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As a complex nonlinear system, the power system in operation may experience chaotic oscillation which can threaten the stability of the system for unexpected events and uncertain factors. Initially, through considering factors such as the generators, the power system node voltage amplitude and phase angle, this article establishes a fourth-order power system dynamic model and a two-parameter fourth-order power system mathematical model with load reactive power and mechanical input power as chaotic parameters to explore the mechanism and characteristics of chaos in the power system with the chaos theory. In addition, a sliding mode controller based on exponential reaching law for four state variables is designed, which is used to suppress the chaotic oscillation of the power system and guarantee the system can work stably at the target operating point within the chaotic parameter range. The designed controller can effectively suppress the chaos in power system and has an ideal performance.

A new global many-body expansion potential energy surface for the ground electronic state of HO2 is constructed. All ab initio energy points are employed using aug-cc-pV(Q+d)Z and aug-cc-pV(5+d)Z basis sets at the multi-reference conformational interaction level and then extrapolated to the complete basis set limit. The topographic characteristics of the global potential energy surface for HO2 (X2A'') are discussed in detail and compared with experimental results, showing a good agreement. We subsequently consider the O(3P) + OH(2Π) → O2(3Σ- g) + H(2S) reaction using the time-dependent wave packet method and calculate dynamic behaviors, including the vibration–rotation distribution and reaction probabilities. The results indicate that the new potential energy surface is suitable for the dynamic investigations of O(3P) + OH(2Π) → O2(3Σ- g) + H(2S), and can be used as a component for potential energy surfaces to construct larger oxygen/hydrogen containing systems.

tRNA-derived small RNAs (also known as tsRNAs) are novel kinds of non-coding RNAs. Although tsRNAs are aberrantly expressed in different tumor types, there is scanty of research investigating their expression profiling and functions in pulmonary adenocarcinoma (PADC). We identified the expression of AS-tDR-007872 in 30 non-small-cell lung carcinoma (NSCLC) patients’ carcinoma tissues and conducted biological function evaluation. We also test the expression levels of AS-tDR-007872 in plasma samples obtained from 35 healthy people and 79 NSCLC cases. The results identified downregulated AS-tDR-007872 in both cancer tissues and plasma samples versus adjacent normal counterparts ( p < 0.05 ) and healthy controls ( p < 0.001 ). The area under the curve of AS-tDR-007872 was identified by receiver operating characteristic curve analysis to be 0.756 (95% CI, 0.663-0.849; p < 0.001 ). Furthermore, overexpression of AS-tDR-007872 in vitro inhibited tumor cell proliferation, invasion, and migration and promoted apoptosis. The knockdown of AS-tDR-007872 showed the opposite results. Meanwhile, we found significantly downregulated BCL2L11 after overexpressing AS-tDR-007872. From the above, our research suggests that AS-tDR-007872 can be a tumor suppressor and a promising biomarker for diagnosing lung cancer.

Melon is an important horticultural crop with a pleasant aromatic flavor and abundance of health-promoting substances. Numerous melon varieties have been cultivated worldwide in recent years, but the high number of varieties and the high similarity between them poses a major challenge for variety evaluation, discrimination, as well as innovation in breeding. Recently, simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs), two robust molecular markers, have been utilized as a rapid and reliable method for variety identification. To elucidate the genetic structure and diversity of melon varieties, we screened out 138 perfect SSRs and 164 perfect SNPs from the resequencing data of 149 accessions, including the most representative lines worldwide. This study established the DNA fingerprint of 259 widely-cultivated melon varieties in China using Target-seq technology. The results showed four subgroups in the melon varieties, including ssp. melo and ssp. agrestis, and two types of intermediate subgroups. Compared with ssp. melo, the ssp. agrestis varieties might be exposed to a high risk of genetic erosion due to their extremely narrow genetic background. Increasing the gene exchange between ssp. melo and ssp. agrestis is therefore necessary in the breeding procedure. In addition, analysis of the DNA fingerprints of the 259 melon varieties showed a good linear correlation (R2 = 0.9722) between the SSR genotyping and SNP genotyping methods in variety identification. The pedigree analysis based on the DNA fingerprint of ‘Jingyu’ and ‘Jingmi’ series melon varieties was consistent with their breeding history. Based on the SNP index analysis, ssp. agrestis had low gene exchange with ssp. melo in chromosome 4, 7, 10, 11and 12, two specific SNP loci were verified to distinguish ssp. agrestis and ssp. melon varieties. Finally, 23 SSRs and 40 SNPs were selected as the core sets of markers for application in variety identification, which could be efficiently applied to variety authentication, variety monitoring, as well as the protection of intellectual property rights in melon.

ImportanceCross-sectional evidence implicates high prevalent frailty in patients with Parkinson disease (PD), whereas the longitudinal association remains unknown.ObjectivesTo examine the longitudinal association of the frailty phenotype with the development of PD and to explore the modification role of genetic risk of PD in such an association.Design, Setting, and ParticipantsThis prospective cohort study launched in 2006 to 2010 with a follow-up of 12 years. Data were analyzed from March 2022 to December 2022. The UK Biobank recruited over 500 000 middle-aged and older adults from 22 assessment centers across the United Kingdom. Participants who were younger than 40 years (n = 101), diagnosed with dementia or PD at baseline, and developed dementia, PD, or died within 2 years from baseline were excluded (n = 4050). Participants who had no genetic data or mismatch between genetic sex and reported gender (n = 15 350), were not of self-reported British White descent (n = 27 850), and had no data for frailty assessment (n = 100 450) or any covariates were also excluded (n = 39 706). The final analysis included 314 998 participants.ExposuresThe physical frailty was assessed by the Fried criteria’s frailty phenotype through 5 domains, ie, weight loss, exhaustion, low physical activity, slow walking speed, and low grip strength. The polygenic risk score (PRS) for PD comprised 44 single-nucleotide variants.Main Outcomes and MeasuresNew-onset PD was identified through the hospital admission electronic health records and death register.ResultsAmong 314 998 participants (mean age, 56.1 years; 49.1% male), 1916 new-onset PD cases were documented. Compared with nonfrailty, the hazard ratio (HR) of incident PD in prefrailty and frailty was 1.26 (95% CI, 1.15-1.39) and 1.87 (95% CI, 1.53-2.28), respectively, and the absolute rate difference per 100 000 person-years was 1.6 (95% CI, 1.0-2.3) for prefrailty and 5.1 (95% CI, 2.9-7.3) for frailty. Exhaustion (HR, 1.41; 95% CI, 1.22-1.62), slow gait speed (HR, 1.32; 95% CI, 1.13-1.54), low grip strength (HR, 1.27; 95% CI, 1.13-1.43), and low physical activity (HR, 1.12; 95% CI, 1.00-1.25) were associated with incident PD. A significant interaction between frailty and PRS on PD was found and the highest hazard was observed in participants with frailty and high genetic risk.Conclusions and RelevancePhysical prefrailty and frailty were associated with incident PD independent of sociodemographic factors, lifestyles, multiple morbidities, and genetic background. These findings may have implications for the assessment and management of frailty for PD prevention.

