Loss of Gst1 enhances resistance to MMS by reprogramming the transcription of DNA damage response genes in a Rad53-dependent manner in Candida albicans.

The DNA damage response is a highly conserved protective mechanism that enables cells to cope with various lesions in the genome. Extensive studies across different eukaryotic cells have identified the crucial roles played by components required for response to DNA damage. When compared to the essential signal transducers and repair factors in the DNA damage response circuitry, the negative regulators and underlying mechanisms of this circuitry have been relatively under-examined. In this study, we investigated Gst1, a putative glutathione transferase in the fungal pathogen Candida albicans. We found that under stress caused by the DNA damage agent MMS, GST1 expression was significantly upregulated, and this upregulation was further enhanced by the loss of the checkpoint kinases and DNA repair factors. Somewhat counterintuitively, deletion of GST1 conferred increased resistance to MMS, potentially via enhancing the phosphorylation of Rad53. Furthermore, overexpression of RAD53 or deletion of GST1 resulted in upregulated transcription of DNA damage repair genes, including CAS1, RAD7, and RAD30, while repression of RAD7 transcription in the GST1 deletion reversed the strain's heightened resistance to MMS. Finally, Gst1 physically interacted with Rad53, and their interaction weakened in response to MMS-induced stress. Overall, our findings suggest a negative regulatory role for GST1 in DNA damage response in C. albicans, and position Gst1 within the Rad53-mediated signaling pathway. These findings hold significant implications for understanding the mechanisms underlying the DNA damage response in this fungal pathogen and supply new potential targets for therapeutic intervention.

Comprehensive pan-cancer analysis reveals ENC1 as a promising prognostic biomarker for tumor microenvironment and therapeutic responses.

Accumulating research showed that ENC1 plays a critical role in maintaining the physiological functions. However, little is known about its role in predicting prognosis and immunotherapy response across cancers. In our results, compared to normal tissues, most cancer tissues exhibit increased ENC1 expression. We found that the most common type of genetic variation was gene mutation. In addition, a positive correlation was found between CNV and ENC1 expression. Moreover, the overexpression of ENC1 was positively correlated with poor clinical outcomes. The GSEA results showed that ENC1 is closely correlated with tumor-promoting biological functions in most cancers. ENC1 is also closely negatively associated with the infiltration levels of T cells, activated NK cells, and B cells. Most immunomodulators are positively associated with ENC1. Further, we verified that inhibition of ENC1 expression suppressed the proliferation and migration of breast cancer, pancreatic cancer and glioma cells. In conclusion, our study demonstrated that ENC1 plays a protumorigenic role in most cancers. Additionally, ENC1 is closely correlated with tumor microenvironment features and immune checkpoint inhibitors expression. Overall, ENC1 could serve as a promising potential prognostic biomarker in various tumors.

Prevalence of and risk factors for low back pain among professional drivers: a systematic review and meta-analysis.

