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In order to solve the problems of difficult data integration, complex governance and low sharing efficiency, this paper proposes a scheme for construction of railway locomotive maintenance data integration and sharing platform. The author first realized the automatic and periodic data acquisition from different systems and saving of the same in a data warehouse through multi-source heterogeneous data acquisition technology, and then classified the data in the data warehouse for standardized management and forming service themes and thematic libraries. At the same time, the author also provided real-time and offline data sharing modes under security control, realizing data sharing in different scenarios. This platform, after being constructed in the field, saves more than 70% of the planned time for locomotive pre-scheduling and maintenance, and reduces the average downtime of locomotive maintenance by about 20 minutes. This shows the platform can help to promote multi-system data fusion and improve the informatization level, production efficiency and management ability of railway locomotive maintenance.

Cervical cancer (CC) remains one of the leading causes of cancer-related deaths worldwide. However, cervical cancer is preceded by the pre-malignant cervical intraepithelial neoplasia (CIN) that can last for up to 20 years before becoming malignant. Therefore, early screening is the key to prevent the progression of cervical lesions into invasive cervical cancer and decrease the incidence. The genes, down-regulated and hypermethylated in cancers, may provide potential drug targets for cervical cancer. In our current study, using the datasets from Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases, we found that endothelin 3 (EDN3) was downregulated and hypermethylated in cervical squamous cell carcinoma (CSCC). The further analysis in GSE63514 (n=128) dataset and in our samples (n=221) found that the expression of EDN3 was decreased with the degree of cervical lesions. Pyrosequencing was performed to evaluate 4 CpG sites of the EDN3 promoter region in our samples (n=469). The data indicated that the methylation level of EDN3 was increased with the degree of cervical lesions. EDN3 silencing mediated by methylation can be blocked by 5-Azacytidine (5-Aza), a DNA methyltransferase 1 (DNMT1) inhibitor, treatment in cervical cancer cell lines. Ethynyldeoxyuridine (EdU) assay, would-healing assay, clone formation assay and transwell assay were conducted to investigate the biological function of EDN3 in cervical cancer cell lines. The results of these experiments confirmed that overexpression of EDN3 could inhibit the proliferation, clone formation, migration and invasion of cervical cancer cells. EDN3 may provide potential biomarker and therapeutic target for CSCC.

Abstract One of the biochemical abnormalities found in diabetic tissues is a decrease in the cytosolic oxidized to reduced forms of the nicotinamide adenine dinucleotide ratio (NAD+/NADH also known as pseudohypoxia) caused by oxidation of excessive substrates (glucose through the polyol pathway, free fatty acids and lactate). Subsequently, a decline in NAD+ levels as a result of the activation of poly adenine nucleotide diphosphate‐ribose polymerase (mainly in type 1 diabetes) or the inhibition of adenine nucleotide monophosphate‐activated protein kinase (in type 2 diabetes). Thus, replenishment of NAD+ levels by nicotinamide‐related compounds could be beneficial. However, these compounds also increase nicotinamide catabolites that cause oxidative stress. This is particularly troublesome for patients with diabetes, because they have impaired nicotinamide salvage pathway reactions at the level of nicotinamide phosphoribosyl transferase and phosphoribosyl pyrophosphate, which occurs by the following mechanisms. First, phosphoribosyl pyrophosphate synthesis from pentose phosphate pathway is compromised by a decrease in plasma thiamine and transketolase activity. Second, nicotinamide phosphoribosyl transferase expression is decreased because of reduced adenosine monophosphate‐activated protein kinase activity, which occurs in type 2 diabetes. The adenosine monophosphate‐activated protein kinase inhibition is caused by an activation of protein kinase C and D1 as a result of enhanced diacylglycerol synthesis caused by pseudohypoxia and increased fatty acids levels. In this regard, nicotinamide‐related compounds should be given with caution to treat diabetes. To minimize the risk and maximize the benefit, nicotinamide‐related compounds should be taken with insulin sensitizers (for type 2 diabetes), polyphenols, benfotiamine, acetyl‐L‐carnitine and aldose reductase inhibitors. The efficacy of these regimens can be monitored by measuring serum NAD+ and urinary nicotinamide catabolites.

Subnanometer noble metal clusters have attracted much attention because of abundant low-coordinated metal atoms that perform excellent catalytic activity in various catalytic processes. However, the surface free energy of metals increases significantly with decreasing size of the metal clusters, which accelerates the aggregation of small clusters. In this work, new Schiff base–imidazole-functionalized MOFs were successfully synthesized via the postsynthetic modification method. Highly dispersed Pd clusters with an average size of 1.5 nm were constructed on this functional MOFs and behaved excellent catalytic activity in the Suzuki coupling of phenyboronic acid and bromobenzene (yield of biaryl >99%) under mild reaction conditions. Moreover, the catalyst can be reused six times without loss of activity. Such catalytic behavior is found to closely related to the surface functional groups that promote the formation of small Pd0 clusters in the metallic state.

