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Background & Aims: Previous studies demonstrated oxytocin treatment effectiveness in reducing mortality and reversing liver fibrosis in mice. However, the underlying mechanism remains obscure, given the absence of oxytocin receptor expression in hepatic stellate cells, the primary liver fibrosis effector cells. Methods: A comprehensive map of cell populations in fibrotic liver was generated using single-cell sequencing. The map enabled our study of the target cells of oxytocin action in the liver in more dimensions. Furthermore, we elucidated the mechanism of the oxytocin signaling system in hepatic macrophages using oxytocin receptor-specific knockout mice and liver fibrosis animal models. Results: The carbon tetrachloride-induced hepatic fibrosis and bile duct ligation hepatic fibrosis mouse models demonstrated that oxytocin reversed hepatic fibrosis in mice. The mapped liver cell populations demonstrated that oxytocin promoted the phenotypic switch from Ly6high to Ly6Clow in myeloid-derived macrophages. The phenotypic control of oxytocin signaling system activation on this phenotypic switch was validated using myeloid-specific oxytocin receptor knockout mice. Subsequent studies demonstrated that the calcium inward flow induced by oxytocin receptor activation activated the key orphan nuclear receptor NR4A1, which controls macrophage phenotypic switching. Specifically, calcium ions activated CREB, a key target regulator of NR4A1 expression. Conclusions: The findings established hepatic macrophages as a hub responsible for the oxytocin-mediated alleviation of liver fibrosis. This study revealed a novel pathway where oxytocin regulates macrophage phenotype. Impact and implications: Previous studies revealed for the first time the expression of oxytocin receptors in the liver. The present study shows that oxytocin reverses hepatic fibrosis and that hepatic macrophages are the central hub of oxytocin-mediated alleviation of hepatic fibrosis by promoting a phenotypic switch in hepatic macrophages, transitioning from Ly6high to Ly6Clow expression. The present study reveals a novel pathway by which oxytocin regulates macrophage phenotype. In addition, the potential applications of oxytocin and its analogues, as traditional drugs for clinical application, in the treatment of liver fibrosis deserve to be further explored.

Abstract Background The association between obstructive sleep apnea syndrome (OSAS) and mortality has not been extensively researched among individuals with varying diabetic status. This study aimed to compare the relationship of OSAS with all‐cause and cause‐specific mortality in US individuals with or without diabetes based on data from the National Health and Nutrition Examination Survey (NHANES). Methods The study included participants from the NHANES 2005–2008 and 2015–2018 cycles with follow‐up information. OSAS data (OSAS.MAP10) was estimated from the questionnaire. Hazard ratios (HRs) and the 95% confidence interval (CI) of OSAS for mortality were calculated by Cox regression analysis in populations with different diabetes status. The relationships between OSAS and mortality risk were examined using survival curves and restricted cubic spline curves. Results A total of 13 761 participants with 7.68 ± 0.042 follow‐up years were included. In the nondiabetic group, OSAS.MAP10 was positively associated with all‐cause, cardiovascular, and cancer mortality. In individuals with prediabetes, OSAS.MAP10 was positively related to all‐cause mortality (HR 1.11 [95% CI: 1.03–1.20]) and cardiovascular mortality (HR 1.17 [95% CI: 1.03–1.33]). The relationship between OSAS.MAP10 and the risk of all‐cause mortality and cancer mortality exhibited L‐shaped curves in diabetes patients (both with nonlinear p values

Abstract Cuproptosis caused by copper overload is mediated by a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to a copper ionophore elesclomol that induced cuproptosis. Maternal embryonic leucine zipper kinase(MELK) promotes tumorigenesis and tumor progression through the PI3K/mTOR pathway, which exerts its effects partly by targeting the pyruvate dehydrogenase complex(PDHc) and reprogramming the morphology and function of mitochondria. However, the role of MELK in cuproptosis remains unclear. Here, we validated that elevated MELK expression enhanced the activity of PI3K/mTOR signaling and subsequently promoted Dihydrolipoamide S-Acetyltransferase (DLAT) expression and stabilized mitochondrial function. This regulatory effect helped to improve mitochondrial respiration, eliminate excessive intracellular reactive oxygen species (ROS), reduce intracellular oxidative stress/damage and the possibility of mitochondria-induced cell fate alternations, and ultimately promote the progression of HCC. Meanwhile, elesclomol reduced translocase of outer mitochondrial membrane 20(TOM 20) expression and increased DLAT oligomers. Moreover, the above changes of MELK to HCC were abolished by elesclomol. In conclusion, MELK enhanced the levels of the cuproptosis-related signature(CRS) gene DLAT (especially the proportion of DLAT monomer) by activating the PI3K/mTOR pathway, thereby promoting elesclomol drug resistance, altering mitochondrial function, and ultimately promoting HCC progression.

AIM: To evaluate the therapeutic effect of folic acid combined with decitabine on diabetic mice. METHODS: The diabetic model of db/db mice were randomly divided into model group, folic acid group, decitabine group, folic acid combined with decitabine group, and C57 mice as normal control group. The density of retinal blood vessels and retinal thickness were detected by fundus photography and optical coherence tomography, respectively. Pathological changes of retina were observed by hematoxylin-eosin (HE) staining. The homocysteine (Hcy) in serum was detected by enzyme linked immunosorbent assay (ELISA). TdT-mediated dUTP nick-end labeling (TUNEL) was used to detect apoptosis in retinal tissue. Evans blue dye was used to detect the permeability of retinal blood vessels. The platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor receptor (VEGFR) protein were detected by Western blot. The 3-nitrotyrosine (3-NT) and 4-hydroxynonanine (4-HNE) were detected by immunohistochemistry. RESULTS: The density of retinal blood vessels, retinal thickness, retinal vascular permeability and the proportion of apoptotic cells of retinal tissue in the model group increased significantly than control group (P

The empirical study aimed to explore the relationships among social media exposure, job stress, anxiety, and identity disturbance in a nonclinical setting in the COVID-19 pandemic context. An online questionnaire was administered to 282 participants in the United States of America (USA) during the COVID-19 pandemic. The study utilized a two-step Structural Equation Modeling (SEM) approach consisting of both measurement model and structural model testing. Relationships between the model variables of social media exposure, identity disturbance, anxiety, and job stress were analyzed using standardized beta coefficients, standard errors, t-values, and p-values. The results indicate that both social media exposure and job stress are associated with increased anxiety levels, which, in turn, influence identity disturbance. Moreover, there is a moderating effect of job stress on the relationship between social media exposure and anxiety, as well as the mediating effect of anxiety on the relationship between social media exposure and identity disturbance. The findings are valuable for organizations and can be used to develop programs aimed at mitigating the adverse effects of social media exposure on mental health. Prioritizing employee mental health through awareness and support initiatives is paramount, especially for those facing high stress and extensive social media use.

