of built-in electric field and the strong coupling interaction in composite catalysts, which pave the way for the design of cost-effective catalysts with excellent adaptability in different water environments.

Targeted delivery of a PD-1-blocking scFv by CD133-specific CAR-T cells using nonviral Sleeping Beauty transposition shows enhanced antitumour efficacy for advanced hepatocellular carcinoma.

BACKGROUND: CD133 is considered a marker for cancer stem cells (CSCs) in several types of tumours, including hepatocellular carcinoma (HCC). Chimeric antigen receptor-specific T (CAR-T) cells targeting CD133-positive CSCs have emerged as a tool for the clinical treatment of HCC, but immunogenicity, the high cost of clinical-grade recombinant viral vectors and potential insertional mutagenesis limit their clinical application. METHODS: CD133-specific CAR-T cells secreting PD-1 blocking scFv (CD133 CAR-T and PD-1 s cells) were constructed using a sleeping beauty transposon system from minicircle technology, and the antitumour efficacy of CD133 CAR-T and PD-1 s cells was analysed in vitro and in vivo. RESULTS: A univariate analysis showed that CD133 expression in male patients at the late stage (II and III) was significantly associated with worse progression-free survival (PFS) (P = 0.0057) and overall survival (OS) (P = 0.015), and a multivariate analysis showed a trend toward worse OS (P = 0.041). Male patients with advanced HCC exhibited an approximately 20-fold higher PD-L1 combined positive score (CPS) compared with those with HCC at an early stage. We successfully generated CD133 CAR-T and PD-1 s cells that could secrete PD-1 blocking scFv based on a sleeping beauty system involving minicircle vectors. CD133 CAR-T and PD-1 s cells exhibited significant antitumour activity against HCC in vitro and in xenograft mouse models. Thus, CD133 CAR-T and PD-1 s cells may be a therapeutically tractable strategy for targeting CD133-positive CSCs in male patients with advanced HCC. CONCLUSIONS: Our study provides a nonviral strategy for constructing CAR-T cells that could also secrete checkpoint blockade inhibitors based on a Sleeping Beauty system from minicircle vectors and revealed a potential benefit of this strategy for male patients with advanced HCC and high CD133 expression (median immunohistochemistry score > 2.284).

BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: In the past decade, the field of tumour immunotherapy has made a great progress. However, the efficacy of immune checkpoint blocking (ICB) in the treatment of hepatocellular carcinoma (HCC) remains limited. Cytotoxic lymphocyte trafficking into tumours is critical for the success of ICB. Therefore, additional strategies that increase cytotoxic lymphocyte trafficking into tumours are urgently needed to improve patient immune responses. METHODS: Paired adjacent tissue and cancerous lesions with HBV-associated HCC were subjected to RNA-seq analysis. Bone morphogenetic protein (BMP9), which reflects vessel normalisation, was identified through Cytoscape software, clinical specimens and Gene Expression Omnibus (GEO) datasets for HCC. The functional effects and mechanism of BMP9 on the tumour vasculature were evaluated in cells and animals. An ultrasound-targeted microbubble destruction (UTMD)-mediated BMP9 delivery strategy was used to normalise the vasculature and evaluate therapeutic efficacy mediated by cytotoxic lymphocytes (NK cells) in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. RESULTS: We discovered that hepatitis B virus (HBV) infection-induced downregulation of BMP9 expression correlated with a poor prognosis and pathological vascular abnormalities in patients with HCC. BMP9 overexpression in HBV-infected HCC cells promoted intra-tumoural cytotoxic lymphocyte infiltration via vascular normalisation by inhibiting the Rho-ROCK-myosin light chain (MLC) signalling cascade, resulting in enhanced efficacy of immunotherapy. Furthermore, UTMD-mediated BMP9 delivery restored the anti-tumour function of cytotoxic lymphocytes (NK cells) and showed therapeutic efficacy in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. CONCLUSIONS: HBV-induced BMP9 downregulation causes vascular abnormalities that inhibit intra-tumoural cytotoxic lymphocyte infiltration, providing a rationale for developing and combining immunotherapy with BMP9-based therapy to treat HBV-associated HCC.