Macrophage activation is a key contributing factor for excessive inflammatory responses of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Geranylgeranyl diphosphate synthase (GGPPS) plays a key role in the development of inflammatory diseases. Our group previously showed that GGPPS in alveolar epithelium have deleterious effects on acute lung injury induced by LPS or mechanical ventilation. Herein, we examined the role of GGPPS in modulating macrophage activation in ALI/ARDS. We found significant increased GGPPS expression in alveolar macrophages in patients with ARDS compared with healthy volunteers and in ALI mice induced by LPS. GGPPS-floxed control ( GGPPSfl/fl) and myeloid-selective knockout ( GGPPSfl/fl LysMcre) mice were then generated. Interestingly, using an LPS-induced ALI mouse model, we showed that myeloid-specific GGPPS knockout significantly increased mortality, aggravated lung injury, and increased the accumulation of inflammatory cells, total protein, and inflammatory cytokines in BALF. In vitro, GGPPS deficiency upregulated the production of LPS-induced IL-6, IL-1β, and TNF-α in alveolar macrophages, bone marrow-derived macrophages (BMDMs), and THP-1 cells. Mechanistically, GGPPS knockout increased phosphorylation and nuclear translocation of NF-κB p65 induced by LPS. In addition, GGPPS deficiency increased the level of GTP-Rac1, which was responsible for NF-κB activation. In conclusion, decreased expression of GGPPS in macrophages aggravates lung injury and inflammation in ARDS, at least partly by regulating Rac1-dependent NF-κB signaling. GGPPS in macrophages may represent a novel therapeutic target in ARDS.

A lanthanide metal–organic framework (MOF) Yb(BTC)(H2O)·(DMF) (BTC = 1,3,5-benzenetricarboxylate, DMF = N,N-dimethylformamide) was prepared from Yb(NO3)3·5H2O and H3BTC using the solvothermal method and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, scanning electron microscopy, N2 adsorption–desorption technology, and temperature-programmed desorption. The results show that Yb(BTC)(H2O)·(DMF) is a lanthanide MOF with an excellent thermal stability. The coordinated water molecules and DMF guest molecules were removed from the channels by calcination to form a porous solid Yb (BTC) with coordinatively unsaturated Yb3+ sites. The BET surface area and pore size of Yb(BTC) are 695 m2/g and 0.68 nm, respectively. As a heterogeneous Lewis acid catalyst, the activity of Yb(BTC) for the synthesis of polycarbonate diol (PCDL) via transesterification between diphenyl carbonate and diol was investigated. Compared with nine reported catalysts, Yb(BTC) exhibits the highest catalytic activity for the synthesis of PCDL.

The doubly fed induction generator with super capacitor is helpful to enhance the system inertia. At the same time, its structural characteristics are more suitable for the power grid topology without communication lines. However, the change of its topology also brings some problems. In this article, when SCESS-DFIG is participating in frequency regulation, DC bus voltage fluctuation caused by power imbalance of multiple converters is studied. The dynamic power response of super capacitor with DC-DC converter is a step load for grid side converter. The load of DC bus is nonlinear and random, so the balance and stability of the original system will change accordingly. Because of the complex topology and system composition of the doubly fed induction generator with super capacitor, the conventional feed-forward compensation control strategy can not be used to improve its dynamic response speed. Therefore, this article designs a control strategy which is applied for DC bus voltage fluctuation of the doubly fed induction generator with super capacitor. The theory proposed in this article is verified by simulation model and experiment.

BackgroundAdherence to a healthy lifestyle (no smoking, consuming a healthy diet, engaging in physical activity, and maintaining a healthy weight) is recommended in current guidelines for hypertension prevention. However, evidence regarding the association between sleep behaviors, independently and jointly with traditional lifestyle factors, and the risk of hypertension is limited.MethodsThis prospective study included 165,493 participants who are free of hypertension at baseline from the UK Biobank. Sleep behaviors, including chronotype, sleep duration, insomnia, snoring, and daytime sleepiness were used to construct a healthy sleep score. We also derived a healthy lifestyle score based on smoking status, diet quality, physical activity, and body mass index (BMI). Cox proportional hazards regression models and competing risk analyses were used to estimate the associations of the healthy sleep score and healthy lifestyle score with the risk of hypertension. The population attributable risk percent (PAR%) was estimated for increased cases of hypertension due to poor adherence to a healthy sleep pattern or a healthy lifestyle.ResultsA total of 10,941 incident hypertension cases were documented during a median of 11.8 years of follow-up. The multivariable-adjusted hazard ratio (HR) for hypertension was 0.58 [95% confidence interval (CI): 0.52, 0.65] for participants with a sleep score of 5 compared with 0–1, and 0.48 (95% CI: 0.43, 0.54) for participants with a lifestyle score of 4 compared with those who scored 0. For joint association, those with a poor sleep pattern and a poor lifestyle had the highest risk of hypertension [HR: 2.41 (95% CI: 2.12, 2.74)]. PAR% was 14.7% (95% CI: 12.3%, 17.1%), 20.1% (95% CI: 17.6%, 22.6%), and 31.7% (95% CI: 27.6%, 35.6%) for poor adherence to a healthy sleep pattern, a healthy lifestyle, and the combination of a healthy sleep pattern and a healthy lifestyle.ConclusionBoth a healthy sleep pattern and a healthy lifestyle were associated with a lower risk of hypertension, and the benefits of adhering to a healthy sleep pattern complement the well-established lifestyle for the optimal primary prevention of hypertension. These findings support the current perspective that a healthy sleep pattern is an important part of a healthful and productive lifestyle for hypertension prevention.

