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Abstract Ivosidenib is a once daily (q.d.), orally available, potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for treatment of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and intensive chemotherapy ineligible AML with a susceptible IDH1 mutation. Population pharmacokinetics (PKs; N = 253), exposure‐response (efficacy [n = 201] and safety [n = 253]), and concentration‐corrected electrocardiogram QT interval (QTc; n = 171) analyses were performed using phase I data (100 mg twice daily and 300–1200 mg q.d.). Ivosidenib disposition was well‐described by a two‐compartment PK model with first‐order absorption and elimination. Between‐subject variability was moderate for PK parameters. Intrinsic factors did not affect ivosidenib PKs. Moderate/strong CYP3A4 inhibitors increased the area under the plasma ivosidenib concentration‐time curve at steady state (AUCss) by 60%. Efficacy responders and nonresponders had similar ivosidenib exposures. Based on AUCss, there was no apparent relationship between ivosidenib exposure and efficacy or adverse events. The plasma ivosidenib concentration‐QT analysis showed a mean change in QTc using Fridericia’s method (ΔQTcF) of 17.2 msec at the approved 500 mg q.d. dose. Because of the direct association between ivosidenib exposure and QTcF, patients should have their electrocardiograms and electrolytes monitored, and comedications that increase ivosidenib exposure or prolong the QT interval should be avoided. These model‐based analyses quantitatively provide a framework to describe the relationship among ivosidenib dose, exposure, and clinical end points. With precautions for QTc prolongation, the exposure‐response analyses support the 500 mg q.d. dose in patients with AML with a susceptible IDH1 mutation.

Abstract Background Osteosarcoma is a disease with high mortality in children and adolescents, and metastasis is one of the important clinical features of osteosarcoma. N6-Methyladenosine (m6A) is the most abundant methylation modification in mRNA, which is regulated by m6A regulators. It is reported that it is related to the occurrence and development of tumors. However, the mechanism of its action in osteosarcoma is rarely known. The purpose of this study was to identify the potential role of m6A regulatory factor in osteosarcoma and its clinical prognostic value. Methods Here, we used The Cancer Genome Atlas (TCGA) to comprehensively analyze the relationship between m6A regulatory factors and osteosarcoma (metastasis group and non-metastasis group). We analyzed their survival relationship and analyzed all the m6A regulatory factors in TCGA tumor data set by using the univariate Cox proportional hazard regression model. Finally, we selected two survival-related methylation regulators (FTO and IGF2BP2) as risk gene signature. Results According to the median risk, patients were divided into low-risk group and high-risk group. Multivariate Cox regression analysis showed that these two risk genes were considered to be the key factors independently predicting the prognosis of patients with osteosarcoma. In addition, we verified their characteristics with gene expression omnibus (GEO) DataSets and confirmed that they are related to tumor and immune-related signaling pathways through gene set enrichment analysis (GESA) and immune infiltration analysis. Conclusions In conclusion, m6A regulators might play an important role in the metastasis of osteosarcoma and have potential important value for the prognosis and treatment strategy of osteosarcoma patients.

The purpose of this study was to investigate the effects of dietary Bopu powder supplementation on the serum antioxidant capacity, serum biochemical indices, egg quality, and intestinal microbiota. Six hundred and forty-eight 33-week-old Lohmann Brown commercial laying hens were randomly allocated into six groups and fed a basal diet supplemented with 0, 25, 50, 100, 200, and 400 mg/kg Bopu powder for 8 weeks, denoted BP0, BP25, BP50, BP100, BP200, and BP400, respectively. The results showed that dietary Bopu powder supplementation reduced serum cholesterol concentrations (linear, p < 0.01) while increasing serum globulin and albumin concentrations (linear, p < 0.05). Furthermore, the BP50 and BP100 groups had greater serum catalase and glutathione peroxidase activity (p < 0.05). The egg Haugh Units were considerably higher in BP25 and BP50 (p < 0.05), and eggshell thickness was higher in BP25, BP200, and BP400 (p < 0.05) when compared to BP0. Dietary treatment with Bopu powder at doses ranging from 25–100 mg/kg improved glutathione peroxidase and catalase activities while decreasing malondialdehyde concentrations in the yolk (p < 0.05). The addition of Bopu powder increased the diversity of microbiota and the relative abundance of Bacteroidota in the gut. For instance, dietary Bopu powder supplementation of 25–50 mg/kg significantly raised the relative abundance of Enterococcus, Bacteroides, and Fusobacterium in the foregut. Supplementing the diet with 50–100 mg/kg of Bopu powder improved the relative abundance of Lactobacillus in the hindgut. In conclusion, dietary Bopu powder supplementation enhanced the abundance of beneficial bacteria in the foregut of laying hens and improved egg quality and antioxidant capacity. Furthermore, in the laying hen diet, the optimal dosage of Bopu powder additive was 25–50 mg/kg.

Background: Ischemic stroke is a leading cause of morbidity and mortality in neurological diseases. Numerous studies have evaluated the efficacy and safety of ischemic stroke therapies, but clinical data were largely inconsistent. Therefore, it is necessary to summarize and analyze the published clinical research data in the field.Objective: We aimed to perform an umbrella review to evaluate the efficacy and safety of ischemic stroke therapies.Methods: We conducted a search for meta-analyses and systematic reviews on PubMed, the Cochrane Library, and the Web of Science to address this issue. We examined neurological function deficit and cognitive function scores, quality of life, and activities of daily living as efficacy endpoints and the incidence of adverse events as safety profiles.Results: Forty-three eligible studies including 377 studies were included in the umbrella review. The results showed that thrombolytic therapy (tPA; alteplase, tenecteplase, and desmoteplase), mechanical thrombectomy (MTE), edaravone with tPA, stem cell-based therapies, stent retrievers, acupuncture with Western medicines, autologous bone marrow stromal cells, antiplatelet agents (aspirin, clopidogrel, and tirofiban), statins, and Western medicines with blood-activating and stasis-dispelling herbs (NaoShuanTong capsule, Ginkgo biloba, Tongqiao Huoxue Decoction, Xuesaitong injection) can improve the neurological deficits and activities of daily living, and the adverse effects were mild for the treatment of ischemic stroke. Moreover, ligustrazine, safflower yellow, statins, albumin, colchicine, MLC601, salvianolic acids, and DL-3-n-butylphthalide showed serious adverse events, intracranial hemorrhage, or mortality in ischemic stroke patients.Conclusion: Our study demonstrated that tPA, edaravone and tPA, tPA and MTE, acupuncture and Western medicines, and blood-activating and stasis-dispelling herbs with Western medicines are the optimum neurological function and activities of daily living medication for patients with ischemic stroke.Systematic Review Registration: https://inplasy.com/, identifier [INPLASY202250145].

AimsTo construct an automatic method for individual parcellation of manganese-enhanced magnetic resonance imaging (MEMRI) of rat brain with high accuracy, which could preserve the inherent voxel intensity and Regions of interest (ROI) morphological characteristics simultaneously.Methods and resultsThe transformation relationship from standardized space to individual space was obtained by firstly normalizing individual image to the Paxinos space and then inversely transformed. On the other hand, all the regions defined in the atlas image were separated and resaved as binary mask images. Then, transforming the mask images into individual space via the inverse transformations and reslicing using the 4th B-spline interpolation algorithm. The boundary of these transformed regions was further refined by image erosion and expansion operator, and finally combined together to generate the individual parcellations. Moreover, two groups of MEMRI images were used for evaluation. We found that the individual parcellations were satisfied, and the inherent image intensity was preserved. The statistical significance of case-control comparisons was further optimized.ConclusionsWe have constructed a new automatic method for individual parcellation of rat brain MEMRI images, which could preserve the inherent voxel intensity and further be beneficial in case-control statistical analyses. This method could also be extended to other imaging modalities, even other experiments species. It would facilitate the accuracy and significance of ROI-based imaging analyses.