Causal relationship between polycystic ovary syndrome and chronic kidney disease: A Mendelian randomization study.

Objective: Polycystic ovary syndrome is one of the most common endocrine disorders among women of childbearing age. The relationship between polycystic ovary syndrome and chronic kidney disease remains unclear and controversial. In this study, we investigated the causal role of polycystic ovary syndrome in the development of chronic kidney disease using the two-sample Mendelian randomization method. Methods: Public shared summary-level data was acquired from European-ancestry genome wide association studies. We finally obtained 12 single nucleotide polymorphisms as instrumental variables, which were associated with polycystic ovary syndrome in European at genome-wide significance (P < 5 × 10-8). Inverse-variance weighted method was employed in the Mendelian randomization analysis and multiple sensitivity analyses were implemented. Outcome data were obtained from the Open GWAS database. Results: A positive causal association was observed between polycystic ovary syndrome and chronic kidney disease (odds ratio [OR]=1.180, 95% confidence interval [CI]: 1.038-1.342; P=0.010). Further analyses clarified that causal relationship exist between polycystic ovary syndrome and some serological indicators of chronic kidney disease (fibroblast growth factor 23: OR= 1.205, 95% CI: 1.031-1.409, P=0.019; creatinine: OR= 1.012, 95% CI: 1.001-1.023, P=0.035; cystatin C: OR= 1.024, 95% CI: 1.006-1.042, P=0.009). However, there was no causal association of polycystic ovary syndrome with other factors in the data sources we employed. Conclusions: Our results indicate an important role of polycystic ovary syndrome in the development of chronic kidney disease. This study suggests that regular follow-up of renal function in patients with polycystic ovary syndrome is necessary for the early treatment of chronic kidney disease.

Alarmin IL-33 orchestrates antitumoral T cell responses to enhance sensitivity to 5-fluorouracil in colorectal cancer.

Rationale: Resistance to 5-fluorouracil (5-FU) chemotherapy remains the main barrier to effective clinical outcomes for patients with colorectal cancer (CRC). A better understanding of the detailed mechanisms underlying 5-FU resistance is needed to increase survival. Interleukin (IL)-33 is a newly discovered alarmin-like molecule that exerts pro- and anti-tumorigenic effects in various cancers. However, the precise role of IL-33 in CRC progression, as well as in the development of 5-FU resistance, remains unclear. Methods: High-quality RNA-sequencing analyses were performed on matched samples from patients with 5-FU-sensitive and 5-FU-resistant CRC. The clinical and biological significance of IL-33, including its effects on both T cells and tumor cells, as well as its relationship with 5-FU chemotherapeutic activity were examined in ex vivo, in vitro and in vivo models of CRC. The molecular mechanisms underlying these processes were explored. Results: IL-33 expressed by tumor cells was a dominant mediator of antitumoral immunity in 5-FU-sensitive patients with CRC. By binding to its ST2 receptor, IL-33 triggered CD4+ (Th1 and Th2) and CD8+ T cell responses by activating annexin A1 downstream signaling cascades. Mechanistically, IL-33 enhanced the sensitivity of CRC cells to 5-FU only in the presence of T cells, which led to the activation of both tumor cell-intrinsic apoptotic and immune killing-related signals, thereby synergizing with 5-FU to induce apoptosis of CRC cells. Moreover, injured CRC cells released more IL-33 and the T cell chemokines CXCL10 and CXCL13, forming a positive feedback loop to further augment T cell responses. Conclusions: Our results identified a previously unrecognized connection between IL-33 and enhanced sensitivity to 5-FU. IL-33 created an immune-active tumor microenvironment by orchestrating antitumoral T cell responses. Thus, IL-33 is a potential predictive biomarker for 5-FU chemosensitivity and favorable prognosis and has potential as a promising adjuvant immunotherapy to improve the clinical benefits of 5-FU-based therapies in the treatment of CRC.

