Reduced bone mineral density (BMD) and osteoporosis are common in chronic liver diseases. However, the causal effect of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) on ...BMD remains uncertain. This study uses a two-sample Mendelian randomization (MR) design to evaluate the genetically predicted effect of ALD and NAFLD on BMDs using summary data from publically available genome-wide association studies (GWASs). The GWAS summary statistics of ALD (1416 cases and 213,592 controls) and NAFLD (894 cases and 217,898 controls) were obtained from the FinnGen consortium. BMDs of four sites (total body, n = 56,284; femoral neck, n = 32,735; lumbar spine, n = 28,498; forearm, n = 8143) were from the GEnetic Factors for OSteoporosis Consortium. Data for alcohol consumption (n = 112,117) and smoking (n = 33,299) and serum 25-Hydroxyvitamin D (25-OHD) level (n = 417,580) were from UK-biobank. We first performed univariate MR analysis with the Inverse Variance Weighted (IVW) method as the primary analysis to investigate the genetically predicted effect of ALD or NAFLD on BMD. Then, multivariate MR and mediation analysis were performed to identify whether the effect was mediated by alcohol consumption, smoking, or serum 25-OHD level. The MR results suggested a robust genetically predicted effect of ALD on reduced BMD in the femoral neck (FN-BMD) (IVW beta = -0.0288; 95% CI: -0.0488, -0.00871; P = 0.00494) but not the other three sites. Serum 25-OHD level exhibited a significant mediating effect on the association between ALD and reduced FN-BMD albeit the proportion of mediation was mild (2.21%). No significant effects of NAFLD, alcohol consumption, or smoking on BMD in four sites, or reverse effect of BMD on ALD or NAFLD were detected. Our findings confirm the genetically predicted effect of ALD on reduced FN-BMD, and highlight the importance of periodic BMD and serum 25-OHD monitoring and vitamin D supplementation as needed in patients with ALD. Future research is required to validate our results and investigate the probable underlying mechanisms.
Pneumonia is an inflammation-related respiratory infection and chlorogenic acid (CGA) possesses a wide variety of bioactive properties, such as anti-inflammation and anti-bacteria.
This study ...explored the anti-inflammatory mechanism of CGA in Klebsiella pneumoniae (Kp)-induced rats with severe pneumonia.
The pneumonia rat models were established by infection with Kp and treated with CGA. Survival rates, bacterial load, lung water content, and cell numbers in the bronchoalveolar lavage fluid were recorded, lung pathological changes were scored, and levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay. RLE6TN cells were infected with Kp and treated with CGA. The expression levels of microRNA (miR)-124–3p, p38, and mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) in lung tissues and RLE6TN cells were quantified by real-time quantitative polymerase chain reaction or Western blotting. The binding of miR-124–3p to p38 was validated by the dual-luciferase and RNA pull-down assays. In vitro, the functional rescue experiments were performed using miR-124–3p inhibitor or p38 agonist.
Kp-induced pneumonia rats presented high mortality, increased lung inflammatory infiltration and the release of inflammatory cytokines, and enhanced bacterial load, while CGA treatment improved rat survival rates and the above situations. CGA increased miR-124–3p expression, and miR-124–3p inhibited p38 expression and inactivated the p38MAPK pathway. Inhibition of miR-124–3p or activation of the p38MAPK pathway reversed the alleviative effect of CGA on pneumonia in vitro.
CGA upregulated miR-124–3p expression and inactivated the p38MAPK pathway to downregulate inflammatory levels, facilitating the recovery of Kp-induced pneumonia rats.
More than 2 months have passed since the novel coronavirus disease 2019 (COVID-19) first emerged in Wuhan, China. With the migration of people, the epidemic has rapidly spread within China and ...throughout the world. Due to the severity of the epidemic, undiscovered transmission of COVID-19 deserves further investigation. The aim of our study hypothesized possible modes of SARS-CoV-2 transmission and how the virus may have spread between two family clusters within a residential building in Guangzhou, China.
In a cross-sectional study, we monitored and traced confirmed patients and their close contacts from January 11 to February 5, 2020 in Guangzhou, China, including 2 family cluster cases and 61 residents within one residential building. The environmental samples of the building and the throat swabs from the patients and from their related individuals were collected for SARS-CoV-2 and tested with real-time reverse transcriptase polymerase chain reaction (RT-PCR). The relevant information was collected and reported using big data tools.
There were two notable family cluster cases in Guangzhou, which included 3 confirmed patients (family No.1: patient A, B, C) and 2 confirmed patients (family No.2: patient D, E), respectively. None of patients had contact with other confirmed patients before the onset of symptoms, and only patient A and patient B made a short stop in Wuhan by train. Home environment inspection results showed that the door handle of family No.1 was positive of SARS-CoV-2. The close contacts of the 5 patients all tested negative of SARS-CoV-2 and in good health, and therefore were released after the official medical observation period of 14-days. Finally, according to the traceability investigation through applying big data analysis, we found an epidemiological association between family No.1 and family No.2, in which patient D (family No.2) was infected through touching an elevator button contaminated by snot with virus from patient A (family No.1) on the same day.