This study aimed to investigate the effects of dietary supplementation with Macleaya cordata extract (MCE) containing protopine and allotypotopine on the growth performance and liver health in broiler chickens. A total of 486 1-day-old male AA broiler chickens were randomly assigned to the following three groups: (1) control (CON) group, broiler chickens fed a basal diet; (2) AGP group (positive control), broiler chickens fed a basal diet supplemented with 50 mg/kg aureomycin; (3) MCE group, broiler chickens fed a basal diet supplemented with 0.6 mg/kg MCE including 0.4 mg/kg protopine and 0.2 mg/kg allotypotopine. The results showed that the MCE group had significantly higher final body weight and average daily gain from d 0 to 42 than the other groups (p < 0.05), and groups MCE and AGP both had significantly lower feed-to-gain ratio from d 0 to 42 than the CON group (p < 0.05). Serum total protein, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, glucose, immunoglobulin A, immunoglobulin M, and complements (C3, C4) concentrations in the MCE group were significantly higher than in the CON group (p < 0.05). Dietary MCE or aureomycin supplementation significantly reduced the hepatic contents of 8-hydroxy-2'-deoxyguanosine, malondialdehyde, interleukin (IL)-1β, IL-6, NLRs family pyrin domain containing 3 (NLRP3), and caspase-1 in the liver (p < 0.05). Moreover, MCE or aureomycin supplementation significantly inhibited mRNA expressions of Toll-like receptor 4, myeloid differentiation factor 88, nuclear factor-κB, and NLRP3, as well as the expression ratio of Bax to Bcl-2 mRNA (p < 0.05). Therefore, our study suggested that dietary supplementation with 0.6 mg/kg MCE containing protopine and allocryptopine improved growth performance and benefited liver health in broiler chickens possibly through inhibiting caspase-1-induced pyroptosis by inactivating TLR4/MyD88/NF-κB/NLRP3 signaling pathway, and provided support for the application of MCE containing protopine and allocryptopine as an alternative to antibiotics in the feed industry.

AimTo identify the association between endoscopic primary prophylaxis and the risk of rebleeding in patients with liver cirrhosis receiving endoscopic therapy.MethodsThis cohort study involved in 944 liver cirrhosis patients with esophagogastric variceal bleeding (EGVB) receiving endoscopic therapy. All participants were divided into two groups: rebleeding group (n = 425) and non-rebleeding group (n = 519) according to the occurrence of rebleeding in patients. Rebleeding indicated any bleeding after endoscopic therapy for the first bleeding of esophagogastric varices in liver cirrhosis patients. Univariate and multivariate logistic analyses were employed to identify the association between endoscopic primary prophylaxis and rebleeding in patients with liver cirrhosis after endoscopic therapy.ResultsIn total, 425 patients rebleeded at the end of the follow-up. The risk of rebleeding in patients with endoscopic primary prophylaxis decreased by 0.773 times (OR = 0.227, 95%CI: 0.139–0.372, P

Climate change and human activities have severely affected the structure and function of vegetation on the Qinghai-Tibet Plateau (QTP). Management practices have contributed to vegetation growth on the QTP, yet the response of vegetation productivity to management during the growing season remains unclear. Here, a fitted sixth-degree polynomial function was used to extract phenology-based vegetation productivity, which was quantified as the integrated normalized difference vegetation index (INDVI) over the length of the season during 2000–2019. Additionally, a new management practice intensity indicator was established to quantify the degree of ecological project and policy effectiveness on vegetation productivity. Three main results were obtained: (1) On a pixel-by-pixel basis, phenology-based vegetation productivity can avoid the impact of start-of-season (SOS) and end-of-season (EOS) variations. Vegetation productivity increased over 66% of the area of the QTP during 2000–2019, and the area with a significant increasing trend in vegetation productivity accounted for 9.15% of the QTP, including 5.65% in grassland and 0.23% in cultivated land. (2) Areas of increased vegetation productivity, grassland productivity, and cultivated land productivity affected by the positive impact from climate change accounted for 23.76%, 16.61%, and 0.31%, respectively, while they accounted for 41.29%, 28.10%, and 0.59% for human activities, respectively. (3) The regions of high-level management practice intensity accounted for 26.51% of the QTP but only 2.57% and 0.03% of grassland and cultivated land productivity, respectively. The regions of decreased grassland productivity still accounted for 21.85% of the QTP. Therefore, improving vegetation management practice intensity on grassland can increase regional vegetation productivity. These findings can provide effective guidance for regional vegetation management.

Abstract Emerging evidence indicates that a vicious cycle between inflammation and microthrombosis catalyzes the pathogenesis of inflammatory bowel disease (IBD). Over‐stimulated inflammation triggers a coagulation cascade and leads to microthrombosis, which further complicates the injury through tissue hypoxia and ischemia. Herein, an injectable protein hydrogel with anti‐thrombosis and anti‐inflammation competency is developed to impede this cycle, cross‐linked by silver ion mediated metal‐ligand coordination and electronic interaction with sulfhydryl functionalized bovine serum albumin and heparin, respectively. The ex vivo experiments show that the hydrogel, HEP‐Ag‐BSA, exhibits excellent self‐healing ability, injectability, biocompatibility, and sustained drug release. HEP‐Ag‐BSA also demonstrates anti‐coagulation and anti‐inflammation abilities via coagulation analysis and lipopolysaccharide stimulation assay. The in vivo imaging confirms the longer retention time of HEP‐Ag‐BSA at inflammatory sites than in normal mucosa owing to electrostatic interactions. The in vivo study applying a mouse model with colitis also reveals that HEP‐Ag‐BSA can robustly inhibit inflammatory microthrombosis with reduced bleeding risk. This versatile protein hydrogel platform can definitively hinder the “inflammation and microthrombosis” cycle, providing a novel integrated approach against IBD.

The flow of ecosystem services between regions as a result of the mismatch of supply and demand has increasingly become a new research focus. Clarifying the spatial regularity of ecosystem service flow is of great significance for realizing regional sustainable development and improving human well-being. This study applied a network model to map the interregional carbon flow based on the supply and demand of carbon sequestration service, and the driving effect of various driving factors was further analyzed. The results showed that the demand for carbon sequestration service on the Qinghai-Tibet Plateau increased steadily from 2000 to 2019, resulting in an increasingly significant difference between supply and demand with more than 20 million tons. In the carbon sequestration service flow network, the number of defined deficit nodes increased to 22 in 2010, but decreased to 21 in 2019. The interrupted edges continued to increase to 16, and the network density dropped to 0.022. The carbon sequestration service flow network on the northeastern parts of the Qinghai-Tibet Plateau was severely damaged. With the high-quality development of animal husbandry, the impact of grazing intensity on the difference between the supply and demand of carbon sequestration service has been weakened. When urbanization reached a certain level, the driving effects of urbanization and agricultural activities increased significantly. The study provided a reference for the use of network models to analyze ecosystem service flow, and provided a theoretical basis and data support for local ecological management decisions.

Peripheral nerve injury is common, and can lead to skeletal muscle atrophy and dysfunction. However, the underlying molecular mechanisms are not fully understood. The transcription factors have been proved to play a key role in denervated muscle atrophy. In order to systematically analyze transcription factors and obtain more comprehensive information of the molecular regulatory mechanisms in denervated muscle atrophy, a new transcriptome survey focused on transcription factors are warranted. In the current study, we used microarray to identify and analyze differentially expressed genes encoding transcription factors in denervated muscle atrophy in a rat model of sciatic nerve dissection. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to explore the biological functions of differentially expressed transcription factors and their target genes related to skeletal muscle pathophysiology. We found that the differentially expressed transcription factors were mainly involved in the immune response. Based on correlation analysis and the expression trends of transcription factors, 18 differentially expressed transcription factors were identified. Stat3, Myod1, Runx1, Atf3, Junb, Runx2, Myf6, Stat5a, Tead4, Klf5, Myog, Mef2a, and Hes6 were upregulated. Ppargc1a, Nr4a1, Lhx2, Ppara, and Rxrg were downregulated. Functional network mapping revealed that these transcription factors are mainly involved in inflammation, development, aging, proteolysis, differentiation, regeneration, autophagy, oxidative stress, atrophy, and ubiquitination. These findings may help understand the regulatory mechanisms of denervated muscle atrophy and provide potential targets for future therapeutic interventions for muscle atrophy following peripheral nerve injury.

