Causal relationship between serum metabolites and juvenile idiopathic arthritis: a mendelian randomization study.

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is a condition that occurs when individuals under the age of 16 develop arthritis that lasts for more than six weeks, and the cause is unknown. The development of JIA may be linked to serum metabolites. Nevertheless, the association between JIA pathogenesis and serum metabolites is unclear, and there are discrepancies in the findings across studies. METHODS: In this research, the association between JIA in humans and 486 serum metabolites was assessed using genetic variation data and genome-wide association study. The identification of causal relationships was accomplished through the application of univariate Mendelian randomization (MR) analysis. Various statistical methods, including inverse variance weighted and MR-Egger, were applied to achieve this objective. To ensure that the findings from the MR analysis were trustworthy, a number of assessments were carried out. To ensure the accuracy of the obtained results, a range of techniques were utilised including the Cochran Q test, examination of the MR-Egger intercept, implementation of the leave-one-out strategy, and regression analysis of linkage disequilibrium scores. In order to identify the specific metabolic pathways associated with JIA, our primary objective was to perform pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes. RESULTS: Two-sample summary data MR analyses and sensitivity analyses showed that five metabolites were significantly causally associated with JIA, including two risk factors-kynurenine (odds ratio [OR]: 16.39, 95% confidence interval [CI]: 2.07-129.63, p = 5.11 × 10- 6) and linolenate (OR: 16.48, 95% CI: 1.32-206.22, p = 0.030)-and three protective factors-3-dehydrocarnitine (OR: 0.32, 95% CI: 0.14-0.72, p = 0.007), levulinate (4-oxovalerate) (OR: 0.40, 95% CI: 0.20-0.80, p = 0.010), and X-14,208 (phenylalanylserine) (OR: 0.68, 95% CI: 0.51-0.92, p = 0.010). Furthermore, seven metabolic pathways, including α-linolenic acid metabolism and pantothenate and CoA biosynthesis, are potentially associated with the onset and progression of JIA. CONCLUSION: Five serum metabolites, including kynurenine and 3-dehydrocarnitine, may be causally associated with JIA. These results provide a theoretical framework for developing effective JIA prevention and screening strategies.

HCA-DAN: hierarchical class-aware domain adaptive network for gastric tumor segmentation in 3D CT images.

BACKGROUND: Accurate segmentation of gastric tumors from CT scans provides useful image information for guiding the diagnosis and treatment of gastric cancer. However, automated gastric tumor segmentation from 3D CT images faces several challenges. The large variation of anisotropic spatial resolution limits the ability of 3D convolutional neural networks (CNNs) to learn features from different views. The background texture of gastric tumor is complex, and its size, shape and intensity distribution are highly variable, which makes it more difficult for deep learning methods to capture the boundary. In particular, while multi-center datasets increase sample size and representation ability, they suffer from inter-center heterogeneity. METHODS: In this study, we propose a new cross-center 3D tumor segmentation method named Hierarchical Class-Aware Domain Adaptive Network (HCA-DAN), which includes a new 3D neural network that efficiently bridges an Anisotropic neural network and a Transformer (AsTr) for extracting multi-scale context features from the CT images with anisotropic resolution, and a hierarchical class-aware domain alignment (HCADA) module for adaptively aligning multi-scale context features across two domains by integrating a class attention map with class-specific information. We evaluate the proposed method on an in-house CT image dataset collected from four medical centers and validate its segmentation performance in both in-center and cross-center test scenarios. RESULTS: Our baseline segmentation network (i.e., AsTr) achieves best results compared to other 3D segmentation models, with a mean dice similarity coefficient (DSC) of 59.26%, 55.97%, 48.83% and 67.28% in four in-center test tasks, and with a DSC of 56.42%, 55.94%, 46.54% and 60.62% in four cross-center test tasks. In addition, the proposed cross-center segmentation network (i.e., HCA-DAN) obtains excellent results compared to other unsupervised domain adaptation methods, with a DSC of 58.36%, 56.72%, 49.25%, and 62.20% in four cross-center test tasks. CONCLUSIONS: Comprehensive experimental results demonstrate that the proposed method outperforms compared methods on this multi-center database and is promising for routine clinical workflows.