Contaminants with virus from confirmed patients can pollute the environment of public places, and the virus can survive on the surface of objects for a short period of time. Therefore, in addition to the conventional droplet transmission, there is also indirect contact transmission such as snot-oral transmission that plays a crucial role in community spread of the virus.
Dermatomyositis (DM) is an autoimmune disease that primarily affects the skin and skeletal muscle. Virus infection and type I interferon-related signaling pathways play an important role in the ...pathogenesis of dermatomyositis. In this study, we found that the skin of patients with DM and the skin of patients with COVID-19 have similar transcriptional profiles, and identified key genes involved in dermatomyositis based on bioinformatics analysis. These hub-genes might be served as potential biomarkers for the early diagnosis and therapy of DM, including MX1, ISG15, IFIT3, IFIT1, RSAD2, IFIT2, IFI6, XAF1, IRF9, MX2.
Recession flow analysis is usually conducted to infer hydraulic parameters of hillslope aquifers. Various Boussinesq equation‐based models, both linear and nonlinear, have been used to analyze the ...recession curves for sloping aquifers, with a focus on the long‐time recession behavior. Based on a modified Boussinesq equation with capillarity incorporated, we demonstrate the significant effect of unsaturated flow on the recession curve, which result in three (instead of two) power law regimes with two transition points (instead of one) corresponding to the formation of a fully unsaturated zone at the adjacent area of the upslope boundary and across the whole domain, respectively. The results show that the power of the second and third recession regime is variable, depending on the slope angles, soil types, and hillslope geometries. The unsaturated flow effects also lead to the absence of drastic drop of
−dQ/dt at the transition between the first and second regime, which was predicted by previous numerical models but has not been observed in the field or laboratory experiments. These findings have important implications for recession flow analysis in studies of hillslope aquifers.
Key Points
Three power law regimes are likely to occur in the hillslope recession process
In certain situations, neglect of capillary effect may lead to incorrect estimate of the slopes of the recession curve
Capillary effect smears the drastic change of the drainage rate at the transition between the first and second regimes of the recession curve
Oncogenic metabolic reprogramming contributes to tumor growth and immune evasion. The intertumoral metabolic heterogeneity and interaction of distinct metabolic pathways may determine patient ...outcomes. In this study, we aim to determine the clinical and immunological significance of metabolic subtypes according to the expression levels of genes related to glycolysis and cholesterol-synthesis in bladder cancer (BCa).
Based on the median expression levels of glycolytic and cholesterogenic genes, patients were stratified into 4 subtypes (mixed, cholesterogenic, glycolytic, and quiescent) in an integrated cohort including TCGA, GSE13507, and IMvigor210. Clinical, genomic, transcriptomic, and tumor microenvironment characteristics were compared between the 4 subtypes.
The 4 metabolic subtypes exhibited distinct clinical, molecular, and genomic patterns. Compared to quiescent subtype, mixed subtype was more likely to be basal tumors and was significantly associated with poorer prognosis even after controlling for age, gender, histological grade, clinical stage, and molecular phenotypes. Additionally, mixed tumors harbored a higher frequency of RB1 and LRP1B copy number deletion compared to quiescent tumors (25.7% vs. 12.7 and 27.9% vs. 10.2%, respectively, both adjusted P value< 0.05). Furthermore, aberrant PIK3CA expression level was significantly correlated with those of glycolytic and cholesterogenic genes. The quiescent subtype was associated with lower stemness indices and lower signature scores for gene sets involved in genomic instability, including DNA replication, DNA damage repair, mismatch repair, and homologous recombination genes. Moreover, quiescent tumors exhibited lower expression levels of pyruvate dehydrogenase kinases 1-3 (PDK1-3) than the other subtypes. In addition, distinct immune cell infiltration patterns were observed across the 4 metabolic subtypes, with greater infiltration of M0/M2 macrophages observed in glycolytic and mixed subtypes. However, no significant difference in immunotherapy response was observed across the 4 metabolic subtypes.
This study proposed a new metabolic subtyping method for BCa based on genes involved in glycolysis and cholesterol synthesis pathways. Our findings may provide novel insight for the development of personalized subtype-specific treatment strategies targeting metabolic vulnerabilities.
Unsaturated flow is an important factor that affects groundwater motion. Among various drainage models, the nonlinear Hillslope‐storage Boussinesq (HSB) model has been commonly used to predict water ...flux along a slope. In this study, we improved this model by considering lateral flow in the unsaturated zone. Using modified van Genuchten functions, we analytically expressed the concept of equivalent propagation thickness in the vadose zone. This analytical expression was then incorporated into the HSB model to reflect two different stages of the drainage process and to simulate the hillslope drainage process more accurately. The model results indicated that lateral flow has significant effects in the unsaturated zone during the hillslope drainage process. Even in sandy aquifers, the amount of water contributed by the unsaturated zone is a key factor that enables a decrease in the water table during the middle and late stages of the process. A comparison between the measured and simulated results based on both convergent‐type and divergent‐type hillslope drainage processes revealed that the thickness of the saturated zone decreases as the unsaturated flow increases. This study emphasizes the necessity of considering unsaturated flow in the HSB model to improve the accuracy of predicting groundwater outflow rates and develop more accurate hydrographs. The concept of equivalent propagation thickness also provides a criterion for assessing the importance of unsaturated lateral flow for future drainage research.