BackgroundAnimal studies have found that GPHB5 has a similar effect on system metabolism as TSH. However, the relationship between GPHB5 and metabolic diseases remains unknown. This study investigates the relationship between GPHB5 and MetS in young women.MethodsBioinformatics analysis was undertaken to explore the relationship between GPHB5 and metabolic-related genes and signaling pathways. EHC and OGTT were performed on all individuals. Lipid-infusion, physical activity, and cold-exposure tests were performed on healthy individuals. Serum GPHB5 concentrations were measured by an ELISA kit.ResultsPPI network showed that 11 genes interacted with GPHB5, in which POMC and KISS1R were involved in glucose and lipid metabolism. GO analysis showed 56 pathways for BP and 16 pathways for MF, in which OPRM1 and MCR families were related to energy metabolism. KEGG analysis found that GPHB5 is associated with lipolysis and neuroactive ligand-receptor interaction pathways. The levels of circulating GPHB5 were significantly increased, while serum adiponectin levels were lower in MetS women compared with healthy women. Obese/overweight individuals had lower adiponectin levels and higher GPHB5 levels. Circulating GPHB5 levels were positively correlated with BMI, WHR, blood pressure, FBG, 2 h-BG, HbA1c, FIns, 2h-Ins, LDL-C, FFA, HOMA-IR, and AUCg, etc. but negatively correlated with HDL-C, adiponectin, and M-values. Serum GPHB5 levels did not change significantly during the OGTT, EHC, and lipid infusion. Physical activity and cold-exposure tests did not lead to changes in GPHB5 levels. GLP-1RA treatment resulted in a significant decrease in serum GPHB5 levels.ConclusionsGPHB5 may be a biomarker for MetS.

This study evaluated the effects of nano-curcumin on growth performance, mucosal immunity, antioxidant response, glucose metabolism, and endoplasmic reticulum stress in largemouth bass. Three groups (three replicates/group) of 270 fish with the mean body weight of 7.00 ± 0.02 g were fed with diets containing 0% (control), 0.1%, and 0.2% nano-curcumin for 60 days. The results showed that dietary supplementation of nano-curcumin had no significant effects on the growth performance, body composition, lysozyme (LYZ), and alkaline phosphatase (AKP) in skin mucus, superoxide dismutase (SOD), and catalase (CAT) activity in serum of largemouth bass. However, dietary supplementation with 0.2% nano-curcumin significantly increased peroxidase (POD) activity in skin mucus and decreased the serum MDA activity compared with the control group. Moreover, dietary supplementation of 0.2% nano-curcumin significantly decreased the levels of serum glucose and liver glycogen, which may be mainly related to the increased gene expression of glucose transporter 2 (GLUT2), glucokinase (GK), phosphofructokinase (PFK), and pyruvate kinase (PK). At the same time, the hepatic gene expression of glucose-regulated protein78 (GRP78), activating transcription factor6 (ATF6), inositol-requiring enzyme 1 (IRE), and eukaryotic initiation factor 2α (eIF2α) in the 0.2% nano-curcumin group were rapidly suppressed, indicating that adding 0.2% nano-curcumin to the diet can alleviate endoplasmic reticulum stress (ERS) in fish. In conclusion, diets supplemented with 0.2% nano-curcumin effectively improved mucosal immunity, antioxidant properties, and glucose metabolism and alleviated ERS induced by long-term carbohydrate intake in largemouth bass.

Diabetes mellitus (DM) is a typical chronic disease that can be divided into 2 types, dependent on insulin deficiency or insulin resistance. Incidences of diabetic complications gradually increase as the disease progresses. Studies in diabetes complications have mostly focused on kidney and cardiovascular diseases, as well as neuropathy. However, DM can also cause skeletal muscle atrophy. Diabetic muscular atrophy is an unrecognized diabetic complication that can lead to quadriplegia in severe cases, seriously impacting patients’ quality of life. In this review, we first identify the main molecular mechanisms of muscle atrophy from the aspects of protein degradation and synthesis signaling pathways. Then, we discuss the molecular regulatory mechanisms of diabetic muscular atrophy, and outline potential drugs and treatments in terms of insulin resistance, insulin deficiency, inflammation, oxidative stress, glucocorticoids, and other factors. It is worth noting that inflammation and oxidative stress are closely related to insulin resistance and insulin deficiency in diabetic muscular atrophy. Regulating inflammation and oxidative stress may represent another very important way to treat diabetic muscular atrophy, in addition to controlling insulin signaling. Understanding the molecular regulatory mechanism of diabetic muscular atrophy could help to reveal new treatment strategies.

In the semiarid grassland ecosystems of eastern Inner Mongolia, the interrelations among the species diversity of different plant communities, productivity, soil nutrients and climate were thoroughly studied through integrated approaches combined with the sample method, correlation analysis and structural equation modelling (SEM) model. The results show that the colonization of perennial grasses was promoted in the wetter and colder climate conditions. The productivity was determined by the perennial grasses, while species diversity was dominated by the perennial forbs. We obtained a U-shaped relationship between biomass and species diversity, which indicated two different strategies for the interaction between grassland biomass and diversity. In our study, air temperature and plant biomass were determined to be the main two indicators of plant species diversity variation. Meanwhile, distinct mutual constraints existed between the biomass of grassland dominant species and species diversity. Furthermore, soil nutrient conditions and climatic factors were found to jointly affect grassland productivity. This study will be helpful in providing deep insight into the dynamics of plant species diversity and the main interactive influencing factors in the semiarid steppe ecosystem and will provide a scientific basis for the maintenance of plant diversity and ecosystem functions in this region.

BackgroundThe relationship between obesity and diabetic retinopathy (DR) remains controversial. The aim of this study was to assess the association of generalized obesity [assessed by body mass index (BMI)] and abdominal obesity [assessed by waist to hip ratio (WHR)] with incident DR, and vision-threatening DR (VTDR), and DR progression among Chinese adults with type 2 diabetic mellitus (T2DM).MethodThis prospective cohort study was conducted at the Zhongshan Ophthalmic Center, from November 2017 to December 2020. DR was assessed based on the 7-filed fundus photographs using the modified Airlie House Classification. Multivariable logistic regression models were used to evaluate the associations of BMI and WHR with the development and progression of DR after adjusting for age, sex, traditional risk factors, and mutually for BMI and WHR.ResultsAmong the 1,370 eligible participants, 1,195 (87.2%) had no sign of any DR and 175 (12.8%) had DR at baseline examination. During the 2 years follow-up visit, 342 (28.6%) participants had incident DR, 11 (0.8%) participants developed VTDR, 15 (8.6%) demonstrated DR progression. After adjusting for confounders, the BMI was negatively associated with incident DR [relative risk (RR) =0.31; 95% confidence interval (CI), 0.26–0.38; P < 0.001] and incident VTDR (RR = 0.22; 95%CI, 0.11–0.43; P < 0.001), while WHR was positively associated with incident DR (RR = 1.47; 95% CI, 1.27–1.71; P < 0.001). BMI and WHR level were not significantly associated with 2-year DR progression in multivariate models (all P > 0.05).ConclusionsThis study provides longitudinal evidence that generalized obesity confer a protective effect on DR, while abdominal obesity increased the risk of DR onset in Chinese patients, indicating that abdominal obesity is a more clinically relevant risk marker of DR than generalized obesity.

Animal contextual fear conditioning (CFC) models are the most-studied forms used to explore the neural substances of posttraumatic stress disorder (PTSD). In addition to the well-recognized hippocampal–amygdalar system, the retrosplenial cortex (RSC) is getting more and more attention due to substantial involvement in CFC, but with a poor understanding of the specific roles of its two major constituents—dysgranular (RSCd) and granular (RSCg). The current study sought to identify their roles and underlying brain network mechanisms during the encoding processing of the rat CFC model. Rats with pharmacologically inactivated RSCd, RSCg, and corresponding controls underwent contextual fear conditioning. [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scanning was performed for each animal. The 5-h and 24-h retrieval were followed to test the formation of contextual memory. Graph theoretic tools were used to identify the brain metabolic network involved in encoding phase, and changes of nodal (brain region) properties linked, respectively, to disturbed RSCd and RSCg were analyzed. Impaired retrieval occurred in disturbed RSCd animals, not in RSCg ones. The RSC, hippocampus (Hip), amygdala (Amy), piriform cortex (Pir), and visual cortex (VC) are hub nodes of the brain-wide network for contextual fear memory encoding in rats. Nodal degree and efficiency of hippocampus and its connectivity with amygdala, Pir, and VC were decreased in rats with disturbed RSCd, while not in those with suppressed RSCg. The RSC plays its role in contextual fear memory encoding mainly relying on its RSCd part, whose condition would influence the activity of the hippocampal–amygdalar system.

