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Background: Z-DNA-binding protein 1 (ZBP1) is a critical Z-DNA- and Z-RNA-binding protein. However, its diagnostic and prognostic significance, as well as its functions in clear cell renal cell carcinoma (ccRCC), are not well understood. Materials and methods: Paired and unpaired differential expression analyses of ZBP1 were performed in pan-cancer cells. Receiver operating characteristic (ROC) curves and survival analyses were used to evaluate the clinical significance of ZBP1. Functional enrichment and immune infiltration analyses were used to explore the mechanisms underlying ZBP1 expression. Western blotting, qRT-PCR, CCK-8, and colony formation assays were used to investigate the potential function of ZBP1 in ccRCC cells. Molecular docking was utilized to identify drugs targeting ZBP1. Results: ZBP1 was highly expressed in ccRCC, demonstrating significant diagnostic and prognostic value. ZBP1 mRNA expression correlated with TNM stage, pathologic stage, and histologic grade. Functional enrichment analyses indicated that ZBP1 is involved in multiple immune processes. Moreover, ZBP1 mRNA expression was positively correlated with the infiltrating levels of T cells and cytotoxic cells, and negatively correlated with the infiltrating levels of mast cells and Th17 cells in ccRCC. Biological experiments confirmed that ZBP1 promotes ccRCC cell proliferation. Molecular docking studies identified rucaparib as a potential drug targeting ZBP1. Conclusion: Our research findings suggest that targeting ZBP1 could represent a novel therapeutic approach to inhibit the progression of ccRCC.

Hexafluoropropylene oxide trimer acid (HFPO-TA) and hexafluoropropylene oxide tetramer acid (HFPO-TeA) are two novel alternatives of perfluorooctanoic acid (PFOA). However, their toxicokinetics and accumulation mechanisms in fish are still unknown. This study provides the first line of in vivo uptake and depuration kinetic, bioaccumulation mechanism and tissue-specific distribution for HFPO-TA and HFPO-TeA, upon a 28-day water exposure and a 14-day depuration in zebrafish (Danio rerio). HFPO-TeA and HFPO-TA could quickly accumulate in zebrafish, and the highest concentrations of HFPO-TeA (15.4 ± 1.6 nmol/g ww), HFPO-TA (4.95 ± 0.19 nmol/g ww) and PFOA (0.47 ± 0.03 nmol/g ww) were consistently present in the blood, which was followed by liver, kidney, intestine, gill, gonad and brain, while the lowest were observed in the muscle (1.01 ± 0.11, 0.16 ± 0.02, and 0.01 ± 0.001 nmol/g ww, respectively), indicating both higher accumulation potentials of both HFPO homologs than their predecessor PFOA. The tissue protein content, rather than lipid content, played an enhancing role in the enrichment of three target chemicals, exhibiting a significant positive correlation (r = 0.735, p = 0.038 for HFPO-TeA; r = 0.770, p = 0.026 for HFPO-TA and r = 0.942, p = 0.001 for PFOA) between the tissue bioconcentration factor (BCF) and the protein contents in corresponding tissues. This phenomenon was validated by the equilibrium dialysis experiment, molecular docking analysis and molecular dynamics simulation, which consistently indicated that the binding affinities of serum and liver proteins were greatest with HFPO-TeA, followed by HFPO-TA and least with PFOA. These results suggested that the binding of the target chemicals to specific proteins determined their tissue-specific accumulation potentials. Nontarget screening by high resolution mass spectrometry (HRMS) did not identify suspicious degradation products for HFPO-TA, implying the strong persistence of HFPO-TA in fish.

Summary: Cancer cachexia mouse models are needed to recapitulate the clinical features of patients with cachexia. Here, we present a protocol for the establishment and evaluation of cancer cachexia mouse models. We delineate the steps in preparing tumor cells for inoculation and surgical procedures. After the establishment of these mouse models, we describe essential techniques to assess cancer cachexia, including grip strength evaluation, tissue collection, and the calculation of cross-sectional areas of muscle tissue.For complete details on the use and execution of this protocol, please refer to Liu et al.,1 Yang et al.,2 Shi et al.,3 and Zhou et al.4 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: Background: Osteoarthritis is a leading cause of disability, and disease-modifying osteoarthritis drugs (DMOADs) could represent a pivotal advancement in treatment. Identifying the potential of antidiabetic medications as DMOADs could impact patient care significantly. Methods: We designed a comprehensive analysis pipeline involving two-sample Mendelian Randomization (MR) (genetic proxies for antidiabetic drug targets), summary-based MR (SMR) (for mRNA), and colocalisation (for drug-target genes) to assess their causal relationship with 12 osteoarthritis phenotypes. Summary statistics from the largest genome-wide association meta-analysis (GWAS) of osteoarthritis and gene expression data from the eQTLGen consortium were utilised. Findings: Seven out of eight major types of clinical antidiabetic medications were identified, resulting in fourteen potential drug targets. Sulfonylurea targets ABCC8/KCNJ11 were associated with increased osteoarthritis risk at any site (odds ratio (OR): 2.07, 95% confidence interval (CI): 1.50–2.84, P

Summary: Background: Synovitis has long been considered a common and modifiable inflammatory feature of osteoarthritis (OA), but current disease-modifying anti-inflammatory treatments appear ineffective in OA clinical trials. Elucidating the temporal relationship between synovitis and OA could provide insight into the role of synovitis in OA. Methods: We conducted a prospective cohort study based on the baseline and three-year follow-up data from the Xiangya Osteoarthritis (XO) Study. We assessed bidirectional associations between ultrasound-detected synovitis and radiographic and symptomatic OA at knee and hand sites using generalized estimating equations. Additionally, we performed bidirectional Mendelian randomization (MR) analyses to test these hypotheses utilising whole-genome sequencing data in the XO population. Age, sex, body mass index, smoking, alcohol consumption, educational level, physical activity, and joint injury history were adjusted for these analyses. Findings: A total of 2211, 2420, 2280, and 2600 participants were enrolled for analyses of radiographic knee OA (RKOA), symptomatic knee OA (SKOA), radiographic hand OA (RHOA) and symptomatic hand OA (SHOA), respectively. The baseline synovitis (i.e., with synovitis vs. without synovitis) was associated with the incident RKOA (76/277 vs. 557/3674 knees), SKOA (49/387 vs. 287/4213 knees), RHOA (171/358 vs. 686/3664 hands) and SHOA (35/689 vs. 76/4327 hands), with adjusted odds ratio (aORs) of 2.2 (95% CI 1.7–3.1), 2.0 (1.3–2.9), 3.4 (2.7–4.4), and 2.4 (1.5–3.8), respectively. The baseline RKOA (with OA vs. without OA: 409/1246 vs. 481/3758 knees), SKOA (200/576 vs. 675/4356 knees), RHOA (192/778 vs. 410/3723 hands), and SHOA (41/162 vs. 548/4285 hands) were also associated with the incident synovitis, with aORs of 3.4 (95% CI 2.9–4.1), 2.7 (2.1–3.4), 2.3 (1.8–2.9) and 1.9 (1.2–2.8), respectively. These bidirectional associations were stronger when more active synovitis was compared with the reference group (all P

