A fast and high precision multi-robot environment modeling based on M-BFSI: Bidirectional filtering and scene identification method.

This article designs and implements a fast and high-precision multi-robot environment modeling method based on bidirectional filtering and scene identification. To solve the problem of feature tracking failure caused by large angle rotation, a bidirectional filtering mechanism is introduced to improve the error-matching elimination algorithm. A global key frame database for multiple robots is proposed based on a pretraining dictionary to convert images into a bag of words vectors. The images captured by different sub-robots are compared with the database for similarity score calculation, so as to realize fast identification and search of similar scenes. The coordinate transformation from local map to global map and the cooperative SLAM exploration of multiple robots is completed by the best matching image and the transformation matrix. The experimental results show that the proposed algorithm can effectively close the predicted trajectory of the sub-robot, thus achieving high-precision collaborative environment modeling.

Human UDP-glucuronosyltransferase 1As catalyze aristolochic acid D O-glucuronidation to form a lesser nephrotoxic glucuronide.

ETHNOPHARMACOLOGICAL RELEVANCE: Aristolochic acids (AAs) are naturally occurring nitro phenanthrene carboxylic acids primarily found in plants of the Aristolochiaceae family. Aristolochic acid D (AAD) is a major constituent in the roots and rhizomes of the Chinese herb Xixin (the roots and rhizomes of Asarum heterotropoides F. Schmidt), which is a key material for preparing a suite of marketed Chinese medicines. Structurally, AAD is nearly identical to the nephrotoxic aristolochic acid I (AAI), with an additional phenolic group at the C-6 site. Although the nephrotoxicity and metabolic pathways of AAI have been well-investigated, the metabolic pathway(s) of AAD in humans and the influence of AAD metabolism on its nephrotoxicity has not been investigated yet. AIM OF THE STUDY: To identify the major metabolites of AAD in human tissues and to characterize AAD O-glucuronidation kinetics in different enzyme sources, as well as to explore the influence of AAD O-glucuronidation on its nephrotoxicity. MATERIALS AND METHODS: The O-glucuronide of AAD was biosynthesized and its chemical structure was fully characterized by both 1H-NMR and 13C-NMR. Reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses were conducted to assess the crucial enzymes involved in AAD O-glucuronidation in humans. Docking simulations were performed to mimic the catalytic conformations of AAD in human UDP-glucuronosyltransferases (UGTs), while the predicted binding energies and distances between the deprotonated C-6 phenolic group of AAD and the glucuronyl moiety of UDPGA in each tested human UGT isoenzyme were measured. The mitochondrial membrane potentials (MMP) and reactive oxygen species (ROS) levels in HK-2 cells treated with either AAI, or AAD, or AAD O-glucuronide were tested, to elucidate the impact of O-glucuronidation on the nephrotoxicity of AAD. RESULTS: AAD could be rapidly metabolized in human liver and intestinal microsomes (HLM and HIM, respectively) to form a mono-glucuronide, which was purified and fully characterized as AAD-6-O-ß-D-glucuronide (AADG) by NMR. UGT1A1 was the predominant enzyme responsible for AAD-6-O-glucuronidation, while UGT1A9 contributed to a lesser extent. AAD-6-O-glucuronidation in HLM, HIM, UGT1A1 and UGT1A9 followed Michaelis-Menten kinetics, with the Km values of 4.27 µM, 9.05 µM, 3.87 µM, and 7.00 µM, respectively. Docking simulations suggested that AAD was accessible to the catalytic cavity of UGT1A1 or UGT1A9 and formed catalytic conformations. Further investigations showed that both AAI and AAD could trigger the elevated intracellular ROS levels and induce mitochondrial dysfunction and in HK-2 cells, but AADG was hardly to trigger ROS accumulation and mitochondrial dysfunction. CONCLUSION: Collectively, UGT1A-catalyzed AAD 6-O-glucuronidation represents a crucial detoxification pathway of this naturally occurring AAI analogs in humans, which is very different from that of AAI.

Application Value of Target Management Mode Based on Chronic Illness Trajectory Framework in Elderly Patients with Diabetes Mellitus and Cardiovascular Diseases.

