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BackgroundThere is a paucity of evidence regarding the definition of the quality of primary health care (PHC) in China. This study aims to evaluate the PHC quality for chronic diseases in rural areas based on a modified conceptual framework tailored to the context of rural China.MethodsThis comprehensive study, involving a patient survey, a provider survey and chart abstraction, and second-hand registered data, was set in three low-resource counties in rural China from 2021 to 2022. Rural patients with hypertension or type 2 diabetes, and health care workers providing care on hypertension or diabetes were involved. The modified PHC quality framework encompasses three core domains: a competent PHC system (comprehensiveness, accessibility, continuity, and coordination), effective clinical care (assessment, diagnosis, treatment, disease management, and provider competence), and positive user experience (information sharing, shared decision-making, respect for patient's preferences, and family-centeredness). Standardized PHC quality score was generated by arithmetic means or Rasch models of Item Response Theory.ResultsThis study included 1355 patients, 333 health care providers and 2203 medical records. Ranging from 0 (the worst) to 1 (the best), the average quality score for the PHC system was 0.718, with 0.887 for comprehensiveness, 0.781 for accessibility, 0.489 for continuity, and 0.714 for coordination. For clinical care, average quality was 0.773 for disease assessment, 0.768 for diagnosis, 0.677 for treatment, 0.777 for disease management, and 0.314 for provider competence. The average quality for user experience was 0.727, with 0.933 for information sharing, 0.657 for shared decision-making, 0.936 for respect for patients' preferences, and 0.382 for family-centeredness. The differences in quality among population subgroups, although statistically significant, were small.ConclusionThe PHC quality in rural China has shown strengths and limitations. We identified large gaps in continuity of care, treatment, provider competence, family-centeredness, and shared decision-making. Policymakers should invest more effort in addressing these gaps to improve PHC quality.

The cell division cycle associated (CDCA) genes regulate the cell cycle; however, their relationship with prognosis in glioma has been poorly reported in the literature. The Cancer Genome Atlas (TCGA) was utilized to probe the CDCA family in relation to the adverse clinical features of glioma. Glioma single-cell atlas reveals specific expression of CDCA3, 4, 5, 8 in malignant cells and CDCA7 in neural progenitor cells (NPC)-like malignant cells. Glioma data from TCGA, the China Glioma Genome Atlas Project (CGGA) and the gene expression omnibus (GEO) database all demonstrated that CDCA2, 3, 4, 5, 7 and 8 are prognostic markers for glioma. Further analysis identified CDCA2, 5 and 8 as independent prognostic factors for glioma. Lasso regression-based risk models for CDCA families demonstrated that high-risk patients were characterized by high tumor mutational burden (TMB), low levels of microsatellite instability (MSI), and low tumor immune dysfunction and rejection (TIDE) scores. These pointed to immunotherapy for glioma as a potentially viable treatment option Further CDCA clustering suggested that the high CDCA subtype exhibited a high macrophage phenotype and was associated with a higher antigen presentation capacity and high levels of immune escape. In addition, hsa-mir-15b-5p was predicted to be common regulator of CDCA3 and CDCA4, which was validated in U87 and U251 cells. Importantly, we found that CDCAs may indicate response to drug treatment, especially rapamycin, in glioma. In summary, our results suggest that CDCAs have potential applications in clinical diagnosis and as drug sensitivity markers in glioma.

BackgroundGefitinib is an orally potent and selective ATP-competitive inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase and is commonly used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC) with sensitive EGFR mutations. Multiple adverse effects associated with gefitinib, including liver and lung injuries, severe nausea, and diarrhea, have limited its clinical application. Xenobiotic-induced bioactivation is thought to be an important reason for gefitinib toxicity, which encouraged us to clarify the metabolism of gefitinib in NSCLC patients.Materials and methodsAn ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry (UPLCQ-TOF-MS) method was established to tentatively identify the metabolites of gefitinib in human plasma. The extracted ion chromatogram peak intensity threshold was set at 1500 cps with minimum MS and MS/MS peak intensities of 400 and 100 cps, respectively.ResultsA total of 18 tentative metabolites were identified. Eight novel tentative metabolites with metabolic changes in dechlorination, defluorination, and hydrogenation on the quinazoline skeleton; removal of a partial or complete 3-chloro-4-fluoroaniline-substituted group; and sulfate conjugation and taurine conjugation were newly discovered in human plasma. Based on structural analysis of the tentative metabolites, the metabolic pathways were proposed. In addition, the pathways of dechlorination, defluorination, and hydrogenation on the quinazoline skeleton; removal of partial or complete 3-chloro-4-fluoroaniline-substituted groups; and sulfate conjugation and taurine conjugation in humans in vivo indicate that novel metabolic pathways exist in humans.ConclusionsIn summary, the metabolism of gefitinib in humans in vivo is extensive and complex. Based on in vivo evidence, the propoxy-morpholine ring side chain and O-methyl group are the critical metabolic regions of gefitinib in humans. The novel metabolic pathways differ from those of in vitro studies, suggesting that intestinal floral metabolism might be involved.

