Effects of temporal changes in resting heart rate on future diabetes-related outcomes.

Background and aims: Most studies have analyzed the relationship between resting heart rate (RHR) measured at only one time point and future clinical events. The current study aims to investigate the impact of long-term RHR changes on future clinical outcomes in a decade-long cohort with type 2 diabetes mellitus (T2DM). Methods: The two-staged follow-up involved 2,513 T2DM participants. The first stage (2008-2014) intended to identify levels and trends in RHR changes, while the second stage (2014-2018) attempted to collect new occurrence records of clinical results. Cox proportional hazards models were applied to predict hazard ratios (HRs), along with 95% confidence interval (CI) for the correlation between RHR changes and future events. Results: There is no significant correlation between baseline RHR levels and long-term clinical events. According to the range of RHR change, compared with the stable RHR group, the adjusted HRs for cardiovascular events and all-cause death in the large increase group were 3.40 (95% CI: 1.33-8.71, p=0.010) and 3.22 (95% CI: 1.07-9.64, p=0.037), respectively. While the adjusted HRs for all-cause death and major adverse cardiac and cerebrovascular events (MACCE) in the moderate decrease group were 0.55 (95% CI: 0.31-0.96, p=0.037) and 0.51 (95% CI: 0.26-0.98, p=0.046). According to the trend of RHR, compared with the normal-normal group, the adjusted HRs for composite endpoint events and cerebrovascular events in the normal-high group were 1.64 (95% CI: 1.00-2.68, p=0.047) and 2.82 (95% CI: 1.03-7.76, p=0.043), respectively. Conclusion: Changes in RHR had predictive value for long-term clinical events in diabetic populations. Individuals with significantly elevated RHR over a particular period of time showed an increased risk of adverse events.

NLRX1 Inhibits LPS-Induced Microglial Death via Inducing p62-Dependent HO-1 Expression, Inhibiting MLKL and Activating PARP-1.

The activation of microglia and the production of cytokines are key factors contributing to progressive neurodegeneration. Despite the well-recognized neuronal programmed cell death regulated by microglial activation, the death of microglia themselves is less investigated. Nucleotide-binding oligomerization domain, leucine-rich repeat-containing X1 (NLRX1) functions as a scaffolding protein and is involved in various central nervous system diseases. In this study, we used the SM826 microglial cells to understand the role of NLRX1 in lipopolysaccharide (LPS)-induced cell death. We found LPS-induced cell death is blocked by necrostatin-1 and zVAD. Meanwhile, LPS can activate poly (ADP-ribose) polymerase-1 (PARP-1) to reduce DNA damage and induce heme oxygenase (HO)-1 expression to counteract cell death. NLRX1 silencing and PARP-1 inhibition by olaparib enhance LPS-induced SM826 microglial cell death in an additive manner. Less PARylation and higher DNA damage are observed in NLRX1-silencing cells. Moreover, LPS-induced HO-1 gene and protein expression through the p62-Keap1-Nrf2 axis are attenuated by NLRX1 silencing. In addition, the Nrf2-mediated positive feedback regulation of p62 is accordingly reduced by NLRX1 silencing. Of note, NLRX1 silencing does not affect LPS-induced cellular reactive oxygen species (ROS) production but increases mixed lineage kinase domain-like pseudokinase (MLKL) activation and cell necroptosis. In addition, NLRX1 silencing blocks bafilomycin A1-induced PARP-1 activation. Taken together, for the first time, we demonstrate the role of NLRX1 in protecting microglia from LPS-induced cell death. The underlying protective mechanisms of NLRX1 include upregulating LPS-induced HO-1 expression via Nrf2-dependent p62 expression and downstream Keap1-Nrf2 axis, mediating PARP-1 activation for DNA repair via ROS- and autophagy-independent pathway, and reducing MLKL activation.

CASK Mediates Oxidative Stress-Induced Microglial Apoptosis-Inducing Factor-Independent Parthanatos Cell Death via Promoting PARP-1 Hyperactivation and Mitochondrial Dysfunction.