Clinical Significance of a Novel Vasculogenic Mimicry-Based Prognostic Model in Hepatocellular Carcinoma.

BACKGROUND: Vasculogenic mimicry, a novel neovascularization pattern of aggressive tumors, is associated with poor clinical outcomes. OBJECTIVE: The aim of this research was to establish a new model, termed VC score, to predict the prognosis, Tumor Microenvironment (TME) components, and immunotherapeutic response in Hepatocellular Carcinoma (HCC). METHODS: The expression data of the public databases were used to develop the prognostic model. Consensus clustering was performed to confirm the molecular subtypes with ideal clustering efficacy. The high- and low-risk groups were stratified utilizing the VC score. Various methodologies, including survival analysis, single-sample Gene Set Enrichment Analysis (ssGSEA), Tumor Immune Dysfunction and Exclusion scores (TIDE), Immunophenoscore (IPS), and nomogram, were utilized for verification of the model performance and to characterize the immune status of HCC tissues. GSEA was performed to mine functional pathway information. RESULTS: The survival and immune characteristics varied between the three molecular subtypes. A five-gene signature (TPX2, CDC20, CFHR4, SPP1, and NQO1) was verified to function as an independent predictive factor for the prognosis of patients with HCC. The high-risk group exhibited lower Overall Survival (OS) rates and higher mortality rates in comparison to the low-risk group. Patients in the low-risk group were predicted to benefit from immune checkpoint inhibitor therapy and exhibit increased sensitivity to immunotherapy. Enrichment analysis revealed that signaling pathways linked to the cell cycle and DNA replication processes exhibited enrichment in the high-risk group. CONCLUSIONS: The VC score holds the potential to establish individualized treatment plans and clinical management strategies for patients with HCC.

Does erectile dysfunction predict cardiovascular risk? A cross-sectional study of clinical characteristics in patients with erectile dysfunction combined with coronary heart disease.

Background: Erectile Dysfunction (ED) is a common sexual dysfunction in men who are unable to consistently obtain and maintain sufficient penile erection to accomplish a satisfactory sexual life. ED is currently considered to be a predictor of cardiovascular disease (CVD), but few studies have observed the association between ED and clinical features of coronary heart disease (CHD). An investigation of the association between ED and clinical characteristics of CHD was carried out using a cross-sectional study design. Methods: This cross-sectional single-center study was conducted in the Department of Cardiology and included 248 patients. Associations between patients' general information, underlying disease information, coronary heart disease information, and ED severity were statistically and analytically analyzed using SPSS 26.0 software. Patients with comparable clinical characteristics were grouped together using K-means clustering. Finally, ordered logistic regression analysis was performed for general and underlying disease information. Results: In the comparison of general data, age, education, and weekly exercise were associated with the distribution of ED severity. In the comparison of underlying disease information, the number of underlying diseases, hypertension, diabetes, hyperlipidemia, anxiety state, and depressive state were associated with the distribution of ED severity. In the comparison of CHD information, the degree of ED severity was associated with CHD subtypes, lesion sites, number of stenoses, degree of stenosis, and interventional interventions. The time from ED to CHD onset was associated with the subtypes of CHD and the number of stenoses. We clustered the main characteristics of low-risk and high-risk patients and ordered logistic regression analysis found that BMI, smoking, alcoholism, number of underlying diseases, diabetes, anxiety state, and depression state were all risk factors for CHD severity (P < 0.05); the higher the value of the above factors, the more severe the degree of CHD. Age was a protective factor for CHD severity; the younger the patient, the lower the likelihood of myocardial infarction. Conclusion: ED severity and the time from ED to CHD onset may be predictive of coronary heart disease severity. Reducing smoking and alcohol consumption, maintaining a healthy body weight, and regular physical activity are important in preventing CVD in ED patients.

Effect of Listening Channels for Sport-Event Theme Songs on Willingness to Share.

