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Melanoma is a malignant tumor derived from melanocytes, which is the most fatal skin cancer. The present study aimed to explore and elucidate the candidate genes in melanoma and its underlying molecular mechanism. A total of 1,156 differentially expressed genes were obtained from the GSE46517 dataset of Gene Expression Omnibus database using the package “limma” in R. Based on two algorithms (LASSO and SVM-RFE), we obtained three candidate DEGs (LTBP4, CDHR1, and MARCKSL1). Among them, LTBP4 was identified as a diagnostic marker of melanoma (AUC = 0.985). Down-regulation of LTBP4 expression was identified in melanoma tissues and cells, which predicted poor prognosis of patients with melanoma. Cox analysis results discovered that LTBP4 with low expression was an independent prognostic factor for overall survival in patients with melanoma. LTBP4 inhibition reduced cell apoptosis and promoted cell proliferation and metastasis. These changes were correlated with the expression levels of caspase-3, Ki67 and E-cadherin. Further, as indicated by tumor formation study of nude mice, LTBP4 silencing improved the tumorigenic ability of melanoma cells. Knockdown of LTBP4 increased the percentage of active TGFβ1 secreted by melanoma cells. CTGF, Gyr61, and Birc5 expression levels were reduced, YAP1 phosphorylation was inhibited, and YAP1 was translocated from the cytoplasm to the nucleus in melanoma cells treated with TGF-β1. These effects were reversed by LTBP4 overexpression. As evidenced by immunofluorescent staining, Western blotting and luciferase reporter assay, LTBP4 overexpression activated the Hippo signaling pathway, which was characterized by the increased nuclear-cytoplasmic translocation of YAP1 and the enhanced phosphorylation of YAP1, MST1, and MOB1. In addition, the effects of LTBP4 overexpression on inhibiting CTGF, Cyr61 and Birc5 expression, promoting the apoptosis, and inhibiting the metastasis and proliferation of melanoma cells were reversed by the overexpression of YAP1 or MST1. In conclusion, the LTBP4-TGFβ1-Hippo-YAP1 axis is a critical pathway for the progression of skin melanoma.

IntroductionCoronavirus Disease 2019 (COVID-19) has made a serious public health threat worldwide. Recent evidence has indicated that COVID-19 patients in convalescence frequently experience insomnia, which reduces their quality of life and causes unknown risks. The positive effect of cognitive behavior on insomnia has been well addressed in previous studies. Given the high infectivity and epidemicity of COVID-19, Internet-delivered intervention may be safer than face-to-face treatment. However, whether Internet-delivered cognitive behavioral therapy can effectively improve the insomnia of COVID-19 patients in convalescence has not been completely determined yet. Therefore, we conducted a meta-analysis and systematic review to evaluate the effects of Internet-delivered cognitive behavioral therapy on insomnia in COVID-19 patients in convalescence, with the aim to confer some guidance for its clinical application.Methods and analysisThis systematic review and meta-analysis has been registered in the International Prospective Register of Systematic Reviews (PROSPERO). Two researchers will retrieve the relevant literature on Internet-delivered cognitive behavioral therapy for insomnia in convalescent patients with COVID-19 in PubMed, Web of Science, Embase, MEDLINE, Cochrane Library, Clinical Trials gov, Chinese Biomedical Literature Database (CBM), and Chinese National Knowledge Infrastructure (CNKI) from inception to 11th of December. In addition, we will review the relevant trials and references of the included literature and manually searched the grey literature. The two researchers will independently extracted data and information and evaluated the quality of the included literature. The Review Manager software (version 5.3) and Stata software (version 14.0) will be used for data analysis. The mean difference or the standardized mean difference of 95% CI will be used to calculate continuous variables to synthesize the data. In addition, I2 and Cochrane will be used for heterogeneity assessment.Trial registrationPROSPERO registration number CRD42021271278.

With the strong development of industrial transformation, the digital economy, as the most dynamic, innovative, and widely radiated economic form at present, has become an important force driving the development of the global economy. Shaanxi Province has accelerated the development of the digital economy, and the development of the province’s digital economy has shown a good trend. However, the current digital economy development measurement is still unable to accurately observe the development law of the digital economy industry, which makes it difficult to measure the control standards for the digital economy industry. Therefore, this study has evaluated the development of digital economy in Shaanxi Province based on machine learning algorithms. This study first puts forward the dimensions of digital economy monitoring and evaluation and then combines the characteristics of digital economy development in Shaanxi Province to determine the quality evaluation indicators of digital economy development. Finally, according to the machine learning algorithm, a quality evaluation model of digital economy development was established, and through the evaluation results, suggestions were put forward for the development plan of digital economy in Shaanxi Province. The experimental results showed that, after re-planning the digital economy in Shaanxi Province according to the evaluation results, the development of the digital economy in Shaanxi Province has increased by 9.82%, indicating that the evaluation model plays a good reference role in the formulation of the digital economy development plan.

The GABAB receptor is a typical G protein–coupled receptor, and its functional impairment is related to a variety of diseases. While the premise of GABAB receptor activation is the formation of heterodimers, the receptor also forms a tetramer on the cell membrane. Thus, it is important to study the effect of the GABAB receptor aggregation state on its activation and signaling. In this study, we have applied single-molecule photobleaching step counting and single-molecule tracking methods to investigate the formation and change of GABAB dimers and tetramers. A single-molecule stoichiometry assay of the wild-type and mutant receptors revealed the key sites on the interface of ligand-binding domains of the receptor for its dimerization. Moreover, we found that the receptor showed different aggregation behaviors at different conditions. Our results offered new evidence for a better understanding of the molecular basis for GABAB receptor aggregation and activation.

The high prevalence of polycystic ovary syndrome (PCOS) among reproductive-aged women has attracted more and more attention. As a common disorder that is likely to threaten women’s health physically and mentally, the detection of PCOS is a growing public health concern worldwide. In this paper, we proposed an automated deep learning algorithm for the auxiliary detection of PCOS, which explores the potential of scleral changes in PCOS detection. The algorithm was applied to the dataset that contains the full-eye images of 721 Chinese women, among which 388 are PCOS patients. Inputs of the proposed algorithm are scleral images segmented from full-eye images using an improved U-Net, and then a Resnet model was applied to extract deep features from scleral images. Finally, a multi-instance model was developed to achieve classification. Various performance indices such as AUC, classification accuracy, precision, recall, precision, and F1-score were adopted to assess the performance of our algorithm. Results show that our method achieves an average AUC of 0.979 and a classification accuracy of 0.929, which indicates the great potential of deep learning in the detection of PCOS.

Against the background of surging globalization and accelerating urbanization, more and more cities are choosing to reposition their urban landscape by hosting sports events at different levels to achieve a great leap forward in urban development. Major sporting events can quickly gather various resources from all over the country and even the world for a city, promoting it to become a world-famous city with international influence. In the twenty-first century, more and more Chinese cities are bidding to host important sporting events at different levels, but historical experience shows that hosting slightly important sporting events is a “double-edged sword” and economic benefits are no longer the main reason for a city to host an event. Using the SWOT-PEST model, this paper provides an in-depth analysis of the advantages, disadvantages, opportunities, and challenges of marginally important sporting events of different levels affecting the regional economy from political, economic, social, and technological aspects, so as to understand in detail the economic impact of sporting events.

One of the most critical systems of any satellite is the Electrical Power System (EPS) and without any available energy, the satellite would simply stop to function. Therefore, the presented research within this paper investigates the areas relating to the satellite EPS with the main focus towards the CubeSat platform. In this paper, an appropriate EPS architecture with the suitable control policy for CubeSat missions is proposed. The suggested control strategy combines two methods, the Maximum Power Point Tracking (MPPT) and the Battery Charge Regulation (BCR), in one power converter circuit, in order to extract the maximum power of the Photovoltaic (PV) system and regulate the battery voltage from overcharging. This proposed combined control technique is using a Fuzzy Logic Control (FLC) strategy serving two main purposes, the MPPT and BCR. Without an additional battery charger circuit and without switching technique between the two controllers, there are no switching losses and the efficiency of the charging characteristic can be increased by selecting this proposed combined FLC. By testing a space-based PV model with the proposed EPS architecture, some simulation results are compared to demonstrate the superiority of the proposed control strategy over the conventional strategies such as Perturb and Observe (P&O) and FLC with a Proportional Integral Derivative (PID) controller.