The traceability method of electronic transformer calibrators based on time series-weighted correlation degree extension integrating Hilbert phase-shift.

The traceability method directly affects the reliability and accuracy of the measurement of electronic transformers. The stability and unreliable traceability performance of analog devices would affect the traditional analog differential method. Thus, we propose a digital differential method combining a time series-weighted correlation degree extension integrating Hilbert phase-shift of four-term continuous third-derivative Nuttall window function, effectively suppressing the end effect problem and realizing the high-precision addition of the differential. Results of simulation experiments showed that the differential's deviation was <10-10, much less than that (1.32 × 10-4) due to the analog differential. The voltage and current ratio difference's combined standard uncertainty was 5.01 × 10-5 and 5.08 × 10-5, respectively, and 0.1718' in the phase error. Finally, an automatic traceability detection system was constructed. Compared with the traditional method, the accuracy and stability of the automatic system were better and could meet the traceability requirements for 0.05-accuracy electronic voltage transformer calibrator.

Synthesis of bifunctional NiFe layered double hydroxides (LDH)/Mo-doped g-C3N4 electrocatalyst for efficient methanol oxidation and seawater splitting.

To boost the oxygen evolution reaction (OER) and methanol oxidation reaction (MOR) of pristine NiFe-layered double hydroxides (LDH), the NiFe-LDH/Mo-doped graphitic carbon nitride (NiFe-LDH/MoCN) heterojunction was synthesized herein through hydrothermal method. The establishment of built-in electric field in NiFe-LDH/MoCN heterojunction enhanced the electrochemical oxidation activities towards both seawater splitting and methanol oxidation, via the improving electrocatalyst surface wettability and conductivity. Almost 10-fold enhancement of turnover frequency (TOF) and electrochemical active surface area (ECSA) than pure NiFe-LDH implied more active sites to participate in catalytic reactions via Mo doping and the formation of heterostructure. Moreover, the local charge redistribution demonstrated in the NiFe-LDH/MoCN interface region may favor the adsorption of methanol and OH- in the seawater. The present work may expound the strong coupling interaction and the establishment of built-in electric field in the interface between NiFe-LDH and semiconductor to enhance both methanol oxidation and seawater oxidation for NiFe-LDH.

Patterning alternate TiO2 and Cu2O strips on a conductive substrate as film photocatalyst for Z-scheme photocatalytic water splitting.

Semiconductor heterostructures mediated by electrical conductors are very promising for Z-scheme photocatalytic water splitting. In contrast to conventional particulate heterostructures, alternate TiO2 and Cu2O film stripes patterned parallel on a fluorine-doped tin oxide (FTO) conductive substrate was fabricated as a model film photocatalyst to study the characteristics of the photogenerated charge transfer process. The Z-scheme transfer process with an effective transport distance of up to 5 µm occurs only in regions distant from the TiO2/Cu2O strip edges through the FTO substrate from the bottom. In contrast, the transfer of charge around their contact regions follows the conventional transfer process through the TiO2/Cu2O strip interface. These results indicate that the Z-scheme transfer process occurring in such a large region dominates the charge transfer processes in the TiO2/FTO/Cu2O pattern film heterostructure. Importantly, unlike the single component film, which is inactive for photocatalytic overall water splitting, the modified TiO2/Cu2O pattern film can induce photocatalytic overall water splitting at a stoichiometric H2/O2 ratio close to 2:1. These findings have significant implications in designing efficient heterostructures by employing a Z-scheme charge transfer process.

Revealing the mechanisms of polypyrrole (Ppy) enhancing methane production from anaerobic digestion of waste activated sludge (WAS).