PURPOSE: A growing body of research indicates a correlation between occupational exposure, particularly among individuals in driving-related occupations, and the incidence of low back pain (LBP). METHODS: Databases were systematically searched, including PubMed, Embase, Web of Science, Cochrane Library, and SinoMed, from their inception through December 2023 for relevant studies of the prevalence and risk factors of LBP among professional drivers. Subsequent meta-analyses were performed utilizing Stata 17.0 and RevMan 5.4 software, while risk factor indicators were assessed using the Grading of Recommendations, Assessment, Development and Evaluation evidence quality grading system. RESULTS: A systematic review and meta-analysis comprising 19 studies involving 7,723 patients indicated that the incidence of LBP among drivers was 39% (95% confidence interval [CI] 0.20-0.57) in the past 7 days and 53% (95% CI 0.43-0.63) in the past 12 months. A subgroup analysis revealed a prevalence of 48% (95% CI 0.33-0.64) in 2005-2015 and 56% (95% CI 0.42-0.70) in 2016-2023. Among the identified factors, robust evidence highlighted age ≥ 41 years (odds ratio [OR] = 2.10; 95% CI 1.36-3.24; P = 0.0008), alcohol consumption (OR = 1.75; 95% CI 1.31-2.34; P = 0.0001), sleeping < 6 h/night (OR = 1.60; 95% CI 1.13-2.24; P = 0.007), uncomfortable seating (OR = 1.71; 95% CI 1.23-2.36; P = 0.001), improper driving posture (OR = 2.37; 95% CI 1.91-2.94; P < 0.00001), and manual handling (OR = 2.23; 95% CI 1.72-2.88; P < 0.00001) as significant risk factors for LBP. There was moderate evidence of a lack of exercise (OR = 1.78; 95% CI 1.37-2.31; P < 0.0001), working > 10 h/day (OR = 2.49; 95% CI 1.89-3.28; P < 0.00001), > 5 years' driving experience (OR = 2.12; 95% CI 1.66-2.69; P < 0.00001), a lack of back support (OR = 1.81; 95% CI 1.25-2.62; P = 0.002), high work-related pressure (OR = 2.04; 95% CI 1.59-2.61; P < 0.00001), and job dissatisfaction (OR = 1.57; 95% CI 1.23-2.01; P = 0.0003) as moderate risk factors. There was no evidence of body mass index or smoking as risk factors for LBP among professional drivers. CONCLUSION: The current evidence indicates an increasing annual trend in the prevalence of LBP among professional drivers. Factors including age ≥ 41 years, alcohol consumption, and sleeping < 6 h/night were among the 12 influential factors contributing to LBP in professional drivers. Enhancing awareness of these factors and formulating targeted preventive strategies may be beneficial.

The Different Influence of Cutibacterium acnes and Staphylococcus epidermidis in the Lumbar Disc : An in Vivo Study in Rabbits.

STUDY DESIGN: Animal laboratory study. OBJECTIVE: This study investigated the effects of Cutibacteriumacnes and Staphylococcusepidermidis on the lumbar discs of rabbits, as well as the outcomes of combined infection. SUMMARY OF BACKGROUND DATA: Many studies have indicated that bacterial infections are associated with lumbar disc degeneration (LDD). The most commonly cultured bacteria from disc tissues are C. acnes and S. epidermidis . METHODS: New Zealand white rabbits (n=40) were randomly divided into control, C. acnes , S. epidermidis , and C. acnes plus S. epidermidis ( i.e. , combined) groups. All groups except the control were injected with 25 µL of saline at L4-L5 and 25 µL of bacteria (1×10 7 CFU/mL) at L5-L6. All injections were performed under x-ray guidance. Weight measurements, haematological evaluations, and magnetic resonance imaging were performed after 4, 8, and 12 weeks. Histological examination and gene expression detection were performed 12 weeks after surgery. RESULTS: Inflammatory factors in the blood and weight did not differ among the groups after 4, 8, and 12 weeks ( P >0.05). However, after 4 weeks, LDD occurred in the C. acnes group, and discitis occurred in the S. epidermidis and combined groups, all of which worsened after 8 weeks. After 12 weeks, the nucleus pulposus (NP) protruded and compressed the spinal cord in the C. acnes group, and tissue staining showed decreased NP tissue and cartilaginous endplate fracture. In the S. epidermidis and combined groups, the discitis was more confined, but tissue staining revealed a significant decrease in NP tissue, and loss of the normal disc structure. CONCLUSIONS: In the early stage of infection in rabbits, C. acnes caused LDD, and S. epidermidis caused discitis. Coinfection with C. acnes and S. epidermidis caused discitis but was more limited in scope than infection with S. epidermidis alone.

The rabbit model for spinal tuberculosis: An overview.