Background/purpose: Composite resin is currently the most widely used dental restoration material. Previous studies have demonstrated that the application of Chlorhexidine (CHX) on the dentin surface after acid etching can result in an improvement in the integrity and stability of tooth restoration through time. In order to better understand whether CHX can help improve the stability of the resin-dentin bond strength, in this study, a comprehensive review of the effect of adding CHX to the adhesive system on the stability of immediate and long-term resin-dentin bond strength was conducted. Materials and methods: This article was written in accordance with the PRISMA Statement and is registered on the International Prospective Register of Systematic Reviews (registration number CRD42018084962). Six electronic databases including PubMed, Embase, Cochrane library, ISI Web of Science, ClinicalTrials.gov and China National Knowledge Infrastructure (CNKI) were searched up to October, 2018. Ten articles were selected from 340 possible eligible articles for meta-analysis, and 41 sets of data were analyzed in the meta-analysis. Results: The results indicated that the use of 0.1% and 0.2% CHX does not adversely affect the immediate bond strength (p > 0.05), but both 0.1% and 0.2% CHX increased bond strength compared with the control group over 12 months (p

Abstract Malignant melanomas (MMs) were the fifth most common cancer in men and the sixth most common cancer in women in 2018, respectively. These are characterized by high metastatic rates and poor prognoses. We systematically reviewed safety and efficacy of carbon‐ion radiotherapy (CIRT) for treating MMs. Eleven studies were eligible for review, and the data showed that MM patients showed better local control with low recurrence and mild toxicities after CIRT. Survival rates were slightly higher in patients with cutaneous or uveal MMs than in those with mucosal MMs. CIRT in combination with chemotherapy produced higher progression‐free survival rates than CIRT only. In younger patients, higher rates of distant metastases of gynecological MMs were observed. The data indicated that CIRT is effective and safe for treating MMs; however, a combination with systemic therapy is recommended to ensure the best possible prognosis for MMs.

Background and objective The incidence of lung cancer is increasing annually. Clinicians pay special attention to lung tests during physical examinations. Due to the popularity of low-dose computed tomography, not only can lung cancer be diagnosed early, but physical examinations often reveal the presence of pulmonary nodules, an important health issue that cannot be ignored. Patients with pulmonary nodules are prone to adverse emotions such as anxiety and depression. Many studies have shown that patients with emotional disorders have immune system dysfunction and changes in inflammation levels. This study aimed to investigate the changes in anxiety, depression, the ratios of T helper cells 17 (Th17) and regulatory T cells (Tregs), and inflammation levels in patients with pulmonary nodules. Methods A total of 143 subjects from The First Affiliated Hospital of Anhui Medical University were included from April 2019 to July 2019. All of the subjects were assessed with the Beck Anxiety Inventory (BAI) and the Beck Depression Inventory-II (BDI-II). Overall, 40 cases were healthy controls (HC) and 103 cases were patients with pulmonary nodules. The patients were divided into two groups according to the scale scores: 62 cases in a non-anxiety and non-depression (NAD) group and 41 cases in an anxiety and/or depression (AD) group. The percentage of Th17 and Tregs in the peripheral blood and inflammatory factors in the serum were detected. The absolute Th17 cell counts were calculated and the differences between the groups and correlations between these indicators were analyzed. Results There were statistically significant differences in the percentage of Th17 cells, the absolute counts of Th17 and Th17/Treg cells, and the levels of interleukin-2 (IL-2), IL-6, and tumor necrosis factor-α (TNF-α) among three groups (all P0.05). The previously described indicators had no significant correlation with the severity of anxiety and depression (P>0.05). There were no significant differences in the percentage of Tregs or levels of IL-4 and IL-10 between the groups (all P>0.05). The proportion of anxiety and/or depression in female patients with pulmonary nodules was higher than that in males (P

Abstract Objective The mechanism between smoking and coronary artery disease (CAD) remains unclear. It is likely that lipid (including triglycerides (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C)) have been functioning as one of the mediators between smoking and the CAD occurrence. The study aimed to investigate the mediating effect of lipid on the relationship between smoking and CAD risk. Methods The case-control study included 2048 subjects. General linear regression analysis was used to corroborate the association between smoking and lipid levels. Univariate and multivariate logistic regression analysis were performed to reveal the relationship between smoking, lipid and the risk of CAD. Mediation analysis was used to investigate whether the association between smoking and CAD risk was mediated by lipid. Results Smoking was found to be associated with the risk of CAD (odds ratio (OR) = 1.34, 95% confidence interval (CI): 1.05–1.71, P = 0.019). Regression analysis showed that TG, TC and HDL-C were associated with CAD (OR = 2.69, 95%CI: 2.12–3.40, P

Introduction and objectives: Hepatic microRNA (miR) expression profiles were explored in aged rats with NAFLD, in order to clarify the molecular mechanisms underlying the pathophysiological processes of aging-related NAFLD. Patients or materials and methods: 24 aged rats (18-month-old) and 24 young rats (2-month-old) were randomly divided into two subgroups according to diet, control group and NAFLD group. After 8 weeks of administering 45% high-fat diet or normal diet, total hepatic RNA was extracted from liver tissues of the aged rats. Differentially expressed microRNAs (DE-miRs) in aged NAFLD group were detected and screened out using high-throughput sequencing technology. The data were subjected to Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses using a bioinformatics approach. The sequencing results were further verified by RT-qPCR. Results: Compared with the aged control liver tissues, 6 significantly upregulated miRs (miR-881-3p, miR-871-3p, miR-335, miR-223-3p, miR-155-5p, miR-146b-5p) and 4 significantly downregulated miRs (miR-182, miR-193-3p, miR-31a-5p and miR-96-5p) were identified in the aged NAFLD liver tissues. These DE-miRs were found to be involved in the regulation of cell signaling transduction and metabolism processes, probably affecting signaling pathways relevant to insulin secretion and some senile diseases. RT-qPCR results corroborated the sequencing results and demonstrated that 6 significantly upregulated miRs were not identified in the young group. Conclusions: A total of 10 DE-miRs identified in the aged NAFLD rats were involved in some certain insulin secretion and age-related functional pathways, which may serve as novel candidate targets for the diagnosis and treatment of aging-associated NAFLD.

Abstract Background Osteosarcoma (OS) is a primary malignant bone tumor with a high rate of metastasis and a short 5-year survival rate. MiR-363 was downregulated in a variety of tumors and played a role in suppressing tumors. However, the roles of miR-363 in osteosarcoma remain unknown; thus, the purpose of this study was to explore the functions of miR-363 in osteosarcoma. Methods CCK-8 and transwell assays were performed to evaluate the proliferation, migration, and invasion abilities of MG63 cells. The epithelial-mesenchymal transition (EMT) and apoptosis-associated proteins were measured by using Western blot assay. Luciferase reporter assay was utilized to verify whether miR-363 directly bound to the 3′-UTR of NOB1 mRNA. Results MiR-363 was downregulated while NOB1 was upregulated in osteosarcoma clinical tissue specimens and cell lines as compared with the adjacent normal tissue specimens and normal cell line. The miR-363 is reversely correlated with the expression of NOB1 in osteosarcoma tissues. Overexpression of miR-363 suppressed the ability of cell migration, invasion, and EMT, whereas low expression of miR-363 promoted this ability. In addition, miR-363 inhibited osteosarcoma proliferation both in vitro and in vivo and inhibited the apoptosis in MG63 cells. Interference of NOB1 could inhibit the migration, invasion, and EMT of osteosarcoma cell line MG63. NOB1 was verified to be a direct target of miR-363 and its expression was mediated by miR-363. Re-expression of NOB1 could partially reverse the inhibitory effect of miR-363 on cell migration and invasion. In addition, low expression of miR-363 or overexpression of NOB1 predicted poor prognosis of osteosarcoma patients. Conclusion MiR-363 inhibited osteosarcoma the proliferation, migration, invasion, and EMT and induced the apoptosis by directly targeting NOB1 in MG63 cells. The newly identified miR-363/NOB1 axis provides novel insights into the pathogenesis of osteosarcoma.

