NAD+ homeostasis and its role in exercise adaptation: A comprehensive review.

Nicotinamide adenine dinucleotide (NAD+) is a crucial coenzyme involved in catalyzing cellular redox reactions and serving as a substrate for NAD+-dependent enzymes. It plays a vital role in maintaining tissue homeostasis and promoting healthy aging. Exercise, a well-established and cost-effective method for enhancing health, can influence various pathways related to NAD+ metabolism. Strategies such as supplementing NAD+ precursors, modulating NAD+ synthesis enzymes, or inhibiting enzymes that consume NAD+ can help restore NAD+ balance and improve exercise performance. Various overlapping signaling pathways are known to play a crucial role in the beneficial effects of both NAD+ and exercise on enhancing health and slowing aging process. Studies indicate that a combined strategy of exercise and NAD+ supplementation could synergistically enhance athletic capacity. This review provides an overview of current research on the interactions between exercise and the NAD+ network, underscoring the significance of NAD+ homeostasis in exercise performance. It also offers insights into enhancing exercise capacity and improving aging-related diseases through the optimal use of exercise interventions and NAD+ supplementation methods.

Prediction of Arteriovenous Access Dysfunction by Mel Spectrogram-based Deep Learning Model.

Background: The early detection of arteriovenous (AV) access dysfunction is crucial for maintaining the patency of vascular access. This study aimed to use deep learning to predict AV access malfunction necessitating further vascular management. Methods: This prospective cohort study enrolled prevalent hemodialysis (HD) patients with an AV fistula or AV graft from a single HD center. Their AV access bruit sounds were recorded weekly using an electronic stethoscope from three different sites (arterial needle site, venous needle site, and the midpoint between the arterial and venous needle sites) before HD sessions. The audio signals were converted to Mel spectrograms using Fourier transformation and utilized to develop deep learning models. Three deep learning models, (1) Convolutional Neural Network (CNN), (2) Convolutional Recurrent Neural Network (CRNN), and (3) Vision Transformers-Gate Recurrent Unit (ViT-GRU), were trained and compared to predict the likelihood of dysfunctional AV access. Results: Total 437 audio recordings were obtained from 84 patients. The CNN model outperformed the other models in the test set, with an F1 score of 0.7037 and area under the receiver operating characteristic curve (AUROC) of 0.7112. The Vit-GRU model had high performance in out-of-fold predictions, with an F1 score of 0.7131 and AUROC of 0.7745, but low generalization ability in the test set, with an F1 score of 0.5225 and AUROC of 0.5977. Conclusions: The CNN model based on Mel spectrograms could predict malfunctioning AV access requiring vascular intervention within 10 days. This approach could serve as a useful screening tool for high-risk AV access.

Brain Network Localization of Gray Matter Atrophy and Neurocognitive and Social Cognitive Dysfunction in Schizophrenia.

BACKGROUND: Numerous studies have established the presence of gray matter atrophy and brain activation abnormalities during neurocognitive and social cognitive tasks in schizophrenia. Despite a growing consensus that diseases localize better to distributed brain networks than individual anatomical regions, relatively few studies have examined brain network localization of gray matter atrophy and neurocognitive and social cognitive dysfunction in schizophrenia. METHODS: To address this gap, we initially identified brain locations of structural and functional abnormalities in schizophrenia from 301 published neuroimaging studies with 8712 individuals with schizophrenia and 9275 healthy control participants. By applying novel functional connectivity network mapping to large-scale resting-state functional magnetic resonance imaging datasets, we mapped these affected brain locations to 3 brain abnormality networks of schizophrenia. RESULTS: The gray matter atrophy network of schizophrenia comprised a broadly distributed set of brain areas predominantly implicating the ventral attention, somatomotor, and default networks. The neurocognitive dysfunction network was also composed of widespread brain areas primarily involving the frontoparietal and default networks. By contrast, the social cognitive dysfunction network consisted of circumscribed brain regions mainly implicating the default, subcortical, and visual networks. CONCLUSIONS: Our findings suggest shared and unique brain network substrates of gray matter atrophy and neurocognitive and social cognitive dysfunction in schizophrenia, which may not only refine the understanding of disease neuropathology from a network perspective but may also contribute to more targeted and effective treatments for impairments in different cognitive domains in schizophrenia.

NADPH mimics the antidepressant effects of exercise in a chronic unpredictable stress rat model.