Background: Diabetes and cardiovascular diseases represent significant global health challenges, leading to organ dysfunction and increased mortality rates. Managing these conditions is complex, especially in the elderly population. The study addresses this pressing issue by exploring the application of the Chronic Illness Trajectory Framework (CITF), aiming to improve self-care and quality of life in elderly patients with diabetes and cardiovascular diseases. Methods: A total of 127 patients with diabetes mellitus and cardiovascular diseases admitted to the hospital were enrolled between January 2020 and January 2022. According to the implementation of CITF management mode, they were divided into a control group (62 cases, non-implementation) and an observation group (65 cases, implementation). The control group was given routine intervention, while the observation group was given CITF-based target management mode for 3 months. The changes in blood glucose, blood lipid, negative emotions, self-efficacy, self-management, compliance, and quality of life before and after intervention in both groups were observed. This study was approved by the Ethics Committee of Zhujiang Hospital. Results: After intervention, levels of fasting plasma glucose (FPG), 2h plasma glucose (2hPG), hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), scores of self-rating depression scale (SDS), self-rating anxiety scale (SAS) and Diabetes Specific Quality of Life Scale (DSQL) were decreased (P < .05), while scores of General Self-Efficacy Scale (GSES) and Scale of the Diabetes Self-Care Activities Chinese version (SDSCA), and compliance rate were increased in both groups (P < .05). The levels of FPG, 2hPG, HbA1c, TC, TG, and LDL-C, scores of SDS, SAS, and DSQL in the observation group were lower than those in the control group (P < .001), and scores of GSES and SDSCA, and compliance rate were higher than those in the control group (P < .001). These results highlight the positive role of comprehensive intervention in improving the physical and mental health of patients with diabetes and provide strong support for the application of comprehensive intervention strategies in diabetes management. Conclusion: CITF-based target management mode can alleviate negative emotions in patients with diabetes mellitus and cardiovascular diseases, improve self-management, self-efficacy, and compliance, effectively control blood glucose and lipids, and improve quality of life. The study conclusions highlight the importance of CITF management models in improving the management of patients with diabetes and cardiovascular disease. This comprehensive intervention helps reduce negative emotions, improve self-management and compliance, effectively control blood sugar and blood lipids, and improve quality of life. These results have important clinical implications and provide strong support for better care of patients with chronic diseases.

Development and Validation of a Risk Nomogram Model for Predicting Constipation in Patients with Type 2 Diabetes Mellitus.

Purpose: Constipation is a common complication of diabetic patients, which has a negative impact on their own health. This study aims to establish and internally validate the risk nomogram of constipation in patients with type 2 diabetes mellitus (T2DM) and to test its predictive ability. Patients and Methods: This retrospective study included 746 patients with T2DM at two medical centers. Among the 746 patients with T2DM, 382 and 163 patients in the Beilun branch of the First Affiliated Hospital of Zhejiang University were enrolled in the training cohort and the validation cohort, respectively. A total of 201 patients in the First Affiliated Hospital of Nanchang University were enrolled in external validation cohorts. The nomogram was established by optimizing the predictive factors through univariate and multivariable logistic regression analysis. The prediction performance of the nomogram was measured by the area under the receiver operating characteristic curve (AUROC), the calibration curve, and the decision curve analysis (DCA). Furthermore, its applicability was internally and independently validated. Results: Among the 16 clinicopathological features, five variables were selected to develop the prediction nomogram, including age, glycated hemoglobin (HbA1c), calcium, anxiety, and regular exercise. The nomogram revealed good discrimination with an area under the receiver operating characteristic curve (AUROC) of 0.908 (95% CI = 0.865-0.950) in the training cohort, and 0.867 (95% CI = 0.790-0.944) and 0.816 (95% CI = 0.751-0.881) in the internal and external validation cohorts, respectively. The calibration curve presented a good agreement between the prediction by the nomogram and the actual observation. The DCA revealed that the nomogram had a high clinical application value. Conclusion: In this study, the nomogram for pretreatment risk management of constipation in patients with T2DM was developed which could help in making timely personalized clinical decisions for different risk populations.

LSD1 in beige adipocytes protects cardiomyocytes against oxygen and glucose deprivation.