Abstract Background The development of somatic reprogramming, especially purely chemical reprogramming, has significantly advanced biological research. And chemical-induced extraembryonic endoderm-like (ciXEN) cells have been confirmed to be an indispensable intermediate stage of chemical reprogramming. They resemble extraembryonic endoderm (XEN) cells in terms of transcriptome, reprogramming potential, and developmental ability in vivo. However, the other characteristics of ciXEN cells and the effects of chemicals and bFGF on the in vitro culture of ciXEN cells have not been systematically reported. Methods Chemicals and bFGF in combination with Matrigel were used to induce the generation of ciXEN cells derived from mouse embryonic fibroblasts (MEFs). RNA sequencing was utilised to examine the transcriptome of ciXEN cells, and PCR/qPCR assays were performed to evaluate the mRNA levels of the genes involved in this study. Hepatic functions were investigated by periodic acid-Schiff staining and indocyanine green assay. Lactate production, ATP detection, and extracellular metabolic flux analysis were used to analyse the energy metabolism of ciXEN cells. Results ciXEN cells expressed XEN-related genes, exhibited high proliferative capacity, had the ability to differentiate into visceral endoderm in vitro, and possessed the plasticity allowing for their differentiation into induced hepatocytes (iHeps). Additionally, the upregulated biological processes of ciXEN cells compared to those in MEFs focused on metabolism, but their energy production was independent of glycolysis. Furthermore, without the cocktail of chemicals and bFGF, which are indispensable for the generation of ciXEN cells, induced XEN (iXEN) cells remained the expression of XEN markers, the high proliferative capacity, and the plasticity to differentiate into iHeps in vitro. Conclusions ciXEN cells had high plasticity, and energy metabolism was reconstructed during chemical reprogramming, but it did not change from aerobic oxidation to glycolysis. And the cocktail of chemicals and bFGF were non-essential for the in vitro culture of ciXEN cells.

Abstract Objective In this study, Mendelian randomization method was used to determine whether there was a causal association between inflammatory cytokine IL-18 and cardiovascular disease risk. Methods We performed a meta-analysis to evaluate the association between IL-18-137G/C and -607C/A polymorphisms and phenotype of IL-18 levels, and also the risks of CVD. All the literatures were searched before September 30, 2019. The logistic regression and linear regression were used to evaluate between IL-18 level and the risk of CVDs. Result Twelve eligible articles of the association between IL-18-137G/C and CVD risks and 8 eligible literatures related to IL-18-607C/A and CVD risks; 2 qualified literatures of the association between IL-18 SNPs and IL-18 levels and 4 eligible literatures related to IL-18 levels and CVD risks. Data of 4 literatures on the correlation between IL-18 level and CVD were summarized. Compared with patients with CVD, the mean of IL-18 level in the normal group was significantly decreased by 50.844 pg/ml (P 0.05), and the association between IL-18-607C/A and IL-18 level was also not significant (P > 0.05), Mendelian randomization study was failed to prove the association between IL-18 level and CVD risk. Conclusion This study does not support a causal association between IL-18 level and the risks of CVD.

Objective: To explore the role of cyclophilin A (CyPA) in sensitization of lung adenocarcinoma to radiotherapy using CRISPR/Cas9 technology. Methods: A CyPA knockout human lung adenocarcinoma cell line H1975 was established by CRISPR/Cas9 technology. Groups included a control group (wildtype), CyPA knockout group, traditional Chinese medicine (TCM) extract with Fuzhengzengxiao decoction group, and TCM extract with Fuzhengzengxiao decoction + CyPA knockout group. Each group was exposed to radiation at doses of 0, 2, 4, 6, and 8 Gy. After 24 h, MTT assays were used to determine the survival rate of lung cancer cells and calculate radiosensitivity. The qPCR was used to measure mRNA expression of DDIT3, CDKN1A, and CDC25A associated with DNA damage repair. Results: Without irradiation, Fuzhengzengxiao decoction reduced the survival rate of lung adenocarcinoma cells (P

Abstract Long noncoding RNAs (lncRNAs) are essential regulators of gene expression and biological behaviors. However, the contribution of lncRNA LUCAT1 to choroidal melanoma (CM) remains unexplored. Here, we examined the expression of LUCAT1 in CM cells by qRT‐PCR and investigated its biological effects by cell counting kit‐8, EdU, TUNEL, transwell assays, and Western blot. Bioinformatics tools were applied to find RNA candidates for further study. Moreover, mechanistic experiments including RNA immunoprecipitation assay, pull‐down assay, and luciferase reporter assay confirmed the relation or interaction among the indicated molecules. Here, we reported ELF1 as the transcription activator of LUCAT1. Functionally, elevated expression of LUCAT1 positively regulated CM cell proliferation, metastasis, and epithelial‐mesenchymal transition process. In addition, we verified the competing endogenous RNA (ceRNA) hypothesis of LUCAT1 and confirmed LUCAT1 modulates CM progression by modulating miR‐514a/b‐3p/RBX1 axis. Meanwhile, miR‐514a/b‐3p was suggested to repress CM progression, whereas RBX1 was unmasked to aggravate CM development. Of note, RBX1 overexpression rescued the inhibitory effect of LUCAT1 silence on the biological processes of CM cells. Altogether, this study unveiled the modulation axis ELF1/LUCAT1/miR‐514a/b‐3p/RBX1 and evidenced LUCAT1 as a promoter in CM for the first time, providing a novel insight into future treatment of CM.

This study investigated the role of ErbB4, the schizophrenia susceptibility gene, in synaptogenesis and synaptic transmission and its association with the pathogenesis of schizophrenia. We found that there was no significant difference in the size of inhibitory synapsin Gephyrin clusters in the dendrites of gamma-aminobutyric acid (GABA) neurons in the cultured cortex of ErbB4 knockout (ErbB4−/−) mice and ErbB4+/+ mice. The density and area of PSD-95 clusters in GABA-labelled neurons were not significantly different from those in the control group (p > 0.05). Specific pIkBα labelling of the pyramidal neurons and the axon initiation segments showed that the number of neuronal dendrites and the inhibitory postsynaptic proteins Gephyrin in the ErbB4 knockout group were significantly lower than those in the control group, whereas the size of the Gephyrin cluster remained unchanged. The number and area of the VGAT clusters on the somaclonal and axonal surfaces of the pyramidal neurons were also similar. ErbB4 knockout influenced excitatory synapses in intermediate neuronal cells and inhibitory synapses in pyramidal neurons, however, did not affect the inhibitory synapses in intermediate neuronal cells and excitatory synapses in pyramidal neurons. The number and area of PSD-95 clusters on the neuronal surface were significantly lower than those of the 1NMPP1 group, but the number and area of Gephyrin clusters on the neuronal surface were not changed (p > 0.05). These findings demonstrated that ErbB4 gene had no effect on the inhibitory synapses in interneurons and the excitatory synapses in pyramidal neurons.