Anaerobic digestion (AD) is a promising method for treating waste activated sludge (WAS), but the low methane yield limits its large-scale application. The addition of conductive nanomaterials has been demonstrated to enhance the activity of AD via promoting the direct interspecies electron transfer (DIET). In this study, novel conductive polypyrrole (Ppy) was prepared to effectively improve the AD performance of WAS. The results showed that the accumulative methane production was enhanced by 27.83% by Ppy, with both acidogenesis and methanogenesis being efficiently accelerated. The microbial community analysis indicated that the abundance of bacteria associated with acidogenesis process was significantly elevated by Ppy. Further investigation by metatranscriptomics revealed that fadE and fadN genes (to express the key enzymes in fatty acid metabolism) were highly expressed in the Ppy-driven AD, suggesting that Ppy promoted electron generation during acid production. For methanogenesis metabolism, genes related to acetate utilization and CO2 utilization methanogenesis were also up-regulated by Ppy, illustrating that Ppy facilitates the utilization of acetate and electrons by methanogenic archaea, thus potentially promoting the methanogenesis through DIET.

2D/1D BiOI/g-C3N4 nanotubes heterostructure for photoelectrochemical overall water splitting.

To boost the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) performances, the BiOI/graphitic carbon nitride nanotubes (g-C3N4 nanotubes) heterojunction was synthesized herein through the hydrothermal method. BiOI in-situ grew on the surface of g-C3N4 nanotubes derived from melamine. The rapid recombination between photoexcited electrons and holes of pristine semiconductors was prevented via building the stable heterojunction. The SEM results indicated that the BiOI was wrapped around the surface of g-C3N4 nanotubes, resulting in an optimized electronic transmission pathway. Much lower charge transfer resistance at the p-n heterojunction was demonstrated compared with pristine BiOI according to the EIS results, thus leading to the faster surface reaction rates. Moreover, the composite exhibited both outstanding OER and HER activities under illuminated conditions. This study may shed light upon establishing a bifunctional photoelectrocatalysis for photoelectrochemical water splitting based on stable 2D metal and 1D metal-free nanocomposite.

Social Media User Behavior and Emotions during Crisis Events.

The wide availability of smart mobile devices and Web 2.0 services has allowed people to easily access news, spread information, and express their opinions and emotions using various social media platforms. However, because of the ease of joining these sites, people also use them to spread rumors and vent their emotions, with the social platforms often playing a facilitation role. This paper collected more than 190,000 messages published on the Chinese Sina-Weibo platform to examine social media user behaviors and emotions during an emergency, with a particular research focus on the "Dr. Li Wenliang" reports associated with the COVID-19 epidemic in China. The verified accounts were found to have the strongest interactions with users, and the sentiment analysis revealed that the news from government agencies had a positive user effect and the national media and trusted experts were more favored by users in an emergency. This research provides a new perspective on trust and the use of social media platforms in crises, and therefore offers some guidance to government agencies.

Enhanced photodegradation of doxycycline (DOX) in the sustainable NiFe2O4/MWCNTs/BiOI system under UV light irradiation.

In this study, a magnetic NiFe2O4/MWCNTs/BiOI composite were fabricated and applied for enhanced and sustainable photocatalytic degradation of doxycycline (DOX) under UV light irradiation. The as-synthesized material was characterized by a series of techniques and its photocatalytic property was assessed via a couple of batch tests. With the pH at 3.0 and NiFe2O4/MWCNTs/BiOI loading of 1.5 g L-1, the DOX degradation (at 45 mg L-1) efficiency could achieve 92.18% with the reaction rate constant k of 0.0072 min-1. The high mineralization of DOX suggests the strong oxidation of both the parent pollutant and the intermediary products in the ternary catalyst system. DRS spectra indicated that compared with BiOI, the introduction of NiFe2O4 and MWCNTs reduces the band gap energy of the NiFe2O4/MWCNTs/BiOI. The quenching test illustrates that h+, OH and O2- all functioned in the developed photocatalytic system, where O2- and h+ play the dominant roles in DOX degradation. The more efficient electron-h+ separation and more oxidizing species induced by UV light resulted in the significant improvement of DOX abatement in the developed coupling system compared with that on either BiOI or NiFe2O4/MWCNTs. The magnetic property of NiFe2O4/MWCNTs/BiOI enables its easy separation of the solid catalyst from the reaction solution and the sustainable application in the photocatalysis. Based on the intermediates of DOX decomposition identified by UPLC-MS, the possible degradation routes were proposed accordingly.