Here, we provide direct evidence that using recombinant proteins expressed in eukaryotic cells as antigen is a practical way to generate monoclonal antibodies (mAbs) against heavily glycosylated proteins. Heavily glycosylated proteins are typically difficult targets for mAb generation, being limited by unsatisfactory affinity and low specificity. Using the heavily glycosylated CD45 protein as an example, we demonstrate the entire process of expressing the protein in eukaryotic cells and using it as an antigen to generate CD45-targeting mAbs in mice. The mAbs generated showed robust affinity and specificity, which are crucial factors for differentiate circulating tumor cells from white blood cells in human breast cancer patient samples. Only 1 cell fusion and 2 cyclic sub-cloning steps were necessary before mAbs with satisfactory performance were obtained.

Dialeurodes citri is a major pest in citrus producing areas, and large-scale outbreaks have occurred increasingly often in recent years. Lecanicillium attenuatum is an important entomopathogenic fungus that can parasitize and kill D. citri. We separated the fungus from corpses of D. citri larvae. However, the sound immune defense system of pests makes infection by an entomopathogenic fungus difficult. Here we used RNA sequencing technology (RNA-Seq) to build a transcriptome database for D. citri and performed digital gene expression profiling to screen genes that act in the immune defense of D. citri larvae infected with a pathogenic fungus. De novo assembly generated 84,733 unigenes with mean length of 772 nt. All unigenes were searched against GO, Nr, Swiss-Prot, COG, and KEGG databases and a total of 28,190 (33.3%) unigenes were annotated. We identified 129 immunity-related unigenes in transcriptome database that were related to pattern recognition receptors, information transduction factors and response factors. From the digital gene expression profile, we identified 441 unigenes that were differentially expressed in D. citri infected with L. attenuatum. Through calculated Log2Ratio values, we identified genes for which fold changes in expression were obvious, including cuticle protein, vitellogenin, cathepsin, prophenoloxidase, clip-domain serine protease, lysozyme, and others. Subsequent quantitative real-time polymerase chain reaction analysis verified the results. The identified genes may serve as target genes for microbial control of D. citri.

Enzymes are important and effective biological catalyst proteins participating in almost all active cell processes. Identification of multi-functional enzymes is essential in understanding the function of enzymes. Machine learning methods perform better in protein structure and function prediction than traditional biological wet experiments. Thus, in this study, we explore an efficient and effective machine learning method to categorize enzymes according to their function. Multi-functional enzymes are predicted with a special machine learning strategy, namely, multi-label classifier. Sequence features are extracted from a position-specific scoring matrix with autocross-covariance transformation. Experiment results show that the proposed method obtains an accuracy rate of 94.1% in classifying six main functional classes through five cross-validation tests and outperforms state-of-the-art methods. In addition, 91.25% accuracy is achieved in multi-functional enzyme prediction, which is often ignored in other enzyme function prediction studies. The online prediction server and datasets can be accessed from the link http://server.malab.cn/MEC/.

OBJECTIVES:The primary objective of this pilot study was to investigate whether the therapeutic drug monitoring of imipenem could be performed with spent effluent instead of blood sampling collected from critically ill patients under continuous renal replacement therapy. METHODS:A prospective open-label study was conducted in a real clinical setting. Both blood and effluent samples were collected pairwise before imipenem administration and 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after imipenem administration. Plasma and effluent imipenem concentrations were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. Pharmacokinetic and pharmacodynamic parameters of blood and effluent samples were calculated. RESULTS:Eighty-three paired plasma and effluent samples were obtained from 10 patients. The Pearson correlation coefficient of the imipenem concentrations in plasma and effluent was 0.950 (P

Androgen receptor (AR) variants are associated with resistance to anti androgen therapy both in human prostate cancer cell lines and clinical samples. These observations support the hypothesis that AR isoform accumulation is a consequence of selective therapeutic pressure on the full length AR. The Pten deficient prostate cancer model proceeds with well-defined kinetics including progression to castration resistant prostate cancer (CRPC). While surgical castration and enzalutamide treatments yield an initial therapeutic response, Pten-/-epithelia continue to proliferate yielding locally invasive primary tumor pathology. That most epithelium remains AR positive, but ligand independent, suggests the presence of oncogenic AR variants. To address this hypothesis, we have used a panel of recently described Pten-/- tumor cell lines derived from both from hormone intact (E4, E8) and castrated Pten mutants (cE1, cE2) followed by RACE PCR to identify and characterize three novel truncated, amino terminus containing AR variants (mAR-Va, b, c). Variants appear not only conserved throughout progression but are correlated with nearly complete loss of full length AR (AR-FL) at castrate androgen levels. The overexpression of variants leads to enhanced transcriptional activity of AR while knock down studies show reduced transcriptional output. Collectively, the identification of truncated AR variants in the conditional PTEN deletion model supports a role for maintaining the CRPC phenotype and provides further therapeutic applications of this preclinical model.