Background longitudinal evidence concerning frailty phenotype and the risk of cardiovascular disease (CVD) remained insufficient, and whether CVD preventive strategies exert low CVD risk on frail adults is unclear. Objectives we aimed to prospectively evaluate the association of frailty phenotype, adherence to ideal cardiovascular health (CVH) and their joint associations with the risk of CVD. Methods a total of 314,093 participants from the UK Biobank were included. Frailty phenotype was assessed according to the five criteria of Fried et al.: weight loss, exhaustion, low physical activity, slow gait speed and low grip strength. CVH included four core health behaviours (smoking, physical activity and diet) and three health factors (weight, cholesterol, blood pressure and glycaemic control). The outcome of interest was incident CVD, including coronary heart disease, heart failure and stroke. Results compared with the non-frail people whose incident rate of overall CVD was 6.54 per 1,000 person-years, the absolute rate difference per 1,000 person-years was 1.67 (95% confidence interval, CI: 1.33, 2.02) for pre-frail and 5.00 (95% CI: 4.03, 5.97) for frail. The ideal CVH was significantly associated with a lower risk of all CVD outcomes. For the joint association of frailty and CVH level with incident CVD, the highest risk was observed among frailty accompanied by poor CVH with an HR of 2.92 (95% CI: 2.68, 3.18). Conclusions our findings indicate that physical frailty is associated with CVD incidence. Improving CVH was significantly associated with a considerable decrease in CVD risk, and such cardiovascular benefits remain for the frailty population.

BackgroundSeveral cardioprotective mechanisms attributed to n-3 polyunsaturated fatty acids (PUFAs) have been widely documented. Significant interest has recently focused on the role of human gut microbiota in metabolic disorders. However, the role of plant-derived n-3 PUFAs on blood lipid profiles is controversial and the effect on gut microbiota is still unclear.ObjectivesWe aimed to perform a double-blind randomized controlled trial to test the effect of plant-derived n-3 PUFAs on the blood lipids and gut microbiota of patients with marginal hyperlipidemia.MethodsAccording to the inclusion and exclusion criteria, 75 participants with marginal hyperlipidemia were randomly assigned to the intervention group (supplied with n-3 PUFA-enriched plant oil) or control group (supplied with corn oil), respectively, for a 3-month treatment. Participants and assessors were blinded to the allocation. The primary outcomes of the trial were the changes in serum lipid levels. Secondary outcomes were changes in gut microbiota and metabolites. For the primary outcomes, we conducted both an intent-to-treat (ITT) analysis and a per protocol (PP) analysis. For the secondary outcomes, we only conducted the PP analysis among the participants who provided fecal sample.ResultsFifty-one participants completed the trial. Relative to the control group, the n-3 PUFA supplementation resulted in significant reduction in total cholesterol (TC) levels (−0.43 mmol/L, 95% CI−0.84 to−0.01 mmol/L, P < 0.05). The n-3 PUFA supplementation was also associated with significantly increased relative abundance of Bacteroidetes in phylum level (P < 0.01; false discovery rate (FDR) corrected p = 0.11), and decreased the ratio between Firmicutes and Bacteroidetes (P < 0.05; FDR corrected p = 0.16). At genus level, the intervention of plant derived n-3 PUFAs resulted in a significant decrease in relative abundance of Phascolarctobacterium (P < 0.01; FDR corrected p = 0.18) and Veillonella (P < 0.01; FDR corrected p = 0.18) after the intervention.ConclusionsOur results demonstrated that plant-derived n-3 PUFAs beneficially affected the serum levels of TC and decreased the ratio between Firmicutes and Bacteroidetes during the 12-week intervention period, which might confer advantageous consequences for lipid metabolism and intestinal health.

Previously, we and other investigators have demonstrated that phosphorylated microtubule-associated protein 4 (p-MAP4) impacts myocardial hypertrophy and ischemic heart failure. However, the detailed mechanism behind this remains under elucidated. Published studies have suggested that impaired mitophagy contributes to hypoxia-induced myocardial damage, hence the involvement of p-MAP4 in mitophagy in cardiomyocytes was investigated. The results herein revealed that there was increased degradation of mitochondria, accumulated mitophagosomes and disrupted autophagic flux in both neonatal and adult ones of MAP4-knockin (KI) mice. This indicated that p-MAP4 persistently degraded mitochondria through activating mitophagy. Next, Tom70 was found as the importer of p-MAP4 in the context of mitochondrial translocation. And, the LC3-interacting region (LIR) motif (47–50aa) caused p-MAP4-induced mitochondrial engulfment, and the ubiquitin-interacting motif (UIM) domain determined the characteristics of p-MAP4-induced mitophagosomes, which were structure and membrane potential-independent. Moreover, p-MAP4 enhanced hypoxia-induced mitophagic flux impairment, and p-MAP4 LIR (47–50aa) mutation decreased hypoxia-induced autophagy both in MAP4 knockout and wildtype cardiomyocytes. Overall, this study identified that p-MAP4 as a novel mediator and cargo receptor in mitophagy, and that the degradation of the MAP4 PJ domain as a promising therapeutic target for improving the cardiac function of hypoxia-related heart failure or cardiac remodelling.

