Mendelian randomization and Bayesian model averaging of autoimmune diseases and Long COVID.

Background: Following COVID-19, reports suggest Long COVID and autoimmune diseases (AIDs) in infected individuals. However, bidirectional causal effects between Long COVID and AIDs, which may help to prevent diseases, have not been fully investigated. Methods: Summary-level data from genome-wide association studies (GWAS) of Long COVID (N = 52615) and AIDs including inflammatory bowel disease (IBD) (N = 377277), Crohn's disease (CD) (N = 361508), ulcerative colitis (UC) (N = 376564), etc. were employed. Bidirectional causal effects were gauged between AIDs and Long COVID by exploiting Mendelian randomization (MR) and Bayesian model averaging (BMA). Results: The evidence of causal effects of IBD (OR = 1.06, 95% CI = 1.00-1.11, p = 3.13E-02), CD (OR = 1.10, 95% CI = 1.01-1.19, p = 2.21E-02) and UC (OR = 1.08, 95% CI = 1.03-1.13, p = 2.35E-03) on Long COVID was found. In MR-BMA, UC was estimated as the highest-ranked causal factor (MIP = 0.488, MACE = 0.035), followed by IBD and CD. Conclusion: This MR study found that IBD, CD and UC had causal effects on Long COVID, which suggests a necessity to screen high-risk populations.

Downregulation of PRKCI inhibits osteosarcoma cell growth by inactivating the Akt/mTOR signaling pathway.

PRKCI is abnormally expressed in various cancers, but its role in osteosarcoma is unknown. This study aimed to explore the biological function of PRKCI in osteosarcoma and its potential molecular mechanism. PRKCI expression was evaluated in osteosarcoma cell lines using Western blot analysis and reverse transcription PCR. The CCK-8 assay, colony formation assay, flow cytometry, Transwell assay, and wound-healing assay were used to detect the proliferation, colony-forming capacity, cell cycle, migration, and invasion of osteosarcoma cells when PRKCI was overexpressed or knocked down. The interaction between PRKCI and SQSTM1 was explored using immunoprecipitation. Finally, the protein molecule expression of the Akt/mTOR signaling pathway in osteosarcoma was detected when PRKCI was knocked down. Our study found that PRKCI was overexpressed in osteosarcoma cell lines. The overexpression of PRKCI promoted the proliferation and colony-forming capacity of osteosarcoma cells, while silencing PRKCI inhibited the proliferation, colony-forming capacity, migration, and invasion of osteosarcoma cells and arrested the cell cycle at the G2/M phase. Both PRKCI and SQSTM1 were overexpressed in osteosarcoma. The expression of PRKCI was only related to histological type, while that of SQSTM1 was not related to clinical characteristics. The expression of PRKCI and SQSTM1 in osteosarcoma was higher than that in chondrosarcoma. Knockdown of PRKCI inhibited the proliferation of osteosarcoma cells by inactivating the Akt/mTOR signaling pathway, suggesting that PRKCI was a potential target for osteosarcoma therapy.

3D Models of Sarcomas: The Next-generation Tool for Personalized Medicine.

Sarcoma is a complex and heterogeneous cancer that has been difficult to study in vitro. While two-dimensional (2D) cell cultures and mouse models have been the dominant research tools, three-dimensional (3D) culture systems such as organoids have emerged as promising alternatives. In this review, we discuss recent developments in sarcoma organoid culture, with a focus on their potential as tools for drug screening and biobanking. We also highlight the ways in which sarcoma organoids have been used to investigate the mechanisms of gene regulation, drug resistance, metastasis, and immune interactions. Sarcoma organoids have shown to retain characteristics of in vivo biology within an in vitro system, making them a more representative model for sarcoma research. Our review suggests that sarcoma organoids offer a potential path forward for translational research in this field and may provide a platform for developing personalized therapies for sarcoma patients.

The causal role of gut microbiota in susceptibility of Long COVID: a Mendelian randomization study.