OBJECTIVE:This study aimed to investigate whether self-rated health status (SRH) and subjective health complaints (SHC) of urban Chinese women are associated with their health-promoting lifestyles (HPL). METHODS:We conducted a cross-sectional study on 8142 eligible Chinese participants between 2012 and 2013. Demographic and SHC data were collected. Each subject completed the SRH questionnaire and the Chinese version of the Health-Promoting Lifestyle Profile-II (HPLP-II). Correlation and binary regression analyses were performed to examine the associations of SRH and SHC with HPL. RESULTS:Both SRH and HPL of urban Chinese women were moderate. The most common complaints were fatigue (1972, 24.2%), eye discomfort (1571, 19.3%), and insomnia (1542, 18.9%). Teachers, highly educated subjects and elderly women had lower SRH scores, while college students and married women had better HPL. All items of HPLP-II were positively correlated with SRH (r = 0.127-0.533, P = 0.000) and negatively correlated with SHC to a significant extent (odds ratio [OR] = 1.40-11.37). CONCLUSIONS:Aspects of HPL, particularly stress management and spiritual growth, are associated with higher SRH and lower SHC ratings among urban Chinese women. Physical activity and health responsibility are additionally related to reduced fatigue and nervousness. We believe that these findings will be instrumental in encouraging researchers and urban women to adopt better health-promoting lifestyles with different priorities in their daily lives.

Shugan Jianpi Zhixie therapy (SJZT) has been widely used to treat diarrhea-predominant irritable bowel syndrome (IBS-D), but the results are still controversial. A meta-analysis of randomized, double-blind, placebo-controlled trials was performed to assess the efficacy and tolerability of SJZT for IBS-D.The MEDLINE, EMBASE, Cochrane Library, the China National Knowledge Infrastructure database, the Chinese Biomedical Literature database and the Wanfang database were searched up to June 2014 with no language restrictions. Summary estimates, including 95% confidence intervals (CI), were calculated for global symptom improvement, abdominal pain improvement, and Symptom Severity Scale (BSS) score.Seven trials (N=954) were included. The overall risk of bias assessment was low. SJZT showed significant improvement for global symptom compared to placebo (RR 1.61; 95% CI 1.24, 2.10; P =0.0004; therapeutic gain = 33.0%; number needed to treat (NNT) = 3.0). SJZT was significantly more likely to reduce overall BSS score (SMD -0.67; 95% CI -0.94, -0.40; P < 0.00001) and improve abdominal pain (RR 4.34; 95% CI 2.64, 7.14; P < 0.00001) than placebo. The adverse events of SJZT were no different from those of placebo.This meta-analysis suggests that SJZT is an effective and safe therapy option for patients with IBS-D. However, due to the high clinical heterogeneity and small sample size of the included trials, further standardized preparation, large-scale and rigorously designed trials are needed.

Human CMTM3 has been proposed as a putative tumor suppressor gene. The loss of CMTM3 has been found in several carcinomas. However, the regulation of CMTM3 expression and its function in tumor progression remain largely unknown. Here, we investigated the regulation of CMTM3 expression, function and molecular mechanism in human testicular cancer cells. CMTM3 was frequently downregulated or silenced in testicular cancer cell lines and tumor tissues but highly expressed in normal testis tissues. The re-expression of CMTM3 significantly suppressed the colony formation, proliferation, and migration capacity of testicular cancer cells by inducing a G2 cell cycle arrest and apoptosis. Moreover, the re-expression of CMTM3 activated the transcription of p53, induced p53 accumulation, up-regulated the expression of p21, and increased the cleavage of caspase 9, 8, 3, and PARP. The downregulation of CMTM3 in clinical tumor tissues was associated with the methylation of a single CpG site located within the Sp1/Sp3-responsive region of the core promoter. These results indicate that CMTM3 can function as tumor suppressor through the induction of a G2 cell cycle arrest and apoptosis. CMTM3 is thus involved in testicular cancer pathogenesis, and it is frequently at least partially silenced by the methylation of a single, specific CpG site in tumor tissues.

Effective treatment of transitional cell carcinoma (TCC) of the bladder requires early diagnosis. Identifying novel molecular markers in TCC would guide the development of diagnostic and therapeutic targets. Ephrins mediate signals via tyrosine kinase activity that modulates diverse physiologic and developmental processes, and ephrins are increasingly implicated in carcinogenesis. The aim of our study was to examine the differential regulation of EphB4 and EphB2 in normal bladder and in TCC of the bladder in 40 patients undergoing radical cystectomy for curative intent. Immunostaining and Western blotting revealed that normal urothelium expresses EphB2 (20 of 24 cases, 83% of the time) not EphB4 (0 of 24 cases, 0%). In sharp contrast, TCC specimens show loss of EphB2 expression (0 of 34 cases, 0%) and gain of EphB4 expression (32 of 34, 94%). Furthermore, EphB4 signal strength statistically correlated with higher tumor stage, and trended toward the presence of carcinoma in situ (CIS). These results are confirmed by analysis of normal urothelial and tumor cell lines. EphB2 is not a survival factor in normal urothelium, while EphB4 is a survival factor in TCC. Treatment of bladder tumor xenograft with an EphB4 inhibitor sEphB4-HSA leads to 62% tumor regression and complete remission when combined with Bevacizumab. Furthermore, tissue analysis revealed that sEphB4-HSA led to increased apoptosis, decreased proliferation, and reduced vessel density, implicating direct tumor cell targeting as well as anti-angiogenesis effect. In summary loss of EphB2 and gain of EphB4 expression represents an inflection point in the development, growth and possibly progression of TCC. Therapeutic compounds targeting EphB4 have potential for diagnosing and treating TCC.