Abstract Aims Huntington's disease (HD) is a progressive neurodegenerative disorder with heterogeneous clinical manifestations. Identifying distinct clinical clusters and their relevant biomarkers could elucidate the underlying disease pathophysiology. Methods Following the Enroll‐HD program initiated in 2018.09, we have recruited 104 HD patients (including 21 premanifest) and 31 health controls at Beijing Tiantan Hospital. Principal components analysis and k‐means cluster analysis were performed to determine HD clusters. Chi‐square test, one‐way ANOVA, and covariance were used to identify features among these clusters. Furthermore, plasma cytokines levels and brain structural imaging were used as biomarkers to delineate the clinical features of each cluster. Results Three clusters were identified. Cluster 1 demonstrated the most severe motor and nonmotor symptoms except for chorea, the lowest whole brain volume, the plasma levels of IL‐2 were higher and significantly associated with cluster 1. Cluster 2 was characterized with the most severe chorea and the largest pallidum volume. Cluster 3 had the most benign motor symptoms but moderate psychiatric problems. Conclusion We have identified three HD clusters via clinical manifestations with distinct biomarkers. Our data shed light on better understanding about the pathophysiology of HD.

The proposed system is designed to address the growing demand for sustainable and efficient energy solutions that can minimize greenhouse gas emissions while meeting the increasing energy needs of a modern world. The integrated approach of the system allows it to produce not only electricity but also hydrogen and fresh water from seawater, making it a comprehensive solution to multiple challenges. The system comprises several components that work together including a gas turbine unit, Rankine and organic Rankine cycles, a multi-effect desalination (MED) system, and a proton exchange membrane (PEM) electrolyzer. One significant characteristic of this system is its ability to generate hydrogen, which is later combined with the inlet fuel of the gas turbine. This novel methodology presents a more environmentally friendly fuel alternative, showcasing its potential to enhance combustion efficiency in a sustainable manner. To ensure the viability and feasibility of the system, a MATLAB function was utilized for calculating the base case scenario, followed by a GA optimization technique with the aid of a machine learning model to minimize run-time. In the given scenario, the total cost rate is measured at 3726 $/h, with an exergy efficiency of 54% and a normalized CO2 emission of 305 kg/GJ. Following the optimization process, significant enhancements can be observed. The cost rate decreases by 2202 $/h, the exergy efficiency improves from 54% to 55.61%, and the annual CO2 emissions decrease from 133,760 metric tons to 50,320 metric tons. Moreover, the implementation of blended fuel leads to a 10% decrease in normalized CO2 emissions.

BackgroundImmune checkpoint therapy, involving the programmed cell death 1 (PD-1) monoclonal antibody, has revolutionized the treatment of cancer. Tertiary lymphatic structure (TLS) serves as an immune indicator to predict the efficacy of PD-1 antibody therapy. However, there is no clear result whether the distribution, quantity, and maturity of TLS can be effective indicators for predicting the clinical efficacy of anti-PD1 immunotherapy in patients with colorectal cancer (CRC).MethodsFifty-seven patients who underwent surgical resection and thirty-nine patients who received anti-PD-1 immunotherapy were enrolled in this retrospective study. Immunohistochemical staining and multiple fluorescence immunohistochemistry were used to evaluate the mismatch repair (MMR) subtypes and TLS distribution, quantity, and maturity, respectively.ResultsA comprehensive patient score system was built based on TLS quantity and maturity. We found that the proportion of patients with score >1 was much higher in the deficient mismatch repair(dMMR) group than in the proficient mismatch repair(pMMR) group, and this difference was mainly due to intratumoral TLS. Patient score, based on the TLS evaluation of whole tumor, peritumor, or intratumor, was used to evaluate the efficacy of anti-PD1 immunotherapy. Based only on the intratumor TLS evaluation, the proportion of patients with a score >1 was higher in the response (PR + CR) group than in the non-response (PD) group. Multivariate analysis revealed that patient scores were positively correlated with the clinical efficacy of immunotherapy. Further analysis of immune-related progression-free survival was performed in patients with CRC who received anti-PD-1 immunotherapy. Patients with score >1 based on the intratumor TLS evaluation had significantly better survival.ConclusionsThese results suggest that the patient score based on intratumor TLS evaluation may be a good immune predictive indicator for PD-1 antibody therapy in patients with CRC.

Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation, invasion, drug resistance, and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.

Customizing the configuration of Tesla valves should be adjusted to match the specific goals of the desired purpose. Channels with Tesla design have various applications in hydraulic and thermal fields. If the purpose is hydraulic application, this design of channels is used in the construction of one-way valves. The main focus may not be on thermal efficiency, instead, the emphasis lies on attaining a strong diode characteristic. However, in situations involving thermal applications, and considering that the thermal performance of these channels is suitable, they are used in the construction of heat sinks and heat exchangers. Microchannel heat sinks with Tesla design are used in cooling of CPUs, batteries, etc. In these situations, the goal is to minimize the pressure drop, while maximizing convective heat transfer. This research introduces an innovative structural design for the Tesla valve and presents two artificial neural network (ANN) models for predicting and optimizing its thermal and hydraulic capabilities. The design parameters being studied are the inner radius of the fins (R), the length of the folded segment of the divider (L), and the angle of the folded segment of the divider (θ). The researchers are examining how these variables affect the Nusselt number (Nu) and pressure drop (ΔP) in both forward and reverse flow directions. Based on the findings, by utilizing variables of optimal design 4 (θ = 130°, L = 3 mm, and R = 0.258 mm) and optimal design 5 (θ = 130°, L = 3 mm, and R = 0.586 mm) during the valve manufacturing process and altering the flow direction from forward to reverse, the thermal performance and diodicity increased by about 26.6% and 78.2%, respectively.

Artificial intelligence (AI) and big data profoundly impact people’s way of life and way of thinking, and college ideological and political education (IPE) has gradually entered the era of online education. On account of this, this study designs an online education algorithm based on AI technology to help teachers better understand the situation of students’ online IPE teaching and improve the management of IPE in universities. Firstly, the learning features of students are extracted through the Back Propagation Neural Network (BP) model. This model summarizes the shortcomings of feature extraction in machine learning, and can simultaneously obtain depth information from the signals of multiple sensors, thus increasing the overall algorithm classification accuracy. Secondly, combined with the human behavior recognition model, the status and behavior of students’ IPE teaching can be obtained in real-time from students’ listening devices. Finally, the algorithm’s classification performance is evaluated by experiments and compared with the designed model. The results reveal that the recognition accuracy of the designed classification algorithms for the sample students is 98.59%, 98.99%, 99.21%, 100%, 97.10%, 95.61%, and 100%, respectively. In addition, comparing the algorithm with similar recognition algorithms, its index values of accuracy and precision are 97.83% and 97.82%, respectively, which are better than similar classification algorithms. Finally, through the experimental samples, the accuracy of the human recognition model is tested and compared with other recognition models. The results reveal that the designed model has high recognition accuracy. This study is of great significance for improving teachers’ innovative IPE methods and optimizing the management level of online IPE teaching.