Screening and identification of hub genes in bladder cancer by bioinformatics analysis and KIF11 is a potential prognostic biomarker.

Bladder cancer (BC) is the ninth most common lethal malignancy worldwide. Great efforts have been devoted to clarify the pathogenesis of BC, but the underlying molecular mechanisms remain unclear. To screen for the genes associated with the progression and carcinogenesis of BC, three datasets were obtained from the Gene Expression Omnibus. A total of 37 tumor and 16 non-cancerous samples were analyzed to identify differentially expressed genes (DEGs). Subsequently, 141 genes were identified, including 55 upregulated and 86 downregulated genes. The protein-protein interaction network was established using the Search Tool for Retrieval of Interacting Genes database. Hub gene identification and module analysis were performed using Cytoscape software. Hierarchical clustering of hub genes was conducted using the University of California, Santa Cruz Cancer Genomics Browser. Among the hub genes, kinesin family member 11 (KIF11) was identified as one of the most significant prognostic biomarkers among all the candidates. The Kaplan Meier Plotter database was used for survival analysis of KIF11. The expression profile of KIF11 was analyzed using the ONCOMINE database. The expression levels of KIF11 in BC samples and bladder cells were measured using reverse transcription-quantitative pCR, immunohistochemistry and western blotting. In summary, KIF11 was significantly upregulated in BC and might act as a potential prognostic biomarker. The present identification of DEGs and hub genes in BC may provide novel insight for investigating the molecular mechanisms of BC.

Development and Validation of a Scoring System Based on 9 Glycolysis-Related Genes for Prognosis Prediction in Gastric Cancer.

Gastric cancer is a malignant tumor with high morbidity and mortality worldwide. However, increasing evidences have revealed the correlation between the glycolysis process and tumorigenesis. This study is aim to develop a list of glycolysis-related genes for risk stratification in gastric cancer patients. We included 500 patients' sample data from GSE62254 and GSE26942 datasets, and classified patients into training (n = 350) and testing sets (n = 150) at a ratio of 7: 3. Univariate and multivariate Cox regression analysis were performed to screen genes having prognostic value. Based on HALLMARK gene sets, we identified 9 glycolysis-related genes (BPNT1, DCN, FUT8, GMPPA, GPC3, LDHC, ME2, PLOD2, and UGP2). On the basis of risk score developed by the 9 genes, patients were classified into high- and low-risk groups. The survival analysis showed that the high-risk patients had a worse prognosis (p < 0.001). Similar finding was observed in the testing cohort and 2 independent cohorts (GSE13861 and TCGA-STAD, all p < 0.001). The multivariate Cox regression analysis showed that the risk score was an independent prognostic factor for overall survival (p < 0.001). Furthermore, we constructed a nomogram that integrated the risk score and tumor stage, age, and adjuvant chemotherapy. Through comparing the results of the receiver operating characteristic curves and decision curve analysis, we found that the nomogram had a superior predictive accuracy than conventional TNM staging system, suggesting that the risk score combined with other clinical factors (age, tumor stage, and adjuvant chemotherapy) can develop a robust prediction for survival and improve the individualized clinical decision making of the patient.In conclusion, we identified 9 glycolysis-related genes from hallmark glycolysis pathway. Based on the 9 genes, gastric cancer patients were separated into different risk groups related to survival.