Study region: The Kunlun Mountains on Tibetan Plateau Study focus: The Tibetan Plateau, well known as Asian Water Tower, holds immense potential for the formation of glacial mineral water. The present research focuses on the hydrochemical and isotopic signatures and formation pattern of natural glacial mineral water in the alpine region on Tibetan Plateau. New hydrological insights for the region: The investigated mineral groundwater has outstanding water quality and slightly alkaline nature. It is with fresh hydrochemical facies of HCO3-Na·Ca type with total dissolved solids (TDS) in the range of 384–964 mg/L, and featured by notably rich strontium with the concentrations of 0.67–0.81 mg/L, far exceeding the recommended mineral water minimum threshold of 0.20 mg/L. The mineral groundwater is originated from the glacier meltwater of mountainous area with elevation over 4500 m. It subsequently infiltrates into the bedrock and move within the groundwater system with a residence time of approximately 52 years. Its hydrochemical constituents are naturally governed by water-rock interactions of silicates dissolution, cation exchange, and celestite and strontianite dissolution. A conceptual model is proposed to outline the formation pattern of glacial mineral water in alpine region on Tibetan Plateau. Findings of this study can fill the study gap regarding glacial mineral water on Tibetan Plateau, and further contribute to the future study and development of natural glacial mineral water in alpine regions worldwide.

To achieve the uniform and fine-grained microstructures during thermal deformation of nickel-based superalloys, a novel two-stage deformation approach was employed, involving prior cold deformation treatment (PCDT) and subsequent thermal deformation. Experimental investigations concerning this two-stage deformation method were carried out on Ni80A superalloy, encompassing various combinations of cold and thermal compression parameters. The analysis of microstructures revealed that PCDT significantly enhances dynamic recrystallization (DRX) process, resulting in fine-grained microstructures during thermal compression and expanding the processing-parameter domains for grain refinement. To clarify the shift of DRX kinetics in thermal compression induced by PCDT, the DRX kinetics models considering this pre-treatment were derived. These models demonstrated a linear inverse correlation between the activation energy within DRX kinetics models and prior stored energy from PCDT. This suggested that PCDT promotes the DRX process by reducing the activation energy during thermal compression. Following, the kinetics curves depicting DRX volume fraction during thermal deformation were drawn. Results indicated that under an identical thermal compression condition, the kinetics curve shifts towards decreasing strain with increasing of prior cold deformation. Under various thermal compression conditions, these kinetics curves for Ni80A superalloy processed with PCDT get shifted to the direction of decreasing strain when compared to the alloy without PCDT. These shifts underscore a pronounced acceleration of DRX process induced by PCDT. Finally, a finite element model incorporating DRX kinetics models was developed to further illustrate the influence of PCDT on the shift of DRX in an upsetting process, which shows a promising potential for theoretical calculations.

This research focuses on achieving sustainable development in residential buildings with energy use. Under the influence of the energy crisis and related problems, research on residential buildings for less energy use has great potential. The literature review, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and including VOSviewer analysis, shows the research is increasing and meaningful. Solar Decathlon buildings are used as the main objects in this research. The fifth Solar Decathlon Europe energy use technologies are examined through onsite investigation and online searching. The Analytic Hierarchy Process method for multi-criteria decision analysis is used for sustainability assessment. Moreover, the Ladybug and ClimateStudio plugins simulated respectively the annual solar radiation and the best angle for receiving it. The main findings show that 34 kinds of technologies used in these buildings can be classified into two categories in three directions. Passive technologies should be applied and prioritized, but generating renewable energy is also important. Some infrequently used technologies are not insignificant. The research shows that the combination of technologies decides sustainability performance, but the quantity used does not. Furthermore, energy use also needs to be balanced and coordinated in combination with architectural aesthetics. This research on energy use in residential buildings is beneficial for achieving sustainable development.

This research aims to estimate the relationship between green bond financing and the OECD nations' performance on the renewable energy indices. The study attempted to quantify the relationship between concepts by analyzing data from OECD countries for 2011–2019. Padroni unit root test, FMOLS, and DOLS method provide evidence for the study's results and convey broad policy implications on this important topic. The robustness is consequently examined through a long-term sensitivity analysis employing the FMOLS, and green bond financing nexus concerning the renewable energy indices is shown for comparison. The study showed that financing of green bonds had a predictable impact on renewable energy indices variables. Green bonds' unequal implications for renewable energy measures across the study period bear out this interpretation. The study's findings call for full suppot from government institutions, energy agencies, and departments to optimize energy efficiency, as green bond financing played a 32% role in OECD nation's renewable energy index constructions and increased per unit improvement in renewable energy sources by 9.6%. The research offers many policy recommendations for improving energy efficiency through renewable energy generation. Recent studies extend and contribute to the existing body of literature, although the scientific discussion on this subject matter still needs to be more detailed and understudied. Financial unpredictability may be transformed into a tremendous opportunity if the renewable energy business is appropriately regulated.