In this paper, a speed-adjustable asynchronous condenser with AC excitation and its excitation control strategy are proposed. Through excitation control, the asynchronous condenser not only can adjust the voltage by reactive power output but also can adjust the speed to release rotational kinetic energy and increase the system inertia to smooth system frequency. In this paper, the model of the asynchronous condenser is established, and then a transiently improved control strategy for the asynchronous condenser considering the change of the stator excitation current, is proposed. It is verified by simulation that after the transient improvement control strategy is adopted, the asynchronous condenser can provide reactive power support and a certain frequency support capability to the system.

A novel ratiometric fluorescence nanoprobe based on long-wavelength emission carbon dots (CDs) was designed for high sensitive and selective detection of Zn

Background: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. In recent years, many studies have been focusing on the ability of exosomal miRNAs secreted by tumor cells to transmit resistance information. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored.Methods: We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The results were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients.Results: Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 (p = 0.0325) and miR-3913-5p (p = 0.0169) expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-184 was correlated with lactate dehydrogenase levels (p = 0.018). Exosomal miR-3913-5p was associated with TNM stage (p = 0.045), platelet count (p = 0.024), tumor marker carcinoembryonic antigen (p = 0.045), and distant metastases (p = 0.049), especially bone metastasis (p = 0.03). In the subgroup of patients with EGFR exon 21 L858R point mutation, miR-184 (p = 0.0104) and miR-3913-5p (p = 0.0085) derived from serum exosomes had both significantly increased expression levels. In the subgroup of T790M-positive patients, miR-3913-5p derived from serum exosomes may also be a good indicator of osimertinib resistance (p = 0.013).Conclusions: The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance.

Actin cytoskeleton is essential for root hair formation. However, the underlying molecular mechanisms of actin dynamics in root hair formation in response to abiotic stress are largely undiscovered. Here, genetic analysis showed that actin-depolymerizing protein ADF7 and actin-bundling protein VILLIN1 (VLN1) were positively and negatively involved in root hair formation of Arabidopsis respectively. Moreover, RT-qPCR, GUS staining, western blotting, and genetic analysis revealed that ADF7 played an important role in inhibiting the expression and function of VLN1 during root hair formation. Filament actin (F-actin) dynamics observation and actin pharmacological experiments indicated that ADF7-inhibited-VLN1 pathway led to the decline of F-actin bundling and thick bundle formation, as well as the increase of F-actin depolymerization and turnover to promote root hair formation. Furthermore, the F-actin dynamics mediated by ADF7-inhibited-VLN1 pathway was associated with the reactive oxygen species (ROS) accumulation in root hair formation. Finally, ADF7-inhibited-VLN1 pathway was critical for osmotic stress-induced root hair formation. Our work demonstrates that ADF7 inhibits VLN1 to regulate F-actin dynamics in root hair formation in response to osmotic stress, providing the novel evidence on the F-actin dynamics and their molecular mechanisms in root hair formation and in abiotic stress.

Three patients of coronavirus disease (COVID-19) showed the symptoms of olfactory dysfunction. Clinical characteristics and treatment were retrospective analyzed. Olfactory disorders are uncommon symptoms of COVID-19 in China. Early diagnosis and intervention are keys to the recovery of olfactory disorders. Particular attention should be devoted to olfactory dysfunction.

Background Neutrophil-to-lymphocyte ratio (NLR) is related to prognosis in non-small cell lung cancer (NSCLC). However, no consensus on the relationship of pretreatment NLR and survival outcomes of systemic therapy in NSCLC exists. This meta-analysis investigated the prognostic role of pretreatment NLR during systemic therapy for NSCLC, including chemotherapy, immunotherapy and targeted therapy. Methods PubMed, Web of Science and Cochrane Library databases were systematically searched up to April 09, 2019. Hazard ratios (HRs) with their 95% confidence intervals (CIs) were pooled to investigate the association of pretreatment NLR with progression-free survival (PFS) and overall survival (OS). Results In total, 27 articles with 4,298 participants were selected. The pooled results showed that elevated pretreatment NLR was associated with inferior PFS (HR, 1.45, 95% CI, 1.28-1.66) and OS (HR, 1.63, 95% CI, 1.43-1.84) during systemic therapy. Subgroup analyses according to the treatment strategy suggested that higher pretreatment NLR was significantly associated with shorter survival in all therapies, including chemotherapy (PFS HR, 1.74, 95% CI, 1.39-2.17; OS HR, 1.73, 95% CI, 1.26-2.36), immunotherapy (PFS HR, 1.53, 95% CI, 1.27-1.84; OS HR, 2.50, 95% CI, 1.60-3.89) and targeted therapy (PFS HR, 1.53, 95% CI, 1.04-2.25; OS HR, 1.92, 95% CI, 1.14-3.24). Conclusions Pretreatment NLR is a promising prognostic indicator for NSCLC patients receiving systemic therapy, including chemotherapy, immunotherapy and targeted therapy.

Aiming at the problem of smooth switching between off-grid mode and grid-connected mode in low-voltage micro-grid, an improved droop control strategy is proposed. In addition, aiming at the problem of power coupling in low-voltage micro-grid, power decoupling control is realized by adding virtual impedance to the control system to change the equivalent resistance into pure inductiveness. Further, for the problem of inrush current and impulse voltage during the mode switching of the micro-grid, smooth and shock-free grid-connected is achieved by adding a grid-connected pre-synchronization control link in the droop control. Then, for the problem of large voltage and frequency fluctuations during the mode switching of the micro-grid, the designed adaptive droop control strategy achieves the voltage and frequency meet the requirements of normal operation. The proposed control strategy can realize the smooth connection of the micro-grid without impact and the off-network mode and the grid-connected mode, so as to ensure the stable operation of the micro-grid system. Finally, the results of simulation and experiment demonstrate the correctness and effectiveness of the proposed theory.

