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Abstract Background Metabolic syndrome (MetS) imposes a significant health burden on patients globally. Chronic low-grade inflammation is pivotal in the onset and progression of this condition. However, the role of the novel inflammatory marker, red cell distribution width to albumin ratio (RAR), in the development of MetS remains unclear. Methods This population-based cross-sectional study utilized data from the 2011–2020 National Health and Nutrition Examination Survey (NHANES). Participants included individuals over 18 years old with complete data on serum albumin concentration, red cell distribution, and MetS and its components. MetS was defined using the criteria established by the National Cholesterol Education Program Adult Treatment Panel III. The calculation formula for RAR is: RAR = Red cell distribution width (%)/serum albumin (g/dL). Study participants were stratified into four quartiles based on RAR levels. Logistic regression analysis and subgroup analysis were employed to explore the independent interaction between RAR and MetS, as well as investigate the relationship between RAR levels and the specific components of MetS. Finally, the receiver operating characteristic (ROC) curve was used to assess the predictive efficacy of RAR for MetS. Results A total of 4899 participants were included in this study, comprising 2450 males and 2449 females; 1715 individuals (35.01%) were diagnosed with MetS. As the quartile of RAR increased, the proportion of individuals with MetS also increased. Spearman correlation analysis indicated a positive correlation between RAR and the insulin resistance index HOMA-IR. Logistic regression analysis, adjusting for multiple confounding factors, showed that each standard deviation increase in RAR was associated with a significant 1.665-fold increase (95% CI, 1.404–1.975; P

Abstract Background The white blood cell count to mean platelet volume ratio (WMR) is considered a promising inflammatory marker, and its recognition is increasing. Inflammation is closely related to metabolic diseases such as diabetes and its complications. However, there are currently no reports on the correlation between WMR and type 2 diabetic peripheral neuropathy (DPN). This study aims to explore the correlation between WMR and DPN in type 2 diabetes patients. By understanding this association, we hope to provide a theoretical basis for preventing DPN through the improvement of inflammatory responses. Methods This was a cross-sectional study involving 2515 patients with T2DM. Logistic regression analysis was conducted to assess the associations between WMR and DPN. Finally, the receiver operating characteristic curve (ROC curve) was employed to evaluate the predictive efficacy of WMR for DPN. Results Patients in higher WMR quartiles exhibited increased presence of DPN. Additionally, WMR remained significantly associated with a higher odds ratio (OR) of DPN (OR 4.777, 95% confidence interval [CI] 1.296–17.610, P

Verticillium longisporum (Vl43) is a soilborne hemibiotrophic fungal pathogen causing stem striping on oilseed rape (OSR) and severe yield losses. Breeding for resistant varieties is the most promising approach to control this disease. Here, we report the identification of Hva22c as a novel susceptibility factor and its potential for improving OSR resistance. Hva22c is a member of the Hva22 gene family, originally described for barley (Hordeum vulgare). Several Hva22 members have been located at the endoplasmic reticulum. Hva22c is up-regulated in response to Vl43 in both Arabidopsis and OSR. We demonstrate that knock-out of Hva22c in OSR by CRISPR/Cas9 and its homolog in Arabidopsis by T-DNA insertion reduced plants’ susceptibility to Vl43 infection and impaired the development of disease symptoms. To understand the underlying mechanism, we analysed transcriptomic data from infected and non-infected roots of hva22c knock-out and wild type plants. We identified a homozygous mutant with frame-shifts in all four BnHva22c loci displaying a vastly altered transcriptional landscape at 6 dpi. Significantly, a large set of genes was suppressed under mock conditions including genes related to the endomembrane systems. Among the up-regulated genes we found several defense-related and phytohormone-responsive genes when comparing mutant to the wild type. These results demonstrate that Hva22c is functionally required for a fully compatible plant-fungus interaction. Its loss of function reduces plant susceptibility, most likely due to endoplasmatic reticulum and Golgi dysfunction accompanied by additionally activated defense responses. These findings can help improve OSR resistance to V. longisporum infection.

Abstract Background Aquaporins (AQPs) facilitate water diffusion across biological membranes and are involved in all phases of growth and development. Small and basic intrinsic proteins (SIPs) belong to the fourth subfamily of the plant AQPs. Although SIPs are widely present in higher plants, reports on SIPs are limited. Rice is one of the major food crops in the world, and water use is an important factor affecting rice growth and development; therefore, this study aimed to provide information relevant to the function and environmental response of the rice SIP gene family. Results The rice (Oryza sativa L. japonica) genome encodes two SIP-like genes, OsSIP1 and OsSIP2, whose products are predominantly located in the endoplasmic reticulum (ER) membrane but transient localization to the plasma membrane is not excluded. Heterologous expression in a yeast aquaglyceroporin-mutant fps1Δ showed that both OsSIP1 and OsSIP2 made the cell more sensitive to KCl, sorbitol and H2O2, indicating facilitated permeation of water and hydrogen peroxide. In addition, the yeast cells expressing OsSIP2 were unable to efflux the toxic methylamine taken up by the endogenous MEP permeases, but OsSIP1 showed subtle permeability to methylamine, suggesting that OsSIP1 may have a wider conducting pore than OsSIP2. Expression profiling in different rice tissues or organs revealed that OsSIP1 was expressed in all tissues tested, whereas OsSIP2 was preferentially expressed in anthers and weakly expressed in other tissues. Consistent with this, histochemical staining of tissues expressing the promoter-β-glucuronidase fusion genes revealed their tissue-specific expression profile. In rice seedlings, both OsSIPs were upregulated to varied levels under different stress conditions, including osmotic shock, high salinity, unfavorable temperature, redox challenge and pathogen attack, as well as by hormonal treatments such as GA, ABA, MeJA, SA. However, a reduced expression of both OsSIPs was observed under dehydration treatment. Conclusions Our results suggest that SIP-like aquaporins are not restricted to the ER membrane and are likely to be involved in unique membrane functions in substrate transport, growth and development, and environmental response.