Background: Long COVID is a major challenge facing the public. Gut microbiota is closely related to Long COVID. However, the causal effects between gut microbiota and Long COVID remains unclear. Methods: Using summary statistics from Genome-Wide Association Studies (GWAS), Mendelian randomization (MR) analyses were performed to investigate the relationship between gut microbiota and Long COVID. The primary statistical method employed was Inverse Variance Weighted (IVW). Sensitivity analyses were then conducted to evaluate the reliability of the findings and account for potential confounding variables. Finally, a reverse MR analysis was conducted to examine potential associations between Long COVID and genetically predicted gut microbiota compositions. Results: There were 2 positive and 1 negative causal effect between gut microbiota and Long COVID. Meta-analysis results show that genus Parasutterella (OR = 1.145, 95%CI = 1.035 ∼ 1.266, P = 0.008) and genus Oscillospira (OR = 1.425, 95%CI = 1.235 ∼ 1.645, P < 0.001) significantly increased the risk of Long COVID. And genus Eisenbergiella (OR = 0.861, 95%CI = 0.785 ∼ 0.943, P = 0.001) significantly decreased the risk of Long COVID. Neither the pleiotropy nor the heterogeneity was observed. Reverse causal effect does not hold. Conclusion: Our research has provided genetic evidence that establishes multiple causal relationships between the gut microbiota and Long COVID, supporting the role of the gut microbiota in Long COVID. It is possible that different taxa play a role in the development of Long COVID. The causal relationships identified in this study require further investigation.

TIPE1 limits virus replication by disrupting PKM2/ HIF-1α/ glycolysis feedback loop.

OBJECTIVE: Virus infection is a major threat to human health and remains a significant cause of death to date. Macrophages are important innate immune cells that exhibit indispensable roles in controlling virus replication. It was recently reported that metabolic adaption determines the functional state of macrophages. Thus, to further unravel the crucial factors involving in metabolic adaption of macrophages might provide the potential candidates for optimizing their anti-viral capabilities. METHODS: RT-PCR, Western blotting, virus plaque assay and HE were used to evaluate the viral load in virus-infected Tipe1M-KO and Tipe1f/f mice or cultured macrophages. RNA sequencing were performed with Tipe1M-KOor Tipe1f/f BMDMs upon virus infection. Extracellular acidification rate (ECAR) was applied for analyzing glycolysis rate in virus-infected BMDMs. Co-immunoprecipitation (Co-IP) assay and LC-MS/MS were used to determine the potential interacting proteins of TIPE1. RESULTS: TIPE1 level was significantly reduced in BMDMs infected with either RNA viruses or DNA virus. Deficiency of Tipe1 in macrophages increased viral load and aggravated tissue damage. Mechanistically, TIPE1 suppressed the glycolytic capacity of macrophages through interacting with PKM2 and promoting its ubiquitination degradation, which in turn decreased HIF1α transcription and viral replication in macrophages. CONCLUSIONS: TIPE1 functions as a novel regulator for metabolic reprogramming and virus infection in macrophages.

Dynamic Hybrid Module-Driven NK Cell Stimulation and Release for Tumor Immunotherapy.

Natural killer (NK) cells have become a powerful candidate for adoptive tumor immunotherapy, while their therapeutic efficacy in solid tumors remains unsatisfactory. Here, we developed a hybrid module with an injectable hydrogel and hydroxyapatite (HAp) nanobelts for the controlled delivery of NK cells to enhance the therapy of solid tumors. Surface-functionalized HAp nanobelts modified with agonistic antibodies against NKG2D and 4-1BB and cytokines IL-2 and IL-21 support survival and dynamic activation. Thus, the HAp-modified chitosan (CS) thermos-sensitive hydrogel not only improved the retention of NK cells for more than 20 days in vivo but also increased NK cell function by more than one-fold. The unique architecture of this biomaterial complex protects NK cells from the hostile tumor environment and improves antitumor efficacy. The generation of a transient inflammatory niche for NK cells through a biocompatible hydrogel reservoir may be a conversion pathway to prevent cancer recurrence of resectable tumors.

The association of hypophysitis with immune checkpoint inhibitors use: Gaining insight through the FDA pharmacovigilance database.