Objectives: Epicardial adipose tissue (EpAT) is known for its role in supporting the cardiomyocytes. Lysine-specific demethylase 1 (LSD1), a typical lysine demethylase, is an essential regulator for the maintenance of beige adipocytes. However, the effect of LSD1 in the adipogenic differentiation of beige adipocytes in EpAT, and its function on oxygen and glucose deprivation (OGD)-injured cardiomyocytes remain unclear. Materials and Methods: Heart tissues from young mice and elder mice were collected for immunohistochemical staining. LSD1 in 3T3-L1 cells was knocked down by LSD1-shRNA lentivirus infection. The qRT-PCR, western blotting, and Oil Red O staining were employed to detect the adipogenic differentiation of 3T3-L1 cells and formation of beige adipocytes. The cardiomyocytes co-cultured with beige adipocytes were used for OGD treatment. Cell apoptosis was analyzed by flow cytometry. The lactate dehydrogenase (LDH) and superoxide dismutase (SOD) activity were analyzed using commercially available kits. Results: The decrease of LSD1 was related to the age-dependent loss of beige adipocytes in mice EpAT. LSD1 knockdown inhibited the adipogenic differentiation of 3T3-L1 cells and formation of beige adipocytes. The down-regulation of LSD1 in 3T3-L1 cells decreased the protective effect of mature adipocytes on OGD-injured cardiomyocytes. Conclusion: The decreased expression of LSD1 in mice EpAT was associated with age-dependent ablation of beige adipocytes. The protective effect of beige adipocytes on OGD-injured cardiomyocytes is reduced by knockdown of LSD1 in adipocytes. The present study provided exciting insights into establishing novel therapies against age-dependent cardiac diseases.

Deciphering the active constituents of Dabushen decoction of ameliorating osteoarthritis via PPARγ preservation by targeting DNMT1.

Osteoarthritis (OA) is a multifactorial and chronic degenerative joint disease. Due to the adverse effects of currently used drugs, a safer and more effective therapy for treating OA is needed. Peroxisome proliferator-activated receptor-γ (PPARγ) is a key protein protecting cartilage. DNMT1-mediated hypermethylation of PPARγ promoter leads to its suppression. Therefore, DNMT1 might be an effective target for exerting cartilage protective effects by regulating the epigenetic expression of PPARγ. Dabushen decoction (DD) is a representative prescription of Dunhuang ancient medical prescription, which has a potential therapeutic effect on OA. So far, the research of the efficacy and material basis of DD in the treatment of OA remains unclear. In this study, Micro-CT, HE staining, S-O staining, and immunohistochemistry analysis were used to demonstrate that DD increased the expression of PPARγ and collagen synthesis in an OA rat model. Next, the structure of DNMT1 was used to screen the active constituents of DD by molecular docking method for treatment OA. Seven potential active constituents, including isoliquiritigenin, emodin, taxifolin, catalpol, alisol A, zingerone, and schisandrin C were hited. The protective effect of the potential active constituents to chondrocytes were evaluated by protein capillary electrophoresis, immunofluorescence assays, and ex vivo culture of rat knee cartilage. The five constituents, such as alisol A, emodin, taxifolin, isoliquiritigenin, and schisandrin C could promote the expression of PPARγ and ameliorate IL-1ß-induced downregulation of collagen II and the production of MMP-13. Alisol A and Emodin could effectively mitigate cartilage damage. At last, molecular dynamics simulations with MM-GBSA method was applied to investigate the interaction pattern of the active constituents and DNMT1 complexes. The five constituents, such as alisol A, emodin, taxifolin, isoliquiritigenin, and schisandrin C achieved a stable binding pattern with DNMT1, in which alisol A has a relatively high binding free energy. In conclusion, this study elucidates that the active constituents of DD (alisol A, emodin, taxifolin, isoliquiritigenin, and schisandrin C) could ameliorate osteoarthritis via PPARγ preservation by targeting DNMT1.These findings facilitated clinical use of DD and provided a valuable strategy for developing natural epigenetic modulators from Chinese herbal formula.

Neratinib plus capecitabine versus lapatinib plus capecitabine as the third-line therapy for HER2-positive metastatic breast cancer in China: a cost-effectiveness analysis.