Abstract The increasing prevalence of antibiotic resistance in Cutibacterium acnes (C. acnes) requires the search for alternative therapeutic strategies. Antimicrobial peptides (AMPs) offer a promising avenue for the development of new treatments targeting C. acnes. In this study, to design peptides with the specific inhibitory activity against C. acnes, we employed a deep learning pipeline with generators and classifiers, using transfer learning and pretrained protein embeddings, trained on publicly available data. To enhance the training data specific to C. acnes inhibition, we constructed a phylogenetic tree. A panel of 42 novel generated linear peptides was then synthesized and experimentally evaluated for their antimicrobial selectivity and activity. Five of them demonstrated their high potency and selectivity against C. acnes with MIC of 2–4 µg/mL. Our findings highlight the potential of these designed peptides as promising candidates for anti-acne therapeutics and demonstrate the power of computational approaches for the rational design of targeted antimicrobial peptides.

Abstract Transarterial chemoembolisation (TACE) is a standard therapy for hepatocellular carcinoma (HCC). However, adverse events, including abdominal pain, are common. This study aimed to investigate and verify the feasibility of a nomogram model to predict severe abdominal pain after first conventional TACE (cTACE) among patients with HCC. Patients with HCC treated with cTACE between October 28, 2019, and August 5, 2022, at a single centre were enrolled (n = 216). Patients were divided into training and validation cohorts (ratio, 7:3). A visual analogue scale score between 7 and 10 was considered severe abdominal pain. A total of 127 (58.8%) patients complained of severe abdominal pain after first cTACE treatment. The nomogram considered age and tumour number and size. The nomogram demonstrated good discrimination, with a C-index of 0.749 (95% confidence interval [CI], 0.617, 0.881). Further, the C-index in the validation cohort reached 0.728 (95% CI 0.592, 0.864). The calibration curves showed ideal agreement between the prediction and real observations, and the nomogram decision curve analysis performed well. The nomogram model can provide an accurate prediction of severe abdominal pain in patients with HCC after first cTACE, aiding in the personalization of pain management and providing novel insights into hospital nursing.

ABSTRACT DEAD-box helicase (DDX) family members play differential roles in regulating innate antiviral immune response. However, the physiological roles played by DDX4 in antiviral innate immunity remain unclear. In this study, we unveiled that DDX4 acts as a positive regulatory molecule of Type-I interferon (IFN-I)-mediated antiviral activity. Our findings demonstrate that IFN-I upregulates DDX4 protein levels, and subsequently, overexpression of DDX4 enhances the IFN-I-mediated signaling pathway. This creates a positive feedback loop that amplifies the antiviral response. DDX4 was found to bind with deubiquitinase ubiquitin-specific protease 7 (USP7), leading to the disruption of the interaction between USP7 and suppressor of cytokine signaling 1 (SOCS1) and the subsequent degradation of SOCS1. This process enhances the antiviral function of IFN-I. Our findings provide new insights into the regulatory role of DDX4 in the IFN-I response.IMPORTANCEDDX4, identified as a putative RNA helicase that modulates RNA secondary structure through RNA binding, is primarily acknowledged for its role in regulating mRNA translation within the germline. Nevertheless, the extent of DDX4’s involvement in the antiviral innate immune response remains largely unexplored. This study presents evidence of a previously unrecognized positive feedback loop between DDX4 and the antiviral response, suggesting that disruption of this loop may serve as a novel mechanism for viral evasion. Furthermore, our findings elucidate a positive regulatory mechanism by which the DDX4/USP7/SOCS1 axis mediates the antiviral activity of Type-I interferon, which provides new insight into strategies for improving the efficacy of IFN-based antiviral therapy.

Land use in karst areas affects soil properties, impacting carbon sinks. Accurate estimation of carbon sink flux in karst areas through zoning and classification is crucial for understanding global carbon cycling and climate change. The peak cluster depression is the largest continuous karst landform region in southern China, with the depressions primarily covered by farmland and influenced by agricultural activities. This study focused on the Guancun Underground River Basin, a typical peak cluster depression basin, where sampling and analysis were conducted during the agricultural period of 2021–2022. Using hydrochemical analysis and isotopic methods, the results indicated that: (1) The primary hydrochemical type in the Guancun Underground River Basin is HCO3-Ca, with hydrochemical composition mainly controlled by carbonate rock weathering. (2) The primary sources of Cl−, SO42−, and NO3− are agricultural activities, with agriculture contributing 0.68 mmol/L to dissolved inorganic carbon (DIC), accounting for about 13.86%, as confirmed by ion concentration analysis and isotope verification. (3) The size of the depression area is proportional to the contribution of agricultural activities to DIC, while also being influenced by dilution effects. A comparison was made regarding the contribution of other land use types to DIC. The impact of land use on DIC in karst processes should not be overlooked, and zoning and classification assessments of carbon sink flux under different influencing factors contribute to carbon peaking and carbon neutrality goals.

Objective The inhibition of the Hippo pathway through targeting the Yes-associated protein (YAP) presents a novel and promising approach for treating tumors. However, the efficacy of YAP inhibitors in the context of breast cancer (BC) remains incompletely understood. Here, we aimed to investigate the involvement of YAP in BC's metabolic reprogramming and reveal the potential underlying mechanisms. To this end, we assessed the function of verteporfin (VP), a YAP-TEAD complex inhibitor, on the glycolytic activity of BC cells. Methods We evaluated the expression of YAP by utilizing immunohistochemistry (IHC) in BC patients who have undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) prior to biopsy/surgery. We employed RNA immunoprecipitation (RIP) and fluorescent in situ hybridization (FISH) assays to assess the interaction between YAP mRNA and human antigen R (HuR) in BC cells. The biological importance of YAP in the metabolism and malignancy of BC was evaluated in vitro. Finally, the effect of VP on glycolysis was determined by using 18F-FDG uptake, glucose consumption, and lactate production assays. Results Our studies revealed that high expression of YAP was positively correlated with the maximum uptake value (SUVmax) determined by 18F-FDG PET/CT imaging in BC samples. Inhibition of YAP activity suppressed glycolysis in BC. The mechanism underlying this phenomenon could be the binding of YAP to HuR, which promotes glycolysis in BC cells. Treatment with VP effectively suppressed glycolysis induced by YAP overexpression in BC cells. Conclusion VP exhibited anti-glycolytic effect on BC cells, indicating its therapeutic value as an FDA-approved drug.