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer that is challenging to diagnose at an early stage. Despite recent advances in combination chemotherapy, drug resistance limits the therapeutic value of this regimen. iCCA reportedly harbors high HMGA1 expression and pathway alterations, especially hyperactivation of the CCND1/CDK4/CDK6 and PI3K signaling pathway. In this study, we explored the potential of targeting CDK4/6 and PI3K inhibition to treat iCCA. Methods The significance of HMGA1 in iCCA was investigated with in vitro/vivo experiments. Western blot, qPCR, dual-luciferase reporter and immunofluorescence assays were performed to examine the mechanism of HMGA1 induced CCND1 expression. CCK-8, western blot, transwell, 3D sphere formation and colony formation assays were conducted to predict the potential role of CDK4/6 inhibitors PI3K/mTOR inhibitors in iCCA treatment. Xenograft mouse models were also used to determine the efficacy of combination treatment strategies related to HMGA1 in iCCA. Results HMGA1 promoted the proliferation, epithelial-mesenchymaltransition (EMT), metastasis and stemness of iCCA. In vitro studies showed that HMGA1 induced CCND1 expression via promoting CCND1 transcription and activating the PI3K signaling pathway. Palbociclib(CDK4/6 inhibitor) could suppress iCCA proliferation, migration and invasion, especially during the first 3 days. Although there was more stable attenuation of growth in the HIBEpic model, we observed substantial outgrowth in each hepatobiliary cancer cell model. PF-04691502(PI3K/mTOR inhibitor) exhibited similar effects to palbociclib. Compared with monotherapy, the combination retained effective inhibition for iCCA through the more potent and steady inhibition of CCND1, CDK4/6 and PI3K pathway. Furthermore, more significant inhibition of the common downstream signaling pathways is observed with the combination compared to monotherapy. Conclusions Our study reveals the potential therapeutic role of dual inhibition of CDK4/6 and PI3K/mTOR pathways in iCCA, and proposes a new paradigm for the clinical treatment of iCCA.

Silicone rubber in power transmission and transformation equipment is subjected to considerable temperature changes under different application environment conditions and in different operational states. In tropical areas and the Turpan region of China, surface temperatures of silicone rubber insulators may reach or exceed 70°C. During in situ testing of silicone rubber, the spectral signal may fluctuate or even be distorted when the temperature changes, and consequently, the accuracy of the analysis may be affected. Therefore, we performed a LIBS-based investigation into the dependence of the spectral signal of rubber silicone on the sample temperature. Using high-temperature vulcanized silicone rubber as the experimental material, we determined the trends in spectral line intensity for different elements, plasma temperature, and electron density with temperature when the sample temperature was increased from 25°C to 310°C. The results indicated that the intensities of the Al I 394.40 nm, Al I 396.15 nm, and Si I 390.55 nm lines in the LIBS spectra underwent a gradual decrease as the temperature was increased, whereas the intensity of the Al I 309.27 nm spectral line was essentially stable. However, the spectral line intensity, plasma temperature, and electron density all exhibited a spike at approximately 260°C, which occurred because of the decomposition of aluminum hydroxide. The results of the present study should prove to be of significance in further increasing the accuracy of LIBS analysis as applied to silicone rubber surface monitoring in high-temperature environments.

Abstract Objective laparoscopic surgical excision is the recommended treatment for liver cancers, yet its benefits in patients aged 60 and older remain poorly understood. Thus, this study evaluated the feasibility, safety, and clinical outcomes of laparoscopic hepatectomy for patients aged 60 and older with intrahepatic cholangiocarcinoma (ICC). Methods After screening, 107 patients who underwent hepatectomy for ICC were enrolled and grouped into either laparoscopic (LH) or open hepatectomy (OH) groups. Baseline characteristics, pathological findings, and long-term outcomes were compared between the two groups. Independent prognostic factors for overall survival (OS) and disease-free survival (DFS) were identified using univariate and multivariate analyses. Results Among baseline characteristics and pathological findings, only pre-operative albumin was higher in the LH group. The LH group had more favorable short-term outcomes such as incision length, level of postoperative total bilirubin, and length of postoperative stays than the OH group. The postoperative complication, lymph node dissection and R0 resection rate, and long-term outcomes including OS and DFS were not significantly different between the two groups. Cancer Antigen-19-9(CA-19-9) and pathological differentiation were independent prognostic factors for OS, whereas CA-19-9 and neutrophil count were independent prognostic factors for DFS. Conclusion LH is safe, reliable, and feasible for treatment of ICC patients aged 60 and older as it had better short-term clinical outcomes than OH and achieved long-term prognoses that were comparable to those of OH.

Abstract Necroptosis, a type of programmed cell death, has become a potential therapeutic target for solid tumors. Nevertheless, the potential roles of necroptosis-related genes (NRGs) in gastric cancer (GC) remain unknown. The objective of the present study was to create a necroptosis-related prognostic signature that can provide more accurate assessment of prognosis in GC. Using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data, we identified differentially expressed NRGs. Univariate analysis and Lasso regression were performed to determine the prognostic signature. Risk scores were calculated and all GC patients were divided into high- and low-risk score group according to the median risk score value. The robustness of this signature was externally validated with data from GSE84437 cohort (n = 431). Survival analysis revealed high-risk score patients had a worse prognosis. Results evidenced that the signature was an independent prognosis factor for survival. Single-sample sequence set enrichment analysis (ssGSEA) exhibited different enrichment of immune cells and immune-related pathways in the two risk groups. Furthermore, a predictive nomogram was generated and showed excellent predictive performance based on discrimination and calibration. In addition, the risk score positively correlated with tumor mutational burden and was associated with sensitivity to multiple anti-cancer drugs. Overall, our work demonstrates a close relationship between necroptosis and the prognosis of GC. The signature we constructed with potential clinical application value, can be used for prognosis prediction and being a potential therapeutic responses indicator in GC patients.

BackgroundThe spindle and kinetochore associated (SKA) complex, which plays important roles in proper chromosome segregation during mitosis by maintaining the stabilization of kinetochore-spindle microtubule attachment during mitosis, has recently been reported to exert regulatory effects on the initiation and progression of various human cancer types. Nevertheless, the prognostic significance and immune infiltration of the SKA family across cancers have not been well elucidated.MethodsUsing data from three large public datasets, including The Cancer Genome Atlas, Genotype-Tissue Expression, and Gene Expression Omnibus databases, a novel scoring system (termed the SKA score) was developed to quantify the SKA family level across cancers. We then evaluated the prognostic impact of the SKA score on survival and assessed the effect of the SKA score on immunotherapy at the pan-cancer level using multiomics bioinformatic analyses. The correlation of the SKA score and the tumor microenvironment (TME) was also explored in depth. Potential small molecular compounds and chemotherapeutic agents were assessed by CTRP and GDSC analyses. Immunohistochemistry was performed to verify the expression of the SKA family genes.ResultsOur results demonstrated a close correlation between the SKA score and tumor development and prognosis in multiple cancers. The SKA score was positively related to cell cycle pathways and DNA replication across cancers, such as E2F targets, the G2M checkpoint, MYC targets V1/V2, mitotic spindles and DNA repair. Additionally, the SKA score was negatively related to the infiltration of various immune cells with antitumor effects in the TME. In addition, the potential value of the SKA score was identified to predict immunotherapy response for melanoma and bladder cancer. We also demonstrated a correlation between SKA1/2/3 and the response to drug treatment across cancers and the promising potential of the SKA complex and its genes as therapeutic targets in cancer. Immunohistochemistry demonstrated that the expression differences of SKA1/2/3 were significant between the breast cancer group and the paracancerous group.ConclusionThe SKA score plays a critical role in 33 cancer types and is highly related to tumor prognosis. Patients with elevated SKA scores have a clear immunosuppressive TME. The SKA score may serve as a predictor for patients receiving anti-PD-1/L1 therapy.