Mycobacterium tuberculosis infection has emerged as a global public health issue, predominantly manifesting as pulmonary tuberculosis. Bone and joint tuberculosis, with spinal tuberculosis accounting for approximately 50%, represents a significant form of extrapulmonary tuberculosis. Over the past years, there has been a rise in the incidence of spinal tuberculosis, and research concerning this area has gained significant attention. At present, animal models provide a means to investigate the pathogenesis, drug resistance, and novel treatment approaches for spinal tuberculosis. New Zealand rabbits, possessing a comparable anatomical structure to humans and capable of reproducing typical pathological features of human tuberculosis, are extensively employed in spinal tuberculosis research using animal models. This article comprehensively evaluates the strengths, considerations in strain selection, various modelling approaches, and practical applications of the rabbit model in studying spinal tuberculosis based on pertinent literature to guide fundamental research in this field by providing valuable insights into appropriate animal model selection.

Interpretation of course conceptual structure and student self-efficacy: an integrated strategy of knowledge graphs with item response modeling.

BACKGROUND: There is a scarcity of studies that quantitatively assess the difficulty and importance of knowledge points (KPs) depending on students' self-efficacy for learning (SEL). This study aims to validate the practical application of psychological measurement tools in physical therapy education by analyzing student SEL and course conceptual structure. METHODS: From the "Therapeutic Exercise" course curriculum, we extracted 100 KPs and administered a difficulty rating questionnaire to 218 students post-final exam. The pipeline of the non-parametric Item Response Theory (IRT) and parametric IRT modeling was employed to estimate student SEL and describe the hierarchy of KPs in terms of item difficulty. Additionally, Gaussian Graphical Models with Non-Convex Penalties were deployed to create a Knowledge Graph (KG) and identify the main components. A visual analytics approach was then proposed to understand the correlation and difficulty level of KPs. RESULTS: We identified 50 KPs to create the Mokken scale, which exhibited high reliability (Cronbach's alpha = 0.9675) with no gender bias at the overall or at each item level (p > 0.05). The three-parameter logistic model (3PLM) demonstrated good fitness with questionnaire data, whose Root Mean Square Error Approximation was < 0.05. Also, item-model fitness unveiled good fitness, as indicated by each item with non-significant p-values for chi-square tests. The Wright map revealed item difficulty relative to SEL levels. SEL estimated by the 3PLM correlated significantly with the high-ability range of average Grade-Point Average (p < 0.05). The KG backbone structure consisted of 58 KPs, with 29 KPs overlapping with the Mokken scale. Visual analysis of the KG backbone structure revealed that the difficulty level of KPs in the IRT could not replace their position parameters in the KG. CONCLUSION: The IRT and KG methods utilized in this study offer distinct perspectives for visualizing hierarchical relationships and correlations among the KPs. Based on real-world teaching empirical data, this study helps to provide a research foundation for updating course contents and customizing learning objectives. TRIAL REGISTRATION: Not applicable.

Risk factors associated with low-grade virulent infection in intervertebral disc degeneration: a systematic review and meta-analysis.

BACKGROUND: An increasing number of research indicates an association between low-grade bacterial infections, particularly those caused by Propionibacterium acnes (P. acnes), and the development of intervertebral disc degeneration (IDD). However, no previous meta-analysis has systematically assessed the risk factors for low-grade bacterial infections that cause IDD. PURPOSE: This study reviewed the literature to evaluate the risk factors associated with low-grade bacterial infection in patients with IDD. STUDY DESIGN: Systematic review and meta-analysis. METHODS: The systematic literature review was conducted using the PubMed, Web of Science, Embase, and Cochrane Library databases. Eligible articles explicitly identified the risk factors for low-grade bacterial infections in IDD patients. Patient demographics and total bacterial infection rates were extracted from each study. Meta-analysis was performed using random- or fixed-effects models, with statistical analyses conducted using Review Manager (RevMan) 5.4 software.aut. RESULTS: Thirty-three studies involving 4,109 patients were included in the meta-analysis. The overall pooled low-grade bacterial infection rate was 30% (range, 24%-37%), with P. acnes accounting for 25% (range, 19%-31%). P. acnes constituted 66.7% of bacteria-positive discs. Fourteen risk factors were identified, of which 8 were quantitatively explored. Strong evidence supported male sex (odds ratio [OR] = 2.15; 95% confidence interval [CI]=1.65-2.79; p<.00001) and Modic changes (MCs) (OR=3.59; 95% CI=1.68-7.76; p=.0009); moderate evidence of sciatica (OR=2.31; 95% CI=1.33-4.00; p=.003) and younger age (OR=-3.47; 95% CI=-6.42 to -0.53; p=.02). No evidence supported previous disc surgery, MC type, Pfirrmann grade, smoking, or diabetes being risk factors for low-grade bacterial infections in patients with IDD. CONCLUSIONS: Current evidence highlights a significant association between IDD and low-grade bacterial infections, predominantly P. acnes being the most common causative agent. Risk factors associated with low-grade bacterial infections in IDD include male sex, MCs, sciatica, and younger age.