ObjectiveThe long-term impact of COVID-19 on patient health has been a recent focus. This study aims to determine the persistent symptoms and psychological conditions of patients hospitalized with COVID-19 15 months after onset, that patients first developed symptoms. The potential risk factors were also explored.MethodsA cohort of COVID-19 patients discharged from February 20, 2020 to March 31, 2020 was recruited. Follow-ups were conducted using validated questionnaires and psychological screening scales at 15 months after onset to evaluate the patients' health status. The risk factors for long-term health impacts and their associations with disease severity was analyzed.Findings534 COVID-19 patients were enrolled. The median age of the patients was 62.0 years old (IQR 52.0–70.0) and 295 were female (55.2%). The median time from onset to follow-up was 460.0 (451.0–467.0) days. Sleep disturbance (18.5%, 99/534) and fatigue (17.2%, 92/534) were the most common persistent symptoms. 6.4% (34/534) of the patients had depression, 9.2% (49/534) were anxious, 13.0% (70/534) had insomnia and 4.7% (25/534) suffered from post-traumatic stress disorder (PTSD). Multivariate adjusted logistic regression analysis showed that glucocorticoid use during hospitalization (OR 3.58, 95% CI 1.12–11.44) was significantly associated with an increased risk of fatigue. The OR values for anxiety and sleep disorders were 2.36 (95% CI 1.07–5.20) and 2.16 (95% CI 1.13–4.14) in females to males. The OR value of PTSD was 25.6 (95% CI 3.3–198.4) in patients with persistent symptoms to those without persistent symptoms. No significant associations were observed between fatigue syndrome or adverse mental outcomes and disease severity.Conclusions15-month follow-up in this study demonstrated the need of extended rehabilitation intervention for complete recovery in COVID-19 patients.

Esophageal cancer (ESCA) is one of the common malignant tumors. The roles and signaling mechanisms of spindle apparatus coiled-coil protein 1 (SPDL1) in ESCA progression have not been reported previously. Therefore, the expression levels and potential clinical roles of SPDL1 were investigated using data from multiple databases and tissue samples of 53 ESCA patients who underwent 18F-FDG positron emission tomography (PET)/computed tomography (CT) before therapy. The signaling mechanisms of SPDL1 involved in ESCA progression were investigated via bioinformatics analysis. The effects of SPDL1 on the growth and migration of ESCA cells were investigated using CCK-8, Edu, and transwell assays. SPDL1 was upregulated in ESCA tissues. Increased SPDL1 expression was associated with age, grade, drinking history, cancer stage, lymph node metastasis, TP53 mutation, and poor prognosis in patients with ESCA. SPDL1 overexpression was significantly correlated with SUVmax, SUVmean, and TLG of PET/CT. SPDL1 silencing inhibited cell proliferation, migration, and invasion. SPDL1 was significantly enriched in cell cycle, spliceosome, DNA replication, and other processes. The hub genes of a constructed protein–protein interaction network included CDK1, BUB1, CCNB1, BUB1B, CCNA2, CDC20, MAD2L1, AURKB, NDC80, and PLK1, which were related to SPDL1 expression. The findings of this study suggest that SPDL1 may serve as a biomarker of ESCA prognosis.

Abstract Osteoporosis is the most prevailing primary bone disease and a growing health care burden. The aim of this study was to clarify the functional roles and mechanisms of the circ-ITCH regulating osteogenic differentiation of osteoporosis. Circ-ITCH and yes-associated protein 1 (YAP1) levels were downregulated, but the miR‐214 level was upregulated in osteoporotic mice and patients. Knockdown of circ-ITCH inhibited the alkaline phosphatase (ALP) activity, mineralized nodule formation, and expression of runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and osteocalcin (OCN) during osteogenic induction. Furthermore, miR-214 was a target of circ-ITCH, knockdown of miR-214 could impede the regulatory effects of sh-circ-ITCH on osteogenic differentiation. Moreover, miR-214 suppressed hBMSCs osteogenic differentiation by downregulating YAP1. Finally, in vivo experiments indicated that overexpression of circ-ITCH could improve osteogenesis in ovariectomized mice. In conclusion, circ-ITCH upregulated YAP1 expression to promote osteogenic differentiation in osteoporosis via sponging miR-214. Circ-ITCH could act as a novel therapeutic target for osteoporosis.

The rapid urbanization process in China has promoted the active state of urban design practice. In the process of solving complex problems, the practical scope of urban design has gradually expanded. This paper took a design institution in Nanjing as a case study and sorted the trends in design project types and themes over the past 20 years, which presented a partial and diverse state of evolution in urban design practice. Concept, technology and management were extracted as the three main dimensions of cognitive urban design practice development. The relative positions and relationships of different types of urban design work were interpreted through mapping analysis of these three dimensions. This study provided a foundation for the practical orientation of urban design in China and a platform for communication among managers, urban design practitioners, scholars of related disciplines, and the public.

Abstract The retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

Abstract Paper, as a foldable, pollution-free, and low-cost material, has become a suitable support substrate for producing flexible thermoelectric (TE) generators to realize waste heat recycling and the application of human-powered electronic devices. We propose a facile fabrication method to modify cellulose paper with inorganic TE powders via vacuum filtration, making a modified paper that possesses good thermoelectric properties. By connecting the modified paper to copper foils, flexible paper-based TE generators (PTGs) are fabricated. The obtained PTG with three units of P–N modules can generate an output voltage of ∼41.2 mV at a temperature difference of 50 K. Based on this modified paper, a thermal sensor that responds to heat sources, such as fingers, is proposed with a rapid response time of 0.25 s. This work offers a promising strategy for the simple fabrication of PTGs, paving the way for achieving the commercial application of self-powered wearable electronics.

Abstract Background Chrysanthemum morifolium is one of the most popular ornamental crops. The capitulum, which is the main ornamental part of chrysanthemum plants, consists of ligulate marginal ray florets, an attractive corolla (petals), and radially hermaphroditic disc florets, but no stamens. In Asteraceae species, the zygomorphic ray florets evolved from the actinomorphic disc florets. During this process, the zygomorphic ligulate corolla arose and the stamens were aborted. Although molecular genetic research has clarified ray floret development to some extent, the precise molecular mechanism underlying ray floret development in chrysanthemum remained unclear. Results A CYC2-like gene, Cyc2CL, was cloned from C. morifolium ‘Fenditan’. Subsequent analyses revealed that the alternative splicing of Cyc2CL, which occurred in the flower differentiation stage, resulted in the production of Cyc2CL-1 and Cyc2CL-2 in the apical buds. Prior to this stage, only Cyc2CL-1 was produced in the apical buds. A fluorescence in situ hybridization analysis of labeled Cyc2CL-1 and Cyc2CL-2 RNA indicated that Cyc2CL-2 was first expressed in the involucre tissue during the final involucre differentiation stage, but was subsequently expressed in the receptacle and floret primordia as the floral bud differentiation stage progressed. Moreover, Cyc2CL-2 was highly expressed in the inflorescence tissue during the corolla formation stage, and the expression remained high until the end of the floral bud differentiation stage. Furthermore, the overexpression of Cyc2CL-1 and Cyc2CL-2 in transgenic Arabidopsis inhibited stamen and petal development. Therefore, both Cyc2CL-1 and Cyc2CL-2 encode candidate regulators of petal development and stamen abortion and are important for the ray floret development in chrysanthemum. Conclusion In this study, we characterized the alternatively spliced transcripts of the CYC2-like gene that differ subtly regarding expression and function. The data presented herein will be useful for clarifying the regulatory mechanisms associated with the CYC2-like gene and may also be important for identifying the key genes and molecular mechanisms controlling the development of ray florets in chrysanthemum.

Importance: The infection of medical personnel with COVID-19 was a disaster for both patients and doctors. However, some effective measures can prevent medical staff from becoming infected. This article introduces those measures and thus provides a reference for other hospitals. Objective: In order to reduce the risk of occupational exposure and of the infection of medical staff, this article analyzed the factors, causes and experience of medical personnel on their occupational exposure to COVID-19. Some effective and targeted intervention measures can be implemented in order to avoid the occupational exposure of medical staff to COVID-19. Evidence review: In this single-center case series involving 196 medical personnel, occupational exposure to COVID-19 was present. Nursing staff accounted for 67.35% of those cases. The relationships with an exposure source were found to be as follows: doctors and patients (87.24%), colleagues (10.20%), and roommates (2.55%). Occupational exposure was found to be present in the clinical department, radiology department, central sterile supply department, as well as in the outpatient clinics and operating rooms. The non-surgical departments accounted for 72.96% and direct contact accounted for 84.69% while failure to wear surgical masks (84.18%) and operating on the patient without wearing goggles/face shield (8.16%) were the main causes of occupational exposure. The occurrence of occupational exposure to COVID-19 declined to 0.19% after an extensive and comprehensive intervention program. Conclusions and relevance: Some effective measures such as hand hygiene, wearing surgical masks in and around the hospital, reasonable use of goggles/face screens, raising awareness of protective measures, minimizing the number of elective operations, strengthening training as well as many other control measures were instrumental in reducing occupational exposure. For any medical institution there is room for improvement in terms of personal protection to reduce occupational exposure.