AbstractPurpose Due to the poor and unpredictable prognosis of breast cancer (BC) patients with bone metastasis, it is necessary to find convenient and available prognostic predictors. This study aimed to recognize the clinical and prognostic factors related to clinical laboratory examination and to construct a prognostic nomogram for BC bone metastasis.Methods We retrospectively analyzed 32 candidate indicators from clinical features and laboratory examination data of 276 BC patients with bone metastasis. Univariate and multivariate regression analyses were performed to identify significant prognostic factors related to BC with bone metastasis. Nomogram was constructed and estimated by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis.Results Patients were randomly grouped into training (n = 197) and validation cohorts (n = 79). In training cohort, the multivariate regression analysis revealed that age, other organ metastasis sites, serum level of lactate dehydrogenase, globulin, white blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, and monocyte ratio were independent prognostic factors for BC with bone metastasis. The prognostic nomogram in training cohort exhibited areas under the ROC curve (AUCs) of 0.797, 0.782, and 0.794, respectively, for predicting 1-, 3-, and 5-year overall survival. In validation cohort, the nomogram still showed acceptable discrimination ability (AUCs: 0.723, 0.742, and 0.704) and calibration.Conclusion This study constructed a novel prognostic nomogram for BC patients with bone metastasis. It could serve as a potential tool of survival assessment to help individual treatment decision-making for clinicians.

Abstract Traffic flow prediction is an important part of intelligent transportation systems (ITS). However, sensor failures or the transmission distortion often occur in the process of data acquisition, which will inevitably cause the loss or abnormality of traffic flow data transmitted to the edge server. In this situation, it is necessary to share traffic flow data among different platforms. However, existing traffic flow prediction methods are facing two challenges in the process of traffic flow data sharing. First, user privacy is often leaked in the process of sharing traffic data on various platforms. Moreover, with the continuous updating of data, the efficiency and scalability of data sharing between different platforms will become lower and lower. In view of the above challenges, in this paper, we propose a novel prediction method for the missing traffic flow data caused by abnormal sensors, named $$ASMVP_{distr-LSH}$$ A S M V P d i s t r - L S H based on distributed locality-sensitive hashing (LSH) technique. At last, a case study is presented to illustrate the feasibility and effectiveness of our approach $$ASMVP_{distr-LSH}$$ A S M V P d i s t r - L S H .

Mycotoxins often contaminate rice, which are the secondary metabolites of fungi. Ustiloxins, a type of mycotoxin that has often been overlooked, pose a significant risk to human health. Therefore, identifying and controlling the pollution of ustiloxins in rice is required. In this study, we examined the natural contamination of rice with ustiloxins and their link to climate conditions. A total of 300 paddy samples were collected from six regions in southern China, and concentrations of ustiloxins A, B, C, D, and F were analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results showed that the occurrence of ustiloxins A, B, C, D, and F in paddies was found to be 55.7%, 41.3%, 29.0%, 93.7%, and 96.7%, respectively. Ustiloxin A had the highest mean (177.8 µg/kg) and maximum (3620.9 µg/kg) concentration, followed, in order, by ustiloxins C, B, D, and F. Furthermore, ustiloxin levels were significantly different depending on their origin, with the highest concentration in rice from Changde and Yueyang. And the regional difference in ustiloxins was related to the diversity of climate. A positive correlation between ustiloxin occurrence and mean humidity and precipitation was found in July and August of different regions, while mean temperature indicated a negative dependence. This is an essential survey of the contamination of rice with ustiloxins throughout southern China. The influence of climatic conditions on ustiloxins contamination was evaluated for the first time in our study. Overall, the rice samples examined in this study exhibited a high distribution of ustiloxins, suggesting that regulatory limits and the establishment of maximum allowable levels of ustiloxins in rice are necessary. This study provides a basis and guidance for the pollution situation and control strategy of ustiloxins in China.

Plant senescence is the last stage of plant development and a type of programmed cell death, occurring at a predictable time and cell. It involves the functional conversion from nutrient assimilation to nutrient remobilization, which substantially impacts plant architecture and plant biomass, crop quality, and horticultural ornamental traits. In past two decades, DNA damage was believed to be a main reason for cell senescence. Increasing evidence suggests that the alteration of epigenetic information is a contributing factor to cell senescence in organisms. In this review, we summarize the current research progresses of epigenetic and epitranscriptional mechanism involved in cell senescence of plant, at the regulatory level of DNA methylation, histone methylation and acetylation, chromatin remodeling, non-coding RNAs and RNA methylation. Furthermore, we discuss their molecular genetic manipulation and potential application in agriculture for crop improvement. Finally we point out the prospects of future research topics.

Servitization and digitalisation are current trends in high-quality sustainable development in manufacturing firms. To clarify how manufacturing companies can improve their environmental, social, and governance (ESG) performance through servitization and digitalisation, this study develops a moderated mediating effects model for analysis and further investigates corporate heterogeneity. This study uses the CSMAR and WIND databases and official website of the National Bureau of Statistics of China to obtain relevant data from 2013 to 2020. Python software was used to crawl corporate annual report data from the CNINFO Website for collation and analysis, obtaining a total of 1261 companies with 9379 sample values. The findings are as follows: (i) Servitization of manufacturing enterprises can significantly enhance their performance. (ii) The service-oriented transformation of manufacturing enterprises can significantly enhance their performance through digitalisation. In contrast to the capabilities of the practical application of digital technology, digital transformation primarily manifests itself as the capability of digital underpinning technology and the practical application of digital technology. (iii) The ESG performance of companies can positively regulate the promotion of service-oriented manufacturing enterprises towards digital transformation, as well as directly foster the development of digital transformation in the manufacturing industry. When examining the individual components of ESG performance, environmental and social performance have a positive effect on regulating the promotion of service-oriented manufacturing towards digital transformation and directly driving the digital transformation of manufacturing companies. However, the governance performance does not have a significant effect. Additionally, environmental performance can restrain the positive effect of digital transformation on performance in manufacturing companies. (iv) Manufacturing companies in the eastern part of the country are improving their performance mainly by promoting digitisation, whereas those in the central and western regions are improving their profitability mainly through servitization. This study reveals the mechanism of ESG performance and the role of servitization and digitalisation of manufacturing companies on performance and suggests new paths for the development of corporate sustainability strategies.

Abstract Alcohol consumption is a proven risk factor of dyslipidemia. In the present analysis, we investigated the association of alcohol intake with dyslipidemia, an emerging epidemic in China, in male patients with hypertension and diabetes mellitus. Our study participants were from a nationwide registry (n = 1181). A questionnaire was administered to collect information on alcohol intake. Dyslipidemia was defined as an elevated concentration of serum triglycerides (≥2.3 mmol/L), total (≥6.2 mmol/L) or low‐density lipoprotein (LDL) cholesterol (≥4.1 mmol/L), or a reduced high‐density lipoprotein (HDL) cholesterol (

Abstract The color of flowers is one of the main characteristics adopted for plants to attract pollinators to ensure the reproductive success of the plant, they are also important in their ornamental appeal in Narcissus plant. In this study, we identified a NtMYB12 locus encoding an R2R3-MYB transcription factor. Comparative transcriptome analysis of loss- and gain- of NtMYB12 tissue relative to wild-type narcissus showed NtMYB12 was mainly involved in flavonol and phenylpropanoid metabolic pathways. Biochemical evidences of dual-luciferase activity and chromatin immunoprecipitation assay supported that MYB12 directly bound to promoters of NtFLS, NtLAR, and NtDFR that were cloned by genome walking assay, and activated NtFLS and NtLAR expression but repressed NtDFR expression. More interestingly, NtMYB12 can interact with NtbHLH1 and NtWD40-1 proteins via R3 domain that were selected by transcriptome-based WGCNA and confirmed by yeast two hybrid, bimolecular fluorescence complementation and coimmunoprecipitation assay. Interaction of NtMYB12 with NtbHLH1 and NtWD40-1 forming MYB-bHLH-WD40 triplex specially activated NtDFR and NtANS expression and promoted (pro)anthocyanin accumulation, while NtMYB12 alone activated NtFLS and NtLAR expression and accumulated flavonols, but repressed NtDFR expression. These results indicated that NtMYB12 alone or NtMYB12-bHLH1-WD40-1 triplex requires for competition of metabolism fluxes between flavonol and (pro)anthocyanin biosynthesis. Graphical Abstract NtMYB12 dually functions on flavonol and proanthocyanin biogenesis via physically binding to NtFLS and NtLAR promoter activating their expression and on (pro)anthocyanin biosynthesis via NtMYB12-NtWD40-NtbHLH (MBW) triplex activating NtDFR and NtANS expression. Requirement of NtMYB12 alone or MBW complex for the competition between flavonol and anthocyanin biosynthesis results in narcissus colorized petal traits.

Retinal ganglion cell apoptotic death is the main pathological characteristic of glaucoma, which is the leading cause of irreversible blindness. Disruption of Ca2+ homeostasis plays an important role in glaucoma. Voltage-gated Ca2+ channel blockers have been shown to improve vision in patients with glaucoma. However, whether and how voltage-gated Ca2+ channels are involved in retinal ganglion cell apoptotic death are largely unknown. In this study, we found that total Ca2+ current densities in retinal ganglion cells were reduced in a rat model of chronic ocular hypertension experimental glaucoma, as determined by whole-cell patch-clamp electrophysiological recordings. Further analysis showed that L-type Ca2+ currents were downregulated while T-type Ca2+ currents were upregulated at the later stage of glaucoma. Western blot assay and immunofluorescence experiments confirmed that expression of the CaV1.2 subunit of L-type Ca2+ channels was reduced and expression of the CaV3.3 subunit of T-type Ca2+ channels was increased in retinas of the chronic ocular hypertension model. Soluble tumor necrosis factor-α, an important inflammatory factor, inhibited the L-type Ca2+ current of isolated retinal ganglion cells from control rats and enhanced the T-type Ca2+ current. These changes were blocked by the tumor necrosis factor-α inhibitor XPro1595, indicating that both types of Ca2+ currents may be mediated by soluble tumor necrosis factor-α. The intracellular mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and nuclear factor kappa-B signaling pathway mediate the effects of tumor necrosis factor-α. TUNEL assays revealed that mibefradil, a T-type calcium channel blocker, reduced the number of apoptotic retinal ganglion cells in the rat model of chronic ocular hypertension. These results suggest that T-type Ca2+ channels are involved in disrupted Ca2+ homeostasis and apoptosis of retinal ganglion cells in glaucoma, and application of T-type Ca2+ channel blockers, especially a specific CaV3.3 blocker, may be a potential strategy for the treatment of glaucoma.

Background In recent decades, ischemic stroke is increasingly prevalent, which has become the second leading cause of death and disability in the world. Insulin resistance and obesity are closely related to the development of ischemic stroke. At present, a number of studies have confirmed that obesity is associated with a variety of metabolic diseases and the role of insulin resistance played in the pathogenesis. But it is still unclear whether TyG, an indicator of insulin resistance, and TyG combined with obesity indicators can be used to predict ischemic stroke. Objective To assess the influencing factors of TyG, and its combination with different obesity indicators for new-onset ischemic stroke in a cohort of middle-aged and elderly people during a 10-year follow-up . Methods A prospective cohort design was used. The cohort included 9 406 middle-aged and elderly individuals who attended the 2011 Epidemiological Survey on Cancer Risk in Type 2 Diabetics conducted in six communities in Luzhou (including Qiancao, Xiaoshi, Longmatan, Baolaiqiao, Dashanping and Yutang) . Baseline data were collected, including TyG and its combination with different obesity indicators〔TyG-waist circumference (WC) , TyG-waist-to-height-ratio (WHtR) , TyG-body mass index (BMI) , and TyG-waist-to-hip-ratio (WHR) 〕. A 5-year follow-up initiated since June to November 2016, and a 10-year follow-up initiated since April to June 2021 were conducted, with new-onset ischemic stroke incidence (obtained through Luzhou Health Commission and Luzhou Center for Disease Control & Prevention) as an endpoint. For assessing the predictive value of baseline TyG, TyG-WC, TyG-WHtR, TyG-BMI, and TyG-WHR for new-onset ischemic stroke, patients were divided into quartiles of TyG〔Q1 (n=2 351) , Q2 (n=2 351) , Q3 (n=2 352) , Q4 (n=2 352) 〕, quartiles of TyG-WC〔Q1 (n=2 351) , Q2 (n=2 352) , Q3 (n=2 352) , Q4 (n=2 351) 〕, quartiles of TyG-WHtR〔Q1 (n=2 349) , Q2 (n=2 349) , Q3 (n=2 348) , Q4 (n=2 348) 〕, and quartiles of TyG-BMI〔Q1 (n=2 351) , Q2 (n=2 352) , Q3 (n=2 352) , Q4 (n=2 351) 〕, quartiles of TyG-WHR〔Q1 (n=2 343) , Q2 (n=2 343) , Q3 (n=2 342) , Q4 (n=2 342) 〕, respectively. Multivariate Logistic regression analysis was used to explore the relationship between TyG, TYG-WC, TYG-WTHR, TYG-BMI, TYG-WHR and new ischemic stroke in the elderly. Results During the follow-up period, 527 (5.6%) of the 9 406 middle-aged and elderly people had new-onset ischemic stroke. After adjusting for multiple confounding variables, multivariate Logistic regression analysis showed that the risk of new ischemic stroke in the fourth quartile group of TyG was 1.569 times higher than that in the first quartile group of TyG〔OR=1.569, 95%CI (1.007, 2.437) , P=0.046〕. The risk of new ischemic stroke increased by a factor of 1.467, 2.012, and 2.132 in the second, third and fourth quartile groups of TyG-WC〔 OR=1.467, 95%CI (1.010, 2.131) , P=0.044; OR=2.012, 95%CI (1.270, 3.187) , P=0.003; OR=2.132, 95%CI (1.119, 4.063) , P=0.021〕compared with that in the first quartile group of TyG-WC. The risk of new ischemic stroke increased by a factor of 1.481, 1.548, and 1.705 in the second, third and fourth quartile groups of TyG-BMI 〔OR=1.481, 95%CI (1.071, 2.048) , P=0.018; OR=1.548, 95%CI (1.066, 2.247) , P=0.022; OR=1.705, 95%CI (1.054, 2.759) , P=0.030〕compared with that in the first quartile group of TyG-BMI. Conclusion The risk of new-onset ischemic stroke in middle-aged and elderly type 2 diabetics in Luzhou increased with the elevation of TyG-WC and TyG-BMI, so TyG-WC and TyG-BMI may be predictors of new-onset ischemic stroke in this population.

Carbonate weathering is an important part of the global carbon cycle, acts as an atmospheric and soil CO2 sink. Driven by ecosystem factors and affected by global change, carbon sinks in karst areas have the characteristics of surface and underground carbon sinks.This work briefly introduces the relationship between the karst carbon cycle and global change, discusses the related scientific issues and main progress of karst carbon sinks, analyzes the potential of karst sink increases and land use changes, and further proposes a conceptual model of carbonate weathering processes based on the concept of karst critical zones.Carbon sink generated by weathering of carbonate rocks may contribute to the "missing sink" of the global carbon cycle and play a role in mitigating the release of soil CO2 to the atmosphere, thus becoming an important regulator of the item of "land use change" (ELUC) in the global carbon cycle model.The carbonate weathering process responds quickly to short-time scale environmental factors, which is the core driving mechanism that connects biological, hydrological, as well as geochemical processes in karst critical zones.The karst carbon cycle can be regarded as an extension or lateral component of the soil-ecosystem carbon cycle, which together constitute a complete terrestrial shallow surface carbon cycle system in karst areas.The negative feedback effect of carbonate weathering on the increase of atmospheric CO2 concentration and the continuous promotion of rock desertification control and ecological restoration contain huge potential for karst carbon sequestration and sink increase.The monitoring and research on seasonal and regional variations in soil CO2 should be strengthened, and an inverse model based on the correlation between soil CO2 and the watershed hydrochemistry index should be constructed to estimate the background of the regional carbon sink and evaluate the annual carbon sink increment and potential, thus providing a clearer and effective scheme and approach for karst sink increase.

Abstract The lithology and genesis of a dark grey clastic interlayer first encountered within the deepest potassium-rich salt body in the Simao Basin, southwestern China, were analysed. Analyses of the petrography, mineralogy, and element geochemistry of the layer revealed that (1) the layer contains quartz crystals with gulf corrosion edges and explosion cracks and angular volcanic ash-sized glasses; (2) the main mineral components of the crystal fragments are chlorite, illite, biotite, quartz, anhydrite, gypsum, magnesite, pyrite, molybdenite, clinopyroxene, and zircon; (3) the rare earth element patterns, Zr/TiO2 and Nb/Y diagrams as well as boron content all indicate a volcanic origin for the layer. Based on these observations, the layer is suggested to be an altered tuff associated with various volcanic fragments dominated by chlorite and formed after alteration of a parent tuff in an alkaline, salty, and low-temperature water body. Discovery of the layer indicates that the potash-bearing salt rocks could have taken in volcanic materials during these volcanic activities and provides the possibility of reliable zircon U‒Pb dating to determine the absolute age of the host rock, which is fundamental in studying the genetic mechanism of this deeply buried salt body.

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and is susceptible to develop gemcitabine (GEM) resistance. Decreased expression of human equilibrative nucleoside transporter 1 (hENT1) accompanied by compensatory increase of glycolysis is strongly associated with GEM resistance in TNBC. In this study, we investigated the treatment feasibility of combined hENT1 upregulation and miR-143-mediated inhibition of glycolysis for reversing GEM resistance in TNBC. Methods Experiments were performed in vitro and in vivo to compare the efficacy of GEM therapies. In this study, we established stable drug-resistant cell line, GEM-R cells, from parental cells (MDA-MB-231) through exposure to GEM following a stepwise incremental dosing strategy. Then GEM-R cells were transfected by lentiviral plasmids and GEM-R cells overexpressing hENT1 (GEM-R-hENT1) were established. The viability and apoptosis of wild-type (MDA-MB-231), GEM-R, and GEM-R-hENT1 cells treated with GEM or GEM + miR-143 were analyzed by CCK8 assay and flow cytometry. The RNA expression and protein expression were measured by RT-PCR and western blotting respectively. GEM uptake was determined by multiple reaction monitoring (MRM) analysis. Glycolysis was measured by glucose assay and 18F-FDG uptake. The antitumor effect was assessed in vivo in a tumor xenograft model by evaluating toxicity, tumor volume, and maximum standardized uptake value in 18F-FDG PET. Immunohistochemistry and fluorescence photography were taken in tumor samples. Pairwise comparisons were performed using Student’s t-test. Results Our results represented that overexpression of hENT1 reversed GEM resistance in GEM-R cells by showing lower IC50 and higher rate of apoptosis. MiR-143 suppressed glycolysis in GEM-R cells and enhanced the effect of reversing GEM resistance in GEM-R-hENT1 cells. The therapeutic efficacy was validated using a xenograft mouse model. Combination treatment decreased tumor growth rate and maximum standardized uptake value in 18F-FDG PET more effectively. Conclusions Combined therapy of exogenous upregulation of hENT1 expression and miR-143 mimic administration was effective in reversing GEM resistance, providing a promising strategy for treating GEM-resistant TNBC.

Cycloheximide (CHX) is a small molecule derived from Streptomyces griseus that acts as fungicide. As a ribosome inhibitor, CHX can restrict the translation elongation of eukaryotic protein synthesis. Once protein synthesis is inhibited by CHX, the level of intracellular proteins decreases by degradation through the proteasome or lysosome system. Thus, the CHX chase assay is widely recognized and used to observe intracellular protein degradation and to determine the half-life of a given protein in eukaryotes. Here, we present a complete experimental procedure of the CHX chase assay.Graphical overview

Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy of the skin, and its incidence is increasing annually. Once cSCC becomes metastatic, its associated mortality rate is much higher than that of cSCC in situ. However, the current treatments for progressive cSCC have several limitations. The aim of this study was to suggest a potential compound for future research that may benefit patients with cSCC. Methods: In this study, we screened the following differentially expressed genes from the Gene Expression Omnibus database: GSE42677, GSE45164, GSE66359, and GSE98767. Using strategies such as protein-protein interaction network analysis and the CYTOSCAPE plugin MCODE, key modules were identified and then verified by Western blotting. Subsequently, related signalling pathways were constituted in the SIGNOR database. Finally, molecular docking analyses and cell viability assay were used to identify a potential candidate drug and verify its growth inhibition ability to A431 cell line. Results: Fifty-one common differentially expressed genes were screened and two key modules were identified. Among them, three core genes were extracted, constituting two signalling pathways, both of which belong to the module associated with mitotic spindles and cell division. A pathway involving CDK1, the TPX2-KIF11 complex, and spindle organization was validated in a series of analyses, including analyses for overall survival, genetic alteration, and molecular structure. Molecular docking analyses identified the pyridine 2-carbaldehyde thiosemicarbazone (NSC689534), which interacts with TPX2 and KIF11, as a potential candidate for the treatment of cSCC. Conclusions: NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC.

Abstract Background Tumor-related osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. The diagnosis of TIO can be very difficult because of its nonspecific nature of clinical manifestations. Here we reported a case of young TIO patient with “painful knee joint with difficulty in moving” to improve the clinical diagnosis and treatment levels. Case presentation The patient’s clinical features were consistent with TIO. A tumor was successfully located in left tibial by 68Ga-DOTATATE PET/CT, and then was surgically resected. Upon pathologic assessment, the tumor was diagnosed as phosphaturia stromal tumor (PMT) with positive Vim staining. After the surgery, serum phosphate level rapidly recovered and symptoms significantly improved. Conclusion TIO should be considered in patients with chronically hypophosphorus osteomalacia in the setting of no family history. Early removal of the responsible tumors is clinically essential for the treatment, and imaging examination is of great significance for tumor localization.