Increased Extracellular Water in Normal-Appearing White Matter in Patients with Cerebral Small Vessel Disease.

BACKGROUND: Microcirculatory variations have been observed in the normal-appearing white matter (NAWM) of individuals affected by cerebral small vessel disease (CSVD). These variations collectively possess the potential to trigger neuroinflammation and edema, ultimately leading to an elevation in extracellular fluid (ECF). Nevertheless, the specific alterations in ECF within the NAWM of CSVD patients have remained inadequately understood. METHODS: We reviewed the clinical and imaging characteristics of a cohort comprising 129 patients diagnosed with CSVD to investigate alterations in the ECF within NAWM. The severity of CSVD was assessed by total CSVD magnetic resonance (MR) score according to the four imaging markers, namely perivascular space, lacunar infarction, white matter hyperintensities and cerebral microbleed. ECF was evaluated by the parameter free water (FW), ranging from 0 to 1 generated from diffusion tensor imaging. RESULTS: Significant differences in NAWM FW were observed in relation to the total CSVD MR score (p < 0.05). Patients with a total CSVD MR score of 0 exhibited significantly lower NAWM free water (FW) values compared to those with a score greater than 0 (p < 0.05). Similarly, patients with a total CSVD MR score of 1 also demonstrated notably lower NAWM FW values than those with a score greater than 1 (p < 0.05). After conducting multivariate regression analysis, age and total CSVD MR score was independently associated with FW in NAWM (p < 0.001). Further, the total CSVD MR score served as a partial mediator in the relationship between age and FW in the NAWM among patients with CSVD. CONCLUSIONS: ECF in NAWM is increased in CSVD patients, even during the early course of CSVD.

CircRNA ARHGAP10 promotes osteogenic differentiation through the miR-335-3p/RUNX2 pathway in aortic valve calcification.

Background: Calcific aortic valve disease (CAVD) is a common cardiovascular disease with high morbidity and mortality, and no effective prevention or treatment is available. In recent years, increasing evidence has shown that noncoding RNAs (ncRNAs) play an important role in the pathogenesis and prognosis of CAVD. Several associated circular RNAs (circRNAs) have been reported to be involved in CAVD, such as circRIC3 and TGFBR2. However, the limited number of circRNAs identified in CAVD warrants further in-depth investigation, and the comprehensive elucidation of their role in the key mechanisms of this disease is needed. Methods: The expression of circRNAs and microRNAs (miRNAs) were analyzed by RNA sequencing. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to analyze the expression of circRNA ARHGAP10 (circARHGAP10), miR-335-3p, and RUNX2. Luciferase reporter assay, pull-down assay, and RNA binding protein immunoprecipitation (RIP) assay were performed to evaluate the binding of miR-335-3p to circARHGAP10 or RUNX2. Alizarin red S staining showed the formation of calcified nodules in valve interstitial cells (VICs). The expression of circARHGAP10 and miR-335-3p was altered through lentivirus infection. Alkaline phosphatase (ALP) activity was used to verify the correlation between circARHGAP10 and miR-335-3p. The expression of proteins was assessed via Western blot. RNA fluorescence in situ hybridization (FISH) was used to confirm the localization of circARHGAP10 in the cytoplasm of VICs. Immunofluorescence was used to detect the expression level of RUNX2. ApoE-/- mice were used to construct a CAVD model, circARHGAP10 short hairpin RNA (shRNA) and miR-335-3p inhibitor lentivirus were intraperitoneally injected, and scramble and inhibitor normal control (NC) lentivirus were injected as controls, followed by hematoxylin and eosin (HE) staining. Results: Through RNA sequencing, we found that circARHGAP10 (hsa_circ_0008975) was highly expressed in calcific aortic valves. CircARHGAP10 knockdown effectively inhibited the extent of osteogenic differentiation of VICs. We then found that circARHGAP10 was a competing endogenous RNA (ceRNA) of miR-355-3p and that miR-355-3p targeted RUNX2. In vitro experiments confirmed that circARHGAP10 regulated the osteogenic differentiation of VICs through the miR-355-3p/RUNX2 pathway, and this was validated in vivo using an ApoE-/- mouse model. Conclusions: These findings provide a foundation for circRNA-directed diagnostics and therapeutics for CAVD.