Objectives: Inflammation is an important predisposing and progressive factor in chronic kidney disease (CKD). Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is associated with many fundamental cellular processes, but in chronic inflammatory pathologies remains unclear. Methods: An in vitro peripheral inflammation model was established using lipopolysaccharide (LPS)-stimulated mouse RAW264.7 macrophages, followed by inflammasome activation by ATP treatment. Knockdown of hnRNPK by sihnRNPK and FLICE-like inhibitory protein (FLIP) by siFLIP transfection were achieved in Raw264.7 macrophages. ELISA was used to determine the expression of IL-1β, IL-18 and TNF-α. Real time PCR was applied to detect the mRNA levels of hnRNPK, NOD-like receptors family pyrin domain-containing 3 (NLRP3), FLIP, Caspase-1, IL-1β and IL-18. Western blot and immunofluorescence were performed to detect relevant protein expressions. Co-immunoprecipitation (Co-IP) was used to assess the interaction of hnRNPK with FLIP. Results: Results showed that LPS plus ATP activated NLRP3 inflammasome, which evidenced by the up-regulation of TNF-α, IL-1β and IL-18. Notably, hnRNPK and FLIP were significantly up-regulated in activated NLRP3 inflammasome of macrophages. HnRNPK or FLIP knockdown significantly suppressed the activation of NLRP3 inflammasome, as reflected by down-regulation of Caspase-1, IL-1β and IL-18. Importantly, hnRNPK could directly bind to FLIP in activated NLRP3 inflammasome. Discussion: Our findings suggest that hnRNPK could promote the activation of NLRP3 inflammasome by directly binding FLIP, which might provide potential new therapeutic targets for CKD.

Abstract Background Proteus syndrome (PS) is an extremely rare disease characterized by excessive chimeric growth of cells, and progressive and irregular asymmetrical hyperplasia. Case presentation Herein, a PS case with atypical clinical features and syndromes was reported, to improve the understanding of the diagnosis and treatment of the disease. The case was a 3-year-and-11-month-old male child. He was admitted due to a primary diagnosis of McCune-Albright syndrome. After admission, the lesion samples from the milk coffee spots, and nodular thickening skin at hands and feet were subjected to genetic screening. Genetic testing results confirmed the diagnosis of PS. Conclusions Based on the clinical manifestations, laboratory tests, imaging data, and literature reviewing, the etiology, diagnosis, treatment and prognosis of PS have been analyzed and discussed.

Abstract Background This retrospective clinical study is to evaluate the safety and efficiency of two different approaches in retroperitoneal laparoscopic adrenalectomy and provide experience and basis for the treatment of adrenal tumors through retroperitoneal approach. Methods From July 2015 to February 2018, 112 patients with adrenal lesions underwent retroperitoneal laparoscopic adrenalectomy (RLA) using a 3-port method. Among them, 56 patients underwent RLA via the extra perinephric fat approach (EPFA), 56 patients underwent RLA via the intra perinephric fat approach (IPFA). Clinical data, including preoperative, operative and postoperative management were recorded. Results All surgeries were successfully completed, and there was no single patient who died during these surgeries. There was no statistically significant difference between the two groups in blood loss, postoperative complications, vena cava injury, renal cortex injury, peripheral organ injury, and post operation hospital stay. Peritoneum injury occurred more frequently in the EPFA group when compared with the IPEA group (p = 0.042). The average surgery time of the IPEA group is significantly shorter when compared with that of the EPEA group (p

Abstract Background To describe the pathological distribution, imaging manifestations, and surgical managements and prognosis of large adrenal tumors (LATs) ≥ 5 cm Methods A total of 251 patients with LATs were analyzed on the basis of pathological or clinical diagnosis. Regarding surgery, open adrenalectomy was performed on 89 patients, and laparoscopic adrenalectomy was performed on 89 patients. Thirty-two patients with bilateral tumors were analyzed in terms of clinical characteristics. The survival rate was determined for 43 patients with adrenal metastases and 29 patients with primary adrenal malignancies. The CT characteristics including tumor diameter, shape, edge, heterogeneity, necrosis, calcification, pre-contrast attenuation, and contrast attenuation were analyzed for 117 patients. Results The majority of LATs were still benign, but they had a higher probability to be malignant. Benign LATs made up 68.13% of all cases, mainly adrenal cysts (19.52%), pheochromocytoma (18.73%), benign adenoma (16.73%), and myelolipoma (7.17%). Malignant LATs accounted for 28.69% of cases, mainly including adrenocortical carcinoma (8.76%) and metastases (17.13%). Laparoscopic surgery was found to involve less trauma than open surgery. It was also safer and postoperative recovery was faster, but it had drawbacks and could not completely replace open surgery. CT features had obvious specificity for the diagnosis of benign and malignant tumors. For example, benign adenomas had a smaller pre-contrast (

Abstract Background Schizophrenia is a complex psychiatric disorder with unknown etiology. A number of recent studies have shown that the polymorphism of the neural precursor cell expressed developmentally down-regulated 4 (NEDD4) gene is associated with a variety of neuropsychiatric disorders, such as schizophrenia, and may also be associated with cognitive dysfunction in these diseases. Methods A case-control study was carried out, the alleles and genotypes distributions of five loci (rs3088077, rs2303579, rs7162435, rs11550869, rs62043855) of the NEDD4 gene from 296 schizophrenia patients and 320 healthy controls were detected by using Taqman single-nucleotide polymorphism (SNP) genotyping technology. The clinical data of case and control group members were collected by self-made questionnaire and the psychotic symptoms of case group members were assessed by the Positive and Negative Syndrome Scale (PANSS). The Matrics Consensus Cognitive Battery (MCCB) was used to test the cognitive function of case group members. Results The alleles and genotypes frequency of two loci (rs3088077, rs2303579) between case and control group showed significant differences (P

Background: The present study aimed to systematically evaluate three prolactin-sparing antipsychotics for treating schizophrenia. Methods: We performed a meta-analysis of three prolactin-sparing antipsychotics in patients with schizophrenia. Endpoints of interest were the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions-Severity (CGI-S) and acceptability (all cause discontinuation). Results: A total of 12 trials (2,723 patients) and three drugs (aripiprazole, quetiapine, and ziprasidone) were included. On the PANSS scale, aripiprazole (mean difference [MD]: −6.98, 95% CrI: −12.35, −1.38) was statistically more effective than placebo. When assessed by BPRS, aripiprazole (MD: −9.01, 95% CrI: −15.81, −3.12), quetiapine (MD: −7.13, 95% CrI: −9.78, −4.29) and ziprasidone (MD: −4.97, 95% CrI: 9.96, −0.21) had greater efficacy, when compared to placebo. Regarding CGI-S, quetiapine (MD: −0.55, 95% CrI: −0.82, −0.25) was significantly superior to placebo. In terms of acceptability, aripiprazole (OR: 0.54, 95% CrI: 0.41, 0.73), quetiapine (OR: 0.49, 95% CrI: 0.36, 0.68) and ziprasidone (OR: 0.68, 95% CrI: 0.48, 0.96) were more acceptable than placebo. The benefit risk analysis revealed that quetiapine has the best efficacy and acceptability profile among the three prolactin-sparing antipsychotics. Conclusions: Quetiapine may offer an optimal benefit-risk balance when a prolactin-sparing antipsychotic is indicated.

We evaluated the efficacy of three vaccine formulations containing different combinations of proteins (43K OMP, leukotoxin recombinant protein PL4 and hemolysin recombinant protein H2) and killed whole cell Fusobacterium necrophorum in preventing liver abscess. Four subcutaneous vaccines were formulated: vaccine 1 (43K OMP), vaccine 2 (PL4 and H2), vaccine 3 (43K OMP, PL4 and H2), and vaccine 4 (killed whole bacterial cell). 43K OMP, PL4, and H2 proteins were produced by using recombinant protein expression. To evaluate vaccine efficacy, we randomly allocated 50 BALB/c female mice to one of five different treatment groups: PBS control group, vaccine 1, vaccine 2, vaccine 3, and vaccine 4. Mice were vaccinated three times, with 14 days between each immunization. After immunization, the mice were challenged with F. necrophorum. The three key findings of this study are as follows: (1) Vaccine 3 has enabled mice to produce higher antibody titer following bacterial challenge, (2) in the liver pathology of mice, the vaccine 3 liver showed the least pathology, and (3) all four vaccines produced high levels of antibodies and cytokines in mice, but the level of vaccine 3 was the highest. Based on our results, it has been demonstrated that a mixture of F. necrophorum 43K OMP, PL4, and H2 proteins inoculated with mice can achieve protection against liver abscess in mice. Our research may therefore provide the basis for the development of a vaccine against F. necrophorum bovine infections.