Wound-healing represents a major health burden, such as diabetes-induced skin ulcers and burning. Many works are being tried to find ideal clinical wound-healing biomaterials. Especially, small molecules with low cost and function to promote production of endogenous wound healing agents (i.e. transforming growth factor beta, TGF-β) are excellent candidates. In this study, a small peptide (tiger17, c[WCKPKPKPRCH-NH2]) containing only 11 amino acid residues was designed and proved to be a potent wound healer. It showed strong wound healing-promoting activity in a murine model of full thickness dermal wound. Tiger17 exerted significant effects on three stages of wound healing progresses including (1) the induction of macrophages recruitment to wound site at inflammatory reaction stage; (2) the promotion of the migration and proliferation both keratinocytes and fibroblasts, leading to reepithelialization and granulation tissue formation; and (3) tissue remodeling phase, by promoting the release of transforming TGF-β1 and interleukin 6 (IL-6) in murine macrophages and activating mitogen-activated protein kinases (MAPK) signaling pathways. Considering its easy production, store and transfer and function to promote production of endogenous wound healing agents (TGF-β), tiger17 might be an exciting biomaterial or template for the development of novel wound-healing agents.

TLR7/8 and TLR9 signaling pathways have been extensively studied in systemic lupus erythematosus (SLE) as possible mediators of disease. Monocytes are a major source of pro-inflammatory cytokines and are understudied in SLE. In the current project, we investigated sex differences in monocyte activation and its implications in SLE disease pathogenesis.Human blood samples from 27 healthy male controls, 32 healthy female controls, and 25 female patients with SLE matched for age and race were studied. Monocyte activation was tested by flow cytometry and ELISA, including subset proportions, CD14, CD80 and CD86 expression, the percentage of IL-6-producing monocytes, plasma levels of sCD14 and IL-6, and urine levels of creatinine.Monocytes were significantly more activated in women compared to men and in patients with SLE compared to controls in vivo. We observed increased proportions of non-classic monocytes, decreased proportions of classic monocytes, elevated levels of plasma sCD14 as well as reduced surface expression of CD14 on monocytes comparing women to men and lupus patients to controls. Plasma levels of IL-6 were positively related to sCD14 and serum creatinine.Monocyte activation and TLR4 responsiveness are altered in women compared to men and in patients with SLE compared to controls. These sex differences may allow persistent systemic inflammation and resultant enhanced SLE susceptibility.

A designed peptide named LZ1 with 15 amino acid residues containing strong antimicrobial activity against bacteria pathogens of acne vulgaris including Propionibacterium acnes, Staphylococcus epidermidis and S. aureus. Especially, it exerted strong anti-P. acnes ability. The minimal inhibitory concentration against three strains of P. acnes was only 0.6 µg/ml, which is 4 times lower than that of clindamycin. In experimental mice skin colonization model, LZ1 significantly reduced the number of P. acnes colonized on the ear, P. acnes-induced ear swelling, and inflammatory cell infiltration. It ameliorated inflammation induced by P. acnes by inhibiting the secretion of inflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β. LZ1 showed little cytotoxicity on human keratinocyte and hemolytic activity on human blood red cells. Furthermore, LZ1 was very stable in human plasma. Combined with its potential bactericidal and anti-inflammatory properties, simple structure and high stability, LZ1 might be an ideal candidate for the treatment of acne.

Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.

Despite successful approaches to preserve organs, tissues, and isolated cells, the maintenance of stem cell viability and function in body fluids during storage for cell distribution and transportation remains unexplored. The aim of this study was to characterize urine-derived stem cells (USCs) after optimal preservation of urine specimens for up to 24 hours. A total of 415 urine specimens were collected from 12 healthy men (age range 20-54 years old). About 6 × 10(4) cells shed off from the urinary tract system in 24 hours. At least 100 USC clones were obtained from the stored urine specimens after 24 hours and maintained similar biological features to fresh USCs. The stored USCs had a "rice grain" shape in primary culture, and expressed mesenchymal stem cell surface markers, high telomerase activity, and normal karyotypes. Importantly, the preserved cells retained bipotent differentiation capacity. Differentiated USCs expressed myogenic specific proteins and contractile function when exposed to myogenic differentiation medium, and they expressed urothelial cell-specific markers and barrier function when exposed to urothelial differentiation medium. These data demonstrated that up to 75% of fresh USCs can be safely persevered in urine for 24 hours and that these cells stored in urine retain their original stem cell properties, indicating that preserved USCs could be available for potential use in cell-based therapy or clinical diagnosis.

Main indoor allergens for humans are from house dust mites. There are more than 30 allergens in Dermatophagoides farinae but only fourteen allergens have been identified from this mite including Der f 1-3, 6, 7, 10, 11, 13-18, and 22. A native allergen protein (Der f 24, 90 kDa) was purified from D. farinae by gel filtration and anionic exchange liquid chromatography combined with IgE immunodetection. Its primary structure was determined by Edman degradation, mass spectrometry analysis and cDNA cloning. Enzyme-linked immunosorbent assay inhibition tests (ELISA-IT), immunoblots, basophil activation test (BAT) and skin prick test (SPT) were performed to evaluate the allergenicity. It was identified as an alpha (α)-actinin containing a CaM-like domain with EF-hand motifs. Der f 24 reacted to sera from 85.4% (35/41) of patients on western blot analysis. It reduced ∼20% sera IgE reactivity to D. farinae extracts on a competitive ELISA. Eighty percent (8/10) of patients with D. farinae allergy showed positive reactions to Der f 24 in skin prick test. The expression of CD63 on basophils from patients was up-regulated by Der f 24 by ∼5.4-fold. Alpha-actinin was identified as a new type of house dust mite allergen. To the best of our knowledge, this is the first report of α-actinin as an allergen.