Exercise is known to be an effective intervention for depression. NADPH has been demonstrated to have neuroprotective effects in our previous studies. This study aimed to investigate if NADPH has antidepressant effects and can mimic the effects of exercise in a chronic unpredictable stress (CUS) rat model. CUS rats underwent an 8-week swimming exercise (30 min/d, 5d/w) or were intraperitoneally administered 4 mg/kg or 8 mg/kg NADPH. The open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), and forced swimming test (FST) were used to examine the antidepressant-like behaviors of the rats. Exercise, 4 mg/kg, and 8 mg/kg NADPH similarly reduced anxiety, as demonstrated by the number of fecal pellets. Meanwhile, exercise and 8 mg/kg NADPH significantly increased locomotion activity in the OFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH effectively reversed CUS-induced anhedonia in rats in the SPT. Exercise, 4 mg/kg, and 8 mg/kg NADPH had no impact on appetite of depressed rats; however, 8 mg/kg NADPH increased the rats' exploratory activity in the NSFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH significantly reduced the immobility time of CUS model rats, while exercise and 8 mg/kg NADPH postponed the early CUS-induced "immobility" in the FST. These results demonstrated that NADPH has similar antidepressant-like effects to exercise in CUS-induced depression model rats and is a potential exercise-mimicking antidepressant.

Agricultural drought-driven mechanism of coupled climate and human activities in the karst basin of southern China.

Timely and accurate agricultural drought monitoring and drought-driven mechanism analysis in karst basins in the context of global warming are highly important for drought disaster monitoring and sustainable ecological development in a basin. In this study, based on MODIS data, meteorological and topographic data and land use data from 2001 to 2020, we used the Sen slope, the Mann-Kendall test and a geographic detector to explore the driving mechanisms of agricultural drought caused by climate change and human activities in the karst basin of southern China from 2001 to 2020. The results showed that (1) the spatial distribution of the TVDI in the karst basin in southern China has obvious regional characteristics, showing a decreasing trend from west to east. (2) According to the interannual trend of drought, the degree of drought in the South China karst basin exhibited a weakening trend over the last 20 years, with the most severe drought occurring in 2003. Regarding the seasonal change in the TVDI, drought in spring, summer and autumn exhibited a decreasing trend, while that in winter exhibited an increasing trend, and the drought intensity decreased in the following order: spring (0.58) > autumn (0.53) > summer (0.5) > winter (0.48). (3) Single-factor detection the results showed that rainfall, temperature and elevation were the main factors driving aridification in the study area; multifactor coupling (mean) drove drought in descending order: rainfall (q = 0.424) > temperature (q = 0.340) > elevation (q = 0.219) > land use (q = 0.188) > population density (q = 0.061) > slope (q = 0.057). Therefore, revealing the mechanism of agricultural drought in karst basins through the study of this paper has important theoretical significance and provides technical guidance for drought relief in karst areas.

Efficacy of etonogestrel subcutaneous implants versus the levonorgestrel-releasing intrauterine system in the conservative treatment of adenomyosis.

To evaluate the clinical efficacy of etonogestrel subcutaneous implant (ENG-SCI) with that of the levonorgestrel-releasing intrauterine system (LNG-IUD) for adenomyosis treatment. A prospective randomized cohort study was conducted including 108 patients (50 patients in ENG-SCI group and 58 in the LNG-IUD group) with adenomyosis from January 2019 to July 2021. After 3 months of treatment, both ENG-SCI group and LNG-IUD group showed significant improvement in patients' visual analog scale, pictorial blood loss assessment chart (PBAC), and uterine volume (P ＜ 0.05). The uterine volume of patients in LNG-IUD group decreased more significantly than that in the ENG-SCI group since 3 months of treatment. The PBAC score in the LNG-IUD group improved better than that in the ENG-SCI group since 6 months of treatment (P ＜ 0.05). No significant difference in the occurrence rate of ideal vaginal bleeding patterns and the hemoglobin levels between the two groups was observed. The ENG-SCI group had a higher probability of weight gain and progesterone-related side effects (P ＜ 0.05). Both ENG-SCI and LNG-IUD were effective in treatment of adenomyosis. However, LNG-IUD had a more significant effect in treating adenomyosis-related dysmenorrhea, excessive menstrual flow, anemia, and uterine enlargement, with relatively fewer side effects.