Calcium/calmodulin-dependent serine protein kinase (CASK) is a scaffold protein and plays critical roles in neuronal synaptic formation and brain development. Previously, CASK was shown to associate with EGFR to maintain the vulval cell differentiation in C. elegans. In this study, we explored the role of CASK in CHME3 microglial cells. We found that CASK silencing protects cells from H2O2-induced cell death by attenuating PARP-1 activation, mitochondrial membrane potential loss, reactive oxygen species production, and mitochondrial fission, but it increases oxidative phosphorylation. The PARP-1 inhibitor olaparib blocks H2O2-induced cell death, suggesting the death mode of parthanatos. CASK silencing also increases AKT activation but decreases AMPK activation under H2O2 treatment. Pharmacological data further indicate that both signaling changes contribute to cell protection. Different from the canonical parthanatos pathway, we did not observe the AIF translocation from mitochondria into the nucleus, suggesting a non-canonical AIF-independent parthanatos in H2O2-treated CHME3 cells. Moreover, we found that CASK silencing upregulates the EGFR gene and protein expression and increases H2O2-induced EGFR phosphorylation in CHME3 microglia. However, EGFR activation does not contribute to cell protection caused by CASK silencing. In conclusion, CASK plays a crucial role in microglial parthanatos upon H2O2 treatment via stimulation of PARP-1 and AMPK but the inhibition of AKT. These findings suggest that CASK might be an ideal therapeutic target for CNS disorders.

A multifunctional flexible sensor based on PI-MXene/SrTiO3 hybrid aerogel for tactile perception.

The inadequacy of tactile perception systems in humanoid robotic manipulators limits the breadth of available robotic applications. Here, we designed a multifunctional flexible tactile sensor for robotic fingers that provides capabilities similar to those of human skin sensing modalities. This sensor utilizes a novel PI-MXene/SrTiO3 hybrid aerogel developed as a sensing unit with the additional abilities of electromagnetic transmission and thermal insulation to adapt to certain complex environments. Moreover, polyimide (PI) provides a high-strength skeleton, MXene realizes a pressure-sensing function, and MXene/SrTiO3 achieves both thermoelectric and infrared radiation response behaviors. Furthermore, via the pressure response mechanism and unsteady-state heat transfer, these aerogel-derived flexible sensors realize multimodal sensing and recognition capabilities with minimal cross-coupling. They can differentiate among 13 types of hardness and four types of material from objects with accuracies of 94% and 85%, respectively, using a decision tree algorithm. In addition, based on the infrared radiation-sensing function, a sensory array was assembled, and different shapes of objects were successfully recognized. These findings demonstrate that this PI-MXene/SrTiO3 aerogel provides a new concept for expanding the multifunctionality of flexible sensors such that the manipulator can more closely reach the tactile level of the human hand. This advancement reduces the difficulty of integrating humanoid robots and provides a new breadth of application scenarios for their possibility.

Intensifying rice production to reduce imports and land conversion in Africa.

Africa produces around 60% of the rice the continent consumes, relying heavily on rice imports to fulfill the rest of the domestic demand. Over the past 10 years, the rice-agricultural area increased nearly 40%, while average yield remained stagnant. Here we used a process-based crop simulation modelling approach combined with local weather, soil, and management datasets to evaluate the potential to increase rice production on existing cropland area in Africa and assess cropland expansion and rice imports by year 2050 for different scenarios of yield intensification. We find that Africa can avoid further increases in rice imports, and even reduce them, through a combination of cropland expansion following the historical trend together with closure of the current exploitable yield gap by half or more. Without substantial increase in rice yields, meeting future rice demand will require larger rice imports and/or land conversion than now.

A flavonoid salt probe for distinguishing between tumor and normal cells.

YH-2 represents an innovative, non-invasive fluorescent probe featuring a structure based on flavonoid onium salts. It is characterized by a well-suited Stokes shift and emits in the near-infrared (NIR) wavelength range. Its capacity to distinguish between HeLa cells, HepG2 cells, and LO2 cells is attributed to differential intracellular viscosity. Experimental results validate the heightened viscosity of organelles, such as the endoplasmic reticulum (ER), mitochondria and lysosomes in tumor cells compared to LO2 cells. Of paramount importance, YH-2 demonstrates the capability to swiftly image tumors within a mere 20 min following tail vein injection and this imaging ability can be sustained for an extended period of up to 5 h. This method offers a potential tumor diagnostic strategy in vivo.