Antimicrobial peptides have been widely identified from amphibian skins except salamanders. A novel antimicrobial peptide (CFBD) was isolated and characterized from skin secretions of the salamander, Cynops fudingensis. The cDNA encoding CFBD precursor was cloned from the skin cDNA library of C. fudingensis. The precursor was composed of three domains: signal peptide of 17 residues, mature peptide of 41 residues and intervening propeptide of 3 residues. There are six cysteines in the sequence of mature CFBD peptide, which possibly form three disulfide-bridges. CFBD showed antimicrobial activities against Staphylococcus aureus, Bacillus subtilis, Candida albicans and Escherichia coli. This peptide could be classified into family of β-defensin based on its sequence similarity with β-defensins from other vertebrates. Evolution analysis indicated that CFBD was close to fish β-defensin. As far as we know, CFBD is the first β-defensin antimicrobial peptide from salamanders.

Recent findings regarding Dll4 function in physiological and pathological conditions indicate that this Notch ligand may constitute an important therapeutic target. Dll4 appears to be a major anti-angiogenic agent, occupying a central role in various angiogenic pathways. The first trials of anti-Dll4 therapy in mice demonstrated a paradoxical effect, as it reduced tumor perfusion and growth despite leading to an increase in vascular density. This is seen as the result of insufficient maturation of the newly formed vasculature causing a circulatory defect and increased tumor hypoxia. As Dll4 function is known to be closely dependent on expression levels, we envisioned that the therapeutic anti-Dll4 dosage could be modulated to result in the increase of adequately functional blood vessels. This would be useful in conditions where vascular function is a limiting factor for recovery, like wound healing and tissue hypoxia, especially in diabetic patients. Our experimental results in mice confirmed this possibility, revealing that low dosage inhibition of Dll4/Notch signaling causes improved vascular function and accelerated wound healing.

Due to poor diagnostic facilities and a lack of medical alertness, allergy to Vespa wasps may be underestimated. Few allergens have been identified from Vespa wasps.Possible native allergen proteins were purified from the wasp venoms (WV) (Vespa magnifica Smith) by gel filtration, ion exchange chromatography, respectively. Their sequences were determined by Edman degradation and cDNA cloning. Their allergenicities were assayed by enzyme-linked immunosorbent assay inhibition tests (ELISA-IT), immunoblots, and skin prick tests (SPTs). Their cross allergencities with Tab y 2 and Tab y 5 purified from the horsefly (Tabanus yao Macquart) were also determined. Two native allergens were identified from the WV, respectively. They are a 25-KDa antigen 5 protein (Ag5) (Vesp ma 5) and a 35-KDa hyaluronidase (Vesp ma 2). They represented major allergens in Vespa magnifica by immunoblots and SPTs. ELISA inhibition of pooled sera IgE reactivity to both the WV and the horsefly salivary gland extracts (HSGE) using four purified allergens (Vesp ma 2, Vesp ma 5 and previously purified Tab y 2 and Tab y 5) was significant. Their cross allergenicities were confirmed by ELISA-IT, immunoblots, and SPTs. They represented the cross reactive allergens from wasp and horsefly and proved the so called wasp-horsefly syndrome.

UNLABELLED: Direct-acting fibrin(ogen)olytic agents such as plasmin have been proved to contain effective and safety thrombolytic potential. Unfortunately, plasmin is ineffective when administered by the intravenous route because it was neutralized by plasma antiplasmin. Direct-acting fibrin(ogen)olytic agents with resistance against antiplasmin will brighten the prospect of anti-thrombosis. As reported in 'Compendium of Materia Medica', the insect of Eupolyphaga sinensis Walker has been used as traditional anti-thrombosis medicine without bleeding risk for several hundreds years. Currently, we have identified a fibrin(ogen)olytic protein (Eupolytin1) containing both fibrin(ogen)olytic and plasminogen-activating (PA) activities from the beetle, E. sinensis. OBJECTIVES: To investigate the role of native and recombinant eupolytin1 in fibrin(ogen)olytic and plasminogen-activating processes. METHODS AND RESULTS: Using thrombus animal model, eupolytin1 was proved to contain strong and rapid thrombolytic ability and safety in vivo, which are better than that of urokinase. Most importantly, no bleeding complications were appeared even the intravenous dose up to 0.12 µmol/kg body weight (3 times of tested dose which could completely lyse experimental thrombi) in rabbits. It is the first report of thrombolytic agents containing both direct-acting fibrin(ogen)olytic and plasminogen-activating activities. CONCLUSIONS: The study identified novel thrombolytic agent with prospecting clinical potential because of its bi-functional merits containing both plasmin- and PA-like activities and unique pharmacological kinetics in vivo.