Purpose: The sport-event theme songs is a crucial means to evoke consumer enthusiasm and boost the influence of sport event. This research aims to examine the effects of direct and indirect listening channels for sport-event theme songs on consumers' willingness to share. Methods: In this research, three between-subjects experiments were conducted to measure the effect of listening channels for sport-event theme songs on the willingness to share, along with the moderating effects of fans' fanaticism and sport-event type. All participants in the experiments were social populations from China. Results: Study 1 reveals that direct listening is more likely to cause consumers to share cognitive information about sport-event theme songs; indirect listening, meanwhile, makes them more willing to share the emotional value of the songs. Study 2 indicates that fans' fanaticism moderates the relationship between listening type and shared content. In the case of low fanaticism, indirect listening can increase consumers' willingness to share sport-event theme songs compared with direct listening. Study 3 reveals that sport-event type moderates the relationship between listening type and shared content. For public welfare sport events, indirect listening is more likely than direct listening to cause consumers to share the emotional value of sport-event theme songs. For commercial events, compared with indirect listening, direct listening is more likely to cause consumers to share cognitive information about sport-event theme songs. Conclusion: The results of this research unveiled the effect of listening channels for sport-event theme songs on the willingness to share, as well as the theoretical mechanisms behind them. In addition, this research enriches the research on listening channels in the field of psychology and provides an important basis for improving the effectiveness of sport-event theme songs.

[Comparative study of minimally invasive titanium elastic nail and steel plate on the treatment of fracture of tibiofibular fracture in adults].

OBJECTIVE: To compare the clinical outcomes of using elastic intramedullary nail and plate to fix fibular fracture. METHODS: The 60 patients with tibiofibular fractures admitted from January 2015 to December 2022 were divided into two groups:intramedullary nail group and plate group, 30 cases each, intramedullary nail group was treated with elastic intramedullary nail fixation group, plate group was treated with steel plate and screw fixation group. Intramedullary nail group, there were 18 males and 12 females, aged from 22 to 75 years old with an average of (39.4±9.8) years old, including 24 cases of traffic accidents injury, 6 cases of falling injury, 23 cases of closed fractures, 7 cases of open fractures. Steel plate group, there were 15 males and 15 females, aged from 24 to 78 years old with an average of (38.6±10.2) years old. The 22 cases were injured by traffic accident, 8 cases were injured by falling. The 24 cases were closed fractures and 6 cases were open fractures. The operation time, intraoperative bleeding, American Orthopedic Foot and Ankle Society (AOFAS) ankle and hind foot scores, clinical healing time of fibula and the incidence of wound complications were compared between the two groups. RESULTS: The patients in both groups were followed up for 6 to 21 months, with an average of (14.0±2.8) months. Compared with plate group, intramedullary nail group had shorter operative time, less bleeding, shorter clinical healing time of fibula, and lower infection rate of incision, and the difference was statistically significant (P<0.05). There were 2 cases of delayed healing in intramedullary nail group, 1 case of nonunion in plate group, and 2 cases of delayed healing in plate group, and there was no statistically significant difference between the two groups (P>0.05). In the last follow-up, according to the AOFAS scoring standard, the ankle function in intramedullary nail group was excellent in 17 cases, good in 12 cases, fair in 1 case, with an average of (88.33±4.57) points, while in plate group, excellent in 16 cases, good in 10 cases, fair in 4 cases, with an average of (87.00±4.14) points;There was no statistical difference between the two groups (P>0.05). CONCLUSION: Elastic intramedullary nail has the advantages of short operation time, less intraoperative bleeding, short fracture healing time and less incision complications in the treatment of fibular fracture, which is worthy of clinical application.

The dynamic features and microbial mechanism of nitrogen transformation for hydrothermal aqueous phase as fertilizer in dryland soil.