Inflammatory bowel disease (IBD), characterized by the chronic inflammation of the gastrointestinal tract, is comprised of two idiopathic chronic intestinal inflammatory diseases. As the incidence of IBD increases, so does the need for safe and effective treatments. Trillions of microorganisms are colonized in the mammalian intestine, coevolve with the host in a symbiotic relationship. Gut microbiota has been reported to be involved in the pathophysiology of IBD. In this regard, phytonutrients flavonoids have received increasing attention for their anti-oxidant and anti-inflammatory activities. In this review, we address recent advances in the interactions among flavonoids, gut microbiota, and IBD. Moreover, their possible potential mechanisms of action in IBD have been discussed. We conclude that there is a complex interaction between flavonoids and gut microbiota. It is expected that flavonoids can change or reshape the gut microbiota to provide important considerations for developing treatments for IBD.

Severe episodic air pollution blankets entire cities and regions and have a profound impact on humans and their activities. We compiled daily fine particle (PM2.5) data from 100 cities in five continents, investigated the trends of number, frequency, and duration of pollution episodes, and compared these with the baseline trend in air pollution. We showed that the factors contributing to these events are complex; however, long-term measures to abate emissions from all anthropogenic sources at all times is also the most efficient way to reduce the occurrence of severe air pollution events. In the short term, accurate forecasting systems of such events based on the meteorological conditions favouring their occurrence, together with effective emergency mitigation of anthropogenic sources, may lessen their magnitude and/or duration. However, there is no clear way of preventing events caused by natural sources affected by climate change, such as wildfires and desert dust outbreaks.

Objective Inflammation is an important factor in the pathological process of cerebral ischemia. Artesunate exhibits a broad range of anti-inflammatory properties in many diseases. We investigated the potential protective effect of artesunate against cerebral ischemia and the related mechanisms. Methods Mice were divided into distal middle cerebral artery occlusion (dMCAO), sham, low dose, and high dose groups and subjected to dMCAO, except for the sham group. The low and high dose groups were administered artesunate (15 and 30 mg/kg), and the neuroprotective effects were analyzed by evaluating infarct volumes and neurological deficits. Microglial activation and neutrophil infiltration were evaluated by immunofluorescence, immunohistochemical staining, and western blotting. Inflammatory mediators were measured by enzyme-linked immunosorbent assays. Nuclear factor (NF)-κB nuclear translocation was detected by immunofluorescence and western blotting. Results Compared with the dMCAO group, artesunate significantly improved neurological deficit scores and infarct volumes and ameliorated inflammation by reducing neutrophil infiltration, suppressing microglial activation, and downregulating tumor necrosis factor-α and interleukin-1β expression. Furthermore, artesunate inhibited nuclear translocation of NF-κB and inhibitor protein α proteolysis. Conclusions Artesunate protected against inflammatory injury by reducing neutrophil infiltration and microglial activation, suppressing inflammatory cytokines, and inhibiting the NF-κB pathway. Therefore, artesunate is a potential ischemic stroke treatment.

Although many studies have suggested that widowhood is related to worse health conditions among older adults, few have examined the mediation effects of social support between widowhood and health. Employing mediation analysis to a sample of data from the 2014 wave of China Longitudinal Aging Social Survey (CLASS), this study examined the mediation effects of social support, including emotional support, instrumental support, and companionship, in the widowhood-health association among older adults. The results indicated that the negative effect of widowhood on older adults' health was in part attributable to decreased emotional support and companionship. Specifically, emotional support exerted a significant role in the widowhood-mental health association, and companionship exerted a significant role in widowhood-physical health and widowhood-mental health associations. In the subsample analysis, the mediation effects were only significant among female older adults, and among rural older adults. Our findings highlight the importance of emotional support and companionship in maintaining health among widowed older adults and strategies should pay more attention to female and rural widowed older adults.

Backgroundm6A-related lncRNAs emerged as potential targets for tumor diagnosis and treatment. This study aimed to identify m6A-regulated lncRNAs in lung squamous cell carcinoma (LUSC) patients.Materials and MethodsRNA sequencing and the clinical data of LUSC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The m6A-related lncRNAs were identified by using Pearson correlation assay. Univariate and multivariate Cox regression analyses were utilized to construct a risk model. The performance of the risk model was validated using Kaplan–Meier survival analysis and receiver operating characteristics (ROC). Immune estimation of LUSC was downloaded from TIMER, and the correlations between the risk score and various immune cells infiltration were analyzed using various methods. Differences in immune functions and expression of immune checkpoint inhibitors and m6A regulators between high-risk and low-risk groups were further explored. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were utilized to explore the biological functions of AL122125.1.ResultsA total of 351 m6A-related lncRNAs were obtained from TCGA. Seven lncRNAs demonstrated prognostic values. A further multivariate Cox regression assay constructed a risk model consisting of two lncRNAs (AL122125.1 and HORMAD2-AS1). The Kaplan–Meier analysis and area under the curve indicated that this risk model could be used to predict the prognosis of LUSC patients. The m6A-related lncRNAs were immune-associated. There were significant correlations between risk score and immune cell infiltration, immune functions, and expression of immune checkpoint inhibitors. Meanwhile, there were significant differences in the expression of m6A regulators between the high- and low-risk groups. Moreover, GO and KEGG analyses revealed that the upregulated expression of AL122125.1 was tumor-related.ConclusionIn this study, we constructed an m6A-related lncRNA risk model to predict the survival of LUSC patients. This study could provide a novel insight to the prognosis and treatment of LUSC patients.

Appetite is the basis for obtaining food and maintaining normal metabolism. Toll-like receptor 4 (TLR4) is an important receptor expressed in the brain that induces inflammatory signaling after activation. Inflammation is considered to affect the homeostatic and non-homeostatic systems of appetite, which are dominated by hypothalamic and mesolimbic dopamine signaling. Although the pathological features of many types of inflammation are known, their physiological functions in appetite are largely unknown. This review mainly addresses several key issues, including the structures of the homeostatic and non-homeostatic systems. In addition, the mechanism by which TLR4-induced inflammatory signaling contributes to these two systems to regulate appetite is also discussed. This review will provide potential opportunities to develop new therapeutic interventions that control appetite under inflammatory conditions.

Background In Western developed countries, food-based dietary patterns have been associated with the risk of cardiometabolic diseases, but little is known about such associations in less developed ethnic minority regions (LEMRs), where the cardiometabolic disease burden is growing rapidly and food patterns differ substantially.Methods Between May 2018 and September 2019, we recruited 99556 participants aged 30-79 years from the China Multi-Ethnic Cohort (CMEC) Study. We measured habitual dietary intake with validated food frequency questionnaire (FFQ) and then calculated dietary pattern scores for two of the most studied a priori dietary patterns, i.e., Dietary Approaches to Stop Hypertension (DASH) and alternative Mediterranean (aMED) style diets, and three a posteriori dietary patterns. Four cardiometabolic risks, including hypertension, diabetes, dyslipidaemia and metabolic syndrome (MetS), were newly diagnosed by medical examination and blood tests. We estimated adjusted odds ratios (OR) relating various dietary pattern scores to cardiometabolic risks using marginal structural models under the guidance of directed acyclic graphs. For the above associations, we further calculated the proportion mediated by overweight (PM) using regression-based mediation analysis for better public health implications.Findings The final study sample consisted of 68834 participants. Among them, we newly diagnosed 12803 hypertension, 3527 diabetes, 16342 hyperlipidaemia, and 8198 MetS cases. Overall, all 5 dietary patterns showed considerable associations with risks of hypertension and MetS. Comparing the highest with the lowest quintiles, the DASH score showed the strongest inverse associations with risks of hypertension (OR=0.74, 95% CI:0.70-0.79; PM=10%) and MetS (OR=0.79, 95% CI:0.74-0.85; PM=35%); conversely, scores of the localized a posteriori Yunnan-Guizhou plateau dietary pattern in LEMRs showed the strongest positive associations with risks of hypertension (OR=1.44, 95% CI:1.35-1.52; PM=10%) and MetS (OR=1.35, 95% CI:1.26-1.46; PM=33%), with all P values for trend