The use of immune checkpoint inhibitor (ICI) marked a revolutionary change in cancer treatment and opened new avenues for cancer therapy, but ICI can also trigger immune-related adverse events (irAEs). Here, we investigated the publicly available US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to gain insight into the possible association between immune checkpoint inhibitors and hypophysitis. Data on adverse events (AEs) due to hypophysitisfor nivolumab, pembrolizumab, ipilimumab, and atezolizumab were collected from the US FDA Adverse Event Reporting System from the first quarter of 2004 to the second quarter of 2021, and the signals for hypophysitis associated with the four drugs were examined using the reporting odds ratio (ROR) method. The number of reported hypophysitis events ≥ 3 and the lower limit of the 95% confidence interval (CI) of the ROR > 1 were considered positive for hypophysitis signals. A total of 1252 AE reports of hypophysitis associated with nivolumab, pembrolizumab, ipilimumab, and atezolizumab were collected, including 419, 149, 643, and 41 cases, respectively. The RORs of hypophysitis were 289.58 (95% CI 258.49-324.40), 171.74 (95% CI 144.91-203.54), 2248.57 (95% CI 2025.31-2496.45), and 97.29 (95% CI 71.28-132.79), respectively. All four drugs were statistically correlated with the target AE, with the correlation being, in descending order, ipilimumab, nivolumab, pembrolizumab, and atezolizumab. Nivolumab, pembrolizumab, ipilimumab, and atezolizumab have all been associated with hypophysitis, which can negatively impact quality of life, and early recognition and management of immune checkpoint inhibitor-related hypophysitis is critical.

Improvement of surface stability of Zn anode by a cost-effective ErCl3 additive for realizing high-performance aqueous zinc-ion batteries.

Rechargeable aqueous-zinc ion batteries (AZIB) have notable benefits in terms of high safety and low cost. Nevertheless, the challenges, such as dendrite growth, zinc anode corrosion, and hydrogen evolution reaction, impede its practical implementation. Hence, this study proposes the introduction of an economical ErCl3 electrolyte additive to stabilize the Zn anode surface and address the aforementioned issues. The introduced Er3+ will cover the raised zinc dendrite surface and weaken the "tip effect" on the surface of the zinc anode via the "electrostatic shielding" effect. Simultaneously, the introduced Cl- can reduce the polarization of the zinc anode. Due to the synergistic effect of Er3+ and Cl-, the zinc anode corrosion, dendrite growth and hydrogen evolution have been efficiently inhibited. As a result, the Zn||Zn-symmetric battery using ErCl3 additive can stably cycle for 1100 h at 1 mA cm-2, 1 mAh cm-2, and exhibit a high average coulomb efficiency (99.2 %). Meanwhile, Zn||MnO2 full battery based on ErCl3-added electrolyte also demonstrates a high reversible capacity of 157.1 mAh/g after 500 cycles. Obviously, the capacity decay rate of the full battery is also improved, only 0.113 % per cycle. This study offers a straightforward and economically efficient method for stabilizing the zinc anode and realizing high-performance AZIBs.

Predicting coronary heart disease in Chinese diabetics using machine learning.

Diabetes, a common chronic disease worldwide, can induce vascular complications, such as coronary heart disease (CHD), which is also one of the main causes of human death. It is of great significance to study the factors of diabetic patients complicated with CHD for understanding the occurrence of diabetes/CHD comorbidity. In this study, by analyzing the risk of CHD in more than 300,000 diabetes patients in southwest China, an artificial intelligence (AI) model was proposed to predict the risk of diabetes/CHD comorbidity. Firstly, we statistically analyzed the distribution of four types of features (basic demographic information, laboratory indicators, medical examination, and questionnaire) in comorbidities, and evaluated the predictive performance of three traditional machine learning methods (eXtreme Gradient Boosting, Random Forest, and Logistic regression). In addition, we have identified nine important features, including age, WHtR, BMI, stroke, smoking, chronic lung disease, drinking and MSP. Finally, the model produced an area under the receiver operating characteristic curve (AUC) of 0.701 on the test samples. These findings can provide personalized guidance for early CHD warning for diabetic populations.

Prognostic and clinical value of circPRKCI expression in diverse human cancers.