Hydrothermal aqueous phase (HAP) contains abundant organics and nutrients, which have potential to partially replace chemical fertilizers for enhancing plant growth and soil quality. However, the underlying reasons for low available nitrogen (N) and high N loss in dryland soil remain unclear. A cultivation experiment was conducted using HAP or urea to supply 160 mg N kg-1 in dryland soil. The dynamic changes of soil organic matters (SOMs), pH, N forms, and N cycling genes were investigated. Results showed that SOMs from HAP stimulated urease activity and ureC, which enhanced ammonification in turn. The high-molecular-weight SOMs relatively increased during 5-30 d and then biodegraded during 30-90 d, which SUV254 changed from 0.51 to 1.47 to 0.29 L-1 m-1. This affected ureC that changed from 5.58 to 5.34 to 5.75 lg copies g-1. Relative to urea, addition HAP enhanced ON mineralization by 8.40 times during 30-90 d due to higher ureC. It decreased NO3-N by 65.35%-77.32% but increased AOB and AOA by 0.25 and 0.90 lg copies g-1 at 5 d and 90 d, respectively. It little affected nirK and increased nosZ by 0.41 lg copies g-1 at 90 d. It increased N loss by 4.59 times. The soil pH for HAP was higher than that for urea after 11 d. The comprehensive effects of high SOMs and pH, including ammonification enhancement and nitrification activity inhibition, were the primary causes of high N loss. The core idea for developing high-efficiency HAP fertilizer is to moderately inhibit ammonification and promote nitrification.

Robotic-assisted total knee arthroplasty results in decreased incidence of anterior femoral notching compared to posterior referenced instrumented total knee arthroplasty.

OBJECTIVE: Periprosthetic fracture (PPF) is an uncommon but devastating complication after total knee arthroplasty (TKA). Anterior femoral notching (AFN) is one of a perioperative risk factor for PPF. The main purpose of this study was to compare between the rates of anterior femoral notching (AFN) and supracondylar periprosthetic femoral fracture (sPPF) of manual TKA and robotic arm-assisted TKA (RATKA). Meanwhile, blood loss, transfusion rates, inflammatory responses, complications, early clinical and radiological outcomes were also assessed. METHODS: This retrospective study included 330 patients (133 RATKA and 197 manual TKA). Differences in risks of inflammatory, blood loss, complications (periprosthetic fracture and periprosthetic joint infection), pre-operative and post-operative distal lateral femoral angle (LDFA), distal femoral width (DFW), prosthesis-distal femoral width (PDFW) ratio, AFN, femoral component flexion angle (FCFA), peri-operative and post-operative functional outcomes between the RATKA and manual TKA groups were compared. RESULTS: The operation time and postoperative CRP level in the RATKA group was significantly longer and higher than that in the manual TKA group (p < .001). However, there was no significant difference in postoperative WBC level (p = .217), hemoglobin loss (p = .362), postoperative drainage (p = .836), and periprosthetic fracture (p = 1.000). There was no significant difference in LDFA (p > .05), DFW(p = .834), PDFW ratio (p = .089) and FCFA (p = .315) between the two groups, but the rate of AFN in the RATKA group was significantly lower than that in the manual TKA group (p < .05). There was no significant difference in ROM between the two groups on POD3, POD 90 and 1 year (p < .05), but the FJS-12 score in the RATKA group was higher than that in the manual TKA group on 1 year (p = .001). CONCLUSION: Robotic-assisted total knee arthroplasty can decrease the incidence of anterior femoral notching compared to posterior referenced instrumented total knee arthroplasty.

Role of IFITM2 in osteogenic differentiation of C3H10T1/2 mesenchymal stem cells.

Interferon-inducible transmembrane (IFITM) are a family of small proteins localized to plasma and endolysosomal membranes. Their functions beyond restricting viral entry and replication have been revealed in recent years. IFITM5 is involved in bone mineralization and is an osteogenic cell surface marker. IFITM1 and 3 interact with desmin and myosin, and are involved in myogenic differentiation. This study found upregulation of Ifitm2 during osteogenic differentiation of C3H10T1/2 cells. This positively correlated to the expression of osteogenic differentiation markers Col1a1, Alp, Runx2, and Ocn. Knockdown of Ifitm2 by siRNAs inhibited osteogenic differentiation, calcium deposition, and osteogenic marker expression of C3H10T1/2 cells. The osteoblast transcriptome revealed that knocking down Ifitm2 affected the expression Wnt signaling pathway-related genes, including Wnt family members, their receptors Lrp, Frizzled, and Lgr, and transmembrane molecule Rnf43 that suppresses the Wnt signaling pathway. Luciferase assays indicated enhancement of canonical Wnt signaling pathways by Ifitm2 overexpression. Furthermore, IFITM2 was colocalized in the metaphyseal bone and growth plate of the mouse tibial bone with SP7, a transcription factor essential for osteoblast differentiation and bone formation. These findings reveal a possible novel function and potential mechanisms of Ifitm2 in osteogenic differentiation.