OBJECTIVE:Regulators of G-protein signaling protein 2 (RGS2) play an irreplaceable role in the control of normal blood pressure (BP). One RGS2 (-391, C>G) genetic variation markedly changes its mRNA expression levels. This study explored the relationship between this genetic variation and the responses to antihypertensive drugs in Chinese patients with essential hypertension. METHODS:Genetic variations of RGS2 were successfully identified in 367 specimens using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. All patients were treated with conventional doses of antihypertensives after a 2-week run-in period and followed-up according to our protocol. A general linear model multivariate analysis of variance (ANOVA) was used for the data analysis. RESULTS:A significant difference in the mean systolic BP change was observed between RGS2 (-391, C>G) CC/CG (n = 82) and GG (n = 38) genotype carriers (-13.6 vs. -19.9 mmHg, P = 0.043) who were treated with candesartan, irbesartan or imidapril at the end of 6 weeks. In addition, the patients' BP responses to α,β-adrenergic receptor blockers exhibited an age-specific association with the RGS2 (-391, C>G) genetic variation at the end of 4 weeks. CONCLUSION:The RGS2 (-391, C>G) genetic polymorphism may serve as a biomarker to predict a patient's response to antihypertensive drug therapy, but future studies need to confirm this.

KCNH2 (hERG) potassium channels have an integral role in regulating the excitability of smooth muscle cells. Some pathways driven by angiotensin II, nitric oxide and adrenergic receptors blocker are involved in modulating the properties of KCNH2 potassium channels. And these pathways are closely related to blood pressure regulation. Therefore, we hypothesized that KCNH2 genetic polymorphisms may affect blood pressure response to the antihypertensive drug therapies.To evaluate the interactions between KCNH2 genetic polymorphisms and individual blood pressure response to antihypertensive drugs, 370 subjects with essential hypertension (EH) were studied. In evaluating the interactions between KCNH2 genetic polymorphisms and drug response to blood pressure, multivariable ANOVA analysis followed by Bonferroni correction were carried out.There were statistically significant interactions between KCNH2 (1956, C>T) polymorphism and DBP change (P = 0.010), MAP change (P = 0.014) on azelnidipine or nitrendipine therapy patients at the end of 6 weeks. We found that the KCNH2 (1956,C>T) polymorphism was associated with the hypotensive effects of α,β-ADR blockers of DBP change at the end of 4 and 6 weeks' treatment in an age- and gender-dependent manner (P = 0.007 and 0.019, respectively). Similar results were also observed for changes in MAP at the end of 4 and 6 weeks (P-values were 0.035 and 0.078, respectively). While patients who received imidapril, candesartan and irbesartan therapy, no significant difference in drug response among KCNH2(1956,C>T) genotype was observed.We have reported for the first time that KCNH2 (1956, C>T) polymorphism is associated with efficacy of antihypertensive drugs CCBs and ADR blockers, and may serve as a novel biomarker for individualized therapy for certain antihypertensive drugs.

BACKGROUND:The pharmacokinetics (PKs) and pharmacodynamics (PDs) of telmisartan varies among the individuals, and the main causes remain unknown. The aim of this study was to evaluate the impact of ORM1, as well as ABCC2, ABCB1, ABCG2 and SLCO1B3 polymorphisms, on the disposition of the drug and BP change after taking 40 mg telmisartan in 48 healthy Chinese males. METHOD:A total of 48 healthy males were included in this trial. Every volunteer ingested a single dose of 40 mg telmisartan, and the plasma drug concentration and blood pressure (BP) were measured up to 48 h. RESULT:In this study, the area under the plasma concentration-time curve (AUC) in the heterozygotes of ORM1 113AG was higher than that in the wild-type homozygotes, AUC(0-48) (113AA vs. 113AG, 1,549.18±859.84 ng·h/ml vs. 2,313.54±1,257.71 ng·h/ml, P = 0.033), AUC(0-∞) (113AA vs. 113AG, 1,753.13±1,060.60 ng·h/ml vs. 2,686.90±1,401.87 ng·h/ml, P = 0.016), and the change(%) of the diastolic blood pressure (DBP) from the baseline BP value also showed a significant difference between the ORM1 113AG and 113AA genotypes at 5 h after taking telmisartan (P = 0.026). This study also showed that the allele of ABCC2 C3972T would affected the disposition of telmsiartan and the DBP change significantly after taking the drug. However, the common SNPs of ABCG2 C421, ABCB1 C3435T, and SLCO1B3 T334G showed no impacts on the PKs of telmisartan or BP change(%) in our trial. CONCLUSION:The ORM1 A113G polymorphism was associated with the PKs variability after taking telmsiartan, as well as ABCC2 C3972T. The heterozygotes of ORM1 113AG showed a larger AUC and a notable BP change(%) from the baseline compared with the wild-type. TRIAL REGISTRATION:Chinese Clinical Trial Registry ChiCTR-TNC-10000898.