Health-related quality of life and its influencing factors among lung cancer patients receiving immune checkpoint inhibitors: A cross-sectional study.

PURPOSE: The aim of this study was to examine the level of health-related quality of life (HRQOL) of lung cancer patients receiving immune checkpoint inhibitors (ICIs) and analyze its influencing factors. METHOD: A cross-sectional study was conducted. From April 2022 to March 2023, 560 lung cancer patients receiving ICIs at three medical bases in Guangzhou, China were recruited using a convenient sampling method. A general information questionnaire, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), the Social Support Rating Scale (SSRS) and the Medical Coping Modes Questionnaire (MCMQ) were used for collecting data on sociodemographic and clinical characteristics, HRQOL, social support and medical coping mode. A descriptive analysis was conducted to describe HRQOL. Multiple regression analysis was applied to determine the factors influencing HRQOL. RESULTS: For lung cancer patients receiving ICIs, the mean score of HRQOL was 59.21 ± 19.86. Multivariate analysis indicated that acceptance-resignation coping mode (ß = -0.37, P < 0.01), Eastern Cooperative Oncology Group (ECOG) score (ß = -0.35, P < 0.01), combination of chemotherapy and/or bevacizumab (ß = -0.14, P < 0.01), and subjective support (ß = 0.07, P = 0.04) all contributed to 42.7% of the variance in HRQOL of the patients receiving ICIs. CONCLUSIONS: It is imperative to address and resolve the HRQOL issue for lung cancer patients receiving ICIs. The findings suggest nurse practitioners should be aware of a variety of factors that influence HRQOL and provide tailored inventions to patients as early as possible to help them achieve better HRQOL.

Real-world Study on the Effect of PARPi as Maintenance Therapy on Platinum Sensitivity after First- and Second-line Chemotherapy in Patients with Recurrent High-grade Serous Epithelial Ovarian Cancer.

BACKGROUND: This study investigated the effect of poly(ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy after first- and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). METHODS: This study retrospectively analyzed 172 patients with rHGSOC treated at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital between January 2017 and December 2021. The 1st-PARPi group comprised patients who received a PARPi as maintenance therapy after first-line chemotherapy (n=23), and the 1st-control group comprised those who did not (n = 105). Similarly, the 2nd-PARPi group comprised patients not given a PARPi in their first-line treatment (n = 30), and the 2nd-control group comprised those who were given a PARPi (n = 89). RESULTS: Among the 23 patients in the 1st-PARPi group and the 105 patients in the 1st-control group, nine and 99 were platinum-sensitive, and 14 and six were platinum-resistant, respectively (hazard ratio [HR]: 14.46, P < 0.0001). Among the 30 patients in the 2nd-PARPi group and 89 patients in the 2nd-control group, 10 and 71 were platinum-sensitive, and 20 and 18 were platinumresistant, respectively (HR: 4.37, P < 0.0001). Age, stage, residual tumor, the courses of platinumbased chemotherapy, and breast cancer susceptibility gene mutations were not associated with platinum sensitivity when using a PARPi as maintenance therapy after first- and second-line chemotherapy. CONCLUSION: Patients with rHGSOC using a PARPi were more likely to be platinum-sensitive and develop platinum resistance independent of PARPi duration. Care should be taken when using a PARPi as maintenance therapy after first- and second-line chemotherapy.

Matrin-3 acts as a potential biomarker and promotes hepatocellular carcinoma progression by interacting with cell cycle-regulating genes.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The oncogenic role of Matrin-3 (MATR3), an a nuclear matrix protein, in HCC remains largely unknown. Here, we document the biological function of MATR3 in HCC based on integrated bioinformatics analysis and functional studies. According to the TCGA database, MATR3 expression was found to be positively correlated with clinicopathological characteristics in HCC. The receiver operating characteristic (ROC) curve and Kaplan-Meier (KM) curve displayed the diagnostic and prognostic potentials of MATR3 in HCC patients, respectively. Pathway enrichment analysis represented the enrichment of MATR3 in various molecular pathways, including the regulation of the cell cycle. Functional assays in HCC cell lines showed reduced proliferation of cells with stable silencing of MATR3. At the same time, the suppressive effects of MATR3 depletion on HCC development were verified by xenograft tumor experiments. Moreover, MATR3 repression also resulted in cell cycle arrest by modulating the expression of cell cycle-associated genes. In addition, the interaction of MATR3 with cell cycle-regulating factors in HCC cells was further corroborated with co-immunoprecipitation and mass spectrometry (Co-IP/MS). Furthermore, CIBERSORT and TIMER analyses showed an association between MATR3 and immune infiltration in HCC. In general, this study highlights the novel oncogenic function of MATR3 in HCC, which could comprehensively address how aberrant changes in the cell cycle promote HCC development. MATR3 might serve as a prognostic predictor and therapeutic target for HCC patients.