Objective: The purpose of this review was to evaluate the effect of exercise therapy on anxiety and depression symptoms in patients with coronary heart disease (CHD).Methods: A systematic review of papers published between January 2000 and February 2021 was conducted. MEDLINE, Embase, the Cochrane Library and Web of Science were searched. Meta-analysis was used to compare the results of the included studies. Bias risk assessment was performed using the Cochrane Collaboration bias risk tool. If half or more of the seven items in Randomized controlled trials (RCTs) were low-risk, then the RCT was considered low-risk research; otherwise, it was high-risk. Statistical analyses were performed using RevMan version 5.3 and STATA version 12.0.Results: We performed a meta-analysis of 11 randomized clinical studies including 771 subjects. Eight studies (73%) were of high quality. Compared with the control group, the exercise group showed a significant improvement in anxiety [standard mean difference (SMD) = −0.61; 95% confidence interval (CI): −0.86, −0.35]. The depression level in the exercise group was also significantly reduced (SMD = −0.48; 95% CI: −0.92, −0.04). Aerobic fitness and athletic endurance also improved [mean difference (MD) = 0.77; 95% CI: 0.58, 0.95; and MD = 20.69; 95% CI: 6.91, 34.46; respectively].Conclusions: This meta-analysis suggests that exercise therapy may be effective in alleviating anxiety and depression symptoms in patients with coronary heart disease. Due to methodological weaknesses, rigorous research needs to be designed to further confirm the effectiveness of exercise therapy in improving the mental health of patients with coronary heart disease.Systematic Review Registration:https://inplasy.com/projects/, identifier: INPLASY202160017.

Binary code similarity measurement is a popular research area in binary analysis with the recent development of deep learning-based models. Current state-of-the-art methods often use the pre-trained language model (PTLM) to embed instructions into basic blocks as representations of nodes within a control flow graph (CFG). These methods will then use the graph neural network (GNN) to embed the whole CFG and measure the binary similarities between these code embeddings. However, these methods almost directly treat the assembly code as a natural language text and ignore its code-specific features when training PTLM. Moreover, They barely consider the direction of edges in the CFG or consider it less efficient. The weaknesses of the above approaches may limit the performances of previous methods. In this paper, we propose a novel method called function similarity using code-specific PPTs and order-sensitive GNN (FUSION). Since the similarity of binary codes is a symmetric/asymmetric problem, we were guided by the ideas of symmetry and asymmetry in our research. They measure the binary function similarity with two code-specific PTLM training strategies and an order-sensitive GNN, which, respectively, alleviate the aforementioned weaknesses. FUSION outperforms the state-of-the-art binary similarity methods by up to 5.4% in accuracy, and performs significantly better.

Diabetes, hypertension, and comorbidity are still crucial public health challenges that Bangladeshis face. Nonetheless, very few studies have been conducted to examine the associated factors, especially the socioeconomic inequalities in diabetes, hypertension, and comorbidity in Bangladesh. This study explored the prevalence of, factors connected with, and socioeconomic inequalities in diabetes, hypertension, and comorbidity among Bangladeshi adults. We used the Bangladesh Demographic and Health Survey (BDHS) data set of 2017–2018. A total of 12,136 (weighted) Bangladeshi adults with a mean age of 39.5 years (±16.2) participated in this study. Multilevel (mixed-effect) logistic regression analysis was employed to ascertain the determinants of diabetes, hypertension, and comorbidity, where clusters were considered as a level-2 factor. The concentration curve (CC) and concentration index (CIX) were utilized to investigate the inequalities in diabetes, hypertension, and comorbidity. The weighted prevalence of diabetes, hypertension, and comorbidity was 10.04%, 25.70%, and 4.47%, respectively. Age, body mass index, physical activity, household wealth status, and diverse administrative divisions were significantly associated with diabetes, hypertension, and comorbidity among the participants. Moreover, participants’ smoking statuses were associated with hypertension. Women were more prone to hypertension and comorbidity than men. Diabetes (CIX: 0.251, p < 0.001), hypertension (CIX: 0.071, p < 0.001), and comorbidity (CIX: 0.340, p < 0.001) were higher among high household wealth groups. A pro-wealth disparity in diabetes, hypertension, and comorbidity was found. These inequalities in diabetes, hypertension, and comorbidity emphasize the necessity of designing intervention schemes geared towards addressing the rising burden of these diseases.

Flexible strain sensor as a measurement tool plays a significant role in agricultural development by long-term stable monitoring of the dynamic progress of plant growth. However, existing strain sensors still suffer from severe drawbacks, such as large hysteresis, insufficient fatigue resistance, and inferior stability, limiting their broad applications in the long-term monitoring of plant growth. Herein, we fabricate a novel conductive hydrogel strain sensor which is achieved through uniformly dispersing the conductive activated charcoal (AC) in high-viscosity polyvinyl alcohol (PVA) solution forming a continuous conductive network and simple preparation by freezing-thawing. The as-prepared strain sensor demonstrates low hysteresis (−2), and long-term sensing stability upon mechanical cycling. We further exhibit the integration and application of PVA-AC strain sensor to monitor the growth of plants for 14 days. This work may offer an effective strategy for monitoring plant growth with conductive hydrogel strain sensor, facilitating the advancement of agriculture.

The production of cucumber (Cucumis sativus L.) is often harmed by biotic and abiotic stresses. Although the dehydration-responsive element-binding (DREB) transcription factors, playing vital roles in stress responses, have been characterized in several plant species, little is known about the pan-genome characteristics of DREB genes and their expression patterns under different stresses in cucumber. In this study, we identified 55 CsDREBs from the cucumber pan-genomes of 13 accessions, but only four accessions had all the genes. Most of the CsDREB proteins had sequence length and/or amino acid variations, and only four of them had no variation among different accessions. Using the 55 CsDREBs from ‘9930’, we analyzed their gene structures, conserved domains, phylogenetic relationships, gene promoter’s cis-elements and syntenic relationships, and classified them into six groups. Expression pattern analysis revealed that eight CsDREBs showed constitutive expression (FPKM > 1 in all samples), and different CsDREBs showed specifically high expression in root, stem, leaf, tendril, male-flower, female flower, and ovary, respectively, suggesting that these genes might be important for morphogenesis and development in cucumber. Additionally, a total of 31, 22, 30 and nine CsDREBs were differentially expressed in responding to the treatments of heat, NaCl and/or silicon, power mildew and downy mildew, respectively. Interestingly, CsDREB33 could respond to all the tested stresses. Our results provide a reference and basis for further investigation of the function and mechanism of the DREB genes for resistance breeding in cucumber.

The poor operational stability of electrolytes is a persistent impediment in building redox flow battery technology; choosing suitable stability additives is usually the research direction to solve this problem. The effects of five phosphate containing additives (including 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP), hexamethylene diamine tetramethylene phosphonic acid (HDTMPA), amino trimethylene phosphonic acid (ATMPA), sodium ethylenediamine tetramethylene phosphonate (EDTMPS), and diethyl triamine pentamethylene phosphonic acid (DTPMP)) on the thermal stability and electrochemical performance of the positive electrolyte of vanadium redox flow battery were investigated. With 0.5 wt% addition, most of the selected additives were able to improve the thermal stability of the electrolyte. HEDP and HDTMPA extended the stability time of the pentavalent vanadium electrolyte at 50 °C from 5 days (blank sample) to 30 days and 15 days, respectively. The electrochemical performance of the electrolyte was further investigated by cyclic voltammetry, steady state polarization, and electrochemical impedance spectroscopy tests. It was found that most of the additives enhanced the electrochemical activity of the positive electrolyte, and the diffusion coefficients, exchange current densities, and reaction rate constants of V(IV) species became larger with the addition of these additives. It is verified that the thermal stability and electrochemical stability of the electrolyte are significantly improved by the combination of ATMPA + HEDP or ATMPA + HDTMPA. This study provides a new approach to improve the stability of the positive electrolyte for vanadium redox flow battery.