Treatment of Hoffa fracture of femoral condyle with anchor combined with auxiliary fixation.

BACKGROUND: A Hoffa fracture is an unstable intra-articular break that is generally treated with surgery. OBJECTIVE: To evaluate the feasibility and clinical outcomes of using a suture anchor combined with auxiliary fixation for the treatment of a lateral femoral condyle Hoffa fracture. METHODS: The study retrospectively reviewed 8 patients (5 males and 3 females) with a lateral femoral condyle Hoffa fracture who had been treated by combining a suture anchor with auxiliary fixation between January 2016 and April 2020. The mean age of patients was 37.5 years (ranging from 23 to 45). According to Letenneur's classification, there were 4 cases of type I, 2 cases of type II, and 2 cases of type III fractures. The clinical outcomes were assessed using Letenneur's functional assessment. RESULTS: The follow-up duration ranged between 14-24 months. All patients achieved primary healing of the incision and fracture union, as well as normal flexion and extension of the knee joint, with 7 cases showing excellent outcomes and 1 case showing a good outcome. No postoperative complications, such as fracture displacement, anchor loosening, or fracture malunion, occurred in this series. CONCLUSION: Our results indicated that a suture anchor, combined with external fixation, was an effective treatment for a lateral femoral condyle Hoffa fracture. Accordingly, this procedure is worthy of wider clinical application.

Productivity and global warming potential of direct seeding and transplanting in double-season rice of central China.

Labor and water scarcity requires crop establishment of double-season rice to be shifted from traditional transplanting to direct seeding. Owing to the limited thermal time, only ultrashort-duration cultivars of about 95 d can be used for direct-seeded, double-season rice (DDR) in central China. However, whether the shift in crop establishment of double-season rice can reduce greenhouse gas emissions without yield penalty remains unclear. Field experiments were conducted in Hubei province, central China with three treatments of crop establishment in the early and late seasons of 2017 and 2018. Treatments included DDR with ultrashort-duration cultivars (DDRU), transplanted double-season rice with ultrashort-duration cultivars (TDRU), or with widely grown cultivars which have short duration of about 110 d (TDRS). It was found that crop growth duration of DDRU was 6-20 days shorter than that of TDRU and TDRS, respectively. Ultrashort-duration cultivars under DDRU achieved 15.1 t ha-1 of annual yield that was 9.4% higher than TDRU, and only 3.2% lower than TDRS. DDRU reduced the annual cumulative CH4 emission by 32.0-46.1%, but had no difference in N2O emission in comparison with TDRU and TDRS. The highest CO2 emission was TDRS followed by DDRU, and then TDRU. As a result, shifting from TDRU and TDRS to DDRU decreased global warming potential and yield-scaled greenhouse gas intensity by 28.9-53.2% and 20.7-63.8%, respectively. These findings suggest that DDR can be a promising alternative to labor- and water-intensive TDR in central China that offers important advantages in mitigating agricultural greenhouse gas emissions without sacrificing grain yield.

Epigenetic upregulation of spleen tyrosine kinase in cancer cells through p53-dependent downregulation of DNA methyltransferase.