Mitochondrial dysfunction and glycolysis activation are improtant hallmarks of hepatocellular carcinoma (HCC). NOP2 is an S-adenosyl-L-methionine-dependent methyltransferase that regulates the cell cycle and proliferation activities. In this study, found that NOP2 contributes to HCC progression by promoting aerobic glycolysis. Our results revealed that NOP2 was highly expressed in HCC and that it was associated with unfavorable prognosis. NOP2 knockout in combination with sorafenib enhanced sorafenib sensitivity, which, in turn, led to marked tumor growth inhibition. Mechanistically, we identified that NOP2 regulates the c-Myc expression in an m5C-modification manner to promote glycolysis. Moreover, our results revealed that m5C methylation induced c-Myc mRNA degradation in an eukaryotic translation initiation factor 3 subunit A (EIF3A)-dependent manner. In addition, NOP2 was found to increase the expression of the glycolytic genes LDHA, TPI1, PKM2, and ENO1. Furthermore, MYC associated zinc finger protein (MAZ) was identified as the major transcription factor that directly controlled the expression of NOP2 in HCC. Notably, in a patient-derived tumor xenograft (PDX) model, adenovirus-mediated knockout of NOP2 maximized the antitumor effect and prolonged the survival of PDX-bearing mice. Our cumulative findings revealed the novel signaling pathway MAZ/NOP2/c-Myc in HCC and uncovered the important roles of NOP2 and m5C modifications in metabolic reprogramming. Therefore, targeting the MAZ/NOP2/c-Myc signaling pathway is suggested to be a potential therapeutic strategy for the treatment of HCC.

Background Gastrodia elata, known as a rootless, leafless, achlorophyllous and fully mycoheterotrophic orchid, needs to establish symbionts with particular Armillaria species to acquire nutrition and energy. Previous research findings had approved that ethylene (ET) played an important role in plant-fungi interaction and some receptors of ET had been discovered in microorganisms. However, the molecular mechanisms underlying the role of ET in the interaction between G. elata and Armillaria species remain unknown. Methods Exiguous ethephon (ETH) was added to agar and liquid media to observe the morphological features of mycelium and count the biomass respectively. Mycelium cultured in liquid media with exiguous ETH (0.1 ppm, 2.0 ppm, 5.0 ppm) were chosen to perform whole-transcriptome profiling through the RNA-seq technology (Illumina NGS sequencing). The DEGs of growth-related genes and candidate ET receptor domains were predicted on SMART. Results ETH-0.1 ppm and ETH-2 ppm could significantly improve the mycelium growth of A. gallica 012m, while ETH-5 ppm inhibited the mycelium growth in both solid and liquid media. The number of up-regulated or down-regulated genes increased along with the concentrations of ETH. The growth of mycelia might benefit from the up-regulated expression of Pyr_redox (Pyridine nucleotide-disulphide oxidoreductase), GAL4 (C6 zinc finger) and HMG (High Mobility Group) genes in the ETH-0.1 ppm and ETH-2 ppm. Therefore, the growth of mycelia might be impaired by the down-regulated expression of ZnF_C2H2 and ribosomal protein S4 proteins in the ETH-5 ppm. Seven ET receptor domains were predicted in A. gallica 012m. Based on cluster analysis and comparative studies of proteins, the putative ETH receptor domains of A. gallica 012m have a higher homologous correlation with fungi. Conclusions The responses of A. gallica 012m to ETH had a concentration effect similar to the plants’ responses to ET. Therefore, the number of up-regulated or down-regulated genes are increased along with the concentrations of ETH. Seven ET receptor protein domains were predicted in the genome and transcriptome of A. gallica 012m. We speculate that ETH receptors exist in A. gallica 012m and ethylene might play an important role in the plant-fungi interaction.

In dental implant planning, the mandibular canal is an important reference for determining the safe position of the implant. Accurate and automatic segmentation of the mandibular canal from CBCT image is of great significance. However, the variable curvature of the mandibular canal and the blurred borders make the process challenging. At present, the segmentation of mandibular canal is usually carried out by experienced, doctors using manual or semi-automatic methods, which are time-consuming and have poor segmentation consistency. For these issues, this paper proposes a mandibular canal segmentation method based on 3D convolutional neural network. Firstly, a mandibular canal segmentation method based on center line combined with region growth and a mandibular canal clipping method based on fixed points are proposed to improve the efficiency of mandibular canal marking and reduce the imbalance between sample categories, respectively. Thereafter, the scSE attention module was added to the network for reducing irrelevant background information. Finally, an weighted BCE loss function was used to prevent the mental foramen and mandibular foramen areas from participating in the back-propagation calculation, and the network is more focused on the feature learning of the mandibular canal. The experimental results show that the proposed segmentation method achieves good segmentation results, with a Dice score of 85.9% and a 95% Hausdorff distance of 0.5371mm. Compared with other methods, the segmentation method proposed in this paper had a higher accuracy and a faster efficiency, which is expected to play a practical role in dental implants.

With the development of the Internet of Things (IoT), most communication systems are difficult to implement on a large scale due to their high complexity. Multiple-input multiple-output (MIMO) precoding is a generally used technique for improving the reliability of free-space optical (FSO) communications, which is a key technology in the 6G era. However, traditional MIMO precoding schemes are typically designed based on the assumption of additive white Gaussian noise (AWGN). In this paper, we present a novel MIMO precoding method based on reinforcement learning (RL) that is specifically designed for the Poisson shot noise model. Unlike traditional MIMO precoding schemes, our proposed scheme takes into account the unique statistical characteristics of Poisson shot noise. Our approach achieves significant performance gains compared to existing MIMO precoding schemes. The proposed scheme can achieve the bit error rate (BER) of 10−5 in a strong turbulence channel and exhibits superior robustness against imperfect channel state information (CSI).

Cold-formed steel (CFS) structures are widely used in construction and infrastructure due to their lightweight and high-strength properties. However, their thin-walled nature makes them geometrically sensitive to compressive loading. The Digital Twin (DT)-based numerical simulation method is developed using the actual geometries of CFS shapes, which are acquired by a 3D laser scanner. The DT-based numerical simulation incorporates the reconstructed measurement point clouds into the finite element modeling, ensuring that actual geometric features are retained. A series of tests, including material and axial compression testing, are conducted to validate the modeling parameters, such as mesh sizes and boundary conditions. The advantages of the DT-based numerical simulation method are highlighted compared to the traditional CFS member numerical simulation, which incorporates only the first mode of geometric imperfection. Additionally, DT-based numerical simulations offer more accurate load capacities and deformation predictions. Moreover, the automated and validated DT-based numerical simulation demonstrates prevalence in modeling efficiency and computation effectiveness. The DT-based numerical simulation method holds potential for application in smart structural analysis, where accurate geometries derived from extensive measurement point clouds are integrated into numerical modeling.

Abstract This paper proposes a decentralized robust dispatch method for multi‐area AC/DC system considering wind power uncertainty. The accommodated wind power interval model is adopted to handle the inherent uncertainty and volatility of wind generation, which is modelled based on the affinely adjustable robust optimization method. The accommodated wind power interval and the automatic generation control participation factors are optimized simultaneously to accommodate more wind energy and ensure operational reliability of the entire multi‐area system. The flexible adjustment model of HVDC converter station is also presented to accommodate more wind power. Then, the resulting economic dispatch model for multi‐area system is solved in a fully decentralized and parallel manner using accelerated alternating direction method of multipliers algorithm to preserve the information privacy and dispatch independence of each region. Case studies illustrate the effectiveness of the proposed model.