BACKGROUND: Highly expressed in various human cancers, circular RNA Protein Kinase C Iota (circPRKCI) has been reported to play an important role in cancer development and progression. Herein, we sought to reveal the prognostic and clinical value of circPRKCI expression in diverse human cancers. METHODS: We searched the Pubmed, Web of Science, and the Cochrane Library databases from inception until May 16, 2021. The relationship between circPRKCI expression and cancer patients' survival, including overall survival (OS) and disease-free survival (DFS), was assessed by pooled hazard ratios (HR) with corresponding 95% confidence interval (CI). The correlation between circPRKCI expression and clinical outcomes was evaluated using odds ratios (OR) with corresponding 95% CI. The data were analyzed by STATA software (version 12.0) or Review Manager (RevMan 5.3). RESULTS: A total of 15 studies with 1109 patients were incorporated into our meta-analysis. The results demonstrated that high circPRKCI expression was significantly related to poor OS (HR = 1.96, 95% CI: 1.61, 2.39, P <0.001) when compared with low circPRKCI expression in diverse human cancers. However, elevated circPRKCI expression was not associated with DFS (HR = 1.34, 95% CI: 0.93, 1.95, P = 0.121). Furthermore, the patient with a higher circPRKCI expression was prone to have a larger tumor size, advanced clinical stage, and lymph node metastasis, but it was not significantly correlated with age, gender, and distant metastasis. CONCLUSION: Elevated circPRKCI expression was correlated with worse OS and unfavorable clinical features, suggesting a novel prognostic and predictive role of circPRKCI in diverse human cancers.

Boosting the Cycle Performance of Iron Trifluoride Based Solid State Batteries at Elevated Temperatures by Engineering the Cathode Solid Electrolyte Interface.

Iron trifluoride (FeF3) is attracting tremendous interest due to its lower cost and the possibility to enable higher energy density in lithium-ion batteries. However, its cycle performance deteriorates rapidly in less than 50 cycles at elevated temperatures due to cracking of the unstable cathode solid electrolyte interface (CEI) followed by active materials dissolution in liquid electrolyte. Herein, by engineering the salt composition, the Fe3O4-type CEI with the doping of boron (B) atoms in a polymer electrolyte at 60 °C is successfully stabilized. The cycle life of the well-designed FeF3-based composite cathode exceeds an unprecedented 1000 cycles and utilizes up to 70% of its theoretical capacities. Advanced electron microscopy combined with density functional theory (DFT) calculations reveal that the B in lithium salt migrates into the cathode and promotes the formation of an elastic and mechanic robust boron-contained CEI (BOR-CEI) during cycling, by which the durability of the CEI to frequent cyclic large volume changes is significantly enhanced. To this end, the notorious active materials dissolution is largely prohibited, resulting in a superior cycle life. The results suggest that engineering the CEI such as tuning its composition is a viable approach to achieving FeF3 cathode-based batteries with enhanced performance.

Comparison of anaesthesia-related outcomes in patients monitored by newly recruited nurse anaesthetists and anaesthesiologists: An observational study.

AIMS: To compare anaesthesia-related outcomes between patients monitored by newly recruited nurse anaesthetists and those monitored by newly recruited anaesthesiologists. DESIGN: This was a retrospective study. METHODS: We conducted a retrospective study that collected demographic information on newly recruited nurse anaesthetists and anaesthesiologists between 2017 and 2022 and recorded information on patients within 6 months of monitoring. Postoperative pain, emergency agitation, nausea, and vomiting were designated anaesthesia-related outcomes. Propensity score matching was used to adjust for covariates. The study adhered to the STROBE guidelines. RESULTS: The study's statistical analysis included 4483 patients monitored by 22 newly recruited nurse anaesthetists and 4959 patients monitored by 23 newly recruited anaesthesiologists. Compared with patients monitored by newly trained anaesthesiologists, the patients monitored by nurse anaesthetists were younger (42.07 ± 20.00 vs. 47.39 ± 18.45 years, p < 0.001) and had a lower body mass index (23.56 ± 4.46 vs. 24.19 ± 4.25, p < 0.001). Patients monitored by anaesthesiologists had a greater proportion of women (61.62% vs. 59.25%, p < 0.001), a high proportion of ASA III and ASA IV (17.1% vs. 8.88%, p < 0.001), and a longer mean surgery duration (78.65 ± 59.01 vs. 70.70 ± 60.65 min, p < 0.001). After propensity score matching was used to adjust for covariates, no statistically significant differences were found in the prevalence of postoperative pain, emergency agitation, or postoperative nausea and vomiting between the two groups (p < 0.05). CONCLUSION: Nurse anaesthetists monitoring alone during anaesthesia maintenance is feasible and safe. The two groups had no significant differences in the incidence of postoperative pain, emergency agitation, or postoperative nausea and vomiting. RELEVANCE TO CLINICAL PRACTICE: The shortage of anaesthesiologists leads to heavy work burden and high incidence of occupational burnout among anaesthesiologists. The study found that it was safe for nurse anaesthetists to perform anaesthetic monitoring alone in the operating room under the supervision of the attending anaesthesiologist and did reduce the burden of anaesthesiologists' work. The results of the current study contribute to the expansion of occupational categories for nurse anaesthetists in countries where anaesthesiologists are in short supply. It provides new ideas for hospital administrators and policy-makers to formulate medical and nursing service policies.