OBJECTIVE: Neratinib plus capecitabine (Ner+Cap) were proved to be clinically beneficial as a third-line treatment for women with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC). The objective of this study was to evaluate the cost-effectiveness of Ner+Cap from the Chinese healthcare perspective. DESIGN: A three-state Markov simulation model was performed based on the results of NALA trial. The utilities of health state and disutilities of adverse events were derived from the published literature. Direct costs of anticancer agents, drug administration, routine follow-up and serious adverse events management were calculated in the model. Uncertainty was evaluated through univariate and probability sensitivity analysis. PARTICIPANTS: Patients with confirmed HER2-positive MBC who previously received at least two HER2-targeted treatments and were aged ≥18 years with an Eastern Cooperative Oncology Group performance status 0 or 1. A total of 621 patients were enrolled in the NALA trial. INTERVENTIONS: Third-line treatment with Ner+Cap or lapatinib plus capecitabine (Lap+Cap). MAIN OUTCOME MEASURES: The primary health outcomes of the model were costs, expected life-years (LYs), quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). RESULTS: When compared with Lap+Cap, Ner+Cap provided an additional 0.431 LYs and 0.339 QALYs, and increased the cost by $4299.2. The corresponding ICERs were 9970.1/LY and $12 670.2/QALY. Univariate sensitivity analyses suggested that the results were generally robust. Besides, Ner+Cap had a 100% probability of being cost-effective according to probabilistic sensitivity analysis. CONCLUSIONS: Ner+Cap was likely to be a cost-effective regimen as the third-line therapy for women with HER2-positive MBC at the willingness-to-pay threshold of $37 653.0/QALY in China.

LSD1 regulates the expressions of core cardiogenic transcription factors and cardiac genes in oxygen and glucose deprivation injured mice fibroblasts in vitro.

Cardiac reprogramming has emerged as a novel therapeutic approach to regenerating the damaged heart by directly converting endogenous cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs). Cardiac reprogramming requires the activation of the cardiogenic transcriptional program in concert with the repression of the fibroblastic transcriptional program. Lysine-specific demethylase 1 (LSD1) plays an instrumental role in many physiological processes such as cell growth, differentiation and metabolism. The epigenetic modifications of histones are essential for the accurate expression of genes in cardiomyocytes and the normal functioning of the heart. However, the effect of LSD1 in regulating the cardiogenic transcriptional program under myocardial ischemia/reperfusion (I/R) injury remains unclear. Thus, mice I/R injury was induced by 4 and 24 h reperfusion after 1-h occlusion of the left anterior descending coronary artery. The primary CFs and CMs were exposed under oxygen and glucose deprivation (OGD) to mimic I/R injury. The expression of LSD1 significantly decreased in I/R injured heart tissue and OGD-injured primary CFs and CM, and methylated histone presented a notable increase in OGD-injured primary CFs. Overexpression of LSD1 inhibited the injury of primary CFs induced by OGD, but showed limited inhibition on injured primary CMs. Under the OGD condition, LSD1 overexpression significantly increased cell viability, decreased cell apoptosis and reactive oxygen species (ROS) production of primary CFs. The expression of core cardiogenic transcription factors and cardiac genes were significantly decreased in OGD injured primary CFs, whereas LSD1 overexpression reversed the decrease of transcription factors and cardiac genes under the OGD condition. In conclusion, the overexpression of LSD1 has a protective role in I/R injury by inhibiting the histone methylation of primary CFs and regulates the expressions of core cardiogenic transcription factors and cardiac genes, which can prove to be a potential approach for direct cardiac reprogramming.

Comparative transcriptomic analysis of the super hybrid rice Chaoyouqianhao under salt stress.