Abstract Background Osteoarthritis (OA) is the most common chronic degenerative joint disorder globally that is characterized by synovitis, cartilage degeneration, joint space stenosis, and sub-cartilage bone hyperplasia. However, the pathophysiologic mechanisms of OA have not been thoroughly investigated. Methods In this study, we conducted various bioinformatics analyses to identify hub biomarkers and immune infiltration in OA. The gene expression profiles of synovial tissues from 29 healthy controls and 36 OA samples were obtained from the gene expression omnibus database to identify differentially expressed genes (DEGs). The CIBERSORT algorithm was used to explore the association between immune infiltration and arthritis. Results Eighteen hub DEGs were identified as critical biomarkers for OA. Through gene ontology and pathway enrichment analyses, it was found that these DEGs were primarily involved in PI3K-Akt signaling pathway and Rap1 signaling pathway. Furthermore, immune infiltration analysis revealed differences in immune infiltration between patients with OA and healthy controls. The hub gene ZNF160 was closely related to immune cells, especially mast cell activation in OA. Conclusion Overall, this study presented a novel method to identify hub DEGs and their correlation with immune infiltration, which may provide novel insights into the diagnosis and treatment of patients with OA.

BackgroundIntrahepatic cholangiocarcinoma is a highly malignant and invasive cancer originating from biliary epithelial cells. The current study was designed to evaluate the feasibility, safety, and clinical outcomes of laparoscopic anatomical hepatectomy in patients with intrahepatic cholangiocarcinoma.MethodsAfter screening, 95 patients who underwent anatomical hepatectomy for intrahepatic cholangiocarcinoma at our center were enrolled and divided into two groups according to the surgical approach; the baseline characteristics, pathological findings, surgical outcomes, and long-term outcomes were compared. Moreover, univariate and multivariate analyses were performed to identify independent prognostic factors for overall survival (OS) and disease-free survival (DFS).ResultsThere were no significant differences in baseline characteristics or pathological findings between the two groups. Regarding short-term outcomes, the intraoperative blood loss, incision length, and length of postoperative hospital stay were more favorable in the laparoscopic anatomical hepatectomy group than the open anatomical hepatectomy group (P 0.05). The median postoperative follow-up times were 10.7 and 13.8 months in the laparoscopic anatomical hepatectomy and open anatomical hepatectomy groups, respectively. Regarding the long-term follow-up results, OS and DFS were similar in the two groups (P > 0.05). On multivariate analysis, the independent prognostic factors for OS were CA-199, CEA, HGB, tumor diameter, and T stage, and those for DFS were CA-199 (P

This case reports a rare case of conjunctival squamous cell carcinoma in China. The elderly (86-year-old) female patient was diagnosed and treated effectively after three times of diagnosis. During this period, she was misdiagnosed and ineffective treatment for many times. Therefore, we propose to make an integrated diagnosis based on histopathological diagnosis, combined with a variety of diagnostic methods including MRI and CDFI, supplemented by updated multiple immunohistochemically techniques, so as to achieve the purpose of accurate diagnosis.

Abstract The aim of this study was to determine the resistance mechanism of Pseudomonas aeruginosa to cefoperazone sodium/sulbactam sodium. We retrospectively analyzed the drug resistance of P.a isolated at the First Affiliated Hospital of Guangxi Medical University. Drug-resistant P.a strains were constructed, then wild-type (WT) and drug-resistant (DR) strains were compared using protein and gene microarrays to determine differences between DR and WT strains. The resistance rates of P. aeruginosa during 2013, 2014 and 2015 were 21.2%, 21.4%, and 24.6% respectively. Among 242 protein peaks of WT and DR bacteriophage proteins, 41 were differentially expressed between the two groups. The expression of 26 and 15 proteins were respectively upregulated and downregulated in the DR compared with the WT group. Gene microarray results revealed 679 mutant loci in the DR group, of which 42 with the top 50 Q values were found in the NCBI database. The rate of P.a resistance to cefoperazone sodium/sulbactam sodium remained high between 2013 and 2015. The numbers of different proteins and genetic variations in the DR strains suggested that the resistance mechanism of P.a to cefoperazone sodium/sulbactam sodium involves multiple genes and proteins that might be key to controlling P.a resistance to cefoperazone sodium/sulbactam sodium.

Abstract Background Full-thickness rectal prolapse (FTRP) frequently occurs in elderly women, and more than 100 surgical procedures have been proposed to restore FTRP. The Gant-Miwa-Thiersch (GMT) procedure is the most used treatment in China. However, the recurrence rate of FTRP post-GMT, which is as high as 23.8%, is concerning. We described a new modified GMT combined with internal and external rectal sclerosant injection (nmGMTSI) procedure to address this problem. Methods The nmGMTSI was performed under spinal anesthesia in 34 frail, elderly female patients with FTRP. The surgical results of FTRP were assessed. Fecal incontinence and constipation were evaluated using the Wexner score, and anal canal rest pressure (ACRP), maximum anal systolic pressure (MASP), anorectal sensation thresholds (AST), and maximum rectal tolerance (MRT) using anorectal manometry preoperatively and postoperatively. The causes of recurrence and complications were analyzed. Results All patients were cured according to the clinical cure standard. The perioperative Wexner fecal incontinence score (WFIS) was 10.3 ± 3.31, which became 3.7 ± 2.43 (P

The perception of duration becomes biased after repetitive duration adaptation; this is known as the duration aftereffect. The duration aftereffect exists in both the sub-second and supra-second ranges. However, it is unknown whether the properties and mechanisms of the adaptation aftereffect differ between sub-second and supra-second durations. In the present study, we addressed this question by investigating the color sensitivity of the duration aftereffect in the sub-second (Experiment 1) and supra-second (Experiment 2) ranges separately. We found that the duration aftereffect in the sub-second range could only partly transfer across different visual colors, whereas the duration aftereffect in the supra-second range could completely transfer across different visual colors. That is, the color-sensitivity of the duration aftereffect in the sub-second duration was stronger than that in the supra-second duration. These results imply that the mechanisms underlying the adaptation aftereffects of the sub-second and supra-second ranges are distinct.

Using educational big data to enhance the performance of the moral education system in colleges and universities is important to smart moral education. However, educational big data has an obvious diversity. For this reason, combined with multiple resources, the “adaptive” data processing method with strong dynamic and active adaptability is cited to analyze the big data in colleges and universities to understand and grasp the dynamic of users’ thoughts and behaviors. At the same time, according to the interest bias, the concept of “interest group” is used to classify the interests of a large number of users form different groups for modeling and use it as the core framework to build an intelligent research model of moral and ideological education. Then, on this basis, the experiment was carried out using the WeChat public account data of 20 universities, and the WeChat Communication Index (WCI), WeChat Service Index (WSI), and WeChat Management Index (WMI) were used to evaluate the function of the WeChat public accounts of universities in ideological and moral education. The roles and characteristics in the system are classified into three categories: communication-oriented, service-oriented, and general type. Among them, the communication-oriented type is mainly used to provide and disseminate educational information, while the service type can be the bridge to build direct connection between teachers and students. Therefore, the performance of ideological and moral education system in universities can be enhanced. While the general type is multifunctional, its performance in information dissemination and interaction is modest. Therefore, it is suggested that the WeChat public account should take the dissemination of information and the interaction between teachers and students into account.