Role of miR-5010-3p in predicting the prognosis of hepatocellular carcinoma. / MiR-5010-3p在预测肝细胞癌预后中的作用（英文）.

OBJECTIVES: Numerous miRNAs have been found to be abnormally expressed in hepatocellular carcinoma (HCC). However, clinical significance of miR-5010-3p in HCC is not elucidated. This study aims to explore the prognostic value and role of miR-5010-3p in HCC. METHODS: The differential gene expression analysis of miR-5010-3p in HCC was performed based on the Cancer Genome Atlas (TCGA) database. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of miR-5010-3p expression level for HCC prognosis. The Kaplan-Meier, Cox univariate, and Cox multivariate analysis were used to predict its role in the prognosis of HCC. The downstream target genes were predicted. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to predict the potential functional pathways they may participate in. Finally, methyl thiazolyl tetrazolium (MTT) assay and 5-ethyl-2'-deoxyuridine (EDU) incorporation experiment were carried out to prove its effect on proliferation. RESULTS: The expression of miR-5010-3p was associated with histological grade (P=0.019), vascular invasion degree (P=0.049), TP53 level (P=0.004), and alpha fetoprotein (AFP) level (P=0.012). A moderate ability to distinguish between tumor and paracancerous tissues of miR-5010-3p in HCC was perceived by ROC curve (AUC: 0.712, 95% CI 0.649 to 0.776). High expression of miR-5010-3p was associated with shorter overall survival (OS) (P=0.003). The results of functional enrichment analysis showed that miR-5010-3p was related to the tumorigenesis process. In vitro experiments verified that miR-5010-3p promoted the proliferation of hepatocellular carcinoma cells. CONCLUSIONS: MiR-5010-3p promotes the proliferation of liver cancer cells, and its high expression is associated with poor prognosis, which may be a potential prognostic marker.

Mechanism underlying the effect of Pulsatilla decoction in hepatocellular carcinoma treatment: a network pharmacology and in vitro analysis.

BACKGROUND: Currently, hepatocellular carcinoma (HCC) is associated with a poor prognosis. Moreover, there exist limited strategies for treating HCC. Pulsatilla decoction (PD), a traditional Chinese medicine formula, has been used to treat inflammatory bowel disease and several cancer types. Accordingly, we explored the mechanism of PD in HCC treatment via network pharmacology and in vitro experiments. METHODS: Online databases were searched for gene data, active components, and potential target genes associated with HCC development. Subsequently, bioinformatics analysis was performed using protein-protein interaction and Network Construction and Kyoto Encyclopedia of Genes and Genomes (KEGG) to screen for potential anticancer components and therapeutic targets of PD. Finally, the effect of PD on HCC was further verified by in vitro experiments. RESULTS: Network pharmacological analysis revealed that 65 compounds and 180 possible target genes were associated with the effect of PD on HCC. These included PI3K, AKT, NF-κB, FOS, and NFKBIA. KEGG analysis demonstrated that PD exerted its effect on HCC mainly via the PI3K-AKT, IL-17, and TNF signaling pathways. Cell viability and cell cycle experiments revealed that PD could significantly inhibit cancer cell proliferation and kill HCC cells by inducing apoptosis. Furthermore, western blotting confirmed that apoptosis was mediated primarily via the PI3K-AKT, IL-17, and TNF signaling pathways. CONCLUSION: To the best of our knowledge, this is the first study to elucidate the molecular mechanism and potential targets of PD in the treatment of HCC using network pharmacology.