Although anti-PD-1 inhibitors exhibit impressive clinical results in non-small cell lung cancer (NSCLC) cases, a substantial percentage of patients do not respond to this treatment. Moreover, the current recommended biomarkers are not perfect. Therefore, it is essential to discover novel molecular determinants of responses to anti-PD-1 inhibitors. We performed Whole Exome Sequencing (WES) in a cohort of 33 Chinese NSCLC patients. Patients were classified into the durable clinical benefit (DCB) and no durable benefit (NDB) groups. Infiltrating CD8+ cells in the tumor microenvironment (TME) were investigated by immunohistochemistry. We also used public datasets to validate our results. In our cohort, good clinical responses to anti-PD-1 inhibitors were more pronounced in younger patients with lower Eastern Cooperative Oncology Group (ECOG) scores and only extra-pulmonary metastasis. More importantly, we identified a novel MUC19 mutation, which was significantly enriched in DCB patients (P = 0.015), and MUC19-mutated patients had a longer progression-free survival (PFS) (hazard ratio = 0.3, 95% CI 0.1–0.9; P = 0.026). Immunohistochemistry results indicated that the MUC19 mutation was associated with increased infiltration by CD8+ T cells in the TME (P = 0.0313). When combining MUC19 mutation with ECOG scores and intra-pulmonary metastasis status, patients with more positive predictors had longer PFS (P = 0.003). Furthermore, MUC19 mutation was involved in immune responses and associated with a longer PFS in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort. Collectively, we identified that MUC19 mutations were involved in immune responses, and NSCLC tumors harboring mutated MUC19 exhibited good responses to anti-PD-1 inhibitors.

Actin dynamics are essential for root hair development, however, the underlying molecular mechanisms of actin binding protein cooperation and plant abiotic stress responses are largely unknown. Here, genetic analysis displayed that actin depolymerizing protein ADF7 and actin bundling protein VLN1 are positively and negatively involved in root hair development in Arabidopsis, respectively. Moreover, ADF7 acts upstream of VLN1 in root hair development by the analysis of RT-qPCR, Gus staining, Western blot and genetics. The observation of F-actin dynamics shows that ADF7 inhibits VLN1, leading to the decline of filament actin (F-actin) bundling and thick bundle formation and the increase of F-actin turnover and depolymerization in epidermal cells of root apices. Actin pharmacological experiments confirm that ADF7 and VLN1 are via regulating F-actin dynamics to active root hair development. Furthermore, F-actin depolymerization coregulated by ADF7 and VLN1 elevates the reactive oxygen species (ROS) level in root tips. Additionally, F-actin depolymerization and ROS accumulation coregulated by ADF7 and VLN1 are involved in osmotic stress-induced root hair development. Our work reveals that ADF7 inhibits VLN1 to induce F-actin turnover and depolymerization and ROS level in root tips, which play an important role in root hair formation responses to osmotic stress .

OBJECTIVE To investigate the association of in-hospital early-phase glycemic control with adverse outcomes among inpatients with coronavirus disease 2019 (COVID-19) in Wuhan, China. RESEARCH DESIGN AND METHODS The study is a large case series, and data were obtained regarding consecutive patients hospitalized with COVID-19 in the Central Hospital of Wuhan between 2 January and 15 February 2020. All patients with definite outcomes (death or discharge) were included. Demographic, clinical, treatment, and laboratory information were extracted from electronic medical records. We collected daily fasting glucose data from standard morning fasting blood biochemistry to determine glycemic status and fluctuation (calculated as the square root of the variance of daily fasting glucose levels) during the 1st week of hospitalization. RESULTS A total of 548 patients were included in the study (median age 57 years; 298 [54%] were women, and n = 99 had diabetes [18%]), 215 suffered acute respiratory distress syndrome (ARDS), 489 survived, and 59 died. Patients who had higher mean levels of glucose during their 1st week of hospitalization were older and more likely to have a comorbidity and abnormal laboratory markers, prolonged hospital stays, increased expenses, and greater risks of severe pneumonia, ARDS, and death. Compared with patients with the lowest quartile of glycemic fluctuation, those who had the highest quartile of fluctuation magnitude had an increased risk of ARDS (risk ratio 1.97 [95% CI 1.01, 4.04]) and mortality (hazard ratio 2.73 [95% CI 1.06, 7.73]). CONCLUSIONS These results may have implications for optimizing glycemic control strategies in COVID-19 patients during the early phase of hospitalization.

Background: The epidemiological and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) have been reported. However, the prevalence of retesting positive by RT-PCR for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated patient characteristics, remain unclear. Methods: We included 90 confirmed cases of COVID-19 treated in the Nanjing Public Health Center from January 20, 2020 to February 16, 2020 in this retrospective study. All patients completed treatment for COVID-19 and were retested by RT-PCR for SARS-CoV-2 4-20 days after completion of therapy. The clinical characteristics between patients with who retested positive versus negative by RT-PCR were compared, and the factors predictive of positive retesting were analyzed. Positive retesting was modeled with the area under the receiver operating characteristic curve (AUC). Results: The age range of the study population was 0.8-97 years, and all patients were cured or showed improvement. A total of 10 (11%) patients retested positive by RT-PCR 4-20 days after completion of therapy. As compared with patients who retested negative, those who retested positive had a lower percentage of pre-admission fever, a higher percentage of post-admission fever, a lower percentage of bilateral lung infection, higher white blood cell (WBC) count and creatine phosphokinase, and lower hypersensitive c-reactive protein (hs-CRP), interleukin-6 and erythrocyte sedimentation rates (all P

Although anti-PD-1 inhibitors exhibit impressive clinical results in non-small cell lung cancer (NSCLC) cases, a substantial percentage of patients do not respond to this treatment. Moreover, the current recommended biomarkers are not perfect. Therefore, it is essential to discover novel molecular determinants of responses to anti-PD-1 inhibitors. We performed Whole Exome Sequencing (WES) in a cohort of 33 Chinese NSCLC patients. Patients were classified into the durable clinical benefit (DCB) and no durable benefit (NDB) groups. Infiltrating CD8+ cells in the tumor microenvironment (TME) were investigated by immunohistochemistry. We also used public datasets to validate our results. In our cohort, good clinical responses to anti-PD-1 inhibitors were more pronounced in younger patients with lower Eastern Cooperative Oncology Group (ECOG) scores and only extra-pulmonary metastasis. More importantly, we identified a novel MUC19 mutation, which was significantly enriched in DCB patients (P = 0.015), and MUC19-mutated patients had a longer progression-free survival (PFS) (hazard ratio = 0.3, 95% CI 0.1–0.9; P = 0.026). Immunohistochemistry results indicated that the MUC19 mutation was associated with increased infiltration by CD8+ T cells in the TME (P = 0.0313). When combining MUC19 mutation with ECOG scores and intra-pulmonary metastasis status, patients with more positive predictors had longer PFS (P = 0.003). Furthermore, MUC19 mutation was involved in immune responses and associated with a longer PFS in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort. Collectively, we identified that MUC19 mutations were involved in immune responses, and NSCLC tumors harboring mutated MUC19 exhibited good responses to anti-PD-1 inhibitors.