Accommodation and Binocular Vision in Children with Myopic Anisometropia.

Purpose: To assess the differences in accommodation and binocular vision in children with myopic anisometropia and determine the correlation with anisometropia. Method: A total of 110 patients with myopia aged 8-15 years were recruited from June 2021 to February 2022 from the Affiliated Hospital of Xuzhou Medical University. Based on the interocular differences of spherical equivalent refraction, patients were divided into the isometropia (35 children), low anisometropia (LA group, 42 children), and high anisometropia (HA group, 33 children). The variables assessed were refraction, heterophoria, amplitude of accommodation (AMP), accommodative response (AR), gradient AC/A, positive and negative relative accommodation (PRA/NRA), and near stereopsis in the three groups. Pearson's correlation coefficient tests were used to investigate the possible association between each parameter and interocular differences (IODs). Results: Among 110 subjects, there were 49 males and 61 females with a mean age of 11.39 ± 2.28 years. Compared with those in the isometropia group, AMP was lower and near stereopsis was higher in the LA group, and the distance and near heterophoria, PRA, AR, and near stereopsis were higher, and PRA, AMP, and gradient AC/A were lower in the HA group (all P < 0.05). Compared with those in the LA group, the near stereopsis, AR, and the near stereopsis were higher in the HA group, and the gradient AC/A was lower (all P < 0.05). However, no significant differences existed in the negative relative accommodation (P > 0.05). The distance and near heterophoria, AR, AMP, and near stereopsis were observed to be correlated with IODs, respectively (r = -0.259, p = 0.006; r = -0.201, p = 0.036; r = 0.306, p = 0.001; r = -0.315, p = 0.001; r = 0.535, p < 0.001). Conclusion: Our results suggested that with the increase of anisometropia, distance and near heterophoria, AR, AMP, and near stereopsis had a tendency to get worse in children with myopic anisometropia.

Co-administration of chicken IL-2 alleviates clinical signs and replication of the ILTV chicken embryo origin vaccine by pre-activating natural killer cells and cytotoxic T lymphocytes.

IMPORTANCE: Chickens immunized with the infectious laryngotracheitis chicken embryo origin (CEO) vaccine (Medivac, PT Medion Farma Jaya) experience adverse reactions, hindering its safety and effective use in poultry flocks. To improve the effect of the vaccine, we sought to find a strategy to alleviate the respiratory reactions associated with the vaccine. Here, we confirmed that co-administering the CEO vaccine with chIL-2 by oral delivery led to significant alleviation of the vaccine reactions in chickens after immunization. Furthermore, we found that the co-administration of chIL-2 with the CEO vaccine reduced the clinical signs of the CEO vaccine while enhancing natural killer cells and cytotoxic T lymphocyte response to decrease viral loads in their tissues, particularly in the trachea and conjunctiva. Importantly, we demonstrated that the chIL-2 treatment can ameliorate the replication of the CEO vaccine without compromising its effectiveness. This study provides new insights into further applications of chIL-2 and a promising strategy for alleviating the adverse reaction of vaccines.

Exercise preconditioning promotes myocardial GLUT4 translocation and induces autophagy to alleviate exhaustive exercise-induced myocardial injury in rats.

Exercise preconditioning (EP) is a line of scientific inquiry into the short-term biochemical mediators of cardioprotection in the heart. This study examined the involvement of autophagy induced by energy metabolism in myocardial remodelling by EP and myocardial protection. A total of 120 healthy male Sprague Dawley (SD) rats were randomly divided into six groups. Plasma cTnI, HBFP staining and electrocardiographic indicators were examined in the context of myocardial ischemic/hypoxic injury and protection. Western blotting and fluorescence double labelling were used to investigate the relationship between energy metabolism and autophagy in EP-resistant myocardial injury caused by exhaustive exercise. Compared with those in the C group, the levels of myocardial ischemic/hypoxic injury were significantly increased in the EE group. Compared with those in the EE group, the levels of myocardial ischemic/hypoxic injury were significantly decreased in the EEP + EE and LEP + EE groups. Compared with that in the EE group, the level of GLUT4 in the sarcolemma was significantly increased, and the colocalization of GLUT4 with the sarcolemma was significantly increased in the EEP + EE and LEP + EE groups (P < 0.05). LC3-II and LC3-II/LC3-I levels of the EEP + EE group were significantly elevated compared with those in the EE group (P < 0.05). The levels of p62 were significantly decreased in the EEP + EE and LEP + EE groups compared with the EE group (P < 0.05). EP promotes GLUT4 translocation and induced autophagy to alleviate exhaustive exercise-induced myocardial ischemic/hypoxic injury.