The diagnosis and treatment of septic hip with osteonecrosis of the femoral head.

This article aims to provide clinical doctors with references for the diagnosis and treatment of osteonecrosis of the femoral head (ONFH) accompanied with septic hip by summarizing and analyzing clinical data and postoperative follow-up information of patients treated with two-stage arthroplasty. We retrospectively analyzed ten patients who underwent two-stage arthroplasty in our hospital due to ONFH accompanied with septic hip. The diagnosis of septic hip includes erythrocyte sedimentation rate (ESR) > 30 mm/h, C-reactive protein (CRP) > 10 mg/L, pus-like synovial fluid, positive microbiological culture, and the findings of septic arthritis on magnetic resonance imaging (MRI) scan. Patient's information was evaluated based on the review of medical records, including gender, age, symptoms, risk factor of ONFH and septic arthritis, blood test, radiograph, MRI scan, microbiological culture, treatment, follow-up period and outcome. A total of ten patients were diagnosed with ONFH accompanied with septic hip. The average follow-up period was 43.5 months. None of the patients experienced failure during the follow-up period. The risk factor of ONFH was alcohol-related (60%), steroid-related (20%) and idiopathic (20%). Nine patients (90%) have no risk factor of septic arthritis and one patient (10%) has nephrotic syndrome. All patients did not experience any fever symptoms before surgery, but all showed worsening symptoms of pain. There were three patients (30%) with abnormal WBC count > 10 × 109/L. All patients had elevated ESR and/or CPR. Nine patients (90%) had positive MRI findings, and seven patients (70%) had positive microbiological culture. When patients with ONFH experience worsening hip joint pain accompanied by unexplained elevated CRP and/or ESR, it should be suspected whether ONFH is accompanied with septic hip. In these cases, MRI scans should be performed to exclude septic hip. Patients with ONFH accompanied with septic hip showed satisfactory results after two-stage arthroplasty.

Prognostic and immune predictive roles of a novel tricarboxylic acid cycle-based model in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. Since the tricarboxylic acid cycle is widely involved in tumor metabolic reprogramming and cuproptosis, investigating related genes may help to identify prognostic signature of patients with HCC. Data on patients with HCC were sourced from public datasets, and were divided into train, test, and single-cell cohorts. A variety of machine learning algorithms were used to identify different molecular subtypes and determine the prognostic risk model. Our findings revealed that the risk score (TRscore), based on the genes OGDHL, CFHR4, and SPP1, showed excellent predictive performance in different datasets. Pathways related to cell cycle and immune inflammation were enriched in the high-risk group, whereas metabolism-related pathways were significantly enriched in the low-risk group. The high-risk group was associated with a greater number of mutations of detrimental biological behavior and higher levels of immune infiltration, immune checkpoint expression, and anti-cancer immunotherapy response. Low-risk patients demonstrated greater sensitivity to erlotinib and phenformin. SPP1 was mainly involved in the interaction among tumor-associated macrophages, T cells, and malignant cells via SPP1-CD44 and SPP1-(ITGA5 + ITGB1) ligand-receptor pairs. In summary, our study established a prognostic model, which may contribute to individualized treatment and clinical management of patients with HCC.

Metformin Increases the Response of Cholangiocarcinoma Cells to Gemcitabine by Suppressing Pyruvate Kinase M2 to Activate Mitochondrial Apoptosis.