Cathelicidins are a family of antimicrobial peptides acting as multifunctional effector molecules in innate immunity. Cathelicidin-BF has been purified from the snake venoms of Bungarus fasciatus and it is the first identified cathelicidin antimicrobial peptide in reptiles. In this study, cathelicidin-BF was found exerting strong antibacterial activities against Propionibacterium acnes. Its minimal inhibitory concentration against two strains of P. acnes was 4.7 µg/ml. Cathelicidin-BF also effectively killed other microorganisms including Staphylococcus epidermidis, which was possible pathogen for acne vulgaris. Cathelicidin-BF significantly inhibited pro-inflammatory factors secretion in human monocytic cells and P. acnes-induced O2.- production of human HaCaT keratinocyte cells. Observed by scanning electron microscopy, the surfaces of the treated pathogens underwent obvious morphological changes compared with the untreated controls, suggesting that this antimicrobial peptide exerts its action by disrupting membranes of microorganisms. The efficacy of cathelicidin-BF gel topical administering was evaluated in experimental mice skin colonization model. In vivo anti-inflammatory effects of cathelicidin-BF were confirmed by relieving P. acnes-induced mice ear swelling and granulomatous inflammation. The anti-inflammatory effects combined with potent antimicrobial activities and O2.- production inhibition activities of cathelicidin-BF indicate its potential as a novel therapeutic option for acne vulgaris.

In vertebrates, non-lens betagamma-crystallins are widely expressed in various tissues, but their functions are unknown. The molecular mechanisms of trefoil factors, initiators of mucosal healing and being greatly involved in tumorigenesis, have remained elusive.A naturally existing 72-kDa complex of non-lens betagamma-crystallin (alpha-subunit) and trefoil factor (beta-subunit), named betagamma-CAT, was identified from frog Bombina maxima skin secretions. Its alpha-subunit and beta-subunit (containing three trefoil factor domains), with a non-covalently linked form of alphabeta(2), show significant sequence homology to ep37 proteins, a group of non-lens betagamma-crystallins identified in newt Cynops pyrrhogaster and mammalian trefoil factors, respectively. betagamma-CAT showed potent hemolytic activity on mammalian erythrocytes. The specific antiserum against each subunit was able to neutralize its hemolytic activity, indicating that the two subunits are functionally associated. betagamma-CAT formed membrane pores with a functional diameter about 2.0 nm, leading to K(+) efflux and colloid-osmotic hemolysis. High molecular weight SDS-stable oligomers (>240-kDa) were detected by antibodies against the alpha-subunit with Western blotting. Furthermore, betagamma-CAT showed multiple cellular effects on human umbilical vein endothelial cells. Low dosages of betagamma-CAT (25-50 pM) were able to stimulate cell migration and wound healing. At high concentrations, it induced cell detachment (EC(50) 10 nM) and apoptosis. betagamma-CAT was rapidly endocytosed via intracellular vacuole formation. Under confocal microscope, some of the vacuoles were translocated to nucleus and partially fused with nuclear membrane. Bafilomycin A1 (a specific inhibitor of the vacuolar-type ATPase) and nocodazole (an agent of microtuble depolymerizing), while inhibited betagamma-CAT induced vacuole formation, significantly inhibited betagamma-CAT induced cell detachment, suggesting that betagamma-CAT endocytosis is important for its activities.These findings illustrate novel cellular functions of non-lens betagamma-cyrstallins and action mechanism via association with trefoil factors, serving as clues for investigating the possible occurrence of similar molecules and action mechanisms in mammals.

BACKGROUND: Cathelicidins are a family of antimicrobial peptides acting as multifunctional effector molecules of innate immunity, which are firstly found in mammalians. Recently, several cathelicidins have also been found from chickens and fishes. No cathelicidins from other non-mammalian vertebrates have been reported. PRINCIPAL FINDINGS: In this work, a cathelicidin-like antimicrobial peptide named cathelicidin-BF has been purified from the snake venoms of Bungarus fasciatus and its cDNA sequence was cloned from the cDNA library, which confirm the presence of cathelicidin in reptiles. As other cathelicidins, the precursor of cathelicidin-BF has cathelin-like domain at the N terminus and carry the mature cathelicidin-BF at the C terminus, but it has an atypical acidic fragment insertion between the cathelin-like domain and the C-terminus. The acidic fragment is similar to acidic domains of amphibian antimicrobial precursors. Phylogenetic analysis revealed that the snake cathelicidin had the nearest evolution relationship with platypus cathelicidin. The secondary structure of cathelicidin-BF investigated by CD and NMR spectroscopy in the presence of the helicogenic solvent TFE is an amphipathic alpha-helical conformation as many other cathelicidins. The antimicrobial activities of cathelicidin BF against forty strains of microorganisms were tested. Cathelicidin-BF efficiently killed bacteria and some fungal species including clinically isolated drug-resistance microorganisms. It was especially active against Gram-negative bacteria. Furthermore, it could exert antimicrobial activity against some saprophytic fungus. No hemolytic and cytotoxic activity was observed at the dose of up to 400 microg/ml. Cathelicidin-BF could exist stably in the mice plasma for at least 2.5 hours. CONCLUSION: Discovery of snake cathelicidin with atypical structural and functional characterization offers new insights on the evolution of cathelicidins. Potent, broad spectrum, salt-independent antimicrobial activities make cathelicidin-BF an excellent candidate for clinical or agricultural antibiotics.