Clinical pathway is a multi-disciplinary treatment plan and work mode, which is favorable for improving healthcare service quality and reducing medical costs. Most of references demonstrate that variance analysis and handling is the key to clinical pathway management. Thus, the clinical pathway variance has become the focus of scholars. This paper uses the text mining technique to present a literature review of 496 academic articles in the field of clinical pathway variance analysis and handling, which published between 1994 and 2018. Moreover, this paper conducts a bibliometric analysis to visualize the clinical pathway variance research. In variance analysis and handling, there are a lot of imprecise knowledge and fuzzy relations to be reasoned with knowledge of different domains. In this study, methods of clinical pathway variance analysis and handling are illustrated. In addition, this paper points out the limitations of each method. Based on the results, the future prospects of clinical pathway variance analysis and handling research is proposed.

Objective: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Neurofilament light protein (NfL) is correlated with clinical severity of HD but relative data are the lack in the Chinese population. Reactive astrocytes are related to HD pathology, which predicts their potential to be a biomarker in HD progression. Our aim was to discuss the role of blood glial fibrillary acidic protein (GFAP) to evaluate clinical severity in patients with HD.Methods: Fifty-seven HD mutation carriers (15 premanifest HD, preHD, and 42 manifest HD) and 26 healthy controls were recruited. Demographic data and clinical severity assessed with the internationally Unified Huntington's Disease Rating Scale (UHDRS) were retrospectively analyzed. Plasma NfL and GFAP were quantified with an ultra-sensitive single-molecule (Simoa, Norcross, GA, USA) technology. We explored their consistency and their correlation with clinical severity.Results: Compared with healthy controls, plasma NfL (p < 0.0001) and GFAP (p < 0.001) were increased in Chinese HD mutation carriers, and they were linearly correlated with each other (r = 0.612, p < 0.001). They were also significantly correlated with disease burden, Total Motor Score (TMS) and Total Functional Capacity (TFC). The scores of Stroop word reading, symbol digit modalities tests, and short version of the Problem Behaviors Assessments (PBAs) for HD were correlated with plasma NfL but not GFAP. Compared with healthy controls, plasma NfL has been increased since stage 1 but plasma GFAP began to increase statistically in stage 2.Conclusions: Plasma GFAP was correlated with plasma NfL, disease burden, TMS, and TFC in HD mutation carriers. Plasma GFAP may have potential to be a sensitive biomarker for evaluating HD progression.

The dysfunction or exhaustion of adult stem cells during aging is closely linked to tissue aging and age-related diseases. Circumventing this aging-related exhaustion of adult stem cells could significantly alleviate the functional decline of organs. Therefore, identifying small molecular compounds that could prevent the age-related decline of stem cell function is a primary goal in anti-aging research. Caffeic acid (CA), a phenolic compound synthesized in plants, offers substantial health benefits for multiple age-related diseases and aging. However, the effects of CA on adult stem cells remain largely unknown. Using the Drosophila midgut as a model, this study showed that oral administration with CA significantly delayed age-associated Drosophila gut dysplasia caused by the dysregulation of intestinal stem cells (ISCs) upon aging. Moreover, administering CA retarded the decline of intestinal functions in aged Drosophila and prevented hyperproliferation of age-associated ISC by suppressing oxidative stress-associated JNK signaling. On the other hand, CA supplementation significantly ameliorated the gut hyperplasia defect and reduced environmentally induced mortality, revealing the positive effects of CA on tolerance to stress responses. Taken together, our findings report a crucial role of CA in delaying age-related changes in ISCs of Drosophila.

Internet addiction is a common and challenging problem among adolescents. Previous studies have shown that future time orientation is an important protective factor against internet addiction. In this study, the mediating effect of intolerance of uncertainty and the moderating role of perceived social support were examined on the association between future expectations, regarded as the “prospective life course” perspective of future time orientation, and internet addiction among adolescents. A total of 1,006 Chinese adolescents (54% male and 46% female; Mage = 15.42 years, SD = 1.32) recruited from middle schools completed questionnaires. Results indicated that future expectations were significantly negatively associated with internet addiction, and the link was mediated by intolerance to uncertainty in adolescents. Further, the latent moderated structural equation showed that perceived social support moderated the association between future expectations and intolerance of uncertainty. The association was significant only for adolescents with a higher level of perceived social support. The findings of this study provide specific guidelines for how to prevent adolescent internet addiction.

In this paper, the retention noise [electron emission statistics (EES)] after program operation of 3-D triple-level program cell (TLC) NAND flash memory is investigated. Three main noise sources, consisting of essential EES (EEES), electron numbers fluctuation, and device parameters fluctuation to broaden the retention Vth distributions are comprehensively considered, and the corresponding analytic models are developed. The impact of device parameters fluctuation is relatively larger than EEES and electron numbers fluctuation for our measured 3-D TLC NAND flash memory devices. Using the proposed models, the calculated Vth distributions after different data retention times have good agreements with the measurements, which validate our proposed models. This paper provides a method to predict the Vth distributions accurately and efficiently, and can help in improving reliability of 3-D TLC and quad-level program cell NAND flash memory.

Image sensor has developed for decades. Now, submicron photo sensor device with high performance is required. In this work, a UTBB (ultra-thin body and box) based single transistor image sensor has been investigated. The light collection and signal readout are accomplished by a single transistor, so the pixel of the UTBB image sensor can shrink down to the submicron. The main parameters impacting the performance of the UTBB image sensor such as back voltage, the thickness of the BOX, well doping concentration and well depth are investigated. Besides, the UTBB image sensor can achieve multi-resolution to adapt to different requirements. The performance of the UTBB image sensor is evaluated by TCAD simulations.

The resistivity of Cu interconnects increases rapidly with continuously scaling down due to scatterings, causing a major challenge for future nodes in M0 and M1 layers. Here, A Boltzmann-transport-equation-based Monte Carlo simulator, including all the major scattering mechanisms of interconnects, is developed for the evaluation of electron transport behaviors. Good agreements between our simulation and the experimental results are achieved for Cu, Ru, Co, and W, from bulk down to 10 nm interconnects. The line resistance values of the four materials with the inclusion of liner and barrier thicknesses are calculated in the same footprint for a fair comparison. The impact of high aspect ratio on resistivity is analyzed for promising buried power rail materials, such as Ru and W. Our results show that grain boundary scattering plays the most important role in nano-scale interconnects, followed by surface roughness and plasma excimer scattering. Surface roughness scattering is the origin of the resistivity decrease for high-aspect-ratio conductive rails. In addition, the grain sizes for the technical nodes of different materials are extracted and the impact of grain size on resistivity is analyzed.