Abstract Foot electrical stimulation (FES) has been considered as a classic stressor that can disturb homeostasis. Acute anemia was observed in the model induced by FES. The aim of this study was to explore the role of inflammatory cytokines underlying the acute anemia and gastrointestinal (GI) mucosal injury in the FES. Twenty-four male Kunming mice (20 ± 2 g) were randomly divided into control group and experimental group. The mice were placed in a footshock chamber that can generate 0.5 mA electrical impulse periodically for 0.5 h. After the process, red blood cell count, hemoglobin concentration and hematocrit, the levels of corticotropin releasing hormone (CRH) in serum and hypothalamus, and adrenocorticotropic hormone (ACTH) in serum and pituitary were detected separately. In addition, we investigated the expressions of inflammatory cytokines (IL-1, IL-6, TNF-α, iNOS, and IL-10) in the hypothalamus and duodenum by Polymerase Chain Reaction (PCR). Results showed that this FES model induced anemia, increased CRH and ACTH activity in the serum after the FES. Moreover, the expressions of IL-1β, IL-6, TNF-α, and iNOS were significantly increased following the process, while IL-10 was not activated. These findings suggest that anemia, the inflammatory cytokines in the hypothalamus and duodenum of the mice in the model induced by FES is closely related to GI mucosal injury/bleeding. Taken together, these results underscore the importance of anemia, GI mucosal injury/bleeding and stress, future studies would be needed to translate these findings into the benefit of affected patients.

Understanding the vertical distribution and driving mechanisms behind soil carbon (C), nitrogen (N), and phosphorus (P) contents and enzyme activities along elevation gradients is of great significance for the healthy and sustainable management of forest ecosystems. For this study, the 0–20 cm soil-layer samples of different natural Quercus spp. secondary forests from eight altitude gradients (ranging from 250 to 950 m) were investigated to quantify their physicochemical properties, ecological stoichiometry characteristics, and enzyme activities. The results indicated that the soil nutrient content of natural secondary Quercus spp. forests in the Dabie Mountains was low, with average soil organic carbon (SOC) and total phosphorus (TP) contents of 19.86 ± 3.56 g·kg−1 and 0.68 ± 0.10 g·kg−1, respectively, which were 19.14% and 12.82% lower, respectively, than the Chinese average. In terms of vertical spatial distribution, the SOC, total nitrogen (TN), and TP contents of the soil at high altitudes (≥750 m) were greater than those at middle- and low-altitude areas and reached the maximum value at or near the top of the mountain (850–950 m). The stoichiometric attributes of the soil ecosystem fluctuated with the higher altitudes in vertical space; however, the fluctuation range was not significant. The C:N, N:P, and C:P ratios reached their maximum values at altitudes of 250, 750, and 850 m, respectively. However, the overall average value remained generally lower than the national average; thus, in forest management, attention should be paid to the supplementation of the soil with C and P. The activities of soil sucrase, urease, acid phosphatase, and catalase were interconnected across the overall space, and increased with altitude. The SOC, TP, and pH were the main factors that influenced the changes in soil enzyme activities.

As the population grows, the development of conservation tillage offers a means of promoting the sustainability of agricultural engineering. Remote sensing images with high spatial and temporal resolutions enable the accurate monitoring of conservation tillage on a broad spatial scale, further promoting conservation tillage research. This paper describes using streamlined time series Sentinel-2 images based on the Google Earth Engine (GEE) cloud platform for mapping maize tillage practices in the Songnen Plain region of Northeast China. Based on the correlation with the normalized difference tillage index (NDTI) and maize residue coverage (MRC) data, the optimal time series and streamlining functions in the GEE cloud platform are determined. Estimates of MRC and the mapping of tillage practices in the Songnen Plain for 2019–2022 are then determined using GEE and a previous model. Geostatistical analysis using ArcGIS is applied to analyze the spatial and temporal distribution characteristics of MRC and conservation tillage over the Songnen Plain. The results show that time series images from 20–30 May achieve an r value of 0.902 and an R2 value of 0.8136 when using the median streamlining function. The mean MRC for the study area in 2022 is 2.3%, and an overall upward trend in conservation tillage is observed (from 0.08% in 2019 to 0.25% in 2022). Our analysis shows that MRC monitoring and conservation tillage mapping can be performed over a broad spatial scale using remote sensing technology based on the GEE cloud platform. Spatial and temporal information on farm practices provides a theoretical basis for agricultural development planning efforts, which can promote sustainable agricultural development.

Promoting carbon reduction in the construction sector is crucial to achieving China’s ‘double carbon’ target. However, due to the interaction of multiple factors, the carbon emission efficiency of Chinese construction industry (CEECI) varies from province to province, and the path to efficient CEECI is not uniform. This study aims to analyze the combined effects of multiple factors on CEECI and to explore the underlying logic behind the formation of efficient CEECI in the province, which measures the CEECI for 2018 and 2019 for 30 provinces, autonomous regions, and municipalities directly under the Central Government of China using the super-slack-based measure (Super-SBM), which includes non-desired outputs. From a group perspective, the qualitative comparative analysis method is applied to analyze the common mechanism of the regional economic development level, energy consumption structure, business management level, market openness, science, and technology innovation level on CEECI. The results show that the regional construction industry has three equivalent low-carbon development paths: “low energy management”, “scale management”, and “scale market opening”. Finally, according to the differences in regional resource endowments, differentiated paths suitable for the low-carbon development of the construction industry in different regions are proposed.

Abstract There is increasing awareness that oxidative stress may be implicated in the pathophysiology of autism spectrum disorder (ASD). Here we aimed to investigate blood oxidative stress marker profile in ASD children by a meta-analysis. Two independent investigators systematically searched Web of Science, PubMed, and Cochrane Library and extracted data from 87 studies with 4928 ASD children and 4181 healthy control (HC) children. The meta-analysis showed that blood concentrations of oxidative glutathione (GSSG), malondialdehyde, homocysteine, S-adenosylhomocysteine, nitric oxide, and copper were higher in children with ASD than that of HC children. In contrast, blood reduced glutathione (GSH), total glutathione (tGSH), GSH/GSSG, tGSH/GSSG, methionine, cysteine, vitamin B9, vitamin D, vitamin B12, vitamin E, S-adenosylmethionine/S-adenosylhomocysteine, and calcium concentrations were significantly reduced in children with ASD relative to HC children. However, there were no significance differences between ASD children and HC children for the other 17 potential markers. Heterogeneities among studies were found for most markers, and meta-regressions indicated that age and publication year may influence the meta-analysis results. These results therefore clarified blood oxidative stress profile in children with ASD, strengthening clinical evidence of increased oxidative stress implicating in pathogenesis of ASD. Additionally, given the consistent and large effective size, glutathione metabolism biomarkers have the potential to inform early diagnosis of ASD.

Peanut diseases seriously threaten peanut production, creating disease-resistant materials via interspecific hybridization is an effective way to deal with this problem. In this study, the embryo of an interspecific F1 hybrid was obtained by crossing the Silihong (Slh) cultivar with Arachis duranensis (ZW55), a diploid wild species. Seedlings were generated by embryo rescue and tissue culture. A true interspecific hybrid was then confirmed by cytological methods and molecular markers. After treating seedlings with colchicine during in vitro multiplication, the established interspecific F1 hybrid produced seeds which were named as Am1210. With oligonucleotide fluorescence in situ hybridization (Oligo FISH), molecular marker evaluations, morphological and web blotch resistance characterization, we found that: 1) Am1210 was an allohexaploid between Slh and ZW55; 2) the traits of spreading lateral branches, single-seeded or double-seeded pods and red seed coats were observed to be dominant compared to the erect type, multiple-seeded pods and brown seed coats; 3) the web blotch resistance of Am1210 was significantly improved than that of Slh, indicating the contribution of the web blotch resistance from the wild parent A. duranensis. In addition, 69 dominant and co-dominant molecular markers were developed which could be both used to verify the hybrid in this study and to identify translocation or introgression lines with A. duranensis chromosome fragments in future studies as well.