BACKGROUND: Soil salinization is a threat to food security. China is rich in saline land resources for potential and current utilization. The cultivation and promotion of salt-tolerant rice varieties can greatly improve the utilization of this saline land. The super hybrid rice Chaoyouqianhao (CY1000) is one of the most salt-tolerant rice varieties and is widely used, but the molecular mechanism underlying its salt tolerance is not clear. RESULTS: In this study, the characteristics of CY1000 and its parents were evaluated in the field and laboratory. The results showed that aboveground parts of CY1000 were barely influenced by salt stress, while the roots were less affected than those of its parents. A comparative transcriptomic strategy was used to analyze the differences in the response to salt stress among the male and female parents of CY1000 at the seedling stage and the model indica rice 93-11. We found that the salt tolerance of CY1000 was mainly inherited from its male parent R900, and its female parent GX24S showed hardly any salt tolerance. To adapt to salt stress, CY1000 and R900 upregulated the expression of genes associated with soluble component synthesis and cell wall synthesis and other related genes and downregulated the expression of most genes related to growth material acquisition and consumption. In CY1000 and R900, the expression of genes encoding some novel key proteins in the ubiquitination pathway was significantly upregulated. After treatment with MG-132, the salt tolerance of CY1000 and R900 was significantly decreased and was almost the same as that of the wild type after salt stress treatment, indicating that ubiquitination played an important role in the salt tolerance mechanism of CY1000. At the same time, we found that some transcription factors were also involved in the salt stress response, with some transcription factors responding only in hybrid CY1000, suggesting that salt tolerance heterosis might be regulated by transcription factors in rice. CONCLUSION: Our results revealed that the ubiquitination pathway is important for salt tolerance in rice, and several novel candidate genes were identified to reveal a novel salt tolerance regulation network. Additionally, our work will help clarify the mechanism of heterosis in rice. Further exploration of the molecular mechanism underlying the salt tolerance of CY1000 can provide a theoretical basis for breeding new salt-tolerant rice varieties.

Astaxanthin improves the development of the follicles and oocytes through alleviating oxidative stress induced by BPA in cultured follicles.

This study is to investigate whether astaxanthin could alleviate the oxidative stress damages of follicles induced by BPA and improve the development of the cultured follicles and oocytes. Compared with BPA group, the survival rate, antrum formation rate, oocyte maturation rate and adherence area of the D8 and D10 follicles of the BPA+Asta group were significantly higher. The estrogen and progesterone in the culture medium of BPA+Asta group were significantly higher. PCNA in D8 and D10 granulosa cells and ERα in D10 granulosa cells of follicles in BPA+Asta group were significantly higher. The levels of malondialdehyde in the follicle culture medium, levels of ROS in the oocytes, the expression levels of caspase 3 and cathepsin B in the oocytes of the BPA+Asta group were significantly lower. However, the mitochondrial membrane potential, and the expression levels of antioxidant genes (CAT, SOD1 and SOD2) and anti-apoptotic gene Bcl-2 in the oocytes in the BPA+Asta group were significantly higher. Astaxanthin improves the development of follicles and oocytes through increasing the antioxidant capacity of follicles and oocytes, and relieving the BPA-induced oxidative stress during follicular development and oocyte maturation.

Tetramethylpyrazine Improves Monocrotaline-Induced Pulmonary Hypertension through the ROS/iNOS/PKG-1 Axis.

Background: Tetramethylpyrazine (TMP), a potent anti-free radical and anti-inflammations substance, has been demonstrated to possess a direct vessel relaxation property. This study aimed to evaluate the effect of TMP treatment in pulmonary hypertension (PH) and test the hypothesis that TMP prevents or reverses the process of PH. Methods: Rats (n = 36) injected with 50 mg/kg of monocrotaline (MCT) subcutaneously 4 weeks to develop PH were then randomized to TMP (5 mg/kg per day) for another 4 weeks. Hemodynamics was evaluated via the right ventricle. Pulmonary vessels structural remodeling and inflammation were examined by histologic and transmission electron microscopy observation. The expression of inducible nitric oxide synthase (iNOS) and cGMP-dependent protein kinases 1 (PKG-1) was detected by immunohistochemical staining and Western blot. Generation of reactive oxygen species (ROS) and antioxidation species was measured by biochemical analyses. Results: MCT increased PH and right ventricle hypertrophy. TMP alleviated pulmonary arterial pressure elevation, leukocyte infiltration, and structural remodeling of pulmonary arterials induced by MCT successfully. TMP treatment significantly increased the PKG-1 expression and suppressed the iNOS expression. The activity of superoxide dismutase (SOD), glutathione peroxidase (GSH), and catalase (CAT) was significantly higher than control group, while malondialdehyde (MDA) levels were lower compared with MCT group. Conclusion: TMP can suppress established MCT-induced PH through the ROS/iNOS/PKG axis. The underlying mechanisms may be associated with its anti-inflammatory, antioxidant, and antiproliferative properties in pulmonary arterial.

Acrocalyenes A and B, Two New Diterpenoids from Sinomenium acutum Associated Fungus Acrocalymma sp.