Windows through heat exchange play a vital role in energy saving for realizing a net‐zero carbon emission society. Dual‐band electrochromic (EC) smart windows by dynamically regulate visible (VIS) and near‐infrared (NIR) light are necessary for improving both building energy efficiency and habitant comfort. However, the rational design of high‐performance electrochromic devices (ECDs) suffers sluggish EC response due to the slow ion transport. In this work, a locally dissociated Li+ concept is proposed to construct a solid‐state polymer electrolyte (SPE) with ultrafast Li+ transport. The succinonitrile (SN) is employed to loosen the Li+‐anion pair and the crystallographic C─O chain in the poly(ethylene glycol) methyl ether methacrylate (PEGMA) electrolyte by its strong solvation capability. The as‐prepared SPE shows a high ionic conductivity of 6.48 mS cm−1 at 30 °C and a high transmittance of >90%. The SPE‐based EC smart windows exhibited a fast switching speed (3.0/3.2 s for coloration/bleaching), a high coloration efficiency (CE) of 373.8 cm2 C−1, and a high optical modulation in the full solar spectrum (85%, 70%, 43% at 673, 1200, and 1600 nm, respectively). Finally, the SPE‐based EC smart windows shows three working modes with a temperature regulation range of 19.1 °C, exhibiting great potential in practical application. [ABSTRACT FROM AUTHOR]

Abstract Intestinal stem cells (ISCs) are responsible for intestinal homeostasis and are important for the regeneration of damaged intestine. We established an ionizing radiation (IR)-induced intestinal injury model and observed that Gelsolin KO mice had increased radiosensitivity. The deletion of Gelsolin aggravated intestinal damage and reduced the number of ISCs after lethal IR. The intestinal organoid experiments showed that Gelsolin deletion inhibited ISCs function after IR. Notably, RNA sequencing and RT-PCR results showed IL-17 signaling pathway was down-regulated and Th17 cells differentiation was inhibited in Gelsolin KO mice. Moreover, recombinant IL-17 A ameliorated IR-induced intestinal injury and promoted ISCs regeneration. To figure out the role of Gelsolin in Th17 cells differentiation, flow cytometry was used and we found that Gelsolin targets Th17 cells functionality via the p-STAT3/RORγt axis. By establishing the co-culture system, we proved that Th17 cells promoted self-renewal and budding abilities in Gelsolin-deficient organoids. Finally, we found that Gelsolin was protective against DSS-induced colitis and that this protective effect was not specific or limited to the IR induced intestinal injury model. Based on these results, we proved Gelsolin maintained the regeneration of ISCs by sustaining Th17 cells functions via the p-STAT3/RORγt axis. Graphical abstract

Background: Immunotherapy has emerged as a novel strategy for cancer treatment following surgery, radiotherapy, and chemotherapy. Immune checkpoint blockade and Chimeric antigen receptor (CAR)-T cell therapies have been successful in clinical trials. Cancer cells evade immune surveillance by hijacking inhibitory pathways via overexpression of checkpoint genes. The Cluster of Differentiation 47 (CD47) has emerged as a crucial checkpoint for cancer immunotherapy by working as a “don’t eat me” signal and suppressing innate immune signaling. Furthermore, CD47 is highly expressed in many cancer types to protect cancer cells from phagocytosis via binding to SIRPα on phagocytes. Targeting CD47 by either interrupting the CD47-SIRPα axis or combing with other therapies has been demonstrated as an encouraging therapeutic strategy in cancer immunotherapy. Antibodies and small molecules that target CD47 have been explored in pre- and clinical trials. However, formidable challenges such as the anemia and palate aggregation cannot be avoided because of the wide presentation of CD47 on erythrocytes. Aim of view: This review summarizes the current knowledge on the regulation and function of CD47, and provides a new perspective for immunotherapy targeting CD47. It also highlights the clinical progress of targeting CD47 and discusses challenges and potential strategies. Key scientific concepts of review: This review provides a comprehensive understanding of targeting CD47 in cancer immunotherapy, it also augments the concept of combination immunotherapy strategies by employing both innate and adaptive immune responses.

The structure of rural household energy consumption is crucial for rural residents' living standards and quality of life, constituting an integral component of energy transition and promoting Chinese-style modernization. Meanwhile, rural human capital is a prerequisite for agricultural and rural modernization. Drawing on survey data from 791 households in Shaanxi Province, this study empirically examines the impact and mechanisms of human capital on the household energy consumption structure with the ordinary least square (OLS) model and instrumental variable (IV) method. The findings indicate that human capital significantly reduces traditional energy consumption while increasing the adoption of transitional and advanced energy. This conclusion remains robust after rigorous testing. Mechanism analysis reveals that human capital facilitates the shift from traditional to transitional and advanced energy by enhancing purchasing power, environmental awareness, and the frequency of energy-saving technology usage within households. Further analysis demonstrates that higher levels of human capital correlate with a greater likelihood of households transitioning from traditional energy to transitional and advanced energy. Particularly, households with a high school education exhibit a significant increase in the consumption of transitional and advanced energy while notably reducing traditional energy consumption. Moreover, compared to low-income households, human capital has a significantly positive effect on increasing the adoption of advanced energy in high-income households. Hence, prioritizing investment in rural education, providing more educational resources, improving school facilities, and implementing incentive policies to emphasize education within households are recommended strategies to enhance rural residents' human capitals. This, in turn, facilitates their adoption of transitional and advanced energy, reducing dependence on traditional energy.