Herein, we report the synthesis of novel worm like structured SnO2 nanoparticles photocatalysts by chemical precipitation route from sodium stannate in the absence of a precipitating agent. The physico-chemical characteristics of the synthesized SnO2 were studied using powder X-ray diffraction (PXRD), Diffuse Reflectance Spectroscopy (DRS), Photoluminescence (PL), and High resolution transmission electron microscope (HRTEM) studies. PXRD and HRTEM analysis reveals the formation of amorphous SnO2 in the tetragonal crystal structure. XPS and PL characterization affirmed the presence of oxygen defects in SnO2, which could be due to Sn2+ present in the lattices. The optical band gap calculated using Kubelka-Munk method to be 3.8 eV. Photocatalytic studies of the prepared SnO2 catalyst showed 92% of Rhodamine-B (RhB) degradation in 120 min under UV irradiation. The enhanced dye degradation activity is attributed to oxygen defects in the SnO2 catalyst, which are responsible for the enhanced charge separation and inhibition of electron-hole pair recombination by trapping photogenerated electrons.

When severely or chronically injured, the liver loses ability to regenerate. Here, the authors utilize transient lipid nanoparticle-enclosed HGF and EGF-encoding mRNA delivery to induce hepatocyte proliferation and harness recovery of liver function in murine acute and chronic liver injury models.

OBJECTIVE: Hybrid debranching technique combined with conventional open surgery and endovascular repair was an effective treatment for thoracoabdominal aortic aneurysm (TAAA). We propose a new technique to reduce the time of RA anastomosis. MATERIALS AND METHODS: The hybrid staged operation procedure was evaluated in the period of 2013 and 2017 in three academic centers. The bilateral renal artery anastomosis in the experimental group used VORTEC technique. In the control group, the bilateral renal artery reconstruction was performed by conventional artificial blood vessel anastomosis. Primary outcome was technical success, the time of renal artery anastomosis, and major complications. Long term follow-up up to 7 years was evaluated as well. RESULTS: In total 57 patients were enrolled. Compared with the control group, there was a statistical difference in the mean time of left RA anastomosing (19.8 vs 4.6 min, p

BackgroundWe previously reported that the larval Echinococcus granulosus (E. granulosus) infection can expand the population of regulatory B cells in mice, thereby inhibiting the anti-infective immunity. However, the underlying mechanism is still largely unknown. This study further investigated the holistic transcriptomic profiles of total splenic B cells following the chronic infection of the parasite.MethodsThe infection model of larval E. granulosus was established by intraperitoneal inoculation with 2000 protoscolexes. Magnetic-Activated Cell Separation (MACS) was used to isolate the total splenic B cells. RNA sequencing was performed to screen the differentially expressed genes (DEGs) after infection. The expression of selected DEGs was verified using qRT-PCR. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Co-expression network analysis were applied to predict these DEGs' underlying biological processes, pathways, and interactions respectively.ResultsA total of 413 DEGs were identified in larval E. granulosus infected B cells, including 303 up- and 110 down-regulated genes. Notably, most DEGs related to inflammation and chemotaxis were significantly upregulated after infection. In line with these changes, significant expression upregulation of DEGs associated with fatty acid oxidation, lipid synthesis, lipolysis, lipid transport, and cholesterol biosynthesis, were observed in infected B cells. Co-expression network analysis showed an intimate interaction between these DEGs associated with immune and metabolism.ConclusionsThe present study revealed that the larval E. granulosus infection induces metabolic reprogramming of B cells, which provides a novel clue to clarify the immunoregulatory mechanism of B cells in parasitic infection.

Ecological degradation is a serious problem across the world constraining regional sustainable development, while ecological restoration is of great significance in alleviating this issue. Cost-benefit analysis of ecological restoration is valid for successful project implementation and planning but large-scale studies are still lacking, especially for the Qinghai-Tibet Plateau (QTP), which has a special geographic location and extremely fragile ecosystems. This study applied patch-generating land use simulation (PLUS) model to simulate different ecological restoration scenarios and quantified their costs and benefits (ecosystem services values). The results indicated that restoration priority areas varied in specific landscapes for different scenarios. For grassland restoration, the scenarios prioritized the southwestern regions with large tracts of grassland. The cost-benefit analysis showed that the benefit cost ratio of farmland afforestation scenario was the largest, with the value of 128.2; and it was the lowest in the degraded land restoration scenario, with the value of 58.44. And the benefit cost ratio of degraded grassland restoration was between the two, which is 80.83. Besides, in the comprehensive restoration scenarios, the benefit cost ratio increased with the increase of the grassland restoration area when the afforestation area and the degraded land restoration area remained unchanged. The results can guide and support ecological restoration planning and policy formulation on the QTP.

Urbanization provides benefit to modern civilization, while it also creates a series of ecological issues at different scales. The study of landscape pattern and connectivity change caused by urban agglomeration is the hotspot of regional ecological security research. In this study, morphological spatial pattern analysis (MSPA) and Patch Importance Index (dPC) were used to evaluate landscape heterogeneity and landscape connectivity in the Huangshui River Valley, Qinghai-Tibet Plateau. Then the spatial relationship was revealed by bivariate spatial autocorrelation analysis and three-dimensional curved surface graph. The results showed that in the past 30 years, urbanization has increased more than 25%, with the decrease of farmland and the fluctuation of natural habitat. Heterogeneity and fragmentation were more obvious in the central region with great urban agglomeration. MSPA revealed significant spatial differences in the interaction between natural habitat and urbanization. The landscape connectivity of natural habitat in the central region was severely damaged by urban agglomeration and was spatially correlated with the landscape pattern index. Three-dimensional surface graph showed that the connectivity of farmland and natural habitat experienced fluctuation to decline trend with the expansion of construction land, which indicating a complex correlation and interaction between different land use types. In order to maintain the integrity of the ecosystem, it was necessary to take effective measures to improve the sustainability of cities and appropriately limit the expansion of urbanization. This study explored the landscape heterogeneity and connectivity from perspectives of the whole landscape, natural habitat, construction land, farmland and their correlation, which provided a theoretical basis for further optimization of urban coordinated ecological management.

The oxidative stress response caused by traumatic brain injury (TBI) leads to secondary damage in the form of tissue damage and cell death. Nuclear transcription-related factor 2 (NRF2) is a key factor in the body against oxidative stress and has an important role in combating oxidative damage in TBI neurons. In the present study, we investigated whether rutaecarpine could activate the PGK1/KEAP1/NRF2 pathway to antagonize oxidative damage in TBI neurons. We performed controlled cortical impact (CCI) surgery on mice and taken H2O2 treatment on PC12 cells to construct TBI models. The results of western blot showed that the expression of PGK1, KEAP and NRF2 was regulated and accompanied by altered levels of oxidative stress, and the use of rutaecarpine in the TBI model mice significantly improved cognitive dysfunction, increased antioxidant capacity and reduced apoptosis in brain tissue. Similar antioxidant damage results were obtained using rutaecarpine in a PC12 cell model. Furthermore, through the use of the protein synthesis inhibitor CHX and the proteasome synthesis inhibitor MG-132, rutaecarpine was found to promote the expreesions of PGK1 and NRF2 by accelerating PGK1 ubiquitination to reduce PGK1 expression. Therefore, rutaecarpine may be a promising therapeutic agent for the treatment of TBI-related neuro-oxidative damage.

IntroductionIncreasing evidence supports the idea that the disruption of epithelial tight junction proteins (TJPs) caused by accumulation of uremia toxins, such as homocysteine (Hcy), is one of the most important mechanisms underlying the damage of intestinal barrier function (IBF) in chronic kidney disease (CKD). Since the decrease of hypoxia inducible factor-1α (HIF-1α) is reported to be involved in Hcy-induced cell injury, and the upregulation of microRNA-223 (miR-223) plays a vital protective role in the impairment of IBF in the experimental colitis, we investigated the effect of HIF-1α stabilizer roxadustat on the disruption of TJPs induced by Hcy and CKD and the underlying mechanism.MethodsChronic kidney disease was induced in rats via 5/6 nephrectomy. In a series of experiments, the rats were treated orally with roxadustat of different doses. The expression of tight junction proteins, HIF-1α, and miR-223 was analyzed in different groups by western blotting analysis, RT-qPCR techniques and immunofluorescence. A series of experiments with cultured Caco2 cells was performed.ResultsThe results showed that the expression of TJPs (occludin, claudin-1, and ZO-1) decreased significantly, accompanied by the reduction of HIF-1α and miR-223 in Hcy-treated Caco2 cells and colonic mucosa of uremic rats. The reduction of HIF-1α and miR-223 was reversed by roxadustat and the decrease of TJPs expression was attenuated in both Caco2 cells induced by Hcy and colon tissue of CKD rats. Furthermore, transfection with miR-223 mimics increased the expression of TJPs, while transfection with miR-223 inhibitor decreased their expression in Caco2 cells. MiR-223 inhibitor applied before roxadustat treatment partly diminished the effect of roxadustat on TJPs expression in Caco2 cells.ConclusionThese results indicated that roxadustat attenuated the disruption of epithelial TJPs induced by Hcy in Caco2 cells and the damage of colonic epithelium in CKD rats through the upregulation of miR-223 induced by HIF-1α. A novel insight into the IBF dysfunction in CKD was provided, and it suggests a potential therapeutic use of roxadustat for the IBF dysfunction besides anemia in CKD.