Pharmacokinetic pharmacodynamic modeling of analgesics and sedatives in children.

Pharmacokinetic pharmacodynamic modeling is an important tool which uses statistical methodology to provide a better understanding of the relationship between concentration and effect of drugs such as analgesics and sedatives. Pharmacokinetic pharmacodynamic models also describe between-subject variability that allows identification of subgroups and dose adjustment for optimal pain management in individual patients. This approach is particularly useful in the pediatric population, where most drugs have received limited evaluation and dosing is extrapolated from adult practice. In children, the covariates of weight and age are used to describe size- and maturation-related changes in pharmacokinetics. It is important to consider both size and maturation in order to develop an accurate model and determine the optimal dose for different age groups. An adequate assessment of analgesic and sedative effect using pain scales or brain activity measures is essential to build reliable pharmacokinetic pharmacodynamic models. This is often challenging in children due to the multidimensional nature of pain and the limited sensitivity and specificity of some measurement tools. This review provides a summary of the pharmacokinetic and pharmacodynamic methodology used to describe the dose-concentration-effect relationship of analgesics and sedation in children, with a focus on the different pharmacodynamic endpoints and the challenges of pharmacodynamic modeling.

Study on the driving mechanism of lagged effects based on different time scales in a karst drainage basin in South China.

Compared to earthquakes and volcanoes, drought is one of the most damaging natural disasters and is mainly affected by rainfall losses, especially by the runoff regulation ability of the underlying watershed surface. Based on monthly rainfall runoff data recorded from 1980 to 2020, in this study, the distributed lag regression model is used to simulate the rainfall-runoff process in the karst distribution region of South China, and a time series of watershed lagged-flow volumes is calculated. The watershed lagged effect is analyzed by four distribution models, and the joint probability between the lagged intensity and frequency is simulated by the copula function family. The results show that (1) the watershed lagged effects simulated by the normal, log-normal, P-III and log-logistic distribution models in the karst drainage basin are particularly significant, with small mean square errors (MSEs) and significant time-scale characteristics. (2) Affected by spatiotemporal distribution differences in rainfall and the impacts of different basin media and structures, the lag response of runoff to rainfall differs significantly among different time scales. Especially at the 1-, 3- and 12-month scales, the coefficient of variation (Cv) of the watershed lagged intensity is greater than 1, while it is less than 1 at the 6- and 9-month scales. (3) The lagged frequencies simulated by the log-normal, P-III and log-logistic distribution models are relatively high (with medium, medium-high and high frequencies, respectively), while that simulated by the normal distribution is relatively low (medium-low and low frequencies). (4) There is a significant negative correlation (R < - 0.8, Sig. < 0.01) between the watershed lagged intensity and frequency. For the joint probability simulation, the fitting effect of the gumbel Copula is the best, followed by the Clayton and Frank-1 copulas, and while that of the Frank-2 copula is relatively weak. Consequently, the propagation mechanism from meteorological drought to agricultural or hydrological drought and the conversion mechanism between agricultural and hydrological drought are effectively revealed in this study, thereby providing a scientific basis for the rational utilization of water resources and drought resistance and disaster relief in karst areas.

Alleviation of ischemic brain injury by exercise preconditioning is associated with modulation of autophagy and mitochondrial dynamics in cerebral cortex of female aged mice.