Cations facilitate sulfidation of zero-valent iron by elemental sulfur: Mechanism and dechlorination application.

The solid-solid reaction of microscale zero-valent iron (mZVI) with elemental sulfur (S0) in water can form sulfidated mZVI (S-mZVI) with high reactivity and selectivity. However, the inherent passivation layer of mZVI hinders the sulfidation. In this study, we demonstrate that ionic solutions of Me-chloride (Me: Mg2+, Ca2+, K+, Na+ and Fe2+) can accelerate the sulfidation of mZVI by S0. The S0 with S/Fe molar ratio of 0.1 was fully reacted with mZVI in all solutions to form unevenly distributed FeS species on S-mZVIs as confirmed by SEM-EDX and XANES characterization. The cations depassivated the mZVI surface by driving the proton release from the surface site (FeOH) and resulting in localized acidification. The probe reaction test (tetrachloride dechlorination) and open circuit potential (EOCP) measurement demonstrated that Mg2+ was most efficient in depassivating the mZVI and therefore promoting sulfidation. The decrease of surface proton for hydrogenolysis on the S-mZVI synthesized in MgCl2 solution also inhibited the formation of cis-1,2-dichloroethylene by 14-79% compared to other S-mZVIs during trichloroethylene dechlorination. In addition, the synthesized S-mZVIs exhibited the highest reduction capacity reported so far. These findings provide a theoretical basis for the facile on-site sulfidation of mZVI by S0 with cation-rich natural waters for sustainable remediation of contaminated sites.

Integrated pan-cancer analysis of centromere protein F and experimental verification of its role and clinical significance in cholangiocarcinoma.

Centromere protein F (CENPF), a protein related to the cell cycle, is a key part of the kinetochore-centromere complex involved in cell division, differentiation, and proliferation. CENPF expression is upregulated in various types of cancer and plays a role in oncogenesis and tumor progression. However, the expression pattern, prognostic significance, and biological role of CENPF in these cancer types are poorly understood. Therefore, in this study, we conducted a pan-cancer analysis of the role of CENPF, which we considered a cut point, to investigate its utility as a prognostic and immunological indicator for malignancies, especially cholangiocarcinoma (CCA). Using systematic bioinformatics analysis, we investigated the expression patterns, prognostic relevance, molecular function, signaling pathways, and immune infiltration patterns of CENPF in the pan-cancer analysis. Western blot and immunohistochemistry staining assays were performed to evaluate the expression profiles of CENPF in CCA tissues and cell lines. Furthermore, Cell Counting Kit-8, colony formation, wound healing, and Transwell assays, as well as CCA xenograft mouse models, were employed to determine the role and function of CENPF in CCA. The results showed that CENPF expression was upregulated and strongly linked to a worse prognosis in most cancer types. CENPF expression was substantially associated with immune cell infiltration, tumor microenvironment, genes related to immune checkpoints, tumor mutational burden, microsatellite instability, and immunotherapy response in diverse malignancies. CENPF was considerably overexpressed in CCA tissues and cells. Functionally, inhibiting CENPF expression significantly reduced the proliferating, migrating, and invading abilities of CCA cells. CENPF expression also affects the prognosis of multiple malignancies, which is highly associated with immunotherapy response and tumor immune cell infiltration. In conclusion, CENPF may act as an oncogene and an immune infiltration-related biomarker and can accelerate tumor development in CCA.

Enhanced removal of hexavalent chromium by lignosulfonate modified zero valent iron: Reaction kinetic, performance and mechanism.