Background Pulmonary embolism is a severe condition prone to misdiagnosis given its nonspecific signs and symptoms. Previous studies on the pneumonia outbreak caused by coronavirus disease 2019 (COVID-19) showed a number of patients with elevated d-dimer, whether those patients combined with pulmonary embolism got our attention. Methods Data on clinical manifestations, laboratory and radiological findings, treatment, and disease progression of 19 patients with laboratory-confirmed COVID-19 pneumonia,who completed computed tomographic pulmonary angiography (CTPA) during hospitalization in the Central Hospital of Wuhan from January 2 to March 26, 2020, were reviewed. Results Of the 19 suspected pulmonary embolism and subjected to CTPA patients, six were diagnosed with pulmonary embolism. The Wells’ score of the six patients with pulmonary embolism was 0–1, which suggested a low risk of pulmonary embolism. The median level of d-dimers collected at the day before or on the day of CTPA completion in the patients with pulmonary embolism was 18.36 (interquartile range [IQR]: 6.69–61.46) µg/mL, which was much higher than that in the patients without pulmonary embolism (median 9.47 [IQR: 4.22–28.02] µg/mL). Of the 6 patients diagnosed with pulmonary embolism, all patients received anticoagulant therapy, 5 of which survived and were discharged and 1 died. Conclusion A potential causal relationship exists between COVID-19 infection and pulmonary embolism, but whether this phenomenon is common remains uncertain. The clinical manifestations of COVID-19 patients who developed pulmonary embolism are similar to those of patients with increased d-dimer alone, prompting a significant challenge on differential diagnoses.

Autophagy is a highly conserved self-protection mechanism that plays a crucial role in cardiovascular diseases. Cardiomyocyte hypoxic injury promotes oxidative stress and pathological alterations in the heart, although the interplay between these effects remains elusive. The transient receptor potential vanilloid 1 (TRPV1) ion channel is a nonselective cation channel that is activated in response to a variety of exogenous and endogenous physical and chemical stimuli. Here, we investigated the effects and mechanisms of action of TRPV1 on autophagy in hypoxic cardiomyocytes. In this study, primary cardiomyocytes isolated from C57 mice were subjected to hypoxic stress, and their expression of TRPV1 and adenosine 5′-monophosphate-activated protein kinase (AMPK) was regulated. The autophagy flux was assessed by Western blotting and immunofluorescence staining, and the cell viability was determined through Cell counting kit-8 assay and Lactate dehydrogenase assays. In addition, the calcium influx after the upregulation of TRPV1 expression in cardiomyocytes was examined. The results showed that the number of autophagosomes in cardiomyocytes was higher under hypoxic stress and that the blockade of autophagy flux aggravated hypoxic damage to cardiomyocytes. Moreover, the expression of TRPV1 was induced under hypoxic stress, and its upregulation by capsaicin improved the autophagy flux and protected cardiomyocytes from hypoxic damage, whereas the silencing of TRPV1 significantly attenuated autophagy. Our observations also revealed that AMPK signaling was activated and involved in TRPV1-induced autophagy in cardiomyocytes under hypoxic stress. Overall, this study demonstrates that TRPV1 activation mitigates hypoxic injury in cardiomyocytes by improving autophagy flux through the AMPK signaling pathway and highlights TRPV1 as a novel therapeutic target for the treatment of hypoxic cardiac disease.

Autophagy protects cardiomyocytes in various pathological and physiological conditions; however, the molecular mechanisms underlying its influence and the promotion of autophagic clearance are not completely understood. The present study aimed to explore the role of H(+)/Cl(−) exchange transporter 7 (CLC-7) in cardiomyocyte autophagy. In this study, rapamycin was used to induce autophagy in mouse cardiomyocytes, and the changes in CLC-7 were investigated. The expression levels of CLC-7 and autophagy-related proteins, such as microtubule associated protein 1 light chain 3, autophagy related 5 and Beclin 1, were detected using western blotting or immunofluorescence. Autolysosomes were observed and analyzed using transmission electron microscopy and immunofluorescence following CLC-7 silencing with small interfering RNAs. Cellular viability was assessed using Cell Counting Kit-8 and lactate dehydrogenase assays. Lysosomal acidification was measured using an acidification indicator. Increased CLC-7 co-localization with lysosomes was identified during autophagy. CLC-7 knockdown weakened the acidification of lysosomes, which are the terminal compartments of autophagy flux, and consequently impaired autophagy flux, ultimately resulting in cell injury. Collectively, the present study demonstrated that in cardiomyocytes, CLC-7 may contribute to autophagy via regulation of lysosomal acidification. These findings provide novel insights into the role of CLC-7 in autophagy and cytoprotection.

Due to the serious overheating problem of end parts in the large turbogenerator end region, accurate calculation of end-part temperature has become a key design factor. In this paper, 3-D fluid and thermal coupling model in the end region of 1250 MW turbogenerator are given. The loss values gained from 3-D transient electromagnetic field calculation are applied to the solving end region as heat sources. Pressure value of fan outlet and fluid velocities of end region inlets from flow network calculation are applied to the solving end region as boundary conditions in the 3-D fluid and thermal coupling analysis model. The fluid flow and temperature distribution of end parts in the end region of large turbogenerator with magnetic shield structure are studied under the different operation conditions. The distribution of fluid velocity in the ventilation duct of stator end core is obtained. The temperature distribution laws of stator-end copper coils, screen plate, finger plate, press plate, and magnetic shield are researched under the different operation conditions. The location of the highest temperature point in the turbogenerator end region with magnetic shield structure is determined. The accuracy of numerical calculation is validated by experimental measured values.