This study aimed to compare tilapia fish cake drying and sterilization conditions (105, 115, and 121 °C) on the quality of the cakes. The impacts of volatile flavor substances, the chroma value, quality and structure characteristics, microscopic structure, and the types and content of volatile flavor substances were also analyzed. The results showed that after drying and sterilization, the L* value, W value and delta-E value of fish cakes decreased significantly from 77.12 to 64.77, 66.21 to 52.57, 10.46 to 24.50, respectively. However, a* value and b* value increased significantly from 0.30 to 6.97 and 24.85 to 30.89, respectively. The elasticity, hardness, and chewiness increased significantly with the drying process but decreased significantly with the increased sterilization temperature. Scanning electron microscopy results showed that the internal pores of the fish cakes became smaller, and the tissue structure was closer after drying. Gas chromatography—ion mobile spectrometry analysis identified a total of 36 volatile flavor compounds. Among these, ketones comprised the largest content, aldehydes represented the largest variety, and all volatile compounds contributed significantly to the flavor of fish cake. PCA results and nearest-neighbor fingerprint analysis showed that there were obvious differences in volatile flavor compounds between different treatments. In summary, this study conducted a detailed comparative analysis of the quality and flavor of fish cakes subjected to different processing methods. These findings contribute suggestions for sterilization temperatures in industrial production processes.

Eimeria species are intracellular parasites residing inside the intestinal epithelial cell, which cause poultry coccidiosis and result in significant financial losses in the poultry industry. Genome editing of Eimeria is of immense importance for the development of vaccines and drugs. CRISPR/Cas9 has been utilized for manipulating the genome of Eimeria tenella (E. tenella). Ectopic expression of Cas9, i.e., via plasmids, would introduce transgene, which substantially limits its application, especially for vaccine development. In this study, we initially optimized the condition of the transfection protocol. We demonstrated that with the optimized condition, the transfection of FnCas12a (also known as “FnCpf1”) protein and crRNA targeting EtHistone H4 triggered DNA double-strand breaks in vivo. We then used this strategy to knock-in a coding cassette for an enhanced yellow fluorescent protein (EYFP) and dihydrofolate reductase–thymidylate synthase gene (DHFR) as a selection marker to tag endogenous EtActin. The engineered E. tenella parasite possesses EYFP expression in its entire life cycle. Our results demonstrated that FnCas12a could trigger genome editing in E. tenella, which augments the applicability of the dissection of gene function and the development of anticoccidial drugs and vaccines for Eimeria species.

Objective: Birth weight, an important indicator of fetal nutrition and degree of development, may affect the risk of subsequent leukemia. At present, little is known about the effect of birth weight on acute myeloid leukemia (AML) and whether there is a dose-dependent relationship of birth weight with acute lymphoid leukemia (ALL) and AML. To address these questions, the present work aimed to systematically investigate the relationship between birth weight and the risk of subsequent leukemia based on the current epidemiological studiesMethods: Relevant studies were systematically retrieved from electronic databases PubMed, Embase, and Cochrane Library, from inception to May 15th, 2021. Finally, 28 studies (including 21 case-control studies and 7 cohort studies) were included for the final meta-analysis. Results in cohort studies were performed by risk ratios (RRs), while those in case-control studies by odds ratios (ORs), and all results were assessed by adopting the random-effect model. Besides, a dose-dependent analysis was conducted based on the cohort studies.Results: Compared with the population with normal birth weight (NBW), the population with high birth weight (HBW) might have an increased risk of leukemia (OR 1.33, 95%CI 1.20–1.49; I2 0%). Meanwhile, low birth weight (LBW) was associated with a decreased risk of ALL, as evidenced from the pooled analysis of case-control studies (OR 0.83, 95% CI 0.75–0.92; I2 23.3%). However, relative to NBW population, the HBW population might have an increased risk of ALL (OR 1.28, 95% CI 1.20–1.35; I2 7%). There was no obvious evidence supporting the relationship between LBW and the risk of AML from the pooled analysis of case-control studies (OR, 1.11 95% CI 0.87–1.42; I2 31.7%).Conclusions: Overall, in children and young adults, HBW population may be associated with the risks of subsequent leukemia and AML relative to NBW population, but the supporting dose-dependent evidence is lacking. In addition, compared with NBW population, there is stronger evidence supporting a significantly increased risk of subsequent ALL in HBW population, and a decreased risk in LBW population in a dose-dependent manner. More prospective studies with large samples are warranted in the future to validate and complement these findings.

Sepsis, a pathology resulting from excessive inflammatory response that leads to multiple organ failure, is a major cause of mortality in intensive care units. Macrophages play an important role in the pathophysiology of sepsis. Accumulating evidence has suggested an upregulated rate of aerobic glycolysis as a key common feature of activated proinflammatory macrophages. Here, we identified a crucial role of myeloid 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3), a glycolytic activator in lipopolysaccharide (LPS)-induced endotoxemia in mice. Pfkfb3 expression is substantially increased in bone marrow derived macrophages (BMDMs) treated with LPS in vitro and in lung macrophages of mice challenged with LPS in vivo. Myeloid-specific knockout of Pfkfb3 in mice protects against LPS-induced lung edema, cardiac dysfunction and hypotension, which were associated with decreased expression of interleukin 1 beta (Il1b), interleukin 6 (Il6) and nitric oxide synthase 2 (Nos2), as well as reduced infiltration of neutrophils and macrophages in lung tissue. Pfkfb3 ablation in cultured macrophages attenuated LPS-induced glycolytic flux, resulting in a decrease in proinflammatory gene expression. Mechanistically, Pfkfb3 ablation or inhibition with a Pfkfb3 inhibitor AZ26 suppresses LPS-induced proinflammatory gene expression via the NF-κB signaling pathway. In summary, our study reveals the critical role of Pfkfb3 in LPS-induced sepsis via reprogramming macrophage metabolism and regulating proinflammatory gene expression. Therefore, PFKFB3 is a potential target for the prevention and treatment of inflammatory diseases such as sepsis.

Autoreactive CD8+ T cells play an indispensable key role in the destruction of pancreatic islet β-cells and the initiation of type 1 diabetes (T1D). Insulin is an essential β-cell autoantigen in T1D. An HLA-A*0201-restricted epitope of insulin A chain (mInsA2-10) is an immunodominant ligand for autoreactive CD8+ T cells in NOD.β2mnull.HHD mice. Altered peptide ligands (APLs) carrying amino acid substitutions at T cell receptor (TCR) contact positions within an epitope are potential to modulate autoimmune responses via triggering altered TCR signaling. Here, we used a molecular simulation strategy to guide the generation of APL candidates by substitution of L-amino acids with D-amino acids at potential TCR contact residues (positions 4 and 6) of mInsA2-10, named mInsA2-10DQ4 and mInsA2-10DC6, respectively. We found that administration of mInsA2-10DQ4, but not DC6, significantly suppressed the development of T1D in NOD.β2mnull.HHD mice. Mechanistically, treatment with mInsA2-10DQ4 not only notably eliminated mInsA2-10 autoreactive CD8+ T cell responses but also prevented the infiltration of CD4+ T and CD8+ T cells, as well as the inflammatory responses in the pancreas of NOD.β2mnull.HHD mice. This study provides a new strategy for the development of APL vaccines for T1D prevention.