Evidence from clinical studies and preclinical studies supports that exercise preconditioning can not only reduce the risk of stroke but also improve brain tissue and functional outcome after stroke. It has been demonstrated that autophagy and mitochondrial dynamics are involved in ischemic stroke. However, it is still unclear whether exercise preconditioning-induced neuroprotection against stroke is associated with modulation of autophagy and mitochondrial dynamics. Although age and sex interactively affect ischemic stroke risk, incidence, and outcome, studies based on young male animals are most often used to explore the role of exercise preconditioning in the prevention of ischemic stroke. In the current study, we examined whether exercise preconditioning could modulate autophagy and mitochondrial dynamics in a brain ischemia and reperfusion (I/R) model of female aged mice. The results showed that exercise preconditioning reduced infarct volume and improved neurological deficits. Additionally, increased levels of autophagy-related proteins LC3-II/LC3-I, LC3-II, p62, Atg7, and mitophagy-related proteins Bnip3L and Parkin, as well as increased levels of mitochondrial fusion modulator Mfn2 and mitochondrial fission modulator Drp1 in the ischemic cortex of female aged mice at 12 h after I/R were present. Our results could contribute to a better understanding of exercise preconditioning-induced neuroprotection against ischemic stroke for the elderly.

LncRNA15691 promotes T-ALL infiltration by upregulating CCR9 via increased MATR3 stability.

Our previous studies demonstrated that CCR9 plays an important role in several aspects of T-cell acute lymphoblastic leukemia progression and that CCR9 is a potential therapeutic target. However, the underlying mechanism that regulates CCR9 expression remains incompletely understood. In this study, bioinformatics analysis and validation in clinical samples revealed the lncRNA15691 to be positively correlated with CCR9 mRNA expression and significantly upregulated in T-cell acute lymphoblastic leukemia samples and CCR9high T-cell acute lymphoblastic leukemia cell lines. LncRNA15691, a previously uncharacterized lncRNA, was found to be located in both the cytoplasm and the nucleus via fluorescence in situ hybridization assay. In addition, lncRNA15691 upregulated the expression of CCR9 and was involved in T-cell acute lymphoblastic leukemia cell invasion. In vivo experiments showed that lncRNA15691 promoted leukemia cell homing/infiltration into the bone marrow, blood, and spleen, whereas the CCR9 ligand, CCL25, augmented the extramedullary infiltration of CCR9low leukemia cells overexpressing lncRNA15691 into blood, spleen, and liver. Subsequently, RNA protein pull-down assays, coupled with liquid chromatography-tandem mass spectrometry, were used to uncover potential lncRNA15691-interacting proteins, which were then validated by RNA immunoprecipitation. These mechanistic studies revealed that lncRNA15691 upregulated CCR9 expression via directly binding to and stabilizing MATR3 by inhibiting its nuclear degradation mediated by PKA. Collectively, our study revealed a novel mechanism of regulating CCR9 expression and implicated lncRNA15691 as a potential novel biomarker for T-cell acute lymphoblastic leukemia infiltration.

MiR-125b-5p Targets MTFP1 to Inhibit Cell Proliferation, Migration, and Invasion and Facilitate Cell Apoptosis in Endometrial Carcinoma.

MicroRNAs (miRNAs) are recognized as latent diagnostic, prognostic, and therapeutic biomarkers for endometrial carcinoma (EC). We attempted to discuss function and mechanism of miR-125b-5p in EC cell progression. This study manifested a decreased miR-125b-5p level and an increased mitochondrial fission process 1 (MTFP1) level in EC, and there was an inverse correlation between them. Moreover, in vitro assays were performed. The results denoted that miR-125b-5p could target a putative binding site on MTFP1 3'UTR to reduce MTFP1 expression, thereby repressing cell malignant behaviors. Besides, the promoting impact of MTFP1 overexpression on malignant phenotypes of EC cells could be restored by miR-125b-5p up-regulation. Considering, our investigation exhibited that miR-125b-5p curbed EC cell malignant phenotypes through targeting MTFP1. This study generates a fresh functional mechanism for EC occurrence and progression, which also lays the groundwork for clinical therapies.

Optimising intravenous salbutamol in children: a phase 2 study.