Emerging evidence indicates that gut dysbiosis may play a regulatory role in the onset and progression of Huntington’s disease (HD). However, any alterations in the fecal microbiome of HD patients and its relation to the host cytokine response remain unknown. The present study investigated alterations and host cytokine responses in patients with HD. We enrolled 33 HD patients and 33 sex- and age- matched healthy controls. Fecal microbiota communities were determined through 16S ribosomal DNA gene sequencing, from which we analyzed fecal microbial richness, evenness, structure, and differential abundance of individual taxa between HD patients and healthy controls. HD patients were evaluated for their clinical characteristics, and the relationships of fecal microbiota with these clinical characteristics were analyzed. Plasma concentrations of interferon gamma (IFN-γ), interleukin 1 beta (IL-1β), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor alpha were measured by Meso Scale Discovery (MSD) assays, and relationships between microbiota and cytokine levels were analyzed in the HD group. HD patients showed increased α-diversity (richness), β-diversity (structure), and altered relative abundances of several taxa compared to those in healthy controls. HD-associated clinical characteristics correlated with the abundances of components of fecal microbiota at the genus level. Genus Intestinimonas was correlated with total functional capacity scores and IL-4 levels. Our present study also revealed that genus Bilophila were negatively correlated with proinflammatory IL-6 levels. Taken together, our present study represents the first to demonstrate alterations in fecal microbiota and inflammatory cytokine responses in HD patients. Further elucidation of interactions between microbial and host immune responses may help to better understand the pathogenesis of HD.

BackgroundManagement of locally recurrent rectal cancer (LRRC) after surgery or external beam radiotherapy (EBRT) remains a clinical challenge, given the limited treatment options and unsatisfactory outcomes. This study aimed to assess long-term outcomes of computed tomography (CT)-guided radioactive 125I seed implantation in patients with LRRC and associated prognostic factors.MethodsA total of 101 patients with LRRC treated with CT-guided 125I seed implantation from October 2003 to April 2019 were retrospectively studied. Treatment procedures involved preoperative planning design, 125I seed implantation, and postoperative dose evaluation. We evaluated the therapeutic efficacy, adverse effects, local control (LC) time, and overall survival (OS) time.ResultsAll the patients had previously undergone surgery or EBRT. The median age of patients was 59 (range, 31–81) years old. The median follow-up time was 20.5 (range, 0.89–125.8) months. The median LC and OS time were 10 (95% confidence interval (CI): 8.5–11.5) and 20.8 (95% CI: 18.7–22.9) months, respectively. The 1-, 2-, and 5-year LC rates were 44.2%, 20.7%, and 18.4%, respectively. The 1-, 2-, and 5-year OS rates were 73%, 31.4%, and 5%, respectively. Univariate analysis of LC suggested that when short-time tumor response achieved partial response (PR) or complete response (CR), or D90>129 Gy, or GTV ≤ 50 cm3, the LC significantly prolonged (P=0.044, 0.041, and

Recognizing locomotion modes is a crucial step in controlling lower-limb exoskeletons/orthoses. Our study proposed a fuzzy-logic-based locomotion mode/transition recognition approach that uses the onrobot inertial sensors for a hip joint exoskeleton (active pelvic orthosis). The method outputs the recognition decisions at each extreme point of the hip joint angles purely relying on the integrated inertial sensors. Compared with the related studies, our approach enables calibrations and recognition without additional sensors on the feet. We validated the method by measuring four locomotion modes and eight locomotion transitions on three able-bodied subjects wearing an active pelvic orthosis (APO). The average recognition accuracy was 92.46% for intrasubject crossvalidation and 93.16% for intersubject crossvalidation. The average time delay during the transitions was 1897.9 ms (28.95% one gait cycle). The results were at the same level as the related studies. On the other side, the study is limited in the small sample size of the subjects, and the results are preliminary. Future efforts will be paid on more extensive evaluations in practical applications.

To analyze the coordination between land use and the ecological economy in China, ecoefficiency and land use intensity were measured using the nonradial, nonoriented slacks-based measure (SBM) and the vertical and horizontal scatter degree method. The TOPSIS method was then used to comprehensively evaluate regional differences in coordination. Our research indicates that the level of coordinated development between intensive urban land use and the ecological economy in China showed an overall upward trend from 2006 to 2017. The level of coordination was high in Beijing, Shanghai, and Tianjin and was low in Gansu, Ningxia, and Xinjiang. Changes in ecoefficiency were not consistent with the degree of coordination, and intensive urban land use was positively correlated with the level of coordination, which showed a mutually reinforcing relationship. Improving ecoefficiency is necessary for intensive urban land use, and for ecological improvement, coordinated development between ecoefficiency and urban land use intensity is essential. The establishment of environmentally friendly land use patterns could promote urban land use.

Background Many people die from cardiovascular diseases each year, and extreme temperatures are regarded as a risk factor for cardiovascular deaths. However, the relationship between temperature and cardiovascular deaths varies in different regions because of population density, demographic inequality, and economic situation, and the evidence in Ganzhou, China is limited and inconclusive. Objective This study aimed to assess extreme temperature-related cardiovascular mortality and identify the potential vulnerable people. Methods After controlling other meteorological measures, air pollution, seasonality, relative humidity, day of the week, and public holidays, we examined temperature-related cardiovascular mortality along 21 lag days by Poisson in Ganzhou, China. Results A J-shaped relationship was observed between mean temperature and cardiovascular mortality. Extremely low temperatures substantially increased the relative risks (RR) of cardiovascular mortality. The effect of cold temperature was delayed by 2–6 days and persisted for 4–10 days. However, the risk of cardiovascular mortality related to extremely high temperatures was not significant (p > 0.05). Subgroup analysis indicated that extremely low temperatures had a stronger association with cardiovascular mortality in people with cerebrovascular diseases (RR: 1.282, 95% confidence interval [CI]: 1.020–1.611), males (RR: 1.492, 95% CI: 1.175–1.896), married people (RR: 1.590, 95% CI: 1.224–2.064), and people above the age of 65 years (RR: 1.641, 95% CI: 1.106–2.434) than in people with ischemic heart disease, females, unmarried people, and the elderly (≥65 years old), respectively. Conclusions The type of cardiovascular disease, sex, age, and marital status modified the effects of extremely low temperatures on the risk of cardiovascular mortality. These findings may help local governments to establish warning systems and precautionary measures to reduce temperature-related cardiovascular mortality.

Although essential for life, copper is also potentially toxic in concentrations that surpass physiological thresholds. The high-osmolarity glycerol pathway of yeast is the main regulator of adaptive responses and is known to play crucial roles in the responses to various stressors. The objective of this research is to determine whether the HOG pathway could be activated and to investigate the possible interplay of the HOG pathway and oxidative stress due to copper exposure. In this research, we demonstrate that copper could induce oxidative stress, including the elevated concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA). Increased combination with GSH, increased intracellular SOD activity, and the up-regulation of relevant genes can help cells defend themselves against oxidative toxicity. The results show that copper treatment triggers marked and prolonged Hog1 phosphorylation. Significantly, oxidative stress generated by copper toxicity is essential for the activation of Hog1. Activated Hog1 is translocated to the nucleus to regulate the expressions of genes such as CTT1, GPD1, and HSP12, among others. Furthermore, copper exposure induced significant G1-phase cell cycle arrest, while Hog1 partially participated in the regulation of cell cycle progression. These novel findings reveal another role for Hog1 in the regulation of copper-induced cellular stress.