The application of lignin derivative as modifier is an economical and efficient approach to improve the reactivity of raw material towards pollutant removal. In this study, lignosulfonate modified zero valent iron (LS-ZVI) was firstly prepared by ball-milling method and utilized for Cr(VI) removal under different conditions. The comparative experiments showed that lignosulfonate modification could significantly enhance the Cr(VI) removal by ZVI from <10 % to 100 % within 90 min reaction. Compared to ZVI, the specific surface area of LS-ZVI increased 3.4 times and surface Fe(0) content increased from 3.4 % to 10.5 % due to the surface erosion, resulting in the high-efficient Cr(VI) removal. Solution and solid-phase analyses indicated that Fe(0) played dominated role and generated Fe(II) involved in Cr(VI) removal process, which mainly included rapid adsorption, reduction and co-precipitation. Batch experiments revealed that lower pH conditions were beneficial for Cr(VI) removal and the effect of co-existing ions (Ca2+, Mg2+, NO3-, Cl-, and SO42-) was negligible except the inhibitory effect of NO3-. Moreover, LS-ZVI also exhibited excellent removal performance for Ni(II), Zn(II), and Cd(II) with removal efficiency beyond 96.6 %. Overall, this work provides a feasible approach for enhancing the reactivity of commercial ZVI in the treatment of heavy metal pollution.

Impact of Decreased Visibility of Deep Medullary Veins on White Matter Integrity in Patients with Cerebral Small Vessel Disease.

BACKGROUND: Based on susceptibility-weighted imaging (SWI) visibility, deep medullary vein (DMV) scores are related to white matter damage (WMD) in patients with cerebral small vessel disease (CSVD). However, whether mechanisms are associated with DMV changes is unclear. We examined extracellular fluid (ECF) roles in white matter associations between DMV scores and white matter integrity (WMI) in patients with CSVD. METHODS: We examined magnetic resonance imaging (MRI) and clinical data from 140 patients with CSVD. DMV scores (0-18) were assigned on SWI according to DMV anatomic regions and signal continuity/visibility. WMI and ECF volumes were evaluated using free water (FW) and fractional anisotropy (FA) values by diffusion tensor imaging (DTI). RESULTS: DMV scores were independently associated with FA after adjusting for vascular risk factors, age, white matter hyperintensity (WMH) volume, and CSVD burden [ß (95% confidence interval (CI)): -0.219 (-0.375, -0.061), p = 0.006]. We also observed a significant indirect effect of DMV scores on FA in white matter (mediated by FW in white matter) after controlling for age, vascular risk factors, WMH volume, and CSVD burden. CONCLUSIONS: DMV scores were independently related to WMI and mediated by ECF in the white matter of patients with CSVD.

TRPM8 contributes to liver regeneration via mitochondrial energy metabolism mediated by PGC1α.

Impairment of liver regeneration leads to severe morbidity in acute and chronic severe liver disease. Transient receptor potential melastain 8 (TRPM8) is involved in a variety of processes, including temperature sensing, ion homeostasis, and cell proliferation. However, whether TRPM8 contributes to liver regeneration is still unclear. We assessed the effect and mechanism of TRPM8 in liver regeneration and hepatocyte proliferation in vivo and in vitro. In this study, we found that TRPM8 deficiency impairs liver regeneration in mice. Mechanistically, the results revealed that mitochondrial energy metabolism was attenuated in livers from TRPM8 knockout (KO) mice. Furthermore, we found that TRPM8 contributes to the proliferation of hepatocytes via PGC1α. Taken together, this study shows that TRPM8 contributes to liver regeneration in mice after hepatectomy. Genetic approaches and pharmacological approaches to regulate TRPM8 activity may be beneficial to the promotion of liver regeneration.

The hypoxia-related signature predicts prognosis, pyroptosis and drug sensitivity of osteosarcoma.