BACKGROUND: Cholangiocarcinoma (CCA) is a malignant tumor with a high mortality rate. Resistance to chemotherapy remains a major challenge related to cancer treatment, and increasing the sensitivity of cancer cells to therapeutic drugs is a major focus of cancer treatment. AIMS: We purposed to explore the role of Metformin in CCA involved in chemotherapeutic sensitivity and Pyruvate kinase M2 (PKM2) through regulating mitochondrial apoptosis in the present study. METHODS: CCA cell lines of HCC9810 and RBE were treated with Metformin companied with antagonists or agonists of PKM2, cells sensitivity to Gemcitabine, cell migration and invasion along with apoptosis, which is mediated by JC-1 and LDH were assayed. RESULTS: Our results indicated that Metformin and Gemcitabine exhibit synergistic effect on inhibition of cholangiocarcinoma cell viability, cell migration and invasion as well as promotion apoptosis of cholangiocarcinoma cells. In vivo, Metformin combined with Gemcitabine has cooperation in inhibiting the growth of cholangiocarcinoma cell-derived tumors. Moreover, Metformin and Gemcitabine inhibited expression of PKM2 and PDHB in HCC9810 and RBE. CONCLUSION: Our study suggested that Metformin may increase the response of cholangiocarcinoma cells to Gemcitabine by suppressing PKM2 to activate mitochondrial apoptosis.

USBDAN: Unsupervised Scale-aware and Boundary-aware Domain Adaptive Network for Gastric Tumor Segmentation.

Accurate segmentation of gastric tumors from computed tomography (CT) images provides useful image information for guiding the diagnosis and treatment of gastric cancer. Researchers typically collect datasets from multiple medical centers to increase sample size and representation, but this raises the issue of data heterogeneity. To this end, we propose a new cross-center 3D tumor segmentation method named unsupervised scale-aware and boundary-aware domain adaptive network (USBDAN), which includes a new 3D neural network that efficiently bridges an Anisotropic neural network and a Transformer (AsTr) for extracting multi-scale features from the CT images with anisotropic resolution, and a scale-aware and boundary-aware domain alignment (SaBaDA) module for adaptively aligning multi-scale features between two domains and enhancing tumor boundary drawing based on location-related information drawn from each sample across all domains. We evaluate the proposed method on an in-house CT image dataset collected from four medical centers. Our results demonstrate that the proposed method outperforms several state-of-the-art methods.

Switch of orbital angular momentum flux density of partially coherent vortex beams.

We investigate the orbital angular momentum (OAM) flux density of beams which are the incoherent superposition of partially coherent vortex (PCV) beams with different topological charges and beam widths. Simulation results show that such beams can exhibit counter-rotating radial regions of the OAM flux density, and that we can "switch" the order of these regions by adjusting the topological charges and beam widths in the source plane. Furthermore, these counter-rotating regions can switch on propagation in free space without any change to the beam parameters. We discuss how these unusual OAM dynamics may find use in OAM-based applications.

Circ_KIAA0922 regulates Saos-2 cell proliferation and osteogenic differentiation by regulating the miR-148a-3p/SMAD5 axis and activating the TGF-ß signaling pathway.

Circular RNAs (circRNAs) are emerging as important regulators in human disease, but their function in osteoporosis (OP) is not sufficiently known. The aim of this study was to identify the possible molecular mechanism of circ_KIAA0922 in osteogenic differentiation of Saos-2 cells in vitro and the interactions among circ_KIAA0922, miR-148a-3p, and SMAD family member 5 (SMAD5). Circ_ KIAA0922, miR-148a-3p, and SMAD5 were overexpressed by transient transfection. Dual-luciferase reporter assay system was used to analyze the combination among circ_KIAA0922, miR-148a-3p, and SMAD5. In addition, the levels of circ_KIAA0922, miR-148a-3p, SMAD5, osteocalcin (OCN), and runt-related transcription factor 2 (RUNX2) were detected using RT-qPCR or western blot analysis. Alizarin red staining was performed to analyze the degree of osteogenic differentiation under the control of circ_KIAA0922, miR-148a-3p, and SMAD5. We found that circ_KIAA0922 knockdown inhibited the proliferation and osteogenic differentiation of Saos-2 cells. Circ_KIAA0922 directly targeted miR-148a-3p, and miR-148a-3p inhibition reversed the effects of circ_KIAA0922 knockdown on the proliferation and osteogenic differentiation of Saos-2 cells. Overexpression of SMAD5 promoted the proliferation and osteogenic differentiation of Saos-2 cells and attenuated the inhibitory effect of miR-148a-3p on cell proliferation and osteogenic differentiation. In conclusion, circ_ KIAA0922 facilitated Saos-2 cell proliferation and osteogenic differentiation via the circ_KIAA0922/ miR-148a-3p/ SMAD5 axes in vitro, thus providing insights into the mechanism of osteogenic differentiation by circ_ KIAA0922.