We identified two new diterpenoidal acrocalyenes A (1) and B (2) through chemical investigation on Acrocalymma sp., a plant-associated fungus from the tender stem isolates of Sinomenium acutum collected from the Qinling Mountains, along with seven already-recognized compounds (3-9). The HR-ESI-TOF-MS and 1D/2D NMR data were utilized for structural elucidation of these compounds, and the single-crystal X-ray diffraction was employed for absolute configuration clarification of the novel acrocalyenes 1 and 2. Bioassays revealed that the cytotoxicities of compounds 2, 4, 6, 7, and 8 against three human carcinoma cells (RKO, HeLa and HCC-1806) were moderate to strong, with IC50 between 6.70-38.82 µM. These isolates were also evaluated for their fungal resistant potentials against Botrytis cinerea, Fusarium culmorum and Fusarium solani, in which 3 displayed significant inhibitory effects on all three phytopathogenic fungi, showing respective MIC of 50, 25 and 25 µM.

New Wenshen Shengjing Decoction Improves Early Embryonic Development by Maintaining Low Levels of H3K4me3 in Sperm.

BACKGROUND: New Wenshen Shengjing Decoction (NWSSJD), a traditional Chinese compound medicine, has significant effect on spermatogenesis disorder and can significantly improve sperm quality. Many components in NWSSJD can induce epigenetic modifications of different types of cells. It is not yet known whether they can cause epigenetic modifications in sperm or early embryos. OBJECTIVE: This study investigated the effect of NWSSJD on mouse early embryonic development and its regulation of H3K4me3 in mouse sperm and early embryos. METHODS: Spermatogenesis disorder was induced in male mice with CPA (cyclophosphamide). NWSSJD was administrated for 30 days. Then, the male mice were mated with the female mice with superovulation, and the embryo degeneration rate of each stage was calculated. Immunofluorescence staining was used to detect the expression of H3K4me3 in sperm and embryos at various stages. Western blotting was performed to detect methyltransferase SETD1B expression. The expressions of development-related genes (OCT-4, NANOG, and CDX2) and apoptosis-related genes (BCL-2 and p53) were measured with qRT-PCR. RESULTS: Compared with the CPA group, NWSSJD significantly reduced the H3K4me3 level in sperms, significantly increased the number of normal early embryos (2-cell embryos, 3-4-cell embryos, 8-16-cell embryos, and blastocysts) per mouse, and reduced the degeneration rate of the embryos. The expression levels of H3K4me3 and methyltransferase SETD1B in early embryos were significantly elevated by NWSSJD. Additionally, NWSSJD significantly promoted BCL-2 expression, while reducing p53 expression, thus inhibiting embryonic cell apoptosis. Moreover, the expressions of development-related genes OCT-4 and CDX2 were significantly increased by NWSSJD, but NANOG expression had no significant difference. CONCLUSION: NWSSJD may promote early embryonic development possibly by maintaining low H3K4me3 levels in sperms and normal H3K4me3 modification in early embryos and by inhibiting embryonic cell apoptosis.

Congenital Hypothyroidism Patients With Thyroid Hormone Receptor Variants Are Not Rare: A Systematic Review.

BACKGROUND: Primary congenital hypothyroidism (CH) is a common endocrine and metabolic disease. Various genetic factors, including the thyroid hormone receptor (TSHR), play an important role in CH. AIM: To explore the occurrence of pathogenic TSHR variants in CH. METHODS: We searched published articles in PubMed, Web of Science, and Cochrane Library databases, from the establishment of the database to September 26, 2021. Studies with sequencing partial or full exons of TSHR in CH patients were included. Gene polymorphism was excluded. RESULTS: A total of 66 articles (44 case-control studies and 22 case reports) were selected from the database. Though case-control studies, we found the incidence of pathogenic TSHR variants were not rare (range from 0% to 30.6%) and varied greatly in different countries and race. The pathogenic genotypes varied in different regions. All the variants were "loss-of-function" mutations, in which the p.(Arg450His) variant was the most common variant. In addition, we analyzed the case reports and found that CH patients with a family genetic background expressed homozygous genotypes. Homozygotes had more obvious symptoms of hypothyroidism and higher risk of comorbidities than heterozygotes. CONCLUSION: Pathogenic TSHR variants are not uncommon cause of the CH, especially in the Arabs. The role of TSHR gene detection in the treatment of children with CH needs to be further studied.