Summary: Background: Since gut microbiome dysbiosis can cause inflammatory disorders by affecting host metabolism, we postulate that the gut microbiome and related metabolites could play a role in hand osteoarthritis. We characterised gut microbiome-related metabolites in people with symptomatic hand osteoarthritis (SHOA) in two independent cohorts. Methods: Using data collected from a large-sample community-based observational study (discovery cohort), we assessed the relations of the microbial function and plasma key metabolites related to altered microbial function with SHOA. Finally, we verified the relations of plasma metabolites to SHOA in an independent observational study (validation cohort). Findings: In the discovery cohort (n = 1359), compared to those without SHOA, participants with SHOA had significantly altered microbial functions related to tryptophan metabolism (Q = 0.025). Therefore we measured the plasma tryptophan metabolites and found that participants with SHOA had higher levels of 5-hydroxyindoleacetic acid (odds ratio [OR] = 1.25, 95% confidence interval [CI]: 1.09–1.42) and 5-hydroxytryptophol (OR = 1.13, 95% CI: 1.04–1.23), but lower levels of indole-3-lactic acid (ILA) (OR = 0.85, 95% CI: 0.72–1.00), skatole (OR = 0.93, 95% CI: 0.88–0.99) and 3-hydroxyanthranilic acid (OR = 0.90, 95% CI: 0.85–0.96). Findings from the validation cohort (n = 142) verified that lower levels of ILA were related to SHOA (OR = 0.70, 95% CI: 0.53–0.92). Interpretation: Alterations of the microbial function of tryptophan biosynthesis and tryptophan metabolites, especially lower levels of ILA, are associated with SHOA. These findings suggest the role of the microbiome and tryptophan metabolites in developing of SHOA and may contribute to future translational opportunities. Funding: National Key Research and Development Plan and National Natural Science Foundation of China.

Photonic convolution processing units are the core components of photonic neural networks (PNNs). Traditionally, for an N × N photonic convolution processing unit, it typically requires O(N2) or O(Nlog2N) cascaded photonic devices, which leads to larger sizes and lower density. Therefore, nanophotonic neural networks (N-PNN) with high density are highly attractive. In this work, we propose an ultra-high density and nonvolatile N-PNN scheme, requiring only a compact photonic device to represent all weight values in the N × N convolution kernel, which results in a computational density of more than 5 petaflop operations per second per square millimeter (POPS/mm2) under ideal conditions. The footprints of the proposed 2 × 2 and 3 × 3 nanophotonic convolution processing units are only 4 × 4 μm2 and 6 × 6 μm2, respectively. Moreover, based on these two types of units, the N-PNN achieves image classification and recognition capabilities comparable to traditional computers. In addition, Owing to its lower insertion loss, our approach holds great significance for the scalability and on-chip integration of large-scale N-PNNs. This facilitated the integration of N-PNNs with existing electronic systems.

Mounting heavy precipitation events (HPEs) caused by the climate change have drawn wide attention. Increased incidences of infectious diseases are known as the common following health impact, while little has been studied about the extremal relationship in between. Therefore, this study aims to investigate the joint extremes of precipitation and infectious disease mortality rate in the USA, using publicly accessible data from the National Centers for Environmental Information and the Centers for Disease Control and Prevention. The study reveals the positive association between heavy precipitations and infectious diseases with slight national and regional differences using multivariate Peaks-Over-Threshold modelling. The strength of extremal dependence is measured by the extreme parameter α from a logistic dependence model in multivariate extreme value theory. The Midwestern USA shows an excessive impact of HPEs on infectious disease mortality (α=0.7524), while the other regions show similar extremal dependence strength with the national one (α values all approximate 0.77). The study also discovered spatial disparities in the extremal dependences for five sub-categories of infectious diseases in each census region, among which mycoses show the strongest extremal dependence with precipitation in almost all regions. These spatial differences of extremal dependence may be attributed to geographic, social-economic factors and the self-inherited characteristics of certain diseases. The findings are expected to assist in developing strategies counteracting extreme risks resulting from weather events and health issues as well. The cutting-edge multivariate Peaks-Over-Threshold (POT) approach employed herein also shows promise for a wide range of extreme risk assessment topics.

DeFi, or Decentralized Finance, is based on a distributed ledger called blockchain technology. Using blockchain, DeFi may customize the execution of predetermined operations between parties. The DeFi system use blockchain technology to execute user transactions, such as lending and exchanging. The total value locked in DeFi decreased from $200 billion in April 2022 to $80 billion in July 2022, indicating that security in this area remained problematic. In this paper, we address the deficiency in DeFi security studies. To our best knowledge, our paper is the first to make a systematic analysis of DeFi security. First, we summarize the DeFi-related vulnerabilities in each blockchain layer. Additionally, application-level vulnerabilities are also analyzed. Then we classify and analyze real-world DeFi attacks based on the principles that correlate to the vulnerabilities. In addition, we collect optimization strategies from the data, network, consensus, smart contract, and application layers. And then, we describe the weaknesses and technical approaches they address. On the basis of this comprehensive analysis, we summarize several challenges and possible future directions in DeFi to offer ideas for further research.

Purpose: The prognostic nutritional index (PNI), which is derived from the albumin concentration and absolute lymphocyte number, is an effective indicator of cancer patients’ nutritional and immunological status. According to multiple studies, PNI was strongly linked to the prognosis of patients with non-small cell lung cancer (NSCLC). The predictive value of PNI for survival outcomes in NSCLC patients receiving immune checkpoint inhibitors (ICIs) is still in dispute at present. This meta-analysis is devoted to fill this information gap and investigate the predictive ability of PNI in NSCLC patients treated with ICIs. Methods: The PubMed, Embase, Cochrane Library databases, and conference proceedings were searched for eligible studies without language restriction. Overall survival (OS) and progression-free survival (PFS) were included. The predictive value of PNI was estimated using hazard ratios and their 95% confidence intervals. Results: Thirteen relevant retrospective cohort studies were included and these studies included 1119 patients with stage III-IV NSCLC. Lower PNI status was found to be an independent risk factor for worse survival outcomes in patients with NSCLC (OS HR = 2.68; 95%CI: 1.76–4.06; P