BACKGROUND: Lectins are sugar-binding proteins that specifically recognize sugar complexes. Based on the specificity of protein-sugar interactions, different lectins could be used as carrier molecules to target drugs specifically to different cells which express different glycan arrays. In spite of lectin's interesting biological potential for drug targeting and delivery, a potential disadvantage of natural lectins may be large size molecules that results in immunogenicity and toxicity. Smaller peptides which can mimic the function of lectins are promising candidates for drug targeting. PRINCIPAL FINDINGS: Small peptide with lectin-like behavior was screened from amphibian skin secretions and its structure and function were studied by NMR, NMR-titration, SPR and mutant analysis. A lectin-like peptide named odorranalectin was identified from skin secretions of Odorrana grahami. It was composed of 17 aa with a sequence of YASPKCFRYPNGVLACT. L-fucose could specifically inhibit the haemagglutination induced by odorranalectin. (125)I-odorranalectin was stable in mice plasma. In experimental mouse models, odorranalectin was proved to mainly conjugate to liver, spleen and lung after i.v. administration. Odorranalectin showed extremely low toxicity and immunogenicity in mice. The small size and single disulfide bridge of odorranalectin make it easy to manipulate for developing as a drug targeting system. The cyclic peptide of odorranalectin disclosed by solution NMR study adopts a beta-turn conformation stabilized by one intramolecular disulfide bond between Cys6-Cys16 and three hydrogen bonds between Phe7-Ala15, Tyr9-Val13, Tyr9-Gly12. Residues K5, C6, F7, C16 and T17 consist of the binding site of L-fucose on odorranalectin determined by NMR titration and mutant analysis. The structure of odorranalectin in bound form is more stable than in free form. CONCLUSION: These findings identify the smallest lectin so far, and show the application potential of odorranalectin for drug delivery and targeting. It also disclosed a new strategy of amphibian anti-infection.