DNA damage repair molecular subtype derived immune signature applicable for the prognosis and immunotherapy response prediction in colon cancer.

Background: The DNA damage repair (DDR) pathway is one of the pathways of tumor pathogenesis, but its relationship with the immunophenotype has not been clarified in colon cancer (CC). Methods: We identified the differentially expressed immune-related genes (DEIRGs) between two DDR molecular subtypes, namely, C1 and C2, and used univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) penalized Cox regression analysis to construct the risk score in the training cohort [n=1,009, a combination of The Cancer Genome Atlas (TCGA) and GSE39582]. Regarding the median risk score as the unified cutoff to classify the patients into high- and low-risk groups. Two independent cohorts (GSE17538, n=232; GSE38832, n=122) were used for external validation of the prognostic value of the risk score. The IMvigor210 cohort (n=348) was used to test the predictive value of the risk score for immunotherapy response. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were performed to discover the underlying mechanism. Immune cell infiltration was quantified by the single sample gene set enrichment analysis (ssGSEA) algorithm. Results: The high-risk group showed significantly reduced overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), progression-free survival (PFS), and relapse-free survival (RFS) compared to the low-risk group, and the two groups differed significantly in lymphatic invasion, American Joint Committee on Cancer (AJCC) TNM stage, preoperative carcinoembryonic antigen (CEA) level, etc. The enrichment levels of pathways related to colorectal cancer, epithelial-mesenchymal transition (EMT), angiogenesis, hypoxia, P53, TGF-ß, KRAS signaling, etc., were upregulated in the high-risk group, but DDR-related pathways were defective in the high-risk group. The immunophenotypes of the high-risk group tended to be desert and excluded, and the risk score of patients who responded to immunotherapy was significantly lower than that of patients who did not respond to immunotherapy. The higher the infiltration levels of gamma delta T cells (γδ T cells), immature dendritic cells, and T follicular helper (Tfh) cells, the more significant adverse impact on the prognosis of CC patients was exhibited and an obviously positive correlation with the risk score was showed. Conclusions: An immune gene risk score associated with the DDR molecular subtype was built and verified herein; that is applicable to the prognosis and immunotherapy response prediction in CC.

Weizmannia coagulans Extracellular Proteins Reduce Skin Acne by Inhibiting Pathogenic Bacteria and Regulating TLR2/TRAF6-Mediated NF-κB and MAPKs Signaling Pathways.

As a probiotic, Weizmannia coagulans (W. coagulans) is often used in food and medicine to regulate intestinal flora and exert anti-inflammatory effects. In this study, the anti-acne efficacy and mechanism of extracellular proteins (YTCY-EPs) from W. coagulans YTCY strain are analyzed. The main components of YTCY-EPs, extracted and separated from the fermentation broth, are peptides ranging from 1.51 to 11.44 kDa, accounting for about 80%. Among the peptides identified by LC/MS-MS, YTCY_A-F possess the properties of antimicrobial peptides, while YTCY_1-4 possess antioxidative properties. These peptides have a strong effect on Cutibacterium acnes (C. acnes) and significantly inhibit Staphylococcus aureus. The inhibition rate of biofilm adhesion of YT-EPs to C. acnes reached 50% under the MIC. It was found that YTCY-EPs possess strong antioxidant and anti-inflammatory properties. It can effectively reduce active oxygen nearly 3 times and can reduce the downstream TLR2/NF-κB and MAPKs/AP-1 pathways by regulating the nuclear translocation of NF-κB and AP-1 in vitro. The transcriptional expression of inflammatory cytokines, inflammatory chemokines, and matrix metalloproteinase genes is also regulated, thereby slowing the recruitment of inflammatory cells and the development of inflammation, and increasing keratinocyte mobility. In addition, the expression levels of inflammatory factors and matrix metalloproteinases in the rabbit ears with acne problems that were tested with YTCY-EPs were significantly reduced, and it was obviously observed that the rabbit ear inflammation, acne, and keratinization problems were repaired. The results of this study prove that YTCY-EPs can be used as a potential anti-acne raw material in cosmetics.