Effects of Wuzhi Capsule on Whole-Blood Tacrolimus Concentration Levels: A Systematic Review and Meta-Analysis.

BACKGROUND: Wuzhi Capsule (WZC) is a traditional Chinese medicinal herb widely used to treat drug-induced hepatitis or liver dysfunction and is usually prescribed in China to increase tacrolimus concentration. Several studies with small sample sizes have shown that WZC can increase tacrolimus concentration levels in clinical practice. This study aimed to evaluate the effect of WZC on whole-blood tacrolimus concentration levels and safety. METHODS: We searched 7 databases for randomized clinical trials (RCTs) and observational studies (OSs) comparing whole-blood tacrolimus concentration levels between WZC and non-WZC treatments. Data analysis was performed using Review Manager version 5.3. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. RESULTS: Eleven studies involving 6 RCTs and 5 OSs were included. The meta-analysis indicated that whole-blood tacrolimus concentration levels in the WZC group was significantly higher than that of the non-WZC group [weighted mean difference = 1.38, 95% CI (confidence interval), 1.21-1.56, P < 0.001], and similar results were shown in all the subgroups of follow-up time, different primary disease, and different WZC doses. In the self-control OSs, the whole-blood tacrolimus concentration levels in the WZC group was significantly higher than the non-WZC group (weighted mean difference = 1.17, 95% CI, 0.71-1.64, P < 0.001). WZC was generally well tolerated and there was no significant difference in the incidence of adverse reactions between the 2 groups. CONCLUSIONS: WZC can increase whole-blood tacrolimus concentration levels. This may be an economical and practical treatment choice for patients, especially those with poor oral tacrolimus absorption capabilities. Nevertheless, RCTs and OSs with large sample sizes and high quality are needed in the future to confirm these positive results.

Antibiotics and antibiotic-associated diarrhea: a real-world disproportionality study of the FDA adverse event reporting system from 2004 to 2022.

BACKGROUND: Our study aimed to assess the risk signals of antibiotic-associated diarrhea (AAD) caused by various antibiotics using real-world data and provide references for safe clinical applications. METHODS: We analyzed data extracted from the FDA Adverse Event Reporting System (FAERS) database, covering the period from the first quarter of 2004 to the third quarter of 2022. We computed the reporting odds ratio (ROR) for each antibiotic or antibiotic class to compare the signal difference. Furthermore, we also examined the differences in the onset times and outcomes of AAD caused by various antibiotics. RESULTS: A total of 5,397 reports met the inclusion requirements. Almost all antibiotics, except tobramycin and minocycline (ROR 0.98; 95%CI: 0.64-1.51 and 0.42; 95%CI: 0.16-1.11, respectively), showed a significant correlation with AAD. The analysis of the correlation between different classes of antibiotics and AAD revealed that lincomycins (ROR 29.19; 95%CI: 27.06-31.50), third-generation cephalosporins (ROR 15.96; 95%CI: 14.58-17.47), and first/second generation cephalosporins (ROR 15.29; 95%CI: 13.74-17.01) ranked the top three. The ROR values for antibiotics from the same class of antibiotics also varied greatly, with the ROR values for third-generation cephalosporins ranging from 9.97 to 58.59. There were also differences in ROR values between ß-lactamase inhibitors and their corresponding ß-lactamase drugs, such as amoxicillin-clavulanate (ROR = 13.31; 95%CI: 12.09-14.65) and amoxicillin (ROR = 6.50; 95%CI: 5.69-7.44). 91.35% of antibiotics have an onset time of less than four weeks. CONCLUSIONS: There is a significant correlation between almost all antibiotics and AAD, particularly lincomycins and ß-lactam antibiotics, as well as a different correlation within the same class. These findings offer valuable evidence for selecting antibiotics appropriately.