Osteosarcoma (OS) is one of the most common types of solid sarcoma with a poor prognosis. Solid tumors are often exposed to hypoxic conditions, while hypoxia is regarded as a driving force in tumor recurrence, metastasis, progression, low chemosensitivity and poor prognosis. Pytoptosis is a gasdermin-mediated inflammatory cell death that plays an essential role in host defense against tumorigenesis. However, few studies have reported relationships among hypoxia, pyroptosis, tumor immune microenvironment, chemosensitivity, and prognosis in OS. In this study, gene and clinical data from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases were merged to develop a hypoxia risk model comprising four genes (PDK1, LOX, DCN, and HMOX1). The high hypoxia risk group had a poor prognosis and immunosuppressive status. Meanwhile, the infiltration of CD8+ T cells, activated memory CD4+ T cells, and related chemokines and genes were associated with clinical survival outcomes or chemosensitivity, the possible crucial driving forces of the OS hypoxia immune microenvironment that affect the development of pyroptosis. We established a pyroptosis risk model based on 14 pyroptosis-related genes to independently predict not only the prognosis but also the chemotherapy sensitivities. By exploring the various connections between the hypoxic immune microenvironment and pyroptosis, this study indicates that hypoxia could influence tumor immune microenvironment (TIM) remodeling and promote pyroptosis leading to poor prognosis and low chemosensitivity.

Effects of Qigong Therapy on the Anaerobic Threshold in Patients with Stable Coronary Artery Disease: A Randomized Controlled Trial.

Objective: This study aims to identify whether Qigong (QG) rehabilitation therapy can significantly improve the cardiac function of patients with stable coronary artery disease (SCAD) compared with routine therapy. Thus, a randomized controlled trial was conducted to evaluate the curative effects of a three-month QG rehabilitation therapy on cardiac rehabilitation. Patients and Methods. In this trial, a total of 68 patients with SCAD were randomly divided into the QG group (34 patients) and the control (CON) group (34 patients). Patients in the CON group received routine cardiologic medication without any special intervention. Based on the treatment in the CON group, patients in the QG group were provided additionally with a 12-week traditional Chinese medicine (TCM) cardiac rehabilitation QG exercise training program. The outcomes of these patients were assessed at baseline and after 12 weeks of intervention through the treadmill (anaerobic threshold (AT)) test. Results: After 12 weeks of intervention, the AT, volume of oxygen (VO2), oxygen uptake/kilogram (VO2/kg), metabolic equivalents (METS), and oxygen pulse (VO2/HR) of patients in the QG group were significantly higher than those of patients in the CON group (P < 0.05). Conclusion: QG therapy can achieve certain curative effects and safety for patients with SCAD. This trial is registered with Clinicaltrials.gov identifier (ChiCTR1800015823).

Transient Receptor Potential Vanilloid-1 (TRPV1) Alleviates Hepatic Fibrosis via TGF-ß Signaling.

Hepatic fibrosis is a major global health problem and considered a leading cause of liver-related morbidity and mortality worldwide. Although previous studies have suggested that transient receptor potential vanilloid-1 (TRPV1) is protective against cardiac and renal fibrosis, its functional role in hepatic fibrosis has remained elusive. Herein, we characterize the effects of TRPV1 on carbon tetrachloride- (CCl4-) induced mice, in vitro transforming growth factor-ß- (TGF-ß-) treated hepatic stellate cells (HSCs), and human fibrosis specimens. Finally, our results demonstrated the significant TRPV1 downregulation in human liver fibrosis tissues. Knocking out TRPV1 significantly increased the expression of various hepatic fibrosis markers, while the expression of these biomarkers declined markedly in capsaicin-activated mice. Moreover, our study revealed that knocking down TRPV1 would enhance the promotive effect of TGF-ß on HSC proliferation, cell cycle, cell apoptosis, and ECM expression. Also, such promotive effect can be partially reversible by capsaicin, an exogenous activator of TRPV1. Collectively, the obtained data suggest that TRPV1 may alleviate CCl4-induced hepatic fibrosis and attenuate the effect of TGF-ß on HSC activation, proliferation, and apoptosis, which overall implies that targeting TRPV1 channel activity may be an effective therapeutic strategy for treating hepatic fibrosis.