ABSTRACT: The objective of the following study was to investigate the effects of naturally oxidized corn oil on the antioxidant capacity and lipid metabolism of broilers. A total of 450, 1-day-old Arbor Acres male broilers were randomly divided into 5 treatments with 6 replicate cages and 15 birds/cage. The dietary treatment array consisted of ratios of naturally oxidized corn oil to non-oxidized corn oil from 0:100, 25:75, 50:50, 75:25, and 100:0, respectively. Serum, liver, and abdominal fat samples were taken at 42 d. The results showed that the liver organ index, liver catalase (CAT) activity, malondialdehyde (MDA) content, and the serum aspartate aminotransferase (AST) content had significant quadratic relationships with the ratio of naturally oxidized corn oil (P < 0.05). Inflammatory infiltrating cells appeared in the liver of the 50% and 75% oxidized corn oil group. The percentage of abdominal fat, and serum free fatty acids (FFA) content increased linearly with the increased proportion of oxidized corn oil (P < 0.05). The mRNA expression of NADH quinone oxidoreductase 1 (NQO-1), nuclear factor kappa B (NF-κB), toll-like receptor-4 (TLR-4), peroxisome proliferators activate receptor-α (PPARα), carnitine acyltransferase (CPT1), and acyl-coenzyme oxidase (ACO) of the liver increased linearly while oxidized corn oil increased in the diet (P < 0.05). Diets containing 100% oxidized corn oil significantly changed the mRNA expression of liver Caveolin compared with other treatment groups (P < 0.05). Taken together, this study demonstrated that naturally oxidized corn oil could change liver lipid metabolism and accelerate lipid deposition of broilers by upregulating PPARα.

In terms of treatment, a particularly targeted drug is needed to combat the COVID-19 pandemic. Although there are currently no specific drugs for COVID-19, traditional Chinese medicine(TCM) is clearly effective. It is recommended that through data analysis and mining of TCM cases (expert experience) and population evidence (RCT and cohort studies), core prescriptions for various efficacy can be obtained. Starting from a multidimensional model of regulating immunity, improving inflammation, and protecting multiple organs, this paper constructs a multidimensional model of targeted drug discovery, integrating molecular, cellular, and animal efficacy evaluation. Through functional activity testing, biophysical detection of compound binding to target proteins, multidimensional pharmacodynamic evaluation systems of cells (Vero E6, Vero, Vero81, Huh7, and caca2) and animals (mice infected with the new coronavirus, rhesus macaques, and hamsters), the effectiveness of effective preparations was evaluated, and various efficacy effects including lung moisturizing, dehumidification and detoxification were obtained. Using modern technology, it is now possible to understand how the immune system is controlled, how inflammation is reduced, and how various organs are protected. Complete early drug characterization and finally obtain effective targeted TCM. This article provides a demonstration resource for the development of new drugs specifically for TCM.

Background: The effect of chemical exposure on obesity has raised great concerns. Real-world chemical exposure always imposes mixture impacts, however their exposure patterns and the corresponding associations with obesity have not been fully evaluated. Objectives: To discover obesity-related mixed chemical exposure patterns in the general U.S. population. Methods: Sparse Decompositional Regression (SDR), a model adapted from sparse representation learning technique, was developed to identify exposure patterns of chemical mixtures with exclusion (non-targeted model) and inclusion (targeted model) of health outcomes. We assessed the relationships between the identified chemical mixture patterns and obesity-related indexes. We also conducted a comprehensive evaluation of this SDR model by comparing to the existing models, including generalized linear regression model (GLM), principal component analysis (PCA), and Bayesian kernel machine regression (BKMR). Results: Eight core exposure patterns were identified using the non-targeted SDR model. Patterns of high levels of MEP, high levels of naphthalene metabolites (ΣOH-Nap), and a pattern of high exposure levels of MCOP, MCNP, and MCPP were positively associated with obesity. Patterns of high levels of BP3, and a pattern of higher mixed levels of MPB, PPB, and MEP were found to have negative associations. Associations were strengthened using the targeted SDR model. In the single chemical analysis by GLM, BP3, MBP, PPB, MCOP, and MCNP showed significant associations with obesity or body indexes. The SDR model exceeded the performance of PCA in pattern identification. Both SDR and BKMR identified a positive contribution of ΣOH-Nap and MCOP, as well as a negative contribution of BP3 and PPB to obesity. Conclusion: Our study identified five core exposure patterns of chemical mixtures significantly associated with obesity using the newly developed SDR model. The SDR model could open a new avenue for assessing health effects of environmental mixture contaminants.

Summary: Background: Epidermal growth factor receptor (EGFR) is an essential target for cancer treatment. However, EGFR inhibitor erlotinib showed limited clinical benefit in pancreatic cancer therapy. Here, we showed the underlying mechanism of tumor microenvironment suppressing the sensitivity of EGFR inhibitor through the pancreatic stellate cell (PSC). Methods: The expression of alpha-smooth muscle actin (α-SMA) and hypoxia marker in human pancreatic cancer tissues were detected by immunohistochemistry, and their correlation with overall survival was evaluated. Human immortalized PSC was constructed and used to investigate the potential effect on pancreatic cancer cell lines in hypoxia and normoxia. Luciferase reporter assay and Chromatin immunoprecipitation were performed to explore the potential mechanisms in vitro. The combined inhibition of EGFR and Met was evaluated in an orthotopic xenograft mouse model of pancreatic cancer. Findings: We found that high expression levels of α-SMA and hypoxia markers are associated with poor prognosis of pancreatic cancer patients. Mechanistically, we demonstrated that hypoxia induced the expression and secretion of HGF in PSC via transcription factor HIF-1α. PSC-derived HGF activates Met, the HGF receptor, suppressing the sensitivity of pancreatic cancer cells to EGFR inhibitor in a KRAS-independent manner by activating the PI3K-AKT pathway. Furthermore, we found that the combination of EGFR inhibitor and Met inhibitor significantly suppressed tumor growth in an orthotopic xenograft mouse model. Interpretation: Our study revealed a previously uncharacterized HIF1α-HGF-Met-PI3K-AKT signaling axis between PSC and cancer cells and indicated that EGFR inhibition plus Met inhibition might be a promising strategy for pancreatic cancer treatment. Funding: This study was supported by The National Natural Science Foundation of China.