Syk is a tumor suppressor gene in some solid tumors. Currently, it remains unknown how Syk gene hypermethylation is controlled by DNA methyltransferase (DNMT) and p53. In colorectal cancer HCT116 cells, we found that protein and mRNA levels of Syk were much higher in WT than in p53-/- cells. Both p53 inhibitor PFT-α and p53 silencing can reduce the protein and mRNA expression of Syk in WT cells, while DNMT inhibitor 5-Aza-2'-dC can increase Syk expression in p53-/- cells. Interestingly, the DNMT expression in p53-/- HCT116 cells was higher than that in WT cells. PFT-α can not only enhance Syk gene methylation but also increase DNMT1 protein and mRNA levels in WT HCT116 cells. In metastatic lung cancer cell lines A549 and PC9, which express WT p53 and gain function of p53, respectively, PFT-α can also downregulate Syk mRNA and protein expression. However, the Syk methylation level was increased by PFT-α in A549 but not in PC9 cells. Likewise, 5-Aza-2'-dC transcriptionally increased Syk gene expression in A549 cells, but not in PC9 cells. In summary methylation of Syk promoter requires DNMT1, and p53 can upregulate Syk expression via downregulation of DNMT1 at the transcriptional level.

Clinical study of suture anchors in the treatment of radial head fractures.

BACKGROUND: This study aimed to analyze and study the clinical effect of suture anchors in the treatment of radial head fractures (RHFs). METHODS: A total of 11 patients (five male and six female) with RHFs who were treated from March 2016 to June 2021 were included in this study. They were 17-61 (average 38.5) years old. In terms of the Johnston-Mason classification, two cases were type II, seven cases were type III, and two cases were type IV. All patients were treated with open reduction and anchor internal fixation. RESULTS: All 11 patients were followed up, all incisions healed by first intention, and the duration of follow-up was 14-20 months. The average operation time was 40 ± 15 min. The clinical healing time was 4-6 (average 5) weeks. No patients had any complications, such as traumatic arthritis, malunion, nerve injury, joint stiffness, or incision infection. The clinical effects were evaluated according to the Mayo Elbow Performance Score. The scores of all 11 cases were 90-95, all excellent. CONCLUSION: The application of suture anchor internal fixation in the treatment of RHFs has the advantages of accurate reduction, no need for a secondary operation to remove the fixation materials, less trauma, fewer complications, good fracture healing, and good recovery of elbow extension, flexion, and rotation functions.

P2X7 Is Involved in the Mouse Retinal Degeneration via the Coordinated Actions in Different Retinal Cell Types.

Adenosine triphosphate (ATP) released from dying cells with high concentrations is sensed as a danger signal by the P2X7 receptor. Sodium iodate (NaIO3) is an oxidative toxic agent, and its retinal toxicity has been used as the model of dry age-related macular degeneration (AMD). In this study, we used NaIO3-treated mice and cultured retinal cells, including BV-2 microglia, 661W photoreceptors, rMC1 Müller cells and ARPE-19 retinal epithelial cells, to understand the pathological action of P2X7 in retinal degeneration. We found that NaIO3 can significantly decrease the photoreceptor function by reducing a-wave and b-wave amplitudes in electroretinogram (ERG) analysis. Optical coherence tomography (OCT) analysis revealed the degeneration of retinal epithelium and ganglion cell layers. Interestingly, P2X7-/- mice were protected from the NaIO3-induced retinopathy and inflammatory NLRP3, IL-1ß and IL-6 gene expression in the retina. Hematoxylin and eosin staining indicated that the retinal epithelium was less deteriorated in P2X7-/- mice compared to the WT group. Although P2X7 was barely detected in 661W, rMC1 and ARPE-19 cells, its gene and protein levels can be increased after NaIO3 treatment, leading to a synergistic cytotoxicity of BzATP [2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethyleneammonium)salt] and NaIO3 administration in ARPE-19 cells. In conclusion, the paracrine action of the ATP/P2X7 axis via cell-cell communication is involved in NaIO3-induced retinal injury. Our results show that P2X7 antagonist might be a potential therapy in inflammation-related retinal degeneration.

Practice of Huzhou in promoting the reform of countywide medical and health governance system / 中华医院管理杂志

The construction of a countywide community for medical and health services is designed to upgrade the service capacity of primary medical and health institutions, to promote resource sharing and collaborative services, and promote the hierarchical medical system. Huzhou of Zhejiang province has launched its initiative in building a countywide community for medical services since 2018. The authors summarized its main practices in promoting the integration of the management system and optimizing operating mechanism of countywide medical and health institutions, promoting the reform of the county medical and health governance system, as well as the achievements and shortcomings, with a view to providing reference for promoting the high-quality development of the countywide medical and health service system.