Induced autophagy is protective against myocardial hypoxia/ischemia (H/I) injury, but evidence regarding the extent of autophagic clearance under H/I and the molecular mechanisms that influence autophagic flux has scarcely been presented. Here, we report that CD38 knockout improved cardiac function and autophagic flux in CD38–/– mice and CD38–/– neonatal cardiomyocytes (CMs) under H/I conditions. Mechanistic studies demonstrated that overexpression of CD38 specifically downregulated the expression of Rab7 and its adaptor protein pleckstrin homology domain-containing protein family member 1 (PLEKHM1) through nicotinamide adenine dinucleotide (NAD)-dependent and non-NAD-dependent pathways, respectively. Loss of Rab7/PLEKHM1 impaired the fusion of autophagosomes and lysosomes, resulting in autophagosome accumulation in the myocardium and consequent cardiac dysfunction under H/I conditions. Thus, CD38 mediated autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner. These findings suggest a potential therapeutic strategy involving targeted suppression of CD38 expression., Graphical Abstract CD38 inhibits transcription of the Plekhm1 gene and Rab7 gene. CD38 mediates autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner.

Phosphatidylinositol-3-kinase (PI3K) has been identified in the expression of central sensitization after noxious inflammatory stimuli. However, its contribution in neuropathic pain remains to be determined. Here we address the role of PI3K signaling in central sensitization in a model of neuropathic pain, and propose a novel potential drug target for neuropathic pain. Chronic constriction injury (CCI) rat model was used in the study as the model for neuropathic pain. Western blotting, whole-cell patch clamp, and von Frey assay were performed to study biochemical, electrical, and behavioral changes in CCI rats, respectively. A steroid metabolite of the fungi (wortmannin) was used to block PI3K signaling and its effects on CCI rats were tested. PI3K/Akt signaling increased in the spinal cord L4-L6 sections in the CCI rats. CCI also facilitated miniature excitatory postsynaptic potential of dorsal horn substantia gelatinosa neurons, increased phosphorylation of glutamate receptor subunit GluA1 and synapsin at the synapse, and induced mechanic allodynia. Wortmannin reversed biochemical, electrical, and behavioral changes in CCI rats. This study is the first to show PI3K/Akt signaling is required for spinal central sensitization in the CCI neuropathic pain model.

The present study aimed to investigate the protective effects of ganoderic acid A (GAA) on lipopolysaccharide (LPS)-induced acute lung injury. In mouse model of LPS-induced acute lung injury, we found that GAA led to significantly lower lung wet-to-dry weight ratio and lung myeloperoxidase activity, and attenuated pathological damages. In addition, GAA increased superoxide dismutase activity, but decreased malondialdehyde content and proinflammatory cytokines levels in the bronchoalveolar lavage fluid. Mechanistically, GAA reduced the activation of Rho/ROCK/NF-κB pathway to inhibit LPS-induced inflammation. In conclusion, our study suggests that GAA attenuates acute lung injury in mouse model via the inhibition of Rho/ROCK/NF-κB pathway.

Endothelial cells play a critical role in the process of angiogenesis during skin wound healing. The migration and proliferation of endothelial cells are processes that are initiated by the hypoxic microenvironment in a wound, but the underlying mechanisms remain largely unknown. Here, we identified a novel role for microtubule-associated protein 4 (MAP4) in angiogenesis. We firstly demonstrated that MAP4 phosphorylation was induced in hypoxic endothelial cells; the increase in MAP4 phosphorylation enhanced the migration and proliferation of endothelial cells. We also found that hypoxia (2% O2) activated p38/mitogen-activated protein kinase (MAPK) signaling, and we identified p38/MAPK as an upstream regulator of MAP4 phosphorylation in endothelial cells. Moreover, we showed that the promigration and proproliferation effects of MAP4 phosphorylation were attributed to its role in microtubule dynamics. These results indicated that MAP4 phosphorylation induced by p38/MAPK signaling promotes angiogenesis by inducing the proliferation and migration of endothelial cells cultured under hypoxic conditions via microtubule dynamics regulation. These findings provide new insights into the potential mechanisms underlying the initiation of the migration and proliferation of endothelial cells.

Both cell migration and proliferation are indispensable parts of reepithelialization during skin wound healing, which is a complex process for which the underlying molecular mechanisms are largely unknown. Here, we identify a novel role for microtubule-associated protein 4 (MAP4), a cytosolic microtubule-binding protein that regulates microtubule dynamics through phosphorylation modification, as a critical regulator of epidermal wound repair. We showed that MAP4 phosphorylation was induced in skin wounds. In an aberrant phosphorylated MAP4 mouse model, hyperphosphorylation of MAP4 (S737 and S760) accelerated keratinocyte migration and proliferation and skin wound healing. Data from both primary cultured keratinocytes and HaCaT cells in vitro revealed the same results. The promigration and proproliferation effects of MAP4 phosphorylation depended on microtubule rearrangement and could be abolished by MAP4 dephosphorylation. We also identified p38/MAPK as an upstream regulator of MAP4 phosphorylation in keratinocytes. Our findings provide new insights into the molecular mechanisms underlying wound-associated keratinocyte migration and proliferation and identify potential targets for the remediation of defective wound healing.