Precipitation extremes are expected to increase in a warming world, which could have substantial impacts on the environment, social property, and human health, especially in densely populated regions. In this study, the Yangtze River Delta (YRD) was used as a case study to investigate the spatiotemporal characteristics of daily, daytime, and nighttime extreme precipitation events (EPEs), and the population exposure to EPEs based on observational precipitation and population data. The EPEs both in days (duration) and amount (magnitude) showed obvious south-north gradients, with high values occurring in the south and low values in the north. A few stations in the northern parts of the YRD showed weak decreasing trends in extreme precipitation days and amounts during 1961–2018, whereas most of the stations showed positive trends. The stations with significantly increasing trends were mainly located in the central and eastern parts of the YRD. All the EPE indices for the whole area showed increasing trends during 1961–2018. Population exposure to daily, daytime, and nighttime extreme precipitation days (amounts) increased by 37% (40%), 34% (39%), and 41% (41%), respectively, from the early period (1984–1993) to the later period (2009–2018). The significant increase in total exposure to EPEs was dominated by the effect of rapid population growth during 1984–2018. An atmospheric circulation analysis of the EPEs in 2016 showed that the anomalously strong warm and wet southwesterly water–vapor transport from April to October (except for August) on the northwest side of the West Pacific subtropical high merged with cold air, resulting in abnormally more EPEs and exposure in 2016 than any other years of the study period in the YRD. The findings provide information useful to adaptation and mitigation policymaking for regions with conditions similar to the YRD.

Summary: Background: Emerging evidence suggests that dysbiosis in gut microbiota may contribute to the occurrence or development of several rheumatic diseases. Since gut microbiota dysbiosis is potentially modifiable, it has been postulated to be a promising preventive or therapeutic target for rheumatic diseases. However, the current understanding on the potential associations between gut microbiota and rheumatic diseases is still inadequate. Therefore, we aimed to synthesise the accumulating evidence for the relation of gut microbiota to rheumatic diseases. Methods: The PubMed, Embase and Cochrane Library were searched from inception to March 11, 2022 to include observational studies evaluating the associations between gut microbiota and rheumatic diseases. Standardised mean difference (SMD) of α-diversity indices between rheumatic diseases and controls were estimated using random-effects model. β-diversity indices and relative abundance of gut microbes were summarised qualitatively. Findings: Of the included 92 studies (11,998 participants), 68 provided data for α-diversity. Taken together as a whole, decreases in α-diversity indices were consistently found in rheumatic diseases (observed species: SMD = −0.36, [95%CI = −0.63, −0.09]; Chao1: SMD = −0.57, [95%CI = −0.88, −0.26]; Shannon index: SMD = −0.33, [95%CI = −0.48, −0.17]; Simpson index: SMD = −0.32, [95%CI = −0.49, −0.14]). However, when specific rheumatic diseases were examined, decreases were only observed in rheumatoid arthritis (observed species: SMD = −0.51, [95%CI = −0.78, −0.24]; Shannon index: SMD = −0.31, [95%CI = −0.49, −0.13]; Simpson index: SMD = −0.31, [95%CI = −0.54, −0.08]), systemic lupus erythematosus (Chao1: SMD = −1.60, [95%CI = −2.54, −0.66]; Shannon index: SMD = −0.63, [95%CI = −1.08, −0.18]), gout (Simpson index: SMD = −0.64, [95%CI = −1.07, −0.22]) and fibromyalgia (Simpson index: SMD = −0.28, [95%CI = −0.44, −0.11]), whereas an increase was observed in systemic sclerosis (Shannon index: SMD = 1.25, [95%CI = 0.09, 2.41]). Differences with statistical significance in β-diversity were consistently reported in ankylosing spondylitis and IgG4-related diseases. Although little evidence of disease specificity of gut microbes was found, shared alterations of the depletion of anti-inflammatory butyrate-producing microbe (i.e., Faecalibacterium) and the enrichment of pro-inflammatory microbe (i.e., Streptococcus) were observed in rheumatoid arthritis, Sjögren's syndrome and systemic lupus erythematosus. Interpretation: Gut microbiota dysbiosis was associated with rheumatic diseases, principally with potentially non-specific, shared alterations of microbes. Funding: National Natural Science Foundation of China (81930071, 81902265, 82072502 and U21A20352).

Background: Exposure to some conventional trace elements has been found to be associated with miscarriage; however, evidence for combined exposure is inconclusive. Therefore, it is important to explore the joint associations between toxic and essential trace elements and miscarriage. Methods: This cross-sectional study measured a wide range of element levels in the whole blood of pregnant women by using inductively coupled plasma mass spectrometry. The associations between individual elements and miscarriage were appraised using logistic regression model. Multi-exposure models, including Bayesian kernel machine regression (BKMR) and weighted quantile sum regression (WQS), were used to explore the mixed exposure to elements. Furthermore, grouped weighted quantile sum (GWQS) considered multiple elements with different magnitudes and directions of associations. Results: In logistic regression, the odds ratios (ORs) with a 95% confidence interval (CI) in the highest quartiles were 5.45 (2.00, 15.91) for barium, 0.28 (0.09, 0.76) for copper, and 0.32 (0.12, 0.83) for rubidium. These exposure–outcome associations were confirmed and supplemented by BKMR, which indicated a positive association for barium and negative associations for copper and rubidium. In WQS, a positive association was found between mixed elements and miscarriage (OR: 1.71; 95% CI: 1.07, 2.78), in which barium (75.7%) was the highest weighted element. The results of GWQS showed that the toxic trace element group dominated by barium was significantly associated with increased ORs (OR: 2.71; 95% CI: 1.74, 4.38). Additionally, a negative association was observed between the essential trace element group and miscarriage (OR: 0.32; 95% CI: 0.18, 0.54), with rubidium contributing the most to the result. Conclusions: As a toxic trace element, barium was positively associated with miscarriage both by individual and multiple evaluations, while essential trace elements, particularly rubidium and copper, exhibited negative associations. Our findings provide significant evidence for exploring the effects of trace elements on miscarriage.