Cognitive effectiveness of high-intensity interval training for individuals with methamphetamine dependence: a study protocol for randomised controlled trial.

INTRODUCTION: Cognitive deficit is a common syndrome of methamphetamine (MA) dependence. It is related to decision-making, control ability, and social functioning. High-intensity interval training (HIIT) is a training technique that requires people to work out at full intensity during a short period. Many studies have already shown the potential effects of HIIT on cognitive functions. The purpose of this trial is to evaluate the cognitive effects of HIIT on individuals with MA dependence. METHODS AND ANALYSIS: A total of 240 individuals with MA dependence will be randomly assigned to the HIIT group, moderate-intensity continuous training (MICT) group and control (CON) group. HIIT will consist of a 24-min HIIT exercise on a treadmill. MICT will consist of a 1-h body-mind exercise. CON will be their traditional intervention. The experimental period will be 12 months with 3 interventions weekly for the first 6 months and follow-up for the next 6 months. All subjects will be given cognitive tests at baseline, after intervention and at follow-up. Cognitive performances will be compared by a mixed-model analysis for repeated measures. DISCUSSION: HIIT training may reduce illicit drug cravings amongst individuals with MA dependence; hence, HIIT may have a good effect on the cognitive functions, such as memory and executive function, of individuals with MA dependence. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000032492 . Registered on April 30, 2020 ( http://www.chictr.org.cn/edit.aspx?pid=52127&htm=4 ).

Alleviation of glucolipotoxicity-incurred cardiomyocyte dysfunction by Z-ligustilide involves in the suppression of oxidative insult, inflammation and fibrosis.

Diabetes mellitus ranks as a major risk cause for disability and death around the world due to its complications, especially diabetic cardiomyopathy (DCM). Glucolipotoxicity is one of the critical causal factors of DCM. Recent finding confirms the beneficial roles of Z-ligustilide in diabetes mellitus. Nevertheless, its efficacy in DCM remains elusive. Here, Z-ligustilide elevated high glucose/high palmitic acid (HG/P)-inhibited cell viability and attenuated HG/P-induced cell apoptosis, caspase-3 activity, pro-apoptotic Bax and anti-apoptotic Bcl-2 protein expression. Furthermore, Z-ligustilide alleviated HG/P-evoked oxidative damage by decreasing HG/P-induced elevation in ROS, lactate dehydrogenase (LDH) and malondialdehyde (MDA) leakage, but increasing antioxidant enzyme-superoxide dismutase (SOD) and glutathione (GSH) levels suppressed by HG/P. Concomitantly, Z-ligustilide attenuated HG/P-induced cardiomyocyte fibrosis by increasing MMP-14 expression and diminishing HG/P-enhanced fibrotic protein expression, including collagen I, collagen II and TGF-ß. Mechanistically, Z-ligustilide offset the adverse effects of HG/P on the activation of the AMPK/GSK-3ß/Nrf2 pathway. Importantly, blocking the AMPK signaling overturned the protective efficacy of Z-ligustilide against HG/P-induced cardiomyocyte oxidative damage, inflammation and fibrosis. Together, these findings highlight that Z-ligustilide may alleviate glucolipotoxicity-induced cardiomyocyte dysfunction by regulating cell oxidative injury, inflammation and fibrosis via the AMPK/GSK-3ß/Nrf2 pathway. Consequently, Z-ligustilide may represent a promising therapeutic agent against DCM by restoring cardiomyocyte dysfunction.

Methylophiopogonanone A is a naturally occurring broad-spectrum inhibitor against human UDP-glucuronosyltransferases: Inhibition behaviours and implication in herb-drug interactions.