Analysis of prognostic factors of extranodal NK/T-cell lymphoma treated with pegaspargase/L-asparaginase: a multicenter retrospective study / 中华血液学杂志

Objective: To explore the prognostic factors of extracellular NK/T cell lymphoma (ENKTL) treated with pegaspargase/L-asparaginase. Methods: The clinical data of 656 ENKTL patients diagnosed at 11 medical centers in the Huaihai Lymphoma Working Group from March 2014 to April 2021 were retrospectively analyzed. The patients were randomly divided into two groups: a training set (460 cases) and a validation set (196 cases) at 7∶3, and the prognostic factors of the patients were analyzed. A prognostic scoring system was established, and the predictive performance of different models was compared. Results: Patients' median age was 46 (34, 57) years, with 456 males (69.5% ) and 561 nasal involvement (85.5% ). 203 patients (30.9% ) received a chemotherapy regimen based on L-asparaginase combined with anthracyclines, and the 5-year overall survival rate of patients treated with P-GEMOX regimen (pegaspargase+gemcitabine+oxaliplatin) was better than those treated with SMILE regimen (methotrexate+dexamethasone+cyclophosphamide+L-asparaginase+etoposide) (85.9% vs 63.8% ; P=0.004). The results of multivariate analysis showed that gender, CA stage, the Eastern Cooperative Oncology Group performance status (ECOG PS) score, HGB, and EB virus DNA were independent influencing factors for the prognosis of ENKTL patients (P<0.05). In this study, the predictive performance of the prognostic factors is superior to the international prognostic index, Korean prognostic index, and prognostic index of natural killer lymphoma. Conclusion: Gender, CA stage, ECOG PS score, HGB, and EB virus DNA are prognostic factors for ENKTL patients treated with pegaspargase/L-asparaginase.

Assay of amino acids in leaves of Eucommia ulmoides under arbor forest mode and leaf-oriented cultivation mode by pre-column derivatization HPLC / 中国中药杂志

This study aims to develop the pre-column derivatization high performance liquid chromatography(HPLC) method for the determination of 16 kinds of amino acids in Eucommia ulmoides leaves, and compare the content of amino acids in the leaves harvested at different time and under leaf-oriented cultivation mode(LCM) and arbor forest mode(AFM). The HPLC conditions are as below: phenyl isothiocyanate(PITC) as pre-column derivatization agent, Agilent ZORBAX C_(18 )column(4.6 mm×250 mm, 5 μm), mobile phase A of acetonitrile-water(80∶20), mobile phase B of 0.1 mol·L~(-1) sodium acetate solution-acetonitrile(94∶6), gradient elution, flow rate of 1.0 mL·min~(-1), injection volume of 5 μL, column temperature of 40 ℃, and detection wavelength of 254 nm. The HPLC profile indicated well separation of 16 kinds of amino acids and the amino acid content in E. ulmoides leaves was up to 16.26%. In addition, the amino acid content in leaves of E. ulmoides under LCM was higher than under AFM. The amino acid content varied with the harvesting time. Through orthogonal partial least squares discriminant analysis, the amino acids of E. ulmoides under LCM and AFM were compared, which can distinguish the leaves under LCM from those under AFM. Principal component analysis was applied to comprehensively score the amino acids of E. ulmoides leaves. The results showed that the score of leaves under LCM was higher than that under AFM. Nutritional evaluation results indicated that the proteins in E. ulmoides leaves belonged to high-quality vegetable proteins. The established method for the determination of amino acid content is reliable. With the amino acid content as index, the leaf quality of E. ulmoides under LCM is better than that under AFM. This study lays a theoretical basis for the promotion of LCM for E. ulmoides and the development of medicinal and edible products from E. ulmoides leaves.