OBJECTIVE: The ß2-agonists such as salbutamol are the mainstay of asthma management. Pharmacokinetic-pharmacodynamic (PKPD) models to guide paediatric dosing are lacking. We explored the relationship between salbutamol dose, serum concentration, effectiveness and adverse effects in children by developing a PKPD model. DESIGN: A prospective cohort study of children admitted to hospital with acute asthma, who received intravenous salbutamol. SETTING: Children were recruited in two cohorts: the emergency departments of two London hospitals or those retrieved by the Children's Acute Transport Service to three London paediatric intensive care units. PATIENTS: Patients were eligible if aged 1-15 years, admitted for acute asthma and about to receive or receiving intravenous salbutamol. INTERVENTIONS: Treatment was according to local policy. Serial salbutamol plasma levels were taken. Effectiveness measurements were recorded using the Paediatric Asthma Severity Score (PASS). Toxicity measurements included lactate, pH, glucose, heart rate, blood pressure and arrhythmias. PKPD modelling was performed with non-linear mixed-effect models. MAIN OUTCOMES: Fifty-eight children were recruited with 221 salbutamol concentration measurements from 54 children. Median (range) age was 2.9 (1.1-15.2) years, and weight was 13.6 (8-57.3) kg. Ninety-five PASS measurements and 2078 toxicity measurements were obtained. RESULTS: A two-compartment PK model adequately described the time course of salbutamol-plasma concentrations. An EMAX (maximum drug effect) concentration-effect relationship described PASS and toxicity measures. PKPD simulations showed an infusion of 0.5 µg/kg/min (maximum 20 µg/min) for 4 hours after bolus achieves >90% maximal bronchodilation for 12 hours. CONCLUSIONS: A paediatric PKPD model for salbutamol is described. An infusion of 0.5 µg/kg/min after bolus achieves effective bronchodilation. Higher rates are associated with greater tachycardia and hyperglycaemia.

Exercise preconditioning improves electrocardiographic signs of myocardial ischemic/hypoxic injury and malignant arrhythmias occurring after exhaustive exercise in rats.

Exercise preconditioning (EP) has a good myocardial protective effect. This study explored whether EP improves electrocardiographic (ECG) signs of myocardial ischemic/hypoxic injury and the occurrence of malignant arrhythmia after exhaustive exercise. A total of 120 male SD rats were randomly divided into the control group (group C), early exercise preconditioning group (group EEP), late exercise preconditioning group (group LEP), exhaustive exercise group (group EE), early exercise preconditioning + exhaustive exercise group (group EEP + EE) and late exercise preconditioning + exhaustive exercise group (group LEP + EE). Changes in heart rate (HR), ST segment, T wave and QT corrected (QTc) intervals on ECG; hematoxylin-basic fuchsin-picric acid (HBFP) staining; and cTnI levels were used to study myocardial injury and the protective effect of EP. Compared with those in group C, the levels of plasma markers of myocardial injury, HBFP staining and ECG in group EE were significantly increased (P < 0.05). Compared with those in group EE, the levels of plasma markers of myocardial injury, HBFP staining and ECG in group EEP + EE and group LEP + EE were significantly decreased (P < 0.05). The results suggested that EP improved ECG signs of myocardial ischemic/hypoxic injury and malignant arrhythmias that occur after exhaustive exercise. The ST segment and T wave could also serve as indexes for evaluating exhaustive exercise-induced myocardial ischemia/hypoxia.

[Efficient biosynthesis of D-mannitol by coordinated expression of a two-enzyme cascade].

D-mannitol is widely used in the pharmaceutical and medical industries as an important precursor of antitumor drugs and immune stimulants. However, the cost of the current enzymatic process for D-mannitol synthesis is high, thus not suitable for commercialization. To address this issue, an efficient mannitol dehydrogenase LpGDH used for the conversion and a glucose dehydrogenase BaGDH used for NADH regeneration were screened, respectively. These two enzymes were co-expressed in Escherichia coli BL21(DE3) to construct a two-enzyme cascade catalytic reaction for the efficient synthesis of d-mannitol, with a conversion rate of 59.7% from D-fructose achieved. The regeneration of cofactor NADH was enhanced by increasing the copy number of Bagdh, and a recombinant strain E. coli BL21/pETDuet-Lpmdh-Bagdh-Bagdh was constructed to address the imbalance between cofactor amount and key enzyme expression level in the two-enzyme cascade catalytic reaction. An optimized whole cell transformation process was conducted under 30 ℃, initial pH 6.5, cell mass (OD600) 30, 100 g/L D-fructose substrate and an equivalent molar concentration of glucose. The highest yield of D-mannitol was 81.9 g/L with a molar conversion rate of 81.9% in 5 L fermenter under the optimal conversion conditions. This study provides a green and efficient biotransformation method for future large-scale production of D-mannitol, which is also of great importance for the production of other sugar alcohols.