Lipid accumulation-mediated histone hypoacetylation drives persistent NK cell dysfunction in anti-tumor immunity.

Hyperlipidemia impairs anti-tumor immune responses and is closely associated with increased human cancer incidence and mortality. However, the underlying mechanisms are not well understood. In the present study, we show that natural killer (NK) cells isolated from high-fat-diet mice or treated with oleic acid (OA) in vitro exhibit sustainable functional defects even after removal from hyperlipidemic milieu. This is accompanied by reduced chromatin accessibility in the promoter region of NK cell effector molecules. Mechanistically, OA exposure blunts P300-mediated c-Myc acetylation and shortens its protein half-life in NK cells, which in turn reduces P300 accumulation and H3K27 acetylation and leads to persistent NK cell dysfunction. NK cells engineered with hyperacetylated c-Myc mutants surmount the suppressive effect of hyperlipidemia and display superior anti-tumor activity. Our findings reveal the persistent dysfunction of NK cells in dyslipidemia milieu and extend engineered NK cells as a promising strategy for tumor immunotherapy.

Analysis on the risk of myasthenia gravis related to immune checkpoint inhibitors based on the US FDA Adverse Event Reporting System.

OBJECTIVE: To evaluate the risk of myasthenia gravis (MG) associated with immune checkpoint inhibitors (ICI). METHODS: Adverse event (AE) reports related to MG, myasthenic syndrome, and MG crisis for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab in the US FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q3 2022 were collected. The proportional reporting odds ratio (PRR) method was used to evaluate the correlation between the six drugs and the three AEs. Statistical significance was defined as having reports ≥3, PRR ≥ 2, and chi-square (χ2 ) ≥ 4. RESULTS: A total of 36, 78, 276, 380, 5, and 53 AE reports were collected for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For myasthenic syndrome, the PRR values reflecting the correlation with the drugs were 27.83 (χ2 = 102.66), 26.20 (χ2 = 235.67), 44.17 (χ2 = 1313.98), 32.09 (χ2 = 1229.54), 21.31 (χ2 = 151.15), and 0 for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG, the PRR values reflecting the correlation with the drugs were 24.21 (χ2 = 682.04), 18.34 (χ2 = 900.27), 39.32 (χ2 = 7945.15), 26.93 (χ2 = 6636.45), 14.73 (χ2 = 566.47), and 15.69 (χ2 = 54.77) for durvalumab, atezolizumab, pembrolizumab, nivolumab, avelumab, and ipilimumab, respectively. For MG crisis, there were no data for durvalumab, atezolizumab, avelumab, and ipilimumab; the PRR values reflecting the correlation with the drugs were 16.54 (χ2 = 225.23) and 9.20 (χ2 = 119.14) for pembrolizumab and nivolumab, respectively. All six drugs were statistically correlated with their corresponding AEs. CONCLUSIONS: ICI may lead to ICIs-associated MG during therapy. Analysis of FAERS data identified signals for AEs of MG with ICI regimens. Practitioners should consider the factors that may increase the likelihood of MG. The findings support a continued surveillance and risk factor identification.

Identification of candidate genes and chemicals associated with osteoarthritis by transcriptome-wide association study and chemical-gene interaction analysis.