The Hylurgini tribe (Coleoptera: Curculionidae: Scolytinae) comprises commercially significant bark beetles, including invasive species within the genera Dendroctonus and Hylurgus. These invasive species coexist with native Tomicus species of Hylurgini and cooperatively infest host trees in China. However, we lack sufficient mitochondrial genome data of Hylurgini to conduct phylogenetic studies, clarify the phylogenetic relationships of the above species, and improve the understanding of niche divergence and common hazards. Here, we sequenced and analyzed the mitochondrial genomes of seven Hylurgini species, including Dendroctonus valens, Hylurgus ligniperda, Hylurgus micklitzi, Tomicus piniperda, Tomicus brevipilosus, Tomicus minor and Tomicus yunnanensis. All sequenced mitochondrial genomes ranged from 15,339 bp to 17,545 bp in length, and their AT contents ranged from 73.24% to 78.81%. The structure of the seven mitochondrial genomes was consistent with that of ancestral insects. Based on 13 protein-coding genes from the reported mitochondrial genomes of 29 species of bark beetles, we constructed phylogenetic trees using maximum likelihood and Bayesian inference methods. The topology of the two phylogenetic trees was almost consistent. The findings elucidated the taxonomy classification of Hylurgini and the evolutionary connections of its sister taxa within the Scolytinae. This study offers insights for examining the evolutionary connections between invasive and native bark beetles, as well as the molecular identification and detection of newly invading species., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 An et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Diabetes is a chronic disease, which is characterized by abnormally high blood sugar levels. It may affect various organs and tissues, and even lead to life-threatening complications. Accurate prediction of diabetes can significantly reduce its incidence. However, the current prediction methods struggle to accurately capture the essential characteristics of nonlinear data, and the black-box nature of these methods hampers its clinical application. To address these challenges, we propose KCCAM&#95;DNN, a diabetes prediction method that integrates Kendall's correlation coefficient and an attention mechanism within a deep neural network. In the KCCAM&#95;DNN, Kendall's correlation coefficient is initially employed for feature selection, which effectively filters out key features influencing diabetes prediction. For missing values in the data, polynomial regression is utilized for imputation, ensuring data completeness. Subsequently, we construct a deep neural network (KCCAM&#95;DNN) based on the self-attention mechanism, which assigns greater weight to crucial features affecting diabetes and enhances the model's predictive performance. Finally, we employ the SHAP model to analyze the impact of each feature on diabetes prediction, augmenting the model's interpretability. Experimental results show that KCCAM&#95;DNN exhibits superior performance on both PIMA Indian and LMCH diabetes datasets, achieving test accuracies of 99.090% and 99.333%, respectively, approximately 2% higher than the best existing method. These results suggest that KCCAM&#95;DNN is proficient in diabetes prediction, providing a foundation for informed decision-making in the diagnosis and prevention of diabetes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Qi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The spatial spillover of urban innovation has increasingly become an important factor affecting urban total factor productivity (TFP) growth. Based on the panel data of 108 cities in the Yangtze River Economic Belt from 2004 to 2020, this paper illustrates the spatial-temporal evolution trend of urban innovation and manufacturing total factor productivity and uses the spatial Dubin model to study the direct and indirect effects of urban innovation on manufacturing total factor productivity. The main conclusions are as follows:(1)Spatial correlation and heterogeneity between urban innovation and manufacturing total factor productivity prove to be significant in the Yangtze River Economic Belt;(2)Urban innovation has a significant positive impact on manufacturing total factor productivity and has a positive spillover effect on surrounding cities; (3)The effect of urban innovation on manufacturing total factor productivity varies with time and region;(4) Mechanism analysis shows that talent agglomeration significantly promotes the positive impact of urban innovation on manufacturing total factor productivity, while the spillover effect is insignificant., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Accurate estimation of traffic emissions and analysis of spatio-temporal distribution on urban roads play a crucial role in the development of low-carbon transportation system. Traditionally, a region's emission characteristics have been studied using numerous emission models with GPS-based spatio-temporal data. Due to the heavy data processing needs of GPS-based data, emission characteristics for a large region have been studied by dividing the region into a limited number of smaller areas or units. Additionally, GPS data are based on a few vehicles in the traffic which does not fully reflect road conditions. This paper proposed an approach that can be used to study and calculate the spatio-temporal emission pattern of a region at a roadway section level by using Baidu's online traffic data and COPERT model. The proposed method can be used to estimate road-level emission patterns while avoiding the impact of redundant data in large datasets, making the dataset more reliable, applicable, and scalable. The proposed approach has been demonstrated through a study of spatio-temporal emission patterns in the Qiaoxi district within city of Shijiazhuang, China. Online data crawling technology was used to obtain data on urban road traffic speed and driving distance. The linear reference technology was used to construct a two-layer road network model to conduct the coupling and matching of traffic data with the road network data. The COPERT model was implemented to calculate the average traffic emissions on each road in the road network, and a traffic emission intensity index was proposed to quantify the CO, VOC, NOx and CO2 emissions on urban roads in the study area. The analysis results show that the traffic emission intensity of the expressway, trunk road, secondary road, and branch road is high during the morning peak (7 AM-9 AM) and evening peak (5 PM-7 PM). The sections with higher traffic emission intensity are mainly concentrated on the main roads and secondary roads such as Jiefang South Street, Shitong Road and Xinhua Road. Nearly one-third of 2nd Ring and 3rd Ring roads also have relatively high emission intensity. The research results provide new ideas for estimating traffic emissions in urban road networks and analyzing the spatio-temporal distribution of traffic emissions. The research results can also provide a decision-making basis for traffic management departments to formulate energy-saving and emission-reduction measures and promote the development of urban green and low-carbon transportation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ren et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Infrared and visible image fusion can generate a fusion image with clear texture and prominent goals under extreme conditions. This capability is important for all-day climate detection and other tasks. However, most existing fusion methods for extracting features from infrared and visible images are based on convolutional neural networks (CNNs). These methods often fail to make full use of the salient objects and texture features in the raw image, leading to problems such as insufficient texture details and low contrast in the fused images. To this end, we propose an unsupervised end-to-end Fusion Decomposition Network (FDNet) for infrared and visible image fusion. Firstly, we construct a fusion network that extracts gradient and intensity information from raw images, using multi-scale layers, depthwise separable convolution, and improved convolution block attention module (I-CBAM). Secondly, as the FDNet network is based on the gradient and intensity information of the image for feature extraction, gradient and intensity loss are designed accordingly. Intensity loss adopts the improved Frobenius norm to adjust the weighing values between the fused image and the two raw to select more effective information. The gradient loss introduces an adaptive weight block that determines the optimized objective based on the richness of texture information at the pixel scale, ultimately guiding the fused image to generate more abundant texture information. Finally, we design a single and dual channel convolutional layer decomposition network, which keeps the decomposed image as possible with the input raw image, forcing the fused image to contain richer detail information. Compared with various other representative image fusion methods, our proposed method not only has good subjective vision, but also achieves advanced fusion performance in objective evaluation., Competing Interests: We also declare that we no competing interests exist., (Copyright: © 2023 Di et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The purpose of this study was to determine whether FABP1 and FAS regulate expression of collagen and its crosslinking via lysyl oxidase in isolated adipocytes from Zongdihua pigs. We aimed to identify biochemical processes affecting meat quality using molecular tools to provide a basis for breeding improvement of these animals. We measured expression levels of FABP1 and related genes using qRT-PCR in longissimus dorsi muscle and subcutaneous adipose tissues. Primary adipocytes from fat tissues were isolated and FABP1 and FAS were over-expressed from recombinant plasmids. Sequence analysis of the cloned genes indicated that FABP1 encodes a hydrophobic protein of 128 amino acids and contained 12 predicted phosphorylation sites and no transmembrane regions. The basal levels of FABP1 and FAS expression in pig tissues were 3-3.5-fold higher in subcutaneous fat compared with muscle (P < 0.01). Recombinant expression plasmids were successfully transfected into the cloned preadipocytes and (a) over-expression of FAS resulted in significantly increased expression of COL3A1 (P < 0.05) and significantly inhibited lysyl oxidase LOX expression (P < 0.01); (b) over-expression of FABP1 significantly increased COL3A1 expression (P < 0.01) and significantly inhibited LOX expression (P< 0.05) and significantly reduced lysyl oxidase activity (P < 0.01). Therefore, FAS enhanced FABP1 expression resulting in increased collagen accumulation and this preliminarily suggested that FAS and FABP1 can serve as fat-related candidate genes and provide a theoretical basis for the study of fat deposition in Zongdihua pigs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To better adapt to seasonal environmental changes, physiological processes and behaviors are regulated seasonally. The gut microbiome interacts with the physiology, behavior, and even the diseases of host animals, including humans and livestock. