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AimThe Triglyceride-Glucose (TyG) index, an indicator of insulin resistance, has been proposed as a predictor of cardiovascular diseases. However, its role in predicting stroke risk, particularly in low-income populations, is not well understood. This study aimed to investigate the predictive value of the TyG index for stroke incidence in a low-income Chinese population, with a focus on gender and age-specific differences.MethodsThis 10-year prospective cohort study included 3,534 participants aged ≥45 years from rural areas in northern China. Baseline data on demographic characteristics, lifestyle factors, and clinical measurements were collected. Participants were followed for stroke incidence, categorized into ischemic and hemorrhagic stroke. Multivariate logistic regression models were used to assess the association between the TyG index and stroke incidence, adjusting for potential confounders.ResultsDuring the follow-up period, 368 participants (10.4%) experienced a stroke, with 327 ischemic and 31 hemorrhagic strokes. TyG index was significantly associated with total and ischemic stroke incidence but not hemorrhagic stroke. After adjusting for confounding factors, for every one standard deviation increase in TyG index, the risk of stroke increased by 32% for overall stroke (RR: 1.32; 95% CI: 1.08-1.61; P=0.006) and 39% for ischemic stroke (RR: 1.39; 95% CI: 1.12-1.73; P=0.003). The risk of stroke in the highest TyG tertile levels (tertile 3) increased by 49% (RR: 1.49; 95% CI 1.11-1.99; P=0.007) for overall stroke, compared to those in the lowest tertile levels (tertile 1). For ischemic stroke, the risk of stroke increased by 53% (RR: 1.53; 95% CI 1.12-2.11; P=0.008) in the highest TyG tertile levels (tertile 3) compared to those in the lowest tertile levels (tertile 1).ConclusionThis 10-year prospective cohort study has established the TyG index as an independent predictor of both total and ischemic stroke incidence in a low-income Chinese population. The findings indicate that the TyG index is particularly effective in predicting stroke risk among women and older adults (≥60 years), but not for hemorrhagic stroke. These insights are crucial for improving clinical practice and stroke prevention strategies.

Abstract Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease.

With the gradual diversification of personalized usage scenarios, user requirements play a direct role in product design decisions. Due to the problem of fuzzy demand caused by user cognitive bias, traditional design methods usually focus on realizing product functions and cannot effectively match user requirements. Therefore, this paper proposes a complex product module division method for user requirements. The method constitutes of three tasks, requirement analysis of module division, design mapping of module division and scheme implementation of module division. Firstly, based on the progressive architecture from initial requirements to precise requirements, the effective user requirements are obtained through similarity recommendation. Secondly, according to the four types of knowledge of function, geometry, physics and design, the design structure matrix is constructed to complete the Requirement-Function-Structure mapping. The improved Fuzzy C-means Algorithm is used to solve the mapping model, and finally a module division scheme that meets the user requirements is obtained. Taking the chip removal machine as an example, the rationality and effectiveness of the method are verified. The results show that the product modules divided by this method can effectively meet the multiple user requirements.

Abstract Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.

Background: Vascular smooth muscle cell (VSMC) injury caused by the inflammatory response plays a key role in cardiovascular disease (CVD), and the vasoprotective effects of mineralocorticoid receptor blockers (MRBs) support the role of mineralocorticoid receptor (MR) activation. Methods: C57BL/6 mice and VSMCs isolated from rats were treated with aldosterone and esaxerenone. Caspase-1, GSDMD-N, IL-1β, and NR3C2 expression and DNA damage in aortic VSMCs were detected using immunohistochemistry, Western blotting, and TUNEL staining. Mitochondrial changes were detected by transmission electron microscopy (TEM). Reactive oxygen species (ROS), MitoTracker, JC-I, mitochondrial respiratory chain complexes I–V, and NR3C2 were detected using immunofluorescence and flow cytometry. Pyroptosis was detected with scanning electron microscopy (SEM). Results: After aldosterone treatment, the number of TUNEL-positive cells increased significantly, and the expression of caspase-1, GSDMD-N, and IL-1β increased. TEM revealed mitochondrial damage, and SEM revealed specific pyroptotic changes, such as cell membrane pore changes and cytoplasmic extravasation. Increased ROS levels and nuclear translocation of NR3C2 were also observed. These pyroptosis-related changes were reversed by esaxerenone. Conclusions: Aldosterone activates the MR and mediates mitochondrial damage, thereby inducing pyroptosis in VSMCs via the NLRP3/caspase-1 pathway. Esaxerenone inhibits MR activation and reduces mitochondrial damage and oxidative stress, thereby inhibiting pyroptosis.

Purpose: Cholestatic liver diseases are groups of hepatobiliary diseases without curative drug-based therapy options. Regulation of bile acid (BA) metabolism, hepatoperiductal fibrosis, and inflammatory response indicated present novel methods for the treatment of cholestatic liver disease. Costunolide (COS) from herb Saussurea lappa exerts a pharmacological effect of regulation of BA metabolism, liver fbrosis and inflammatory response. The present study aimed to clarify the pharmacodynamic effects of COS against the murine model of cholestatic liver disease. Methods: We established a murine model of cholestatic liver disease through chronic feeding of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 28 days. Two independent in vivo experiments were designed to reveal the pharmacological effect of COS against cholestatic liver disease. In the first experiment, two dosages of COS (10 and 30 mg/kg) were intraperitoneally injected into model mice daily for 14 days. In the second experiment, high dosage of COS (30 mg/kg) was intraperitoneally injected into control and model mice daily for 28 days. Results: In the evaluation of the hepatoprotective effect of COS, COS showed dosage-dependent improvement of cholestatic liver disease, including ductular reaction, hepatoperiductal fibrosis, and inflammatory response. The mechanism of COS-mediated hepatoprotective effects mainly relies on the regulation of BA metabolism, and the inflammatory response. DDC diet feed induced hepatic BA metabolism, transport and circulation dysfunction. COS treatment not only regulated the BA metabolism and transport gene, but also reprogrammed hepatic primary and secondary BA concentrations. DDC induced hepatic infiltrated monocytes derived macrophages and lymphocytes were inhibited, while Kupffer cells were preserved by COS treatment. The liver elevating inflammatory cytokines of DDC diet feed were alleviated by COS. Moreover, high dosage of 30 mg/kg COS treatment for 28 days resulted in no significant serological changes and no obvious hepatic histopathological changes when compared with control mice. Conclusion: COS protected against DDC diet feeding-induced cholestatic liver disease since COS regulated BA metabolism, ductular reaction, hepatoperiductal fibrosis and inflammatory response. COS is suggested as a potential natural product for the treatment of cholestatic liver disease.

Background: Cholestatic liver disease (CLD) encompasses a broad spectrum of etiologically heterogeneous hepatobiliary disorders with common features, including ductal reaction, periductal fibrosis, and inflammatory response. Scoparone (SCO) is a bioactive component of the herbal medicine Artemisia capillaris Thunb that is used clinically for the treatment of hepatic dysfunction, cholestasis and jaundice. Aim: To investigate the therapeutic effect of SCO against 3,5-diethoxycarbonyl- 1,4- dihydrocollidine (DDC) induced CLD. Materials and methods: In the present study, two independent experiments were conducted to comprehensively analyze the hepatoprotective and hepatotoxicity effects of SCO against DDC diet-induced CLD. First, three doses of SCO (5, 15, and 45 mg/kg) were injected intraperitoneal daily for 14 days in DDC diet-induced CLD for the pharmacological research. Then, a high dose of SCO (45 mg/kg) was used for 28 days in negative and CLD model mice to evaluate the therapeutic potential of SCO. Results: DDC-induced CLD mice exhibited hepatomegaly and weight loss with hepatic pathological features including hepatocyte and bile duct damage, bile acid metabolism abnormalities, peribiliary fibrosis, and inflammatory factor infiltration. Treatment with three doses of SCO (5, 15 and 45 mg/kg) produced dose-dependent hepatoprotective effects, attenuated fine bile duct responses, ameliorated peribiliary fibrosis and suppressed intrahepatic inflammatory responses. SCO inhibited the expression of Cyp2b10, a bile acid phase I metabolizing enzyme, and Sult2a1, a phase II metabolizing enzyme, in DDC diet-induced CLD mice. Meanwhile, SCO inhibited the expression of Tgfb1, aSMA, Timp1 and Col1a1. SCO suppressed liver inflammation by reducing the infiltration of myeloid cells and lymphocytes. SCO suppressed DDC-induced lymphocyte infiltration. In addition, normal control mice treated with SCO showed no significant changes in liver injury, bile duct reaction, peribiliary fibrosis and inflammatory infiltration. Conclusion: SCO exerts a pharmacological effect on the reprogramming of hepatic bile acid metabolism, hepatic fibrosis and inflammatory response, thus having potential for the treatment of CLD.

Abstract Background Metabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells. Methods A retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage. Results We found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression. Conclusions Our data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.

Chronic cholestasis liver injury occurs in progressive hepatobiliary diseases that eventually lead to end-stage liver problems without curable treatment. Great advances in the molecular mechanism suggest the therapeutic pathways for the regulation of bile acid (BA) metabolism and inflammation response. Honokiol (HNK) is a natural ingredient from herb Magnolia officinalis that is used for eliminating toxins, reducing stagnation, resolving stasis and enhancing body immunity. In the present study, we designed two dependent experiments for the evaluation of the hepatoprotective and hepatotoxicity effects of HNK. Chronic cholestasis liver injury model was established by 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet feed for 4 weeks that featured as a ductular reaction, BAs accumulation, fibrosis and inflammatory response. In the first experiment, two dosages of HNK (2 and 10 mg/kg) were daily intraperitoneal injected from day 15 to day 28 for the treatment of chronic cholestasis liver injury. HNK displayed a dosage-dependent reduction of ductular reaction, regulation of BAs metabolism, remission of fibrosis and inhibition of inflammatory response. In the second experiment, the high dosage of HNK (10 mg/kg) was daily intraperitoneal injected into normal control and model mice for 4 weeks. HNK-mediated hepatoprotective effect is mainly involved in the regulation of BAs metabolism, decrease of inflammatory cell infiltration and inhibition of pro-inflammatory cytokines production. Moreover, HNK showed no hepatotoxicity even though the high dosage of HNK treatment for 28 days in control mice resulted in no obvious change in hepatic histopathological and serological changes. In conclusion, HNK exerts dosage-dependent pharmacological effect against DDC diet-induced chronic cholestasis liver injury. Further investigation of the preclinical pharmacodynamics effect and toxicity research about HNK is helpful for active therapeutic drug development for the treatment of cholestasis liver disease.

IntroductionThe anti-tumor vindoline and catharanthine alkaloids are naturally existed in Catharanthus roseus (C. roseus), an ornamental plant in many tropical countries. Plant-specific TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factors play important roles in various plant developmental processes. However, the roles of C. roseus TCPs (CrTCPs) in terpenoid indole alkaloid (TIA) biosynthesis are largely unknown.MethodsHere, a total of 15 CrTCP genes were identified in the newly updated C. roseus genome and were grouped into three major classes (P-type, C-type and CYC/TB1).ResultsGene structure and protein motif analyses showed that CrTCPs have diverse intron-exon patterns and protein motif distributions. A number of stress responsive cis-elements were identified in promoter regions of CrTCPs. Expression analysis showed that three CrTCP genes (CrTCP2, CrTCP4, and CrTCP7) were expressed specifically in leaves and four CrTCP genes (CrTCP13, CrTCP8, CrTCP6, and CrTCP10) were expressed specifically in flowers. HPLC analysis showed that the contents of three classic TIAs, vindoline, catharanthine and ajmalicine, were significantly increased by ultraviolet-B (UV-B) and methyl jasmonate (MeJA) in leaves. By analyzing the expression patterns under UV-B radiation and MeJA application with qRT-PCR, a number of CrTCP and TIA biosynthesis-related genes were identified to be responsive to UV-B and MeJA treatments. Interestingly, two TCP binding elements (GGNCCCAC and GTGGNCCC) were identified in several TIA biosynthesis-related genes, suggesting that they were potential target genes of CrTCPs. DiscussionThese results suggest that CrTCPs are involved in the regulation of the biosynthesis of TIAs, and provide a basis for further functional identification of CrTCPs.

Accumulated oncometabolites in the tumor microenvironment (TME) suppresses the metabolism, expansion, and function of T cells. Immunosuppressive TME also impeded Chimeric Antigen Receptor (CAR)-T cells mediated cytotoxicity since CAR-T cells had to adapt the in vivo metabolic characteristics with high levels of oncometabolites. We screened oncometabolites for the inhibition of glucose uptake in CD8 + T cells and found Kynurenine (Kyn) showed the strongest inhibiting effect on glucose uptake. In vitro experiments showed that 120 μM Kyn treatment in CD8 + T cells resulted in inhibiting the expansion of CD8 + T cells, decreasing the production of granzyme B and interferon-γ. CAR-T cells mediated cytotoxicity was also impaired by the high Kyn treatment from killing assay. We then explored the anti-tumor effect of Kynureninase (KYNU) modified CAR-T cells through catabolism o oncometabolites Kyn. KYNU over-expression (OE) CAR-T cells showed a superior killing effect against cancer cells even in the immunosuppressive TME with high Kyn levels. In vivo experiments confirmed KYNU-OE CAR-T cells showed an excellent anti-tumor effect in a TME with high Kyn levels since it improved the survival of mice bearing NALM6 cancer cells and NALM6-IDO1 cancer cells. The KYNU-modified CAR-T cells displayed distinct phenotypes related to the expansion, function, and memory differentiation status of CAR-T cells. This study explores an immunotherapy strategy for patients with alterations in Kyn metabolism. KYNU-OE CAR-T cells take advantage of Kyn catabolism to improve anti-tumor activity in the metabolic immunosuppressive TME with high Kyn.

Renal fibrosis is the inevitable pathway of the progression of chronic kidney disease to end-stage renal disease, which manifests as progressive glomerulosclerosis and renal interstitial fibrosis. In a previous study, we observed severe interstitial fibrosis in the contralateral kidneys of 6-month unilateral ureteral obstruction (UUO) rats, which was accompanied by increased macrophage infiltration and phenotypic transformation; after eplerenone administration, these effects were reduced. Therefore, we hypothesized that this effect was closely related to mineralocorticoid receptor (MR) activation induced by the increased aldosterone (ALD) level. In this study, we used uninephrectomy plus continuous aldosterone infusion in mice to observe whether aldosterone induced macrophage-to-myofibroblast transition (MMT) and renal fibrosis and investigated the signaling pathways. Notably, aldosterone induced predominantly M1 macrophage-to-myofibroblast transition by activating MR and upregulating TGF-β1 expression, which promoted renal fibrosis. These effects were antagonized by the MR blocker esaxerenone. These findings suggest that targeting the MR/TGF-β1 pathway may be an effective therapeutic strategy for renal fibrosis.

Conceptual design is a key link in the process of complex product design, and it is very important to select the appropriate design scheme; however, there are many types and inaccuracies of the evaluation data, and there is a problem of mutual influence between the evaluation criteria, which leads to unreliable decision making of the optimal solution. In order to solve this problem, a decision-making method based on intuitionistic fuzzy sets (IFS) and prospect theory is proposed. This method can be used for symmetric and asymmetric evaluation data. The evaluation data are classified according to different expression types and unified using intuitionistic fuzzy numbers. The intuitionistic fuzzy prospect value of decision information is calculated using prospect theory, and the prospect transformation of decision information is completed. At the same time, the Gray Relational Analysis (GRA) method and the Criteria Importance Though Intercriteria Correlation (CRITIC) method are used to calculate the subjective and objective weights of the technical and economic evaluation indexes of the product, and the combination weights are given; then, based on the evidence theory, the basic probability distribution of the evidence chain of all conceptual design schemes is synthesized, and the comprehensive prospect evaluation results of the schemes are obtained to complete the optimization of the conceptual design schemes. Finally, the effectiveness of the proposed method is verified by the conceptual design of the chip removal system of the deep hole machining machine tool. This work provides a promising method for decision makers to optimize the design scheme and provides insights into multi-objective decision-making problems.

Abstract In the study, well-crystallized nano-diamonds with an average size of 3.8 nm are obtained via femtosecond laser ablation. Both steady-state and transient luminescence are observed. The luminescence peaks of nano-diamonds shift from 380 to 495 nm when the excitation wavelength changes from 280 to 420 nm. After passivation by polyethylene glycol-400N, the surface of nano-diamonds is significantly oxidized, which is verified by Raman and UV-Vis absorption spectra. Furthermore, there is no change in all the luminescence wavelengths, although the maximum intensity increases by 10 times. Time-resolved luminescence spectra reveal that trapping states can be modified by surface passivation, and this leads to stronger luminescence with a longer lifetime.

ObjectiveCalcium is present in serum mainly in filterable and bound forms, and Ca2+ is a major key to modulate signaling pathways that control oncogenesis and oncochannels associated with several types of cancer. However, the biological significance of serum calcium and its related mechanism with estrogen in endometrial cancer (EC) still remains elusive. This study aims to ascertain the relationship between serum calcium and clinicopathology in EC.MethodsRetrospective assessment of a total of 502 patients diagnosed with EC after surgery in Peking University People's Hospital from 2010 to 2018. Preoperative serum ionized calcium and the albumin corrected calcium was calculated in quartiles for various postoperative clinicopathological characteristics, logistic regression adjusted for potential confounders. Intracellular calcium homeostasis change induced by estrogen was detected by confocal analysis. Downstream pathways were analyzed by transcriptome and proteomics. Mitochondrial Ca2+ and ROS (reactive oxygen species) level was detected by confocal and flow cytometry. Lysosomal morphological and membrane changes were verified by confocal or Western blot assays.ResultsHigh level of albumin-corrected serum calcium was significantly correlated with EC clinicopathological characteristics progression include lymph vascular space invasion, lymph nodes metastasis, myometrial invasion, and cervical invasion. Calcium homeostasis regulated by estrogen in EC cells derived from extracellular calcium influx but not the release of the endoplasmic reticulum. Proteomic and bioinformatic analysis revealed the calcium influx might be involved in the regulation of autophagy and mitochondrial-related pathways. Mechanistic investigation demonstrated that calcium influx acted on the function of mitochondrial ROS and lysosomal activity.ConclusionOur findings revealed that serum calcium level was significantly related to poor outcomes. The extracellular calcium influx induced by estrogen was targeted to mitochondrial ROS and lysosome activity, which should be oriented to improve EC therapeutic strategies.

A novel direct electrochemical sensor, based on a pyridine diketopyrrolopyrrole/graphene oxide nanocomposite-modified glass carbon electrode (PDPP/GO/GCE), was developed herein for chloramphenicol (CAP) detection. In this research, PDPP was grafted onto GO by C-N bonds and π-π conjugation, which were synergistically confirmed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The morphology study shows that PDPP was uniformly dispersed on the GO in the form of particles. The constructed PDPP/GO/GCE showed the strongest response signal to CAP in the evaluation of electrocatalytic activity by cyclic voltammetry compared to that of GO-modified and unmodified GCE, revealing that the introduction of PDPP can effectively improve the electrocatalytic activity of sensors. Moreover, PDPP/GO/GCE had a noticeable current signal when the concentration of CAP was as low as 0.001 uM and had a wide line range (0.01–780 uM) with a low limit of detection (1.64 nM). The sensor properties of the as-obtained PDPP/GO/GCE involved anti-interference, reproducibility, and stability, which were also evaluated and revealed satisfactory results.

TCP transcription factors play important roles in diverse aspects of plant development as transcriptional activators or repressors. However, the functional mechanisms of TCPs are not well understood, especially in cotton fibers. Here, we identified a total of 37 non-redundant TCP proteins from the diploid cotton (Gossypium raimondii), which showed great diversity in the expression profile. GrTCP11, an ortholog of AtTCP11, was preferentially expressed in cotton anthers and during fiber initiation and secondary cell wall synthesis stages. Overexpression of GrTCP11 in Arabidopsis thaliana reduced root hair length and delayed flowering. It was found that GrTCP11 negatively regulated genes involved in jasmonic acid (JA) biosynthesis and response, such as AtLOX4, AtAOS, AtAOC1, AtAOC3, AtJAZ1, AtJAZ2, AtMYC2, and AtERF1, which resulted in a decrease in JA concentration in the overexpressed transgenic lines. As with the JA-deficient mutant dde2-2, the transgenic line 4-1 was insensitive to 50 μM methyl jasmonate, compared with the wild-type plants. The results suggest that GrTCP11 may be an important transcription factor for cotton fiber development, by negatively regulating JA biosynthesis and response.

AIM: To investigate whether the gene variants in MYOC and ABCA1 are associated with primary angle-closure glaucoma (PACG) and anterior chamber depth (ACD) and axial length (AL) in samples from northern China. METHODS: The present case-control association study consisted of 500 PACG patients and 720 unrelated controls. Each participant was genotyped for eleven single nucleotide polymorphisms (SNPs) in MYOC and ABCA1 genes (rs12076134, rs183532, rs235875 and rs235913 in MYOC, rs2422493, rs2487042, rs2472496, rs2472493, rs2487032, rs2472459 and rs2472519 near ABCA1) using an improved multiplex ligation detection reaction (iMLDR) technique. The genetic association analyses were performed by PLINK using a logistic regression model. The association between genotypes and ocular biometric parameters was performed by SPSS using generalized estimation equation. Bonferroni corrections were implemented and the statistical power was calculated by the Power and Sample Size Calculation. RESULTS: Two SNPs rs183532 and rs235875 as well as a haplotype TTC in MYOC were nominally associated with PACG despite the significance was lost after Bonferroni correction. No association was observed between ABCA1 and PACG, neither did the association between these variants and ACD as well as AL. CONCLUSION: The present study suggests MYOC and ABCA1 do not play a part in the pathogenesis of PACG as well as the regulation of ocular biometric parameters in a northern Chinese population. Further investigations with large sample size are needed to verify this consequence.

Severe renal fibrosis often occurs in obstructive kidney disease, not only in the obstructed kidney but also in the contralateral kidney, causing renal dysfunction. Although the mechanisms of injury in obstructed kidney have been studied for years, the pathogenesis of fibrosis in the contralateral kidney remains largely unknown. Here, we examined long-term unilateral ureteral obstruction (UUO) model in male Sprague–Dawley rats and found that macrophage-to-myofibroblast transition (MMT) is contributing to renal fibrosis in the contralateral kidney of UUO rats. Interestingly, this process was attenuated by treatment of eplerenone, a specific blocker of the mineralocorticoid receptor (MR). In-vitro, stimulating MR in primary cultured or cell line macrophages enhances MMT, which were also inhibited by MR blockade. Collectively, these findings provide a plausible mechanism for UUO-induced injury in the contralateral kidney, suggesting the benefit of using MR blockage as a part of treatment to UUO to protect the contralateral kidney thereby preserve renal function.

As an important abiotic stress factor, ultraviolet-B (UV-B) light can stimulate the accumulation of antioxidants in plants. In this study, the possibility of enhancing antioxidant capacity in pakchoi (Brassica rapa L.) by UV-B supplementation was assessed. Irradiation with 4 µmol·m−2·s−1 UV-B for 4 h or 2 µmol·m−2·s−1 UV-B for 24 h significantly increased the 1,1–diphenyl–2–picrylhydrazyl (DPPH) scavenging activity and total reductive capacity, as a result of inducing a greater accumulation of total polyphenols and flavonoids without affecting the plant biomass. A high performance liquid chromatography (HPLC) analysis showed that the concentrations of many flavonoids significantly increased in response to UV-B treatment. The activities of three enzymes involved in the early steps of flavonoid biosynthesis, namely phenylalanine ammonia-lyase (PAL), cinnamate-4-hydroxylase (C4H), and 4-coumarate: coenzyme A (CoA) ligase (4CL), were significantly increased after the corresponding UV-B treatment. Compared with the control, the expression levels of several flavonoid biosynthesis genes (namely BrPAL, BrC4H, Br4CL, BrCHS, BrF3H, BrF3′H, BrFLS, BrDFR, BrANS, and BrLDOX) were also significantly up–regulated in the UV-B treatment group. The results suggest that appropriate preharvest UV-B supplementation could improve the nutritional quality of greenhouse-grown pakchoi by promoting the accumulation of antioxidants.

Herein, we identified the tomato SlMYB102 gene as a MYB family transcription factor of the R2R3-MYB subfamily. We additionally determined that the SlMYB102 promoter region contains photoresponsive, abiotic stress-responsive, and hormone-responsive regulatory elements, and we detected higher SlMYB102 expression in the reproductive organs of tomato than that in vegetative organs, with the expression being highest in ripe fruits and in roots. SlMYB102 expression was also shown to be cold-inducible. The protein encoded by SlMYB102 localized to the nucleus wherein it was found to mediate the transcriptional activation of target genes through its C-terminal domain. Overexpression of SlMYB102 in tomato plants conferred enhanced tolerance to cold stress. Under such cold stress conditions, we found that proline levels in the leaves of SlMYB102 overexpressing transgenic plants were higher than those in WT plants. In addition, S1MYB102 overexpression was associated with the enhanced expression of cold response genes including SlCBF1, SlCBF3, SlDREB1, SlDEB2, and SlICE1. We also found that the overexpression of SlMYB102 further enhanced the cold-induced upregulation of SlP5CS and SlAPX2. Taken together, these results suggest that SlMYB102 may be involved in the C-repeat binding transcription factor (CBF) and proline synthesis pathways, thereby improving tomato plant cold resistance.

Abstract Background The membrane frizzled-related protein (MFRP) gene is involved in axial length (AL) regulation and MFRP mutations cause nanophthalmos; also, the hepatocyte growth factor (HGF) gene is reported to result in morphologic changes of the anterior segment and abnormal aqueous regulation that increases the risk of primary angle-closure glaucoma (PACG), while the zinc ring finger 3 (ZNRF3) gene is associated with AL. The present study investigated the association of single nucleotide polymorphisms (SNPs) in ZNRF3, HGF and MFRP with PACG in a northern Chinese population, as well as the association of these SNPs with the ocular biometric parameters of anterior chamber depth (ACD) and AL. Methods A total of 500 PACG patients and 720 controls were recruited. All individuals were genotyped for 12 SNPs in three genes (rs7290117, rs2179129, rs4823006 and rs3178915 in ZNRF3; rs5745718, rs12536657, rs12540393, rs17427817 and rs3735520 in HGF, rs2510143, rs36015759 and rs3814762 in MFRP) using an improved multiplex ligation detection reaction (iMLDR) technique. Genotypic distribution was analyzed for Hardy-Weinberg equilibrium. Differences in the allelic and genotypic frequencies were evaluated and adjusted by age and sex. Linkage disequilibrium (LD) patterns were tested and haplotype analysis was conducted by a logistic regression model. Generalized estimation equation (GEE) analysis was conducted using SPSS for primary association testing between genotypes and ocular biometric parameters. Bonferroni corrections for multiple comparisons were performed, and the statistical power was calculated by power and sample size calculations. Results The rs7290117 SNP in ZNRF3 was significantly associated with the AL, with a p-value of 0.002. We did not observe any significant associations between the SNPs and PACG or ACD. In a stratification analysis by ethnicity, rs12540393 and rs17427817 in HGF showed a nominal association with PACG in the Hui cohort, although significance was lost after correction. Conclusions The present study suggests rs7290117 in ZNRF3 may be involved in the regulation of AL, though our results do not support a contribution of the SNPs we tested in ZNRF3, HGF and MFRP to PACG in northern Chinese people. Further studies in a larger population are warranted to confirm this conclusion.

Abstract Background Plants of the genus Taxus have attracted much attention owing to the natural product taxol, a successful anti-cancer drug. T. fuana and T. yunnanensis are two endangered Taxus species mainly distributed in the Himalayas. In our study, an untargeted metabolomics approach integrated with a targeted UPLC-MS/MS method was applied to examine the metabolic variations between these two Taxus species growing in different environments. Results The level of taxol in T. yunnanensis is much higher than that in T. fuana, indicating a higher economic value of T. yunnanensis for taxol production. A series of specific metabolites, including precursors, intermediates, competitors of taxol, were identified. All the identified intermediates are predominantly accumulated in T. yunnanensis than T. fuana, giving a reasonable explanation for the higher accumulation of taxol in T. yunnanensis. Taxusin and its analogues are highly accumulated in T. fuana, which may consume limited intermediates and block the metabolic flow towards taxol. The contents of total flavonoids and a majority of tested individual flavonoids are significantly accumulated in T. fuana than T. yunnanensis, indicating a stronger environmental adaptiveness of T. fuana. Conclusions Systemic metabolic profiling may provide valuable information for the comprehensive industrial utilization of the germplasm resources of these two endangered Taxus species growing in different environments.

Triboelectric separation, as an entirely dry technology, is a prospective method to process fine minerals. The aim of this paper is to investigate the performance of triboelectric separation of ilmenite and quartz minerals in a lab unit and to get ready for the separation of ilmenite ore. A tribocharge measurement system was used to test the triboelectric properties of ilmenite and quartz particles with tribochargers respectively made of PVC, PPR, PMMA, Teflon, copper, stainless steel and quartz glass. The results show that the ilmenite particles charged positively while quartz charged negatively when tribocharged with PVC tribocharger. The mixture of 12% ilmenite and 88% quartz was prepared for the triboelectric separation. The recovery of ilmenite increases with the increase of airflow rate, decreases with the increasing feed rate, and grows up firstly and then decreases with the increasing voltage. A maximum ilmenite recovery of 51.71% with ilmenite content 32.72% was obtained at 40 m3/h airflow rate, 6 g/s feed rate and 20 kV voltage. According to the optimal parameters of the separation of ilmenite and quartz mixture, fine ilmenite ore with 7.55% Ti content was beneficiated using the unit and the Ti content increased to12.32% in concentrate product. Keywords: Triboelectric separation, Tribocharge, Ilmenite, Quartz, Ilmenite ore

Abstract Background Cachexia is a multifactorial metabolic syndrome with high morbidity and mortality in patients with advanced cancer. The diagnosis of cancer cachexia depends on objective measures of clinical symptoms and a history of weight loss, which lag behind disease progression and have limited utility for the early diagnosis of cancer cachexia. In this study, we performed a nuclear magnetic resonance‐based metabolomics analysis to reveal the metabolic profile of cancer cachexia and establish a diagnostic model. Methods Eighty‐four cancer cachexia patients, 33 pre‐cachectic patients, 105 weight‐stable cancer patients, and 74 healthy controls were included in the training and validation sets. Comparative analysis was used to elucidate the distinct metabolites of cancer cachexia, while metabolic pathway analysis was employed to elucidate reprogramming pathways. Random forest, logistic regression, and receiver operating characteristic analyses were used to select and validate the biomarker metabolites and establish a diagnostic model. Results Forty‐six cancer cachexia patients, 22 pre‐cachectic patients, 68 weight‐stable cancer patients, and 48 healthy controls were included in the training set, and 38 cancer cachexia patients, 11 pre‐cachectic patients, 37 weight‐stable cancer patients, and 26 healthy controls were included in the validation set. All four groups were age‐matched and sex‐matched in the training set. Metabolomics analysis showed a clear separation of the four groups. Overall, 45 metabolites and 18 metabolic pathways were associated with cancer cachexia. Using random forest analysis, 15 of these metabolites were identified as highly discriminating between disease states. Logistic regression and receiver operating characteristic analyses were used to create a distinct diagnostic model with an area under the curve of 0.991 based on three metabolites. The diagnostic equation was Logit(P) = −400.53 – 481.88 × log(Carnosine) −239.02 × log(Leucine) + 383.92 × log(Phenyl acetate), and the result showed 94.64% accuracy in the validation set. Conclusions This metabolomics study revealed a distinct metabolic profile of cancer cachexia and established and validated a diagnostic model. This research provided a feasible diagnostic tool for identifying at‐risk populations through the detection of serum metabolites.

Abstract Background Lysine succinylation is a ubiquitous and important protein post-translational modification in various eukaryotic and prokaryotic cells. However, its functions in Dendrobium officinale, an important traditional Chinese orchid herb with high polysaccharide contents, are largely unknown. Results In our study, LC-MS/MS was used to identify the peptides that were enriched by immune-purification with a high-efficiency succinyl-lysine antibody. In total, 314 lysine succinylation sites in 207 proteins were identified. A gene ontology analysis showed that these proteins are associated with a wide range of cellular functions, from metabolic processes to stimuli responses. Moreover, two types of conserved succinylation motifs, ‘***Ksuc******K**’ and ‘****EKsuc***’, were identified. Our data showed that lysine succinylation occurred on five key enzymes in the glycolysis pathway. The numbers of average succinylation sites on these five enzymes in plants were lower than those in bacteria and mammals. Interestingly, two active site amino acids residues, K103 and K225, could be succinylated in fructose-bisphosphate aldolase, indicating a potential function of lysine succinylation in the regulation of glycolytic enzyme activities. Furthermore, the protein–protein interaction network for the succinylated proteins showed that several functional terms, such as glycolysis, TCA cycle, oxidative phosphorylation and ribosome, are consisted. Conclusions Our results provide the first comprehensive view of the succinylome of D. officinale and may accelerate future biological investigations of succinylation in the synthesis of polysaccharides, which are major active ingredients.

Abstract Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease associated with profound metabolic changes. The purpose of this study was to identify a distinctive metabolic signature from the training set with 29 PBC patients, 30 hepatitis B virus (HBV)-caused cirrhosis (HBC) and 41 healthy controls, and to validate the applicability and stability of the distinctive model from the validation set with 21 PBC patients, 7 autoimmune hepatitis (AIH) and 9 HBC. The sera were investigated using high resolution nuclear magnetic resonance (NMR) and the datasets were analyzed pairwise using pattern recognition methods. 45 distinguishable metabolites were identified and 15 metabolic pathways were reprogrammed. The altered metabolic pathways were associated with glucose, fatty acid and amino acid metabolites. Logistic regression and ROC analysis were used to establish a diagnostic model with the equated (p) = −12.22–3.46*log(4-hydroxyproline) + 6.62*log(3-hydroxyisovalerate) − 2.44*log(citraconate) − 3.80*log(pyruvate). The area under the curve (AUC) of the optimized model was 0.937 (95% confidence interval (CI): 0.868–0.976) in the training set and 0.890 (95% CI: 0.743–0.969) in the validation set. These results not only revealed the potential pathogenesis of PBC, but also provided a feasible diagnostic tool for PBC populations through detection of serum metabolites.

Composite workpieces, especially the complex-curved surfaces composite workpieces, have been increasingly used in different industries. Non-destructive testing of these parts has become an urgent problem to be addressed. To solve the problem, this article presents a dual-robot air-coupled ultrasonic non-destructive testing scheme and introduces the structure of the system and a general calibration method for the workpiece frame of a dual-robot system in detail. Importantly, this article proposes a tangential constraint method, which makes the probes completely aligned during the inspection process. Verification experiments and ultrasonic testing experiments for a glued multilayered composite workpiece were performed using the dual-robot air-coupled ultrasonic non-destructive testing system. A comparative experiment was also performed using a dual-robot water jet-coupling ultrasonic testing system. Experimental results show that the dual-robot non-destructive testing scheme and the tangential constraint method function well, and all the artificial defects on the sample can be detected by both kinds of testing methods. Vivid 3-D C-scan image based on the test result is provided for convenience of observation. In other words, a kind of flexible versatile testing platform with multiple degrees of freedom is established.

The tunable photoluminescence (PL) property is very important for gallium nitride (GaN) nanoparticles in the application of ultraviolet and blue optoelectronic devices, while conventional methods are not so satisfactory that alternative methods for preparing GaN nanoparticles should be studied. In this paper, ultra-small and well dispersed GaN nanoparticles are fabricated through femtosecond pulse laser ablation in air, water and ethanol. For the PL spectra of GaN nanoparticles, there are no shifts in air, red shifts in water and blue shifts in ethanol compared with the intrinsic PL spectra of bulk GaN. The X-ray photoelectron spectroscopy (XPS) results demonstrate that the various PL spectra can be due to the different components inside the GaN nanoparticles, which not only have effect on the PL emissions, but also greatly influence the intensity of PL. This study validates that the ablation environment has a great adjustable effect on the properties of GaN nanoparticles.

PURPOSE:Recent genome-wide association studies (GWAS) have verified eight genetic loci that were significantly associated with primary angle-closure glaucoma (PACG). The present study investigated whether these variants are associated with the ocular biometric parameters of anterior chamber depth (ACD) and axial length (AL) in a northern Chinese population, as well as whether there were differences in the association of genetic markers in our cohort based on ethnicity. METHODS:A case-control association study of 500 patients and 720 controls was undertaken. All individuals were genotyped for eight single nucleotide polymorphisms (SNPs) (rs11024102 in PLEKHA7, rs3753841 in COL11A1, rs1015213 located between PCMTD1 and ST18, rs3816415 in EPDR1, rs1258267 in CHAT, rs736893 in GLIS3, rs7494379 in FERMT2, and rs3739821 mapping between DPM2 and FAM102A) using an improved multiplex ligation detection reaction (iMLDR) technique. Allelic and genotypic frequency differences were evaluated using a logistic regression model. Generalized estimation equation (GEE) analysis was conducted for association testing between genotypes and ocular biometric parameters. False discovery rate (FDR) correction for multiple comparisons was employed, and the statistical power was calculated via power and sample size calculation. RESULTS:Four of the eight SNPs, rs3753841, rs1258267, rs736893 and rs7494379, were associated with PACG (p = 0.007, 0.0016, 0.0045, 0.045, respectively), and only rs3753841, rs1258267 and rs736893 surpassed the FDR correction. For subgroup analysis, only rs1258267 could withstand multiple testing correction in the Han nationality (p = 0.00571). In the GEE tests, rs3753841, rs1258267 and rs736893 were found to be nominally associated with ACD (p = 0.023, 0.016, 0.01, respectively). However, these associations could not survive FDR correction. CONCLUSIONS:The SNP rs3753841 in COL11A1, rs1258267 in CHAT and rs736893 in GLIS3 are associated with PACG in northern Chinese people, and the association of genetic markers manifests a tendency of ethnic diversity. Larger population-based studies are warranted to reveal additional PACG loci and ethnic aspects of PACG.

The flavonoids in the extracts of Ginkgo leaves have been shown to have great medical value: thus, a method to increase the flavonoid contents in these extracts is of significant importance for human health. In the present study, we investigated the changes in flavonoid contents and the corresponding gene expression levels in post-harvest Ginkgo leaves after various treatments. We found that both ultraviolet-B and NaCl treatment induced flavonoid accumulation. However, gene expression analysis showed that the increases in flavonoid contents were achieved by different pathways. Furthermore, post-harvest Ginkgo leaves responded differently to NaCl treatment compared with naturally grown leaves in both flavonoid contents and corresponding gene expression. In addition, combined treatment with ultraviolet-B and NaCl did not further increase the flavonoid contents compared with ultraviolet-B or NaCl treatment alone. Our results indicate the existence of a novel mechanism in response to NaCl treatment in post-harvest Ginkgo leaves, and provide a technique to increase flavonoid content in the pharmaceutical industry.

With the rapid development of material science, more and more workpieces, especially workpieces with complex curved surfaces, are being made of composite materials. Robotic non-destructive testing (NDT) systems for complex curved surface composite material parts are being used more and more. Despite the emergence of such flexible NDT systems, the detection of semi-enclosed parts is also a challenge for robotic NDT systems. In order to overcome the problem, this paper establishes an NDT solution for semi-enclosed workpieces based on a dual-robot system of synchronous motion, in which an extension arm is installed on one of the robots and presents a trajectory planning method that always ensures the extension arm is parallel to the rotary axis of a semi-enclosed workpiece and that the ultrasonic probes are perpendicular to the workpiece surface. Trajectory analysis experiments and ultrasonic NDT experiments utilizing the optimal water path distance determined by simulation result of multi-Gaussian beam model for two types of semi-enclosed workpieces are performed with the dual-robot NDT system. Experimental results prove that the dual-robot NDT scheme functions well and the planned trajectories are correct. All the hole-shaped artificial defects with diameters ≥3 mm are detected by using 2.25 MHz ultrasonic probes through the transmission testing method. Vivid 3D C-scan image of a small diameter cylindrical workpiece based on the testing result is provided for convenience of observation.

This study applies two variables in the measurement of company patent deployment strategies: patent family depth and earn plan ratio. Patent family depth represents the degree to which certain fields and markets are valued by the patent owner. Earn plan ratio defined as the ratio of the number of patent forward citations to patent family size. Earn plan ratio indicates the degree to which a patent family could be cited by later innovators and competitors. This study applies a logistic regression model in the analysis LED industry data. The results demonstrate that patent value has a positive relationship with the patent family depth, and earn plan ratio.

Gibberellic acids (GAs) are plant hormones that play fundamental roles in plant growth and developmental processes. Previous studies have demonstrated that three key enzymes of GA20ox, GA3ox, and GA2ox are involved in GA biosynthesis. In this study, the Arabidopsis DREB1A gene driven by the CaMV 35S promoter was introduced into soybean plants by Agrobacterium- mediated transformation. The results showed that the transgenic soybean plants exhibited a typical phenotype of GA-deficient mutants, such as severe dwarfism, small and dark-green leaves, and late flowering compared to those of the non-transgenic plants. The dwarfism phenotype was rescued by the application of exogenous GA(3) once a week for three weeks with the concentrations of 144 µM or three times in one week with the concentrations of 60 µM. Quantitative RT-PCR analysis revealed that the transcription levels of the GA synthase genes were higher in the transgenic soybean plants than those in controls, whereas GA-deactivated genes except GmGA2ox4 showed lower levels of expression. The transcript level of GmGA2ox4 encoding the only deactivation enzyme using C(20)-GAs as the substrates in soybean was dramatically enhanced in transgenic plants compared to that of wide type. Furthermore, the contents of endogenous bioactive GAs were significantly decreased in transgenic plants than those of wide type. The results suggested that AtDREB1A could cause dwarfism mediated by GA biosynthesis pathway in soybean.

A highly enantioselective Pd/Bim-catalyzed dearomative Michael reaction applying polycyclic tropones as non-benzenoid aromatic Michael acceptors and arylboronic acids as aryl pronucleophiles has been developed. The bridged biaryls bearing central and axial chirality, including pentacyclic cyclohepta[b]indoles and 6,7-dihydrodibenzo- [a,c][7]annulen-5-ones, are generally generated in good to high yields and excellent enantioselectivities and can be readily transformed into useful derivatives. [ABSTRACT FROM AUTHOR]

A palladium/chiral N,N'-disulfonyl bisimidazoline (Bim)-catalyzed asymmetric addition of arylboronic acids to isoquinoline-1,3,4-trione-derived ketimines is reported, leading to the generation of a series of functionalized isoquinoline-1,3(2H,4H)-diones bearing one quaternary carbon-amino functionality in good to excellent yields with ≥95% ee in most cases. The reaction has remarkable compatibility with both substrate scopes, providing a highly enantioselective entry to chiral heterocyclic a-tertiary amines. [ABSTRACT FROM AUTHOR]