Objectives: Based on data for a large population of patients from a single center accumulated over 22 years, the present study aimed to reveal an overall profile of movement disorders (MDs) in terms of their demographic features and surgical treatment. Methods: This study was conducted on 21,005 outpatients (2008–2019) and 5,126 inpatients (1998–2019) with MDs who underwent radiofrequency ablation (RFA) or deep-brain stimulation (DBS). Patients were categorized into those with Parkinson’s disease (PD), essential tremor (ET), dystonia, tics, or involuntary movements (IMs). The clinical data of these patients were analyzed retrospectively. Results: PD accounted for the largest proportion (75.4%) among surgically treated MD patients, and was associated with the highest surgical rate (18.8%), followed by ET (proportion: 12.1%, surgical rate: 10.4%) and dystonia (proportion: 5.7%, surgical rate: 5.7%). The male:female ratio was higher in surgical patients than in outpatients (1.49 vs. 1.27, p

[Cancer Treatment and Research Communications 32 (2022) 100582]This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors. A diagnostic discordance in the original pathology reports has been noticed and requires further evaluation, therefore the paper will be retracted.

ABSTRACT: This study was conducted to investigate the effects of naturally oxidized corn oil on the inflammatory reaction and intestinal health of broilers. Total 450, one-day-old Arbor Acres male broilers were randomly divided into 5 treatments with 6 replicate cages (15 birds in each replicate cage). The dietary treatment array consisted of the varying ratio of nonoxidized corn oil to naturally oxidized corn oil from 0:100, 25:75, 50:50, 75:25, and 100:0, respectively. The experimental period was 42 d. Serum, jejunum, and contents of cecum samples were taken at the age of 42 d of broilers. The results showed no significant difference in the body weight gain (BWG) with a different proportion of oxidized corn oil compared with the 0% oxidized oil group on d 42. The feed intake (FI), the concentration of immunoglobulin G (IgG), interferon-γ (IFN-γ), and interleukin-10 (IL10) in serum showed a significant quadratic response with the increase of oxidized oil concentration on d 42. The serum's concentration of IgG, IFN-γ, and IL-10 reached the highest value at 75% oxidized corn oil. In addition, the mRNA expression levels of interleukin-1β (IL-1β), IFN-γ, nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), and myeloid differentiation factor-88 (MyD88) in the jejunum were significantly affected by different proportions of oxidized corn oil, and the gene expression levels were highest at 75% oxidized corn oil on d 42. The mRNA expression of Bcl2-associated X (Bax) in the jejunum showed a significantly quadratic curve with the increase of oxidized oil concentration, and its gene expression was the highest after adding 50% oxidized corn oil according to the regression equation on d 42. The villus height/crypt depth and goblet cells of jejunum decreased linearly with the increasing proportion of oxidized corn oil and reached the lowest point after adding 100% oxidized corn oil on d 42. The β diversity showed the remarkable differentiation of microbial communities among 5 groups, and the microbial community of the 0% oxidized oil group was significantly separated from that of 75 and 100% oxidized oil groups in the cecum. Taken together, these results showed that a low dose of naturally oxidized corn oil is not harmful to the growth of broilers, while a high dose of oxidized corn oil will trigger the inflammatory response and adversely affect the gut health of broilers.

Neurofibromatosis type 1 is a rare genetic disorder, which is a benign nerve tumor resulting from aberrant growth of the cells of nerve sheath. NF1 patients were associated with multisystem involvement, characterized by neurofibroma, of which 50% were associated with plexus neurofibroma. Characteristically benign plexiform neurofibromas can cause pain, disfigurement, compression and functional changes. Although plexiform neurofibroma is common in the head and neck, the orbital plexiform neurofibroma is rare and easily confused with other orbital tumors. There is no consensus with regard to the treatment strategy of plexiform neurofibromas, current treatment has remained largely surgical, but comes with a high recurrence rate after partial removal. We describe a case of a 4-year-old patient with orbital plexiform neurofibroma who has a 3-year history of ptosis in the right eye. At the begining, we misdiagnosed it as hemangioma. After surgical resection, it was confirmed as plexiform neurofibroma by histopathological examination. One year after surgery, the tumor recurred, so surgical resection was performed again, and the ptosis was corrected. After that, the patients were followed up and examined annually, and no recurrence was found so far. This case shows that an infant or a child present with unilateral eye swelling and ptosis of the upper eyelid should be evaluated for orbital neurofibroma.

Fatigue cracking of viscoelastic asphalt composite materials is one of the major distresses in asphalt pavements. To quantify the weakening effect of the fatigue cracks on the mechanical properties of the viscoelastic asphalt composite materials, this study takes an asphalt-filler composite system as an example, and micromechanics models are proposed by combining Eshbely’s equivalent inclusion theory and Mori-Tanaka approach. Dynamic shear rheometer (DSR) tests are performed on the viscoelastic asphalt-filler composite systems with two volumetric contents of inclusion (10% and 27%) at different frequencies (0.1–100 Hz), temperatures (15℃, 20℃, 25℃) and strain levels (0.01%-0.1% for nondestructive DSR tests; 5%, 6%, 7% for destructive DSR tests). Results show that the predicted shear modulus results by a modified viscoelastic strengthening coefficient (VSC) model match with the test results at both low and high filler contents. Then a viscoelastic strengthening coefficient with fatigue cracks (VSC-f) model is proved being capable of accurately predicting the shear modulus for the viscoelastic asphalt-filler composite systems at different strain levels, temperatures, filler contents and damage levels. Both the VSC and the VSC-f model are derived to be dependent of loading frequency, temperature and filler content, but independent of strain level.

Gut microbiota forms a symbiotic relationship with the host and maintains the ecological balance of the internal and external environment of the human body. However, dysbiosis of the gut microbiota and immune deficiency, as well as environmental changes, can destroy the host-microbial balance, leading to the occurrence of a variety of diseases, such as polycystic ovary syndrome (PCOS), type 2 diabetes mellitus (T2DM), and obesity. Meanwhile, diseases can also affect gut microbiota, forming a vicious cycle. The role of the intestinal microbiota in different diseases have been proven by several studies; however, as a common target of PCOS and T2DM, there are few reports on the treatment of different diseases through the regulation of intestinal microbiota as the critical correlation. This review analyzed the common mechanisms of intestinal microbiota in PCOS and T2DM, including the dysbiosis of gut microbiota, endotoxemia, short-chain fatty acids, biotransformation of bile acids, and synthesis of amino acid in regulating insulin resistance, obesity, chronic inflammation, and mitochondrial dysfunction. The possible therapeutic effects of probiotics and/or prebiotics, fecal microbiota transplantation, bariatric surgery, dietary intervention, drug treatment, and other treatments targeted at regulating intestinal microbiota were also elucidated.