Based on 2018 China's Human Resource Employees Survey Data, this study uses the probit model to examine the impact of entrepreneurial ability and career development on HR's entrepreneurial intention. In terms of entrepreneurial ability, the results show that the educational background of Human Resource Management, cross-disciplinary knowledge, job-hopping experience, and the number of subordinates have significant positive impacts on HR's entrepreneurial intention. In terms of career development, lack of promotion space, skill upgrading opportunities, and lower than expected income have significant positive impacts on HR's entrepreneurial intention, and these impacts are heterogeneous among different enterprises. This study suggests that potential entrepreneurs can be identified from the explicit characteristics, which reflect HR's entrepreneurial abilities, and it is necessary to face up to the influence of career development on HR's entrepreneurial intention and encourage them to participate in on-the-job entrepreneurship. This study suggests that HR's entrepreneurial ability should be regarded as an important starting point for entrepreneurial success, and it is necessary to improve HR's career development system to create more opportunities for on-the-job entrepreneurship, and government should implement differentiated and precise entrepreneurial support policies to encourage HR's entrepreneurship.

BackgroundGastric cancer (GC) is one of the most common malignant cancers worldwide. The development of potential antitumor agents is being investigated and stimulates more clinical trials. Overall survival (OS) is consistently considered the primary endpoint for clinical trials on treatment effect assessment. However, finding an appropriate endpoint more sensitive and easy for trials is vital. For adjuvant chemotherapy, current evidence has shown that disease-free survival (DFS) could be a surrogate endpoint for randomized controlled trials (RCTs) with GC, but evidence for neoadjuvant chemotherapy (NCT) or chemoradiotherapy (NCRT) is inadequate. This study was designed to evaluate the possibility that event-free survival (EFS) surrogates OS in RCTs of NCT/NCRT of gastric orss gastroesophageal (GC or GEJ) adenocarcinoma patients (ADK).MethodsA literature search was conducted through databases including PubMed, the Cochrane Library, and Embase. References and articles from other sources were also included. A total of 8 RCTs with 2,837 patients were eventually analyzed. Hazard ratios (HRs) of OS and EFS were directly approached. The surrogacy of EFS was assessed through the correlation of determination R2. We used Review Manage pooling HRs of OS and EFS at the trial level. I2 was used to demonstrate the heterogeneity of inclusions. Publication bias was summarized and illustrated through funnel plots. All analyses were on two sides with a setting statistical significance as p < 0.05.ResultsEight RCTs of 2,837 patients were analyzed at the trial level. The I2 for OS was 21% and 51% for EFS, and a fixed-effect model was used. The pooled HR of OS was 0.83 (95% CI: 0.75–0.92, p < 0.001), and that of EFS was 0.78 (95% CI: 0.71–0.86, p < 0.001). The regression correlation coefficient between EFS and OS was 0.76 (95% CI: 0.41–1.11, p = 0.002), and the coefficient of determination R2 = 0.826.ConclusionsA strong correlation was observed between OS and EFS at the trial level. EFS could be a surrogate endpoint for neoadjuvant RCTs of GC and GEJ adenocarcinoma. Further studies and evidence from individual data are expected.

BackgroundRecently, increasing evidence has suggested that Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) is related to carcinogenesis. However, the potential roles of GFPT2 in colon cancer still need to be fully investigated.MethodsWe examined the protein levels of GFPT2 by immunohistochemistry (IHC) in tissues collected from 83 patients with colon cancer. We further detected GFBPT2 protein levels by Western Blot assay. We checked the relationship between GFPT2 expression levels and overall survival (OS), stromal and immune scores and immune components from The Cancer Gene Atlas (TCGA) database. GFBP2-related pathways were validated in the Cancer Cell Line Encyclopedia (CCLE) database. Expression of GFPT2 in single cell subpopulations was calculated from The Tumor Immune Single Cell Center (TISCH). The levels of GFPT2 and drug sensitivity data were performed from CellMiner dataset.ResultsGFPT2 was highly expressed and correlated with poor pathological features in 83 colon cancer patients. Moreover, increased GFPT2 expression was significantly associated with poorer OS in 329 colon adenocarcinoma (COAD) patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed the differentially expressed genes of GFPT2 were mostly enriched in focal adhesion, ECM receptor interaction, JAK/STAT signaling pathway and immune related pathways. In addition, GFPT2 expression was correlated with the tumor microenvironment (TME). GFPT2 expression was linked to cancer-associated fibroblasts (CAFs)-associated factors and epithelial-mesenchymal transition (EMT)-related factors. GFPT2 was positively correlated with immunosuppressive cells and regulated immunosuppressive factors and T-cell exhaustion. Finally, our data suggested that the expression of GFPT2 may be a judgment of the sensitivity of a certain class of drugs.ConclusionsOur work reveals the roles of GFPT2 in tumorigenesis, particularly in immune response, TME and drug resistance, which are crucial for the development of customized cancer therapies.

Pod size is an important yield-influencing trait in peanuts. It is affected by plant hormones and identifying the genes related to these hormones may contribute to pod-related trait improvements in peanut breeding programs. However, there is limited information on the molecular mechanisms of plant hormones that regulate pod size in peanuts. We identified a mutant with an extremely small pod (spm) from Yuanza 9102 (WT) by 60Co γ-radiation mutagenesis. The length and width of the natural mature pod in spm were only 71.34% and 73.36% of those in WT, respectively. We performed comparative analyses for morphological characteristics, anatomy, physiology, and global transcriptome between spm and WT pods. Samples were collected at 10, 20, and 30 days after peg elongation into the soil, representing stages S1, S2, and S3, respectively. The differences in pod size between WT and spm were seen at stage S1 and became even more striking at stages S2 and S3. The cell sizes of the pods were significantly smaller in spm than in WT at stages S1, S2, and S3. These results suggested that reduced cell size may be one of the important contributors for the small pod in spm. The contents of indole-3-acetic acid (IAA), gibberellin (GA), and brassinosteroid (BR) were also significantly lower in spm pods than those in WT pods at all three stages. RNA-Seq analyses showed that 1,373, 8,053, and 3,358 differently expressed genes (DEGs) were identified at stages S1, S2, and S3, respectively. Functional analyses revealed that a set of DEGs was related to plant hormone biosynthesis, plant hormone signal transduction pathway, and cell wall biosynthesis and metabolism. Furthermore, several hub genes associated with plant hormone biosynthesis and signal transduction pathways were identified through weighted gene co-expression network analysis. Our results revealed that IAA, GA, and BR may be important regulators in controlling pod size by regulating cell size in peanuts. This study provides helpful information for the understanding of the complex mechanisms of plant hormones in controlling pod size by regulating the cell size in peanuts and will facilitate the improvement of peanut breeding.

Abstract Porous mullite hollow fiber membranes were prepared with a combined phase-inversion and sintering method, using three sintering additives including yttrium stabilized zirconia (YSZ), small mullite particles (SMP), and titanium oxide (TiO2) to promote the particle sintering. The results indicated that all the three additives could improve the sintering performance of mullite hollow fiber membranes due to the decrease in activation energy of mullite grains. Both YSZ and TiO2 could react with mullite grains to generate composite oxides (e.g., ZrSiO4 and Al2TiO5) during sintering, following a reaction-sintering mechanism. Interestingly, the newly generated ZrSiO4 was instable and further decomposed into monoclinic ZrO2 and SiO2 in the sintering process. The decomposition could avoid excessive embedment of composite oxides among mullite grains which have negative impact on mechanical strength of mullite hollow fibers. Overall, the doping of YSZ provided a better promotion effect on the sintering of mullite hollow fiber membranes, where the microstructural and mechanical properties are insensitive to the doping content and sintering temperatures, so it could be used as the candidate for the large-scale preparation of mullite hollow fibers.