The novel role of IFITM1-3 in myogenic differentiation of C2C12 cells.

Interferon-induced transmembrane proteins (IFITMs 1, 2, and 3) play a critical role in preventing pathogen infection in vertebrates. They are also involved in the occurrence and prognosis of cancer. Myogenesis is a complex process regulated by several factors. This study disclosed that Ifitm1-3 were upregulated in the process of myogenic differentiation of C2C12 myoblasts on days 3, 5, and 7. This positively correlated with the expression of differentiation factors MyoD, myogenin, Mrf5, and desmin. Furthermore, knockdown of Ifitm1-3 by their individual siRNAs inhibited myogenesis of C2C12 myoblasts, with relative downregulation of MyoD, myogenin, Mrf5, and desmin. Subsequently, myotube formation and fusion percentage decreased. Co-immunoprecipitation combined with LC-MS/MS analysis uncovered the interaction proteins of IFITM1 and IFITM3 in C2C12 myoblasts. A total of 84 overlapped interaction proteins of IFITM1 and IFITM3 were identified, and one of the clusters was engaged in cytoskeletal and sarcomere proteins, including desmin, myosin, actin, vimentin, nestin, ankycorbin, and nucleolin. Hence, we hypothesize that these interacting proteins may function as scaffolds for IFITM1-3, possibly through the interaction protein desmin to initiate further interaction with other proteins to participate in myogenesis; however, the molecular mechanisms remain unclear. Our study may contribute to the development of novel therapeutics for myopathic diseases.

A general urban spreading pattern of COVID-19 and its underlying mechanism.

Currently, the global situation of COVID-19 is aggravating, pressingly calling for efficient control and prevention measures. Understanding the spreading pattern of COVID-19 has been widely recognized as a vital step for implementing non-pharmaceutical measures. Previous studies explained the differences in contagion rates due to the urban socio-political measures, while fine-grained geographic urban spreading pattern still remains an open issue. Here, we fill this gap by leveraging the trajectory data of 197,808 smartphone users (including 17,808 anonymous confirmed cases) in nine cities in China. We find a general spreading pattern in all cities: the spatial distribution of confirmed cases follows a power-law-like model and the spreading centroid human mobility is time-invariant. Moreover, we reveal that long average traveling distance results in a high growth rate of spreading radius and wide spatial diffusion of confirmed cases in the fine-grained geographic model. With such insight, we adopt the Kendall model to simulate the urban spreading of COVID-19 which can well fit the real spreading process. Our results unveil the underlying mechanism behind the spatial-temporal urban evolution of COVID-19, and can be used to evaluate the performance of mobility restriction policies implemented by many governments and to estimate the evolving spreading situation of COVID-19.

Enhanced piezocatalytic hydrogen evolution performance of bismuth vanadate by the synergistic effect of facet engineering and cocatalyst engineering.

Developing piezocatalysts with excellent piezocatalytic hydrogen evolution reaction (HER) performance is highly desired but also challenging. Here, facet engineering and cocatalyst engineering are employed to synergistically improve the piezocatalytic HER efficiency of BiVO4 (BVO). Monoclinic BVO catalysts with distinct exposed facets are synthesized by adjusting pH of hydrothermal reaction. The BVO with highly exposed {110} facet exhibits a superior piezocatalytic HER performance (617.9 µmol g-1h-1) compared with that with {010} facet, owing to the strong piezoelectric property, high charge transfer efficiency, and excellent hydrogen adsorption/desorption capacity. The HER efficiency is enhanced by 44.7% by selectively depositing cocatalyst of Ag nanoparticles specifically on the reductive {010} facet of BVO, where the Ag-BVO interface provides the directional electron transport for high-efficiency charge separation. Under the collaboration between cocatalyst of CoOx on {110} facet and the hole sacrificial agent of methanol, the piezocatalytic HER efficiency is evidently enhanced by 2 times because CoOx and methanol can impede the water oxidation and improve the charge separation. This easy and simple strategy provides an alternative perspective on designing high-performance piezocatalysts.