BackgroundThe pandemic of Coronavirus Disease 2019 (COVID-19) brings new challenges for pediatricians, especially in the differentiation with non-COVID-19 pneumonia in the peak season of pneumonia. We aimed to compare the clinical characteristics of pediatric patients with COVID-19 and other respiratory pathogens infected pneumonias.MethodsWe conducted a multi-center, cross-sectional study of pediatric inpatients in China. Based on pathogenic test results, pediatric patients were divided into three groups, including COVID-19 pneumonia group, Non-COVID-19 viral (NCV) pneumonia group and Non-viral (NV) pneumonia group. Their clinical characteristics were compared by Kruskal-Wallis H test or chi-square test.ResultsA total of 636 pediatric pneumonia inpatients, among which 87 in COVID-19 group, 194 in NCV group, and 355 in NV group, were included in analysis. Compared with NCV and NV patients, COVID-19 patients were older (median age 6.33, IQR 2.00-12.00 years), and relatively fewer COVID-19 patients presented fever (63.2%), cough (60.9%), shortness of breath (1.1%), and abnormal pulmonary auscultation (18.4%). The results were verified by the comparison of COVID-19, respiratory syncytial virus (RSV) and influenza A (IFA) pneumonia patients. Approximately 42.5%, 44.8%, and 12.6% of the COVID-19 patients presented simply ground-glass opacity (GGO), simply consolidation, and the both changes on computed tomography (CT) scans, respectively; the proportions were similar as those in NCV and NV group (p>0.05). Only 47.1% of COVID-19 patients had both lungs pneumonia, which was significantly lower than that proportion of nearly 80% in the other two groups. COVID-19 patients presented lower proportions of increased white blood cell count (16.5%) and abnormal procalcitonin (PCT) (10.7%), and a higher proportion of decreased lymphocyte count (44.0%) compared with the other two groups.ConclusionMajority clinical characteristics of pediatric COVID-19 pneumonia patients were milder than non-COVID-19 patients. However, lymphocytopenia remained a prominent feature of COVID-19 pediatric pneumonia.

Perineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus play an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.

Abstract Aim Heparin, a widely used antithrombotic drug has many other anticoagulant‐independent physiological functions. Here, we elucidate a novel role of heparin in glucose homeostasis, suggesting an approach for developing heparin‐targeted therapies for diabetes. Methods For serum heparin levels and correlation analysis, 122 volunteer’s plasma, DIO (4 weeks HFD) and db/db mice serums were collected and used for spectrophotometric determination. OGTT, ITT, 2‐NBDG uptake and muscle GLUT4 immunofluorescence were detected in chronic intraperitoneal injection of heparin or heparinase (16 days) and muscle‐specific loss‐of‐function mice. In 293T cells, the binding of insulin to its receptor was detected by fluorescence resonance energy transfer (FRET), Myc‐GLUT4‐mCherry plasmid was used in GLUT4 translocation. In vitro, C2C12 cells as mouse myoblast cells were further verified the effects of heparin on glucose homeostasis through 2‐NBDG uptake, Western blot and co‐immunoprecipitation. Results Serum concentrations of heparin are positively associated with blood glucose levels in humans and are significantly increased in diet‐induced and db/db obesity mouse models. Consistently, a chronic intraperitoneal injection of heparin results in hyperglycaemia, glucose intolerance and insulin resistance. These effects are independent of heparin’s anticoagulant function and associated with decreases in glucose uptake and translocation of glucose transporter type 4 (GLUT4) in skeletal muscle. By using a muscle‐specific loss‐of‐function mouse model, we further demonstrated that muscle GLUT4 is required for the detrimental effects of heparin on glucose homeostasis. Conclusions Heparin reduced insulin binding to its receptor by interacting with insulin and inhibited insulin‐mediated activation of the PI3K/Akt signalling pathway in skeletal muscle, which leads to impaired glucose uptake and hyperglycaemia.

The reinforcement and durability of loess are of great importance for road performance. In this study, a self-designed grouting system and newly permeable polymers were adopted to investigate the mechanical properties and durability of solidified loess (SL), considering different dry densities and water contents. The unconfined compression test and piezocone penetration (CPTU) test were used to examine the mechanical properties. The mechanism of the loess solidified by permeable polymer was analyzed from the micro-level by SEM, MIP, and XRD tests. The test results show that the effect of polymer grouting is obvious, the unconfined compressive strength (UCS) of the SL after grouting is as high as 3.05–5.42 MPa; it is 11.83–20.99 times that of unsolidified loess (UL). The UCS of the SL after grouting is inversely proportional to the dry densities and water contents. After 56 days of immersion, the SL still shows a high compressive strength. The additional erosion of the SL was not caused by the salt solution; the durability is significantly better than that of cement mixing soil. The sensitivity of various factors on the UCS of the SL are service environment > water content > dry density. The SEM tests clearly show that the gel formed by the reaction of the polymer with water on the surface of soil particles makes the bond of soil particles tighter. It can be observed from the MIP test that the cumulative mercury of SL was 0.115 mL/g, which was 33.72% of UL (0.341 mL/g), and the cumulative mercury of SL after immersion in water and salt solutions was 0.183 mL/g and 0.175 mL/g, which was 53.7% and 51.3% of UL (0.341 mL/g), respectively. The XRD results show that there are no other new mineral components produced after grouting and the spacing between crystalline planes decreases, which proves that permeable polymer grouting makes the soil denser and does not erode the soil particles.

Fruit shape, an important agronomic trait of cucumber (Cucumis sativus L.), is tightly controlled by a series of genes such as CsSUN, a homologue of SlSUN that is responsible for the tomato (Solanum lycopersicum) fruit shape via the modulation of cell division. However, the direct genetic evidence about the CsSUN-mediated regulation of fruit shape is still scarce, limiting our mechanistic understanding of the biological functions of CsSUN. Here, we introduced CsSUN into the round-fruited tomato inbred line ‘SN1′ (wild type, WT) via the Agrobacterium tumefaciens-mediated method. The high and constitutive expression of CsSUN was revealed by real-time PCR in all the tested tissues of the transgenic plants, especially in the fruits and ovaries. Phenotypic analyses showed that the ectopic expression of CsSUN increased fruit length while it decreased fruit diameter, thus leading to the enhanced fruit shape index in the transgenic tomato lines relative to the WT. Additionally, the reduction in the seed size and seed-setting rate and the stimulation of seed germination were observed in the CsSUN-expressed tomato. A histological survey demonstrated that the elongated fruits were mainly derived from the significant increasing of the longitudinal cell number, which compensated for the negative effects of decreased cell area in the central columellae. These observations are different from action mode of SlSUN, thus shedding new insights into the SUN-mediated regulation of fruit shape.

The authors studied the direct conversion of syngas to light paraffins in a dual-bed fixed-bed reactor. A dual-bed catalyst composed of three catalysts, a physically mixed methanol synthesis catalyst (CZA), and a methanol dehydration to dimethyl ether (DME) catalyst (Al2O3(C)) were put in the upper bed for direct conversion of syngas to DME, while the SAPO-34 (SP34-C) zeolite was put in the lower bed for methanol and DME conversion. The effects of the mass ratio of CZA to Al2O3(C), the H2/CO molar ratio, and the space velocity on catalytic performance of syngas to DME were studied in the upper bed. Moreover, a feed gas with a CO/CO2/DME/N2/H2 molar ratio of 9/6/4/5 balanced with H2 was simulated and studied in the lower bed over SP34-C; after optimizing the reaction conditions, the selectivity of light paraffins reached 90.8%, and the selectivity of propane was as high as 76.7%. For the direct conversion of syngas to light paraffins in a dual bed, 88.9% light paraffins selectivity in hydrocarbons was obtained at a CO conversion of 33.4%. This dual-bed strategy offers a potential route for the direct conversion of syngas to valuable chemicals.

Postherpetic neuralgia (PHN) is a chronic neuropathic pain syndrome, similar to other chronic pains, the mechanisms of which are not fully understood. To further understand the neural mechanism of this chronic pain and its transition, we performed functional magnetic resonance imaging (fMRI) scans on PHN rat models. Twelve PHN rat models were established by intraperitoneal injection of resiniferatoxin, with an additional 12 rats serving as controls. Nociceptive behavioral tests were performed on these rats and fMRI scans were performed on days 7 and 14 after modeling. Functional connection (FC) analysis was used to investigate the brain FC alterations associated with chronic pain in PHN rats, with the anterior cingulate cortex (ACC) as a seed. Nociceptive behavioral tests showed that PHN rats presented symptoms similar to those of PHN patients. FC analysis showed that compared to the control group, the PHN group showed different FC patterns on days 7 and 14. As can be seen, the brain FC alterations in the rat model of PHN changed dynamically, shifting from brain regions processing sensory information to regions processing emotions and motives.