BACKGROUND: Osteoarthritis (OA) is a common degenerative joint disease and causes chronic pain and disability to the elderly. Several risk factors are involved, such as aging, obesity, genetic susceptibility, and environmental factors. We conducted a transcriptome-wide association study (TWAS) and chemical-related gene set enrichment analysis (CGSEA) to investigate the susceptibility genes and environmental factors. METHODS: TWAS analysis was conducted to identify the susceptibility genes by integrating the summary-level genome-wide association study data of knee OA (KOA) and hip OA (HOA) with the precomputed expression weights from the Genotype-Tissue Expression Project (Version 8). The FUSION software was used for both single-tissue and cross-tissue TWAS, which were combined using an aggregate Cauchy association test. The biological function and pathways of the TWAS genes were explored using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases, and the human cartilage mRNA expression profiles were utilized to validate the TWAS genes. CGSEA analysis was performed to scan the OA-associated chemicals by integrating the TWAS results with the chemical-related gene sets. RESULTS: There were 44 and 93 unique TWAS genes identified in 7 and 11 chromosomes for KOA and HOA, respectively, fourteen and four of which showed significantly differential expression in the mRNA profiles, such as CRHR1, LTBP1, WWP2, LMX1B, and PTHLH. OA-related pathways were found in the KEGG and GO analysis, such as TGF-beta signaling pathway, MAPK signaling pathway, hyaluronan metabolic process, and chondrocyte differentiation. Forty-five OA-associated chemicals were identified, including quercetin, bisphenol A, and cadmium chloride. CONCLUSIONS: Several candidate OA-associated genes and chemicals were identified through TWAS and CGSEA analysis, which expanded our understanding of the relationship between genes, chemicals, and their impact on OA.

A gender specific risk assessment of coronary heart disease based on physical examination data.

Large-scale screening for the risk of coronary heart disease (CHD) is crucial for its prevention and management. Physical examination data has the advantages of wide coverage, large capacity, and easy collection. Therefore, here we report a gender-specific cascading system for risk assessment of CHD based on physical examination data. The dataset consists of 39,538 CHD patients and 640,465 healthy individuals from the Luzhou Health Commission in Sichuan, China. Fifty physical examination characteristics were considered, and after feature screening, ten risk factors were identified. To facilitate large-scale CHD risk screening, a CHD risk model was developed using a fully connected network (FCN). For males, the model achieves AUCs of 0.8671 and 0.8659, respectively on the independent test set and the external validation set. For females, the AUCs of the model are 0.8991 and 0.9006, respectively on the independent test set and the external validation set. Furthermore, to enhance the convenience and flexibility of the model in clinical and real-life scenarios, we established a CHD risk scorecard base on logistic regression (LR). The results show that, for both males and females, the AUCs of the scorecard on the independent test set and the external verification set are only slightly lower (<0.05) than those of the corresponding prediction model, indicating that the scorecard construction does not result in a significant loss of information. To promote CHD personal lifestyle management, an online CHD risk assessment system has been established, which can be freely accessed at http://lin-group.cn/server/CHD/index.html .

Amino acids 1811-1960 of myosin heavy chain 9 is involved in murine gammaherpesvirus 68 infection.

Myosin heavy chain 9 (MYH9) has been identified as a crucial factor in gammaherpesvirus infection. Murine gammaherpesvirus 68 (MHV-68) was used as an appropriate viral model for investigating gammaherpesviruses in vivo and developing antiviral treatments. However, the roles of MYH9 in MHV-68 infection have not been documented. In the study, the relationship between the expression of MYH9 and MHV-68 infection and MYH9 as the antiviral target were analyzed. The results revealed that MYH9 was enriched on the cell surface and co-localized with MHV-68 upon viral infection. Knocking down MYH9 with siRNA or using the specific inhibitor of MYH9 activity, Blebbistatin, resulted in the decreasing of MHV-68 infection. Furthermore, polyclonal antibodies against MYH9 reduced infection by approximately 74% at a dose of 100 µg/ml. The study determined that MYH9 contributes to MHV-68 infection by interacting with viral glycoprotein 150 (gp150) in the BHK-21 cell membrane. The specific region of MYH9, amino acids 1811-1960 (C-150), was identified as the key domain involved in the interaction with MHV-68 gp150 and was found to inhibit MHV-68 infection. Moreover, C-150 was also shown to decrease HSV-1 infection in Vero cells by approximately 73%. Both C-150 and Blebbistatin were found to inhibit MHV-68 replication and reduce histopathological lesions in vivo in C57BL/6J mice. Taken together, these findings suggested that MYH9 is crucial for MHV-68 infection through its interaction with viral gp150 and that C-150 may be a promising antiviral target for inhibiting MHV-68 infection in vitro and in vivo.