Background: A healthy gut microbiome is critical for glucose metabolism during pregnancy. In vivo studies indicate that trace element affects the composition and function of the gut microbiome and potentially leads to metabolic disorders but their relationships are largely unknown. We aimed to investigate whether the gut microbiome plays a role in the relationship between trace element exposure and gestational diabetes mellitus (GDM). Methods: In a prospective cohort study, serum levels of 22 trace elements and the fecal gut microbiome composition were assessed in 837 pregnant women in the second trimester between 22 and 24 weeks of pregnancy prior to GDM diagnosis. Regression and mediation analysis were used to explore the link between element exposure, the gut microbiome, and GDM. Results: 128 pregnant women (15.3%) were diagnosed with GDM. No individual trace elements were found significantly associated with GDM. In contrast, the composition of the gut microbiome was dramatically altered in women later diagnosed with GDM and characterized by lower alpha diversity and lower abundance of co-abundance groups (CAGs) composed of genera belonging to Ruminococcaceae, Coriobacteriales, and Lachnospiraceae. Rubidium (Rb) was positively associated with alpha diversity indices while mercury (Hg) and vanadium (V) showed negative associations. Elements including rubidium (Rb), thallium (Tl), arsenic (As), and antimony (Sb) were significantly correlated with GDM-related CAGs and mediation analysis revealed that Rb and Sb were inversely related to GDM risk by altering abundance levels of CAGs enriched for Lachnospiraceae, Coriobacteriales, and Ruminococcaceae. Conclusion: Our study indicates that trace element exposure is associated with specific gut microbiome features that may contribute to GDM development, which could provide a new avenue for intervening in environmental exposure-related GDM.

Compound precipitation and wind speed extremes can significantly impact ecosystems, socio-economies, and human health. The characteristics of precipitation or wind speed extremes have been extensively studied, however, concurrent precipitation and wind speed extremes have received very little attention to date. This study focused on the characteristics of concurrent precipitation and wind speed extremes from 1981 to 2018 in China based on daily precipitation and maximum wind speed observations. The results showed that concurrent precipitation and wind speed extremes were most likely to occur in southern China, especially in the southeast coastal areas (frequent tropical cyclones). The concurrent extremes showed a downward trend in 1981–2010 followed by an upward trend in 2011–2018. The reversal of the concurrent extremes around 2011 may be related to the increase in individual extreme precipitation and wind speed. We divided the concurrent extremes into four grades based on the magnitudes: mild, moderate, severe, and extreme. Concurrent extremes of all four grades all reversed around 2011; the mild and moderate events in particular showed significant increasing trends from 2011 to 2018. High percentages (more than 50%) of concurrent precipitation and wind extremes were found in summer months. We ranked the top 10 concurrent precipitation and wind speed extremes in 1981–2018 by magnitude to observe their spatial characteristics. We analyzed the mechanisms of the strongest concurrent event (top 1 on August 19, 1997) and the most recent concurrent event (top 2 on July 20, 2016) to conclude that the typhoon and strong convective weather systems can cause high-magnitude concurrent precipitation and wind speed extremes.

Background: The evaluation of the chemical impact on human health is usually constrained to the analysis of the health effects of exposure to a single chemical or a group of similar chemicals at one time. The effects of chemical mixtures are seldom analyzed. In this study, we applied three statistical models to assess the association between the exposure to a mixture of seven xenobiotics (three phthalate metabolites, two phenols, and two pesticides) and obesity. Methods: Urinary levels of environmental phenols, pesticides, and phthalate metabolites were measured in adults who participated in the U.S.-based National Health and Nutrition Examination Survey (NHANES) from 2013 to 2014. Body examination was conducted to determine obesity. We fitted multivariable models, using generalized linear (here both logistic and linear) regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models to estimate the association between chemical exposures and obesity. Results: Of 1269 individuals included in our final analysis, 38.5% had general obesity and 58.0% had abdominal obesity. In the logistic regression model established for each single chemical, bisphenol S (BPS), mono (carboxyoctyl) phthalate (MCOP), and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) were associated with both general and abdominal obesity (fourth vs. first quartile). In linear regression, MCOP was associated with BMI and waist circumference. In WQS regression analysis, the WQS index was significantly associated with both general obesity (OR = 1.63, 95% CI: 1.21–2.20) and abdominal obesity (OR = 1.66, 95% CI: 1.18–2.34). MCOP, bisphenol A (BPA), bisphenol S (BPS), and mono ethyl phthalate (MEP) were the most heavily weighing chemicals. In BKMR analysis, the overall effect of mixture was significantly associated with general obesity when all the chemicals were at their 60th percentile or above it, compared to all of them at their 50th percentile. MCOP, BPA, and BPS showed positive trends. By contrast, MECPP showed a flat and modest inverse trend. Conclusion: When comparing results from these three models, MCOP, BPA, and BPS were identified as the most important factors associated with obesity. We recommend estimating the joint effects of chemical mixtures by applying diverse statistical methods and interpreting their results together, considering their advantages and disadvantages. Keywords: Chemical mixture, Weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), Obesity, Obesogen

Background: N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Methods: An integrated model named “m6Ascore” is constructed based on RNA-seq data of m6A regulators in PDAC. Association of m6Ascore and overall survival is validated across several different datasets. Overlaps of m6Ascore and established molecular classifications of PDAC is examined. Immune infiltration, enriched pathways, somatic copy number alterations (SCNAs), mutation profiles and response to immune checkpoint inhibitors are compared between m6Ascore-high and m6Ascore-low tumors. Findings: m6Ascore is associated with dismal overall survival and increased tumor recurrence in PDAC as well as several other solid tumors including colorectal cancer and breast cancer. Basal-like (Squamous) PDAC has higher m6Ascore than that in the classical PDAC. Mechanism study showed m6Ascore-high tumors are characterized with reduced immune infiltration and T cells exhaustion. Meanwhile, m6Ascore is associated with genes regulating cachexia and chemoresistance in PDAC. Furthermore, distinct SCNAs patterns and mutation profiles of KRAS and TP53 are present in m6Ascore-high tumors, indicating immune evasion. m6Ascore-low tumors have higher response rates to immune checkpoint inhibitors (ICIs). Interpretation: These findings indicate m6Ascore can predict aggressiveness and immune evasion in pancreatic cancer. This model has implications for pancreatic cancer prognosis and treatment response to ICIs. Funding: This work was supported in part by National Institutes of Health (NIH) grants to M. Li (R01 CA186338, R01 CA203108, R01 CA247234 and the William and Ella Owens Medical Research Foundation) and NIH/National Cancer Institute Q39 award P30CA225520 to Stephenson Cancer Center.