Aims: To determine whether irisin could improve endothelial dysfunction by regulating heme oxygenase-1(HO-1)/adiponectin axis in perivascular adipose tissue (PVAT) in obesity. Methods: Male C57BL/6 mice were fed with a high-fat diet (HFD) with or without irisin treatment. Endothelium-dependent vasorelaxation of the thoracic aorta with or without PVAT (PVAT+ or PVAT–) was determined. Western blot was employed to determine the levels of HO-1 and adiponectin in PVAT. UCP-1, Cidea, and TNF-α gene expression in PVAT were tested by real-time PCR. Results: The presence of PVAT significantly impaired endothelial function in the HFD mice. Treatment of HFD mice with irisin significantly restored this impairment and improved endothelial function in vivo or ex vivo. Incubated aortic rings (PVAT-) with PVAT-derived conditioned medium (CM) from HFD mice impaired endothelial function in control mice. This impairment was prevented by incubating the aortic rings (PVAT-) from HFD mice with PVAT-derived CM from irisin. However, the beneficial effects were partly attenuated in the presence of HO-1 inhibitor and adiponectin receptor blocking peptide. Treatment of HFD mice with irisin significantly increased NO production, protein levels of HO-1 and adiponectin, mRNA expressions of UCP-1 and Cidea, and decreased superoxide production and TNF-α expression in PVAT. Conclusion: Irisin improved endothelial function by modulating HO-1/ adiponectin axis in PVAT in HFD-induced obese mice. These findings suggest that regulating PVAT function may be a potential mechanism by which irisin improves endothelial function in obesity.

The present study explored cross-cultural differences in future time perspective (FTP) and self-esteem and investigated whether the relationship between FTP and self-esteem differs between China and America. The FTP Scale and Rosenberg Self-Esteem Scale were administered to 460 Chinese and 340 American undergraduates. Results showed that American undergraduates scored higher on the future-negative, future-positive, future-confusion, future-perseverant, and future-perspicuity subscales than did Chinese undergraduates; American undergraduates also had higher self-esteem than did Chinese undergraduates. The dimensions of FTP (future-negative, future-positive, future-confusion, and future-perseverant) significantly predicted self-esteem in both the Chinese and American samples. These results broaden our understanding of cross-cultural differences in FTP and self-esteem. Implications and future directions are discussed.

Adipocytes attached to the extracellular matrix (ECM) mainly consist of collagen in adipose tissues, while the degradation of ECM by collagenase induces the apoptosis of adipocytes, leading to a decrease in local subcutaneous adipose. To achieve this goal, we are developing a mutant collagenase H (ColH) to remove local subcutaneous fat such as submental fat (SMF). Three vectors were constructed for expressing rColH(FM, mutant for fat melting, with 6xHis tag), rColH(WT, wild-type, with 6xHis tag), and rColH(E451D, E451D mutant, without 6xHis tag) in Escherichia coli. rColH(FM) & rColH(WT) were purified by Ni Sepharose on a laboratory scale, while rColH(E451D) was purified by five chromatography purification steps on a large scale. Then, the stability of rColH(FM) and rColH(WT) was tested by SDS-PAGE to investigate the influence of the E451D mutation on stability. Afterwards, the enzyme kinetics of ColH (mutant or wild-type, with or without His tag) were investigated and compared. Finally, the adipolysis of rColH(E451D) at various doses was tested in vitro and in vivo. The ultrasound results in minipigs suggested that effective adipolysis was induced by rColH(E451D) compared with the negative control, and the histological results suggest dose-dependent fibrosis, necrosis, inflammation and cholesterol cleft formation. These findings indicate the possibility of rColH(E451D) becoming a new injectable drug to safely remove subcutaneous adipose.

ABSTRACT Iron is an indispensable micronutrient for all eukaryotic organisms due to its participation as a redox cofactor in many metabolic pathways. Iron imbalance leads to the most frequent human nutritional deficiency in the world. Adaptation to iron limitation requires a global reorganization of the cellular metabolism directed to prioritize iron utilization for essential processes. In response to iron scarcity, the conserved Saccharomyces cerevisiae mRNA-binding protein Cth2, which belongs to the tristetraprolin family of tandem zinc finger proteins, coordinates a global remodeling of the cellular metabolism by promoting the degradation of multiple mRNAs encoding highly iron-consuming proteins. In this work, we identify a critical mechanism for the degradation of Cth2 protein during the adaptation to iron deficiency. Phosphorylation of a patch of Cth2 serine residues within its amino-terminal region facilitates recognition by the SCFGrr1 ubiquitin ligase complex, accelerating Cth2 turnover by the proteasome. When Cth2 degradation is impaired by either mutagenesis of the Cth2 serine residues or deletion of GRR1, the levels of Cth2 rise and abrogate growth in iron-depleted conditions. Finally, we uncover that the casein kinase Hrr25 phosphorylates and promotes Cth2 destabilization. These results reveal a sophisticated posttranslational regulatory pathway necessary for the adaptation to iron depletion. IMPORTANCE Iron is a vital element for many metabolic pathways, including the synthesis of DNA and proteins, and the generation of energy via oxidative phosphorylation. Therefore, living organisms have developed tightly controlled mechanisms to properly distribute iron, since imbalances lead to nutritional deficiencies, multiple diseases, and vulnerability against pathogens. Saccharomyces cerevisiae Cth2 is a conserved mRNA-binding protein that coordinates a global reprogramming of iron metabolism in response to iron deficiency in order to optimize its utilization. Here we report that the phosphorylation of Cth2 at specific serine residues is essential to regulate the stability of the protein and adaptation to iron depletion. We identify the kinase and ubiquitination machinery implicated in this process to establish a posttranscriptional regulatory model. These results and recent findings for both mammals and plants reinforce the privileged position of E3 ubiquitin ligases and phosphorylation events in the regulation of eukaryotic iron homeostasis.

Background: Diabetic nephropathy (DN) is the most important complication of diabetes and the most common cause of end-stage renal disease (ESRD). Aims: A recent study established that the Ramulus mori polysaccharides (RMP) exert antioxidant effects on DN in rats. Methods: The diabetic rats which induced by high-fat diet and streptozotocin injection were orally administered RMP by doses of 250, 500 and 1000 mg/kg daily for 8 weeks. The effects of RMP on hyperglycemia and other biochemical changes were examined in the sera and kidney tissues. Additionally, the pathological and ultrastructural changes and expressions of nuclear-factor kappa B (NF-κB) and transforming growth factor-ß1 (TGF-ß1) were assessed. Results: The results revealed that the serum levels of blood glucose, total cholesterol (TC) and triglycerides (TG) were significantly decreased by RMP. Furthermore, the blood urea nitrogen (BUN), serum creatinine (SCr) and 24-hour urine protein levels in the RMP-medicated rats were lower than those in untreated diabetic rats. Moreover, treatment of the DN rats with RMP normalized all biochemical changes, including the malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels in the serum and kidney tissues. In contrast, the protein expression levels of NF-κB and TGF-ß1, which were enhanced in the kidneys of DN rats, were reduced by RMP. Conclusion: These results suggest that RMP improving the renal function of diabeitc rats possibly via its ameliorating antioxidant activities.