AIM: To analyse the characteristic of macular microcirculation detected by optical coherence tomography angiography(OCTA)in nonproliferative diabetic retinopathy(NPDR).METHODS: Vessel density of 3mm×3mm centered on the fovea(3mm×3mm VD), parafoveal vessel density(parafoveal VD)and foveal vessel density(foveal VD)were measured by OCTA in healthy people, NDR, mild NPDR, moderate NPDR, and severe NPDR groups. RESULTS: Deep 3mm×3mm VD, deep parafoveal VD and deep foveal VD were decreased gradually in groups. There was statistically significant difference between moderate NPDR, severe NPDR and others in deep 3mm×3mm VD and parafoveal VD(PP=0.006). Superficial 3mm×3mm VD and superficial parafoveal VD are statistically significant in groups. There was statistically significant difference between moderate NPDR group and control group in superficial 3mm×3mm VD and parafoveal VD(PPCONCLUSION: Deep vessel density decreased more significantly in moderate NPDR and severe NPDR groups and deep parafoveal vessel density might be a potential biomarker of DR.

Abstract Background A simulation and model (SM) teaching aid using 3D printing was developed to improve a training course for total hip arthroplasty of adult developmental dysplasia of the hip (adult DDH-THA). We named this new method Surgery Simulation Teaching based on a Real Reconstruction Aid (RRA-SST). A prospective randomized comparison was performed with the traditional surgical live teaching method to evaluate the training effectiveness of RRA-SST for adult DDH-THA. Methods Twenty-six trainees, who were already practicing but were not experienced, participated in the study. We randomly divided the trainees into two groups: Group A (n = 13) received RRA-SST and group B (n = 13) received traditional surgical live teaching. A surgery simulation test and a questionnaire were used for evaluation. Next, each group received training with the other teaching method, and then the test and questionnaire were used again for evaluation. Results After the first test, the RRA-SST method was shown to produce better results than the traditional surgical live teaching method. After the second test, the results showed the training effect in both groups reached the same level, which was level as Group A RRA-SST results. Analysis of the questionnaire results showed that the training effect of RRA-SST was higher than that of traditional surgical live teaching, from multiple perspectives. Conclusions The use of RRA-SST improved participant performance according to simulation assessment. RRA-SST can be helpful for trainees who are already practicing but not experienced when developing proficiency in adult DDH-THA surgical techniques.

AIM:To study azelastine hydrochloride combined with praprofen for the treatment of allergic conjunctivitis in children.METHODS: Totally 80 children with allergic conjunctivitis who were admitted to our hospital from May 2016 to June 2018, they were randomly divided into the control group and the observation group, 40 cases in each group. The control group was given pranoprofen eye drops, on the basis of the control group, the observation group was combined with azelastine hydrochloride eye drops for adjuvant treatment. The two groups children were treated continuously for 1wk. The clinical efficacy, the changes of the clinical symptoms, tear film stability, inflammatory factors and adverse reactions were compared between the two groups.RESULTS: After 1wk of treatment, the clinical efficacy of the observation group was 95.0%, higher than that of the control group, 85.0%(P=0.035); the itching, tearing, foreign body sensation and photophobia scores in the observation group were lower than that of the control group \〖(1.13±0.36)vs (2.28±0.41)scores,(1.05±0.33)vs (2.14±0.49)scores,(1.17±0.46)vs (2.28±0.59)scores(1.29±0.37)vs (1.84±0.55)scores\〗(Pvs (5.85±0.92)s,(2.85±0.33)vs (6.21±0.68)scores\〗(Pvs (65.03±6.48)μg/L,(2.20±0.28)vs (7.26±0.72)μg/L,(0.06±0.01)vs (0.18±0.04)mg/L\〗(P2=1.897, P=0.168).CONCLUSION: The clinical efficacy of azelastine hydrochloride combined with pranoprofen in the treatment of allergic conjunctivitis in children is significant, which can effectively improve the level of inflammatory factors, promote the tear film stability recovery, and have good safety, the clinical value is high.

Abstract Background Web blotch is one of the most important foliar diseases worldwide in peanut (Arachis hypogaea L.). The identification of quantitative trait loci (QTLs) for peanut web blotch resistance represents the basis for gene mining and the application of molecular breeding technologies. Results In this study, a peanut recombinant inbred line (RIL) population was used to map QTLs for web blotch resistance based on high-throughput genome-wide sequencing. Frequency distributions of disease grade and disease index in five environments indicated wide phenotypic variations in response to web blotch among RILs. A high-density genetic map was constructed, containing 3634 bin markers distributed on 20 peanut linkage groups (LGs) with an average genetic distance of 0.5 cM. In total, eight QTLs were detected for peanut web blotch resistance in at least two environments, explaining from 2.8 to 15.1% of phenotypic variance. Two major QTLs qWBRA04 and qWBRA14 were detected in all five environments and were linked to 40 candidate genes encoding nucleotide-binding site leucine-rich repeat (NBS-LRR) or other proteins related to disease resistances. Conclusions The results of this study provide a basis for breeding peanut cultivars with web blotch resistance.

Abstract Background Traditional methods for minimally invasive internal fixation (MIIF) of calcaneal fractures require extensive intraoperative fluoroscopy, and fracture recovery is usually not ideal. We developed a new surgical procedure using digital surgical simulation and constructed a patient-specific instrument (PSI) for calcaneal fracture that we used during the operation. This study investigated whether PSI-assisted MIIF of calcaneal fracture enables rapid and accurate execution of the preoperative plan. Methods We retrospectively analyzed patients with Sanders type III or IV fresh calcaneal fractures who had undergone PSI-assisted MIIF at our hospital from January 2016 to December 2018. We analyzed perioperative data including intraoperative fluoroscopy time, concurrence of internal fixation actual usage (IFAU) with the preoperative plan, surgery time, and complications. We also compared pre- and postoperative actual measurements from X-ray radiographs and computed tomography images including Böhler, Gissane, and calcaneus valgus angles; subtalar joint width; and calcaneal volume overlap ratio with the preoperative design. All patients had been followed up and their American Orthopedic Foot and Ankle Score (AOFAS) score was available. Results Mean intraoperative fluoroscopy time was 3.95 ± 1.78 h; IFAU in 16 patients (16 ft) was the same as the preoperative plan; mean surgery time was 28.16 ± 10.70 min; and none of the patients developed complications. Böhler, Gissane, and calcaneus valgus angles and subtalar joint width did not differ between pre- and postoperative plans; however, the actual preoperative values of each of these parameters differed significantly from those measured postoperatively. The calcaneal volume overlap ratio with the preoperative design was 91.2% ± 2.3%. AOFAS scores increased with time, with significant differences in the score at each time point. Conclusions The newly developed PSI-assisted calcaneal fracture MIIF method can rapidly and accurately execute the preoperative plan.

Spatial variation of Urban Land Surface Temperature (ULST) is a complex function of environmental, climatic, and anthropogenic factors. It thus requires specific techniques to quantify this phenomenon and its influencing factors. In this study, four models, Random Forest (RF), Generalized Additive Model (GAM), Boosted Regression Tree (BRT), and Support Vector Machine (SVM), are calibrated to simulate the ULST based on independent factors, i.e., land use/land cover (LULC), solar radiation, altitude, aspect, distance to major roads, and Normalized Difference Vegetation Index (NDVI). Additionally, the spatial influence and the main interactions among the influential factors of the ULST are explored. Landsat-8 is the main source for data extraction and Tehran metropolitan area in Iran is selected as the study area. Results show that NDVI, LULC, and altitude explained 86% of the ULST °C variation. Unexpectedly, lower LST is observed near the major roads, which was due to the presence of vegetation along the streets and highways in Tehran. The results also revealed that variation in the ULST was influenced by the interaction between altitude – NDVI, altitude – road, and LULC – altitude. This indicates that the individual examination of the underlying factors of the ULST variation might be unilluminating. Performance evaluation of the four models reveals a close performance in which their R2 and Root Mean Square Error (RMSE) fall between 60.6–62.1% and 2.56–2.60 °C, respectively. However, the difference between the models is not statistically significant. This study evaluated the predictive performance of several models for ULST simulation and enhanced our understanding of the spatial influence and interactions among the underlying driving forces of the ULST variations.