Objective • The IKZF4(Ikaros family zinc finger 4) gene encodes Eos, a zinc finger transcription factor that belongs to the Ikaros family. High expression of Eos on Treg cells is important for the suppression of autoimmune responses and immune homeostasis. It has been suggested that the SNP in IKZF4 may influence the pathogenesis of AA(alopecia areata). The purpose of this study was to explore the relationship between IKZF4 polymorphism and AA in the Chinese Han population. Methods • We examined 459 patients and 434 controls in this study. The rs1701704 polymorphism was evaluated using HRM analysis and direct sequencing. Results • The prevalence of the C/C, A/C, and A/A genotypes in AA patients was 7.4%, 37.5% and 55.1%, respectively. There were significant differences in genotype distribution and allele frequencies between AA and the control group (P < .0001). The frequency of the C allele in the AA group was significantly higher (P < .0001), and the frequencies of the C allele and C/C genotype in patients with family history were higher (P < .0001; P = .001). Conclusions • The rs1701704 SNP of IKZF4 may be a genetic marker for assessing the risk of AA in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Background: Engineering thermal adaptations of enzymes is a popular field of study. Enzymes active at low temperature have been used in many industries; however, reports seldom describe improvements in enzyme activity at low temperatures using protein engineering. Results: Multiple amino acid sequence alignment of glycoside hydrolase (GH) family 32 showed an unconserved region located in the catalytic pocket. The exo-inulinase InuAGN25 showed the highest frequency of charged amino acid residues (47.4%) in this region among these GH 32 members. Notably, five consecutive charged amino acid residues (137EEDRK141) were modeled as a loop fragment in this region of InuAGN25. Deletion of the loop fragment broke two salt bridges, one cation–π interaction, and the α-helix–loop–310-helix structure at the N-terminal tail. The mutant exo-inulinase RfsMutE137Δ5 without the loop fragment was expressed in Escherichia coli, digested using human rhinovirus 3C protease for removal of the fused sequence at the N-terminus, and purified using immobilized metal affinity chromatography. Compared to the wild-type enzyme, the optimum temperature and t1/2 at 50°C of purified RfsMutE137Δ5 decreased by 10°C and 31.7 min, respectively, and the activities at 20°C and 30°C increased by 11% and 18%, respectively. Conclusions: In this study, we engineered the loop to obtain the mutant exo-inulinase that showed an improved performance at low temperatures. These findings suggest that the loop may be a useful target in formulating rational designs for engineering thermal adaptations of GH 32 exo-inulinases.How to cite: He L, Zhang R, Shen J. et al. Improving the low-temperature properties of an exo-inulinase via the deletion of a loop fragment located in its catalytic pocket. Electron J Biotechnol 2021;55. https://doi.org/10.1016/j.ejbt.2021.09.004

ObjectiveDespite previous research that focused on aspartate aminotransferase/alanine aminotransferase ratio (AAR) as predictors of type 2 diabetes mellitus (T2DM) and cardiovascular disease, there has been limited research evaluating the association between AAR and diabetic microvascular complications. This study aimed to investigate the association of AAR with diabetic peripheral neuropathy (DPN).MethodsA total of 1562 hospitalized patients with T2DM were divided into four groups according to AAR quartiles. The relationship between AAR and DPN and related parameters was explored by the Spearman correlation coefficients, multivariable logistic regression analysis, and receiver operating characteristic (ROC) curves.ResultsPatients with higher AAR quartiles had higher levels of vibration perception threshold (VPT) and presence of DPN, and AAR was positively associated with VPT and presence of DPN independent of sex, age, body mass index, and diabetic duration (P

The mometasone furoate (MF) and formoterol fumarate dihydrate (FF) inhalable microparticles prepared by different methods, such as micronized active pharmaceutical ingredients (APIs), microparticles of APIs prepared by spray-freeze drying technique (SFD APIs), and phospholipid microparticles of APIs prepared by SFD (SFD Lip-APIs), showed different inhaled drug delivery characteristics. Study on the physicochemical characteristics of those microparticles and the effect of matrix excipients on pharmacokinetic (PK) behaviors of inhalable microparticles is helpful for the development of new methods for inhalable microparticles with excellent performance of inhalation characteristics. In this study, the crystal state of the microparticles was investigated by powder X-ray diffraction and differential scanning calorimetry. The density was investigated by a bulk density method. The suspension and dispersion characteristics were determined by observing its state in hydrofluoroalkane (HFA). Meanwhile, the PK behaviors of SFD Lip-APIs in beagle dogs were also investigated by airway administration to evaluate the effect of phospholipids on drug release. The results indicated that the presence of phospholipids prevents the formation of solid bridges bonding to each other during SFD of pure drug solutions. In comparison to the conventional micronized microparticles, inhalable drug–phospholipid microparticles were easily dispersed and suspended in HFA. The embedded drugs were in a crystal state that endowed a better physical stability, and most interestingly, have similar PK behavior to the control (a mixed solution of MF/FF), suggesting that the phospholipids, as matrix excipients, had no effect on absorption. Given above, our designed SFD phospholipid microparticles may represent an efficient carrier for pulmonary delivery of MF and FF for further clinical treatment.

The m7G modification has been proven to play an important role in RNA post-transcriptional modification and protein translation. However, the potential role of m7G modification patterns in assessing the prognosis of Skin cutaneous melanoma (SKCM) and tumor microenvironment (TME) has not been well studied. In this study, we investigated and finally identified 21 available m7G-related genes. We used hierarchical clustering (K-means) to classify 743 SKCM patients into three m7G-modified subtypes named m7G/gene cluster-A, B, C. We found that both m7G cluster B and gene cluster B exhibited higher prognosis and higher immune cell infiltration in TME compared to other subtypes. EIF4E3 and IFIT5, two m7G related genes, were both markedly elevated in Cluster B. Then, we constructed an m7G score system utilizing principal component analysis (PCA) in order to evaluate the patients' prognosis. High m7G score subtype was associated with better survival prognosis and active immune response. Overall, this article revealed that m7G modification patterns were involved in the development of the tumor microenvironment. Evaluating patients' m7G modification patterns will enhance our understanding of TME characteristics and help to guide personal treatment in clinics in the future.

Abstract Background We investigated the association of alcohol consumption with cardiovascular and non-cardiovascular mortality in elderly Chinese men. Methods Our participants were recruited from residents living in a suburban town of Shanghai (≥60 years of age, n = 1702). Alcohol intake was classified as non-drinkers, past drinkers (stopped drinking for ≥12 months), and current light-to-moderate (1 to 299 g/week) and heavy drinkers (≥300 g/week). Alcoholic beverages were classified as beer/wine, rice aperitif and liquor/mix drinking. Results During 5.9 years (median) of follow-up, all-cause, cardiovascular and non-cardiovascular deaths occurred in 211, 98 and 113 participants, respectively. The corresponding incidence rates were 23.6/1000, 10.9/1000 and 12.6/1000 person-years, respectively. Both before and after adjustment for confounding factors, compared with non-drinkers (n = 843), past drinkers (n = 241), but not the current light-to-moderate (n = 241) or heavy drinkers (n = 377), had a higher risk of all-cause (adjusted hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.35–2.68, P = 0.0003) and non-cardiovascular mortality (HR 2.46, 95% CI 1.55–3.91, P = 0.0001). Similar trends were observed for cardiovascular mortality (HR 1.44, 95% CI 0.85–2.44, P = 0.18). In similar unadjusted and adjusted analyses, compared with the current beer/wine drinkers (n = 203), liquor/mix drinkers (n = 142), but not aperitif drinkers (n = 273), had a significantly higher risk of all-cause (HR 3.07, 95% CI 1.39–6.79, P = 0.006), and cardiovascular mortality (HR 10.49, 95% CI 2.00–55.22, P = 0.006). Similar trends were observed for non-cardiovascular mortality (HR 1.94, 95% CI 0.73–5.16, P = 0.18). Conclusions Our study showed risks of mortality associated with past drinking and liquor drinking in the elderly Chinese men.