Background The head and neck regions are frequent sites of burns, but few studies have analysed and reported the epidemiology of facial burns. As the face is the centre of one’s identity and persona, facial injuries often result in physical and psychological morbidity. The aim of this article is to describe the epidemiology and outcome of facial burns in China and to suggest future preventive strategies. Methods This retrospective analysis included all patients with facial burns in a database at eight institutions from 2011–2015. The data collected included sex, age, month distribution, aetiology, location, presence of inhalation injury, total burn surface area, burn surface area with full-thickness and outcome including Post-traumatic stress disorder Checklist-Civilian Version scores and mortality. SPSS 19.0 software was used to analyse the data. Results A total of 1126 patients were included; 65.63% (739) had facial burns, of which 546 (73.88%) were male patients and 193 (26.12%) were female patients. Predictors of facial burns were being of male sex, working-related place, flame burns, total body surface area, and full-thickness burns. In addition, total body surface area and full-thickness burns increased the risk of poor prognosis for post-traumatic stress disorder and mortality. Conclusions Facial burns benefit not only the healing of wound, but also the prevention of their incidence and PTSD symptom. This study may contribute to the elaboration of strategies to prevent facial burns and the establishment of a nationwide burn database in China.

BackgroundTumor necrosis factor receptor-associated protein 1 (TRAP1) plays a protective effect in hypoxic cardiomyocytes, but the precise mechanisms are not well clarified. The study is aimed to identify the mechanism of TRAP1 on hypoxic damage in cardiomyocytes.MethodsIn this study, the effects of TRAP1 and cytochrome c oxidase subunit II (COXII) on apoptosis in hypoxia-induced cardiomyocytes were explored using overexpression and knockdown methods separately.ResultsHypoxia induced cardiomyocyte apoptosis, and TRAP1 overexpression notably inhibited apoptosis induced by hypoxia. Conversely, TRAP1 silencing promoted apoptosis in hypoxic cardiomyocytes. Further investigation revealed that the proapoptotic effects caused by the silencing of TRAP1 were prevented by COXII overexpression, whereas COXII knockdown reduced the antiapoptotic function induced by TRAP1 overexpression. Additionally, changes in the release of cytochrome c from mitochondria into the cytosol and the caspase-3 activity in the cytoplasm, as well as reactive oxygen species production, were found to be correlated with the changes in apoptosis.ConclusionsThe current study uncovered that TRAP1 regulates hypoxia-induced cardiomyocyte apoptosis through a mitochondria-dependent apoptotic pathway mediated by COXII, in which reactive oxygen species presents as an important component.

Diagnosis and treatment at an early stage may improve survival of non-small-cell lung cancer (NSCLC). Previous studies have found that long noncoding RNA growth arrest-specific transcript 5 (GAS5) is essential to cancer progression. However, the expression and diagnostic value of GAS5 in exosomes (Exo-GAS5) remain unclear. One hundred and four participants were enrolled, including subjects with NSCLC (n = 64) and healthy subjects ( n = 40). The total Exosome Isolation Kit was applied to isolate exosomes from serum. Total RNA was extracted and the AS5 expression was analyzed using quantitative reverse transcription polymerase chain reaction. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic value of Exo-GAS5 in NSCLC. Our data indicated that the Exo-GAS5 was downregulated in patients with NSCLC compared with healthy controls ( p

Arsenic (As) contamination in soil can lead to elevated transfer of As to the food chain. One potential mitigation strategy is to genetically engineer plants to enable them to transform inorganic As to methylated and volatile As species. In this study, we genetically engineered two ecotypes of Arabidopsis thaliana with the arsenite (As(III)) S-adenosylmethyltransferase (arsM) gene from the eukaryotic alga Chlamydomonas reinhardtii. The transgenic A. thaliana plants gained a strong ability to methylate As, converting most of the inorganic As into dimethylarsenate [DMA(V)] in the shoots. Small amounts of volatile As were detected from the transgenic plants. However, the transgenic plants became more sensitive to As(III) in the medium, suggesting that DMA(V) is more phytotoxic than inorganic As. The study demonstrates a negative consequence of engineered As methylation in plants and points to a need for arsM genes with a strong ability to methylate As to volatile species.

The mechanism underlying the effect of bioelectric field on wound healing in vivo has not been previously investigated. Here, we aimed to investigate the effects of an applied electric field (EF) on epidermal cell migration during wound healing. Using a Bama miniature pig wound model, we applied a power-up device (negative electrode in the wound centre and positive electrode around the wound) with pulsed electrical power, to apply a continuous, stable, and tolerable EF to the wound and provide directional signals for keratinocyte migration towards the wound centre. An EF of 100 mV/mm applied in the same direction as the bioelectric field accelerated wound healing. The keratinocytes exhibited regular and similar shapes, uniform arrangement, and an organised migration pattern. In contrast, 100 mV/mm applied countercurrent to the bioelectric field, delayed wound healing and hindered the keratinocyte migration towards the wound centre. Further, the cells were disorganised, misshapen, irregular, and disoriented. Via the application of a directional stable EF, this study morphologically identified the relationships among wound EF, keratinocyte migration, and wound healing and established theoretical and empirical foundations for the clinical application of bioelectric fields.

During keratinocyte stratification and wound healing, keratinocytes undergo a switch between differentiation and motility. However, limited knowledge exists on the mechanisms of the switch. We have previously demonstrated that the expression of CD9 was changed in different wound stages and involved in the regulation of keratinocyte migration. In this study, we showed that CD9 expression was increased in both human and mouse keratinocytes undergoing differentiation. CD9 overexpression in keratinocytes stimulated terminal differentiation and reduced cell motility. CD9 silencing inhibited calcium-induced keratinocyte differentiation and increased cell motility. Furthermore, CD9 overexpression recruited E-cadherin to the plasma membrane and subsequently activated PI3K/Akt signaling, while CD9 knockdown inhibited the recruitment of E-cadherin to the plasma membrane and PI3K/Akt activation. Importantly, silencing E-cadherin expression or inhibiting PI3K/Akt signaling reversed CD9 overexpression-induced differentiation and -reduced motility. These results demonstrate that CD9 acts as an important node that regulates keratinocyte differentiation and motility. The recruitment of E-cadherin to the plasma membrane and activation of the PI3K/Akt signaling pathway mediated by CD9 play an important role in these processes.