Rapid prediction of G protein-coupled receptor structures using nanoluciferase assay / 药学学报

Using beta-2 adrenergic receptor, 5-hydroxytryptamine and angiotensin II type 1 receptor as control, we here established a method for rapid prediction of the initial position amino acids of N-terminal, C-terminal, intracellular loops, extracellular loops and transmembrane (TM) regions in G protein-coupled receptors (GPCRs), and successfully predicted the structure of Mas-related G protein-coupled receptors X3 (MRGPRX3). To achieve this purpose, nanoluciferase (Nluc) was inserted into the different sites of these GPCRs′ sequence by sequence and ligation-independent cloning (SLIC) method, and the luminescence value were measured to distinguish the different parts of GPCRs. The results showed that luminescence values of NLuc luciferase at TM region were less than 100 000, and the values were higher than 1 000 000 at N terminal, C terminal, or extracellular loops and intracellular loops, and the values were between 100 000 and 500 000 at junction. The predicted MRGPRX3 structure was analyzed in detail and was compared with AlphaFold predicted structure. In conclusion, this method could provide useful information of GPCR structure model for the ligand virtual screening, and could provide certain experimental basis for structural pharmacology.

Association between muscle mass and quality of life in Shaanxi adults / 中华流行病学杂志

Objective: To investigate the association between muscle mass and quality of life in adults in Shaanxi adults. Methods: The data in this analysis were part of the baseline survey of the Regional Ethnic Cohort Study in Northwest China from June 2018 to May 2019 in Shaanxi Province. The participants' quality of life, including physical component summary (PCS) and mental component summary (MCS), was assessed by the 12-Item Short Form Survey, and the Body Fat Determination System measured muscle mass. A logistic regression model with adjustment for confounding factors was established to analyze the association between muscle mass and quality of life in different genders. Further, sensitivity and subgroup analyses were conducted to explore its stability. Finally, a restricted cubic spline was employed to investigate the dose-response relationship between muscle mass and quality of life in different genders. Results: A total of 20 595 participants were included, with an average age of 55.0, and 33.4% were male. After controlling for potential confounders, compared with the Q1 group, the risk of low PCS was reduced by 20.6% (OR=0.794, 95%CI: 0.681-0.925) and the risk of low MCS was lower reduced by 20.1% (OR=0.799, 95%CI: 0.689-0.926) in female Q5 groups. Compared with the Q1 group, the risk of low PCS was reduced by 24.4% (OR=0.756, 95%CI: 0.644-0.888) in the male Q2 group. However, no significant association between muscle mass and MCS in males has been found. In females, restricted cubic spline analysis showed a significant linear dose-response relationship between muscle mass and PCS and MCS. Conclusions: There is a positive association between muscle mass and quality of life in Shaanxi adults, especially females. With the increase in muscle mass, the physical and mental functions of the population continue to improve.

Estimation of the bio-accessibility of methylmercury from aquatic foods using a PBTK model with an approximate Bayesian computation method in Chinese pregnant women.

BACKGROUND: Fish are the primary source of protein and docosahexaenoic acid (DHA) for pregnant women and children, but methylmercury (MeHg) pollution is the potential hazard of fish consumption. In risk assessments, the bio-accessibility of MeHg is usually assumed to be 100%, which could lead to overestimation of dietary exposure. METHOD: An existing PBTK model was adapted to estimate parameters of the bio-accessibility based on MeHg exposure data from a cohort of 397 Chinese pregnant women. The posterior distributions of parameters were determined by using the ABC - MCMC. RMSEP and Spearman's rank correlation coefficients (Rho) were calculated to determine the goodness of model fitting. The Monte Carlo analysis was performed for the parameter distributions to estimate the model variability. RESULT: The median of daily MeHg intake and maternal MeHg levels were 0.018 µg/kg bw and 3.01 µg/kg in the early and middle terms of pregnancy. The estimated bio-accessibility of freshwater fish, marine fish and others were 46.1, 17.3 and 58.2%, separately. The RMSEP improved from 11.18 to 2.54 and the Rho improved from 0.19 to 0.22 after bio-accessibility optimization. The model variability was estimated to be 2.6. CONCLUSION: The bio-accessibility estimated in this study was comparable to that determined in previous in vitro studies. The optimized model could improve the prediction performance on the MeHg body burden by dietary exposure.