Abstract Background Limited studies regarding the correlation of lipid accumulation product (LAP) with a decreased estimated glomerular filtration rate (eGFR) have yielded conflicting findings, and no report has demonstrated the relationship of LAP with chronic kidney disease (CKD), defined as the presence of albuminuria and/or a decreased eGFR. The purpose of this study was to estimate the possible correlation of LAP with CKD prevalence in Chinese community adults. Method In this cross-sectional study, LAP level of 7202 participants (age ≥ 40 years) was determined, and its possible association with CKD was evaluated by a multiple logistic regression model. Results Compared with subjects with non-CKD, non-albuminuria, and high eGFR, LAP levels significantly increased in female not male subjects with CKD, albuminuria, and low eGFR, respectively (all P

Abstract Background Previous studies that explored the relationship of serum albumin with diabetic peripheral neuropathy (DPN) have indicated inconsistent results. Thus, the present study aimed to evaluated the association between serum albumin and DPN, defined as vibration perception threshold (VPT) values ≥ 25 V and/or inability to feel the monofilament, in Chinese patients with type 2 diabetes mellitus (T2DM). Methods 1465 T2DM patients aged ≥ 16 years, who completed the measurement of serum albumin and DPN screening between 2012 and 2015, were included in the cross-sectional study. Correlation and multivariate logistic regression analysis models were used to evaluate the possible relationship between serum albumin and DPN. Results Patients with higher quartiles of serum albumin had significantly lower VPT values and prevalence of DPN compared with those with lower quartiles (P for trend

Clinically available pressurized metered-dose inhalers (pMDIs) mainly directly use micronized drugs as inhalable microparticles. Although technology for preparing pMDIs has proven to obtain clinically appropriate aerosol performance, the fine particle fraction and delivered dose content uniformity (DDCU) of pMDIs still need to be improved. DDCU problem is usually exacerbated by patients' handling errors prior to taking a dose. In this study, novel phospholipid microparticle inhalation pMDIs were prepared by a spray-freeze-drying process using mometasone furoate and formoterol fumarate dihydrate as model drugs and distearoylphosphatidylcholine as an excipient. Combined with the material composition, the atomization and freeze-drying processes were also studied. Our data showed that both atomization parameters of gas–liquid ratio and freeze-drying curve settings met the requirements of drug design. According to aerodynamic performance in vitro and DDCU evaluation, the performance of the phospholipid microparticle inhalation pMDI was better than that of the micronized drug microparticle pMDI. In conclusion, preparing pMDIs with particle engineering has the potential to ensure accuracy of quantification and to improve the efficiency of drug deposition in lungs in clinical practice.

Abstract Dyslipidemia is an emerging disease in China, especially in the presence of hypertension and diabetes mellitus. We investigated the association of dyslipidemia with the use of antihypertensive and antidiabetic agents. The study participants (n = 2423) were hypertensive and diabetic patients enrolled in a China nationwide registry. Serum mean ± (SD, except for serum triglycerides, median [interquatile range]) concentrations were 1.38 (0.97‐2.02) mmol/L, 4.85 ± 1.12 mmol/L, 1.30 ± 0.36 mmol/L, and 2.89 ± 0.92 mmol/L for triglycerides and total, high‐density lipoprotein (HDL), and low‐density lipoprotein (LDL) cholesterol, respectively. The prevalence of dyslipidemia was 18.9%, 13.5%, 16.6%, and 37.7% for hypertriglyceridemia (serum triglycerides ≥2.3 mmol/L), hypercholesterolemia (total cholesterol ≥6.2 mmol/L or LDL cholesterol ≥4.1 mmol/L), low HDL cholesterol (HDL cholesterol

Background: Long non-coding RNAs (lncRNAs) regulate gene expression in concert with microRNAs (miRNAs) and mRNAs. This study was designed to explore the potential roles of lncRNAs and their related competing endogenous RNA (ceRNA) networks in alopecia areata (AA). Methods: This study comprised six participants (three AA patients and three healthy individuals) whose serum lncRNA profiles were evaluated by lncRNA sequencing. Following differential expression analysis, and function enrichment analysis, a lncRNA-miRNA-mRNA network was then constructed using various bioinformatics tools and validated using quantitative reverse-transcription PCR (qRT-PCR). Results: We identified 220 mRNAs and 166 lncRNAs that were differentially expressed in AA patients. The differentially expressed mRNAs were predominantly associated with cytokine-cytokine receptor interactions, MAPK signaling and Ras signaling pathways. The differentially expressed lncRNAs were primarily associated with cytokine-cytokine receptor interactions, chemokine signaling pathways, axon guidance, and legionellosis. In addition, qRT-PCR analyses verified the upregulation of AC005562.1, AF131217.1, and RP11-251G23.5 and downregulation of RP11-231E19.1 in AA patients. Conclusion: We constructed a complex ceRNA network for AA and discovered that various RP11 lncRNAs including RP11-251G23.5 and RP11-231E19 may play a crucial role in the pathogenesis of AA via the regulation of the cytokine-cytokine receptor interaction pathway, which could serve as a therapeutic target for alopecia areata in clinical interventions.