Methylophiopogonanone A (MOA) is an abundant homoisoflavonoid in the Chinese herb Ophiopogonis Radix. Recent investigations revealed that MOA inhibited several human cytochrome P450 enzymes (CYPs) and stimulated OATP1B1. However, the inhibitory effects of MOA on phase II drug-metabolizing enzymes, such as human UDP-glucuronosyltransferases (hUGTs), have not been well investigated. Herein, the inhibition potentials of MOA on hUGTs were assessed. The results clearly demonstrated that MOA dose-dependently inhibited all tested hUGTs including UGT1A1 (IC50 = 1.23 µM), one of the most important detoxification enzymes in humans. Further investigations showed that MOA strongly inhibited UGT1A1-catalysed NHPH-O-glucuronidation in a range of biological settings including hUGT1A1, human liver microsomes (HLM) and HeLa cells overexpressing UGT1A1. Inhibition kinetic analyses demonstrated that MOA competitively inhibited UGT1A1-catalysed NHPH-O-glucuronidation in both hUGT1A1 and HLM, with Ki values of 0.52 and 1.22 µM, respectively. Collectively, our findings expanded knowledge of the interactions between MOA and human drug-metabolizing enzymes, which would be very helpful for guiding the use of MOA-related herbal products in clinical settings.

Loss of nocturnal dipping pattern of skin sympathetic nerve activity during and following an extended-duration work shift in residents in training.

BACKGROUND: Extended-duration work shifts (EDWSs) might affect the health of physician residents, causing autonomic alteration. Skin sympathetic nerve activity (SKNA) recorded by noninvasive neuro-electrocardiography (neuECG) is used to estimate cardiac sympathetic tone. In this study, we aim to evaluate the impact of EDWSs on nocturnal SKNA assessed in resident doctors. METHODS: Twenty-four residents working EDWSs and 12 PhD students not working nightshift schedules were prospectively recruited. The neuECG was performed between 12 am and 6 am for 5 consecutive nights. SKNA was filtered from neuECG recorded signals. The questionnaires regarding work stress and sleep quality, blood pressure, and salivary alpha-amylase and cortisol levels were administered. RESULTS: The hours of weekly working and sleep opportunities were similar between residents and students, while residents reported more work stress and worse sleep quality. In residents, SKNA at 6 am (SKNA6am) was significantly higher than SKNA2am during the precall night, revealing a dipping pattern. However, the SKNA dipping disappeared during the on-call night and prominently flattened during the first postcall night, the full recovery of which was delayed until the second postcall nights. The morning blood pressure and salivary alpha-amylase and cortisol levels were similar between the precall and postcall days. In contrast, SKNA in students exhibited a constant dipping profile for all recorded nights. CONCLUSIONS: In healthy young adults, SKNA presents a dip night. The SKNA dip is impaired by working a nightshift, with a delayed recovery. The neuECG might serve as a useful tool to detect subclinical autonomic disturbances in shiftworkers.

Effects of Tai Chi on the Executive Function and Physical Fitness of Female Methamphetamine Dependents: A Randomized Controlled Trial.

Purpose: Exercise improves the health and mental status of drug dependents. The way by which Tai Chi (TC) as a special exercise treatment affects executive functions (EFs) of methamphetamine (MA) dependents is yet to be established. This study aimed to explore the effects of TC on the EFs and physical fitness of MA dependents. Methods: A total of 76 female MA dependents were randomly assigned to the exercise and control groups. The exercise group underwent three 60-min sessions of TC training per week for 12 weeks. The control group was trained with conventional exercises including the 9th Guang Bo Ti Cao and square dance. Physical fitness and EF assessments that evaluated inhibitory control (IC, go/no-go task), working memory (3-back task) and cognitive flexibility (switching task) were performed at baseline and at 12 weeks. A repeated-measures ANOVA was applied to analyze the differences of group and time. Results: The exercise group showed decreased response time (RT) with a significant main effect of time on the go/no-go task [F (1, 68) = 9.6, p < 0.05]. The interaction effect between time and group was significant on accuracy [F (1, 61) = 4.73, p < 0.05], and the main effect of time was significant on RT [F (1, 61) = 4.66, p < 0.05] in the 3-back task of the exercise group. Significant changes in BMI [F (1, 68) = 19.57, p < 0.05], vital capacity [F (1, 68) = 6.00, p < 0.05], and systolic blood pressure [F (1, 68) = 6.11, p < 0.05] were observed in the exercise group. Conclusion: These findings showed that 3 months of TC training can improve the IC and maintain the working memory and cognitive flexibility of MA dependents. Other data implied that TC may improve the physical fitness of MA dependents. Clinical Trial Registration: http://www.chictr.org.cn/, ChiCTR1900022091.