Human gut virome play critical roles in maintaining gut microbial composition and functionality, as well as host physiology and immunology. Yet, there are insufficient amount of studies on this topic mainly due to methodological limitations, including enrichment of viruses (phages and host viruses) as well as short read-length from current sequencing technology. Here we developed a full working protocol for analyzing human gut virome using physical enrichment, reverse transcription and random amplification, and eventually the state-of-art single-molecule real-time sequencing (SMRT) platform of Oxford Nanopore Technology (ONT). We demonstrate that sequencing viral DNA directly, or viral cDNA/DNA after amplification using ONT achieves much longer reads and provides more information regarding virome diversity, many of the virome sequences do not have match in current databases. Moreover, direct DNA sequencing of virome provides first insights into the epigenetic modifications on phages, where signals of methylations can be directly detected. Our study demonstrates that progressing sequencing technology and bioinformatic improvements will bring more knowledge into virome composition, diversity and potentially their important functions.

Background: China, a developing country, has a particularly serious problem with metal pollution. We evaluated the association of metal exposure during pregnancy with maternal and neonatal thyroid function, and identified the critical window for maternal metal exposure effects on maternal and neonatal thyroid functions. Methods: The maternal urinary concentrations of mercury (Hg), cadmium (Cd), arsenic (As) and cesium (Cs) were determined in pregnant women during their first (n = 389) or third (n = 257) trimesters in a prospective cohort from 2014 to 2015 in Nanjing, China, using an inductively coupled plasma mass spectrometry (ICP-MS) instrument. Maternal serum-free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were measured by electrochemiluminescent microparticle immunoassays in the second and third trimesters. Neonatal TSH levels were detected 72 h after birth. Results: Hg (>0.162 µg/L), Cd (>0.084 µg/L), As (>0.348 µg/L) and Cs (>0.093 µg/L) were detectable in 76.9%, 90.1%, 100% and 100% of maternal urine samples from women in the first trimester of pregnancy. In the multiple adjusted linear regression models, maternal exposures to Hg and Cd in the first trimester were positively associated with maternal TSH levels in the second trimester (P

Endothelial-to-mesenchymal transition (EndMT) is closely related to the pathogenesis of various diseases, including cardiac fibrosis. Transforming growth factor (TGF)-β1 strongly induces EndMT, and sirtuin 1 (SIRT1) may play vital roles in TGF-β/Smad pathway inhibition. This study aimed to determine whether SIRT1 activation inhibits EndMT, thereby attenuating cardiac fibrosis. Cardiac fibrosis was induced in C57BL/6 mice by subcutaneously injecting isoproterenol. SIRT1 was activated and then suppressed by intraperitoneally injecting resveratrol (RSV) and EX527, respectively. EndMT was induced by adding TGF-β1 to H5V cells and measured by immunofluorescence and western blot. The role of SIRT1 in EndMT was determined by lentivirus-mediated overexpression of SIRT1. Interactions between SIRT1 and Smad2/3 in the TGF-β/Smad2/3 pathway were examined by immunoprecipitation. SIRT1 activation upregulated CD31 and vascular endothelial-cadherin, and downregulated α-smooth muscle actin, fibroblast-specific protein 1, and vimentin. SIRT1 upregulated and EX527 inhibited TGF-β receptor 1 (TGF-βR1) and P-Smad2/3 expression, respectively. SIRT1 activation and overexpression by RSV/SRT2104 and lentivirus transfection, respectively, reduced TGF-β1-induced EndMT. SIRT1 and Smad2/3 interaction was shown by immunoprecipitation in vivo and in vitro. TGF-βR1 and P-Smad2/3 expression was downregulated and Smad2/3 nuclear translocation was inhibited. In conclusion, SIRT1 activated by RSV attenuated isoproterenol-induced cardiac fibrosis by regulating EndMT via the TGF-β/Smad2/3 pathway.

In order to screen better flavone prescriptions of anti-Newcastle disease virus (NDV), four flavone ingredients of epimedium flavones (EF), baikal skullcap root flavones (BSRF), wild dendranthema flower flavones (WDFF), and sanchi flavones (SF) screened in previous experiments and their prescriptions were added into chicken embryo fibroblast monolayer with three drug-adding modes respectively. The cellular A(570) values, the highest virus inhibitory rates and the score based on virus inhibitory rate were calculated to compare their antiviral activity. In immune protective test, the effects of three preparations (EF-BSRF, EF-SF-WDFF-BSRF and EF-WDFF-BSRF screened by the results in vitro experiment) on NDV infection were compared in chickens vaccinated with ND vaccine then challenged with NDV. Blood was regularly sampled for serum antibody titer determination. The pathogenic and dead statuses of chickens were clinically examined. The results indicated that the A(570) values of the nine prescriptions, especially the foresaid three prescriptions at almost all concentrations in three drug-adding modes were significantly higher than that of the virus control group. The foresaid three prescriptions presented at the top five of the highest virus inhibitory rate, and located at the highest three of the score rank. The antibody titers and protective rates of the three prescriptions groups were higher than that of VC group, especially EF-SF-WDFF-BSRF group showed significant difference. These results indicated that flavone prescriptions composed with suitable compatibility could possess synergistical action of antiviral effect, ES-SF-WDFF-BSRF prescription could inhibit the cellular infectivity of NDV, improve the protective effect of ND vaccine and would be expected to exploit into a new-type antiviral drug., (Copyright © 2012 Elsevier B.V. All rights reserved.)