Key Points:
Unsaturated lateral flow plays an important role in the hillslope drainage process
Lateral flow in the unsaturated zone is considered in the HSB model
An equivalent propagation thickness in the vadose zone is analytically expressed
Fouling and mud-pumping problems in ballasted track significantly degrade serviceability and jeopardize train operational safety. The phenomenological approaches for post hoc forensic investigation ...and remedies of mud pumps have relatively been well studied, but there still lacks studies on inherent mechanisms and ex ante approaches for early-age detection of mud pumps. This paper was aimed to exploring the feasibility of using particle acceleration responses to diagnose and identify early-age mud-pumping risks in real-world field applications. The innovative wireless sensors with 3D-printed shells resembling real shape of ballast particles were instrumented in the problematic railway section to monitor ballast particle movement prior to, during, and after maintenance operations, respectively. The real-time particle-scale acceleration data of ballast bed under both degraded and maintenance-restored clean conditions were recorded. The time histories, power spectra, and marginal spectra of 3D acceleration were comparatively analyzed. The results showed the 3D acceleration of ballast particles underneath rail-supporting tie plates displayed relatively clear periodicity of about 0.8 s with adjacent bogies regarded as a loading unit. The tamping operation was effective for compacting ballast bed laterally and improving the lateral interlocking of ballast particles, whereas the stabilizing operation was effective mainly in the lateral direction and for ballast particles underneath the sleepers. The mud pumps caused intensive particle-scale acceleration, and ballast particles underneath the sleepers were affected more severely than those in between adjacent sleepers. The ballast particles directly underneath tie plates exhibit dramatic acceleration variations due to maintenance operations as compared to those in other positions studied; hence, it seems promising to use particle-scale acceleration underneath tie plates as readily-implementable indicators for smart in-service track health monitoring.
Huntingtin-associated protein 1 (HAP1) was the first protein discovered to interact with huntingtin. Besides brain, HAP1 is also expressed in the spinal cord, dorsal root ganglion, endocrine, and ...digestive systems. HAP1 has diverse functions involving in vesicular transport, receptor recycling, gene transcription, and signal transduction. HAP1 is strongly linked to several neurological diseases, including Huntington’s disease, Alzheimer’s disease, epilepsy, ischemic stroke, and depression. In addition, HAP1 has been proved to participate in cancers and diabetes mellitus. This article provides an overview of HAP1 regarding the tissue distribution, cell localization, functions, and offers fresh perspectives to investigate its role in diseases.
Nickel oxide nanoparticles (NiONPs) are toxic heavy metal compounds that induce liver fibrosis and metabolic disorders. Current research shows that the intestinal microbiota regulates liver ...metabolism through the gut-liver axis. However, it is unclear whether NiONPs affect the intestinal microbiota and the relationship between microbiota and liver metabolic disorders. Therefore, in this study, we established liver fibrosis model by administering 0.015, 0.06 and 0.24 mg/mL NiONPs through tracheal instillation twice a week for 9 weeks in rats, then we collected serum and fecal sample for whole metabolomics and metagenomic sequencing. As the result of sequencing, we screened out seven metabolites (beta-D-glucuronide, methylmalonic acid, linoleic acid, phosphotidylcholine, lysophosphatidylinositol, docosapentaenoic acid and progesterone) that related to functional alterations (p < 0.05), and obtained a decrease of probiotics abundances (p < 0.05) as well as a variation of the microbiota enzyme activity (p < 0.05), indicating that NiONPs inhibited the proliferation of probiotics. As the result of correlation analysis, we found a positive correlation between differential metabolites and probiotics, such as lysophosphatidylinositol was positively correlated with Desulfuribacillus, Jeotgallibacillus and Rummeliibacillus (p < 0.05). We also found that differential metabolites had correlations with differential proteins and enzymes of intestinal microbiota, such as glucarate dehydratase, dihydroorotate dehydrogenase and acetyl-CoA carboxylase (p < 0.05). Finally, we screened six metabolic pathways with both differential intestinal microbiota enzymes and metabolites were involved, such as pentose and glucuronate interconversions, and linoleic acid metabolism. In vitro experiments showed that NiONPs increased the transcriptional expression of Col1A1 in LX-2 cells, while reducing the mRNA expression of serine/threonine activators, acetyl coenzyme carboxylase, and lysophosphatidylinositol synthase, and short chain fatty acid sodium butyrate can alleviate these variation trends. The results proved that the intestinal microbiota enzyme systems were associated with serum metabolites, suggesting that the disturbance of intestinal microbiota and reduction of probiotics promoted the occurrence and development of NiONPs-induced liver fibrosis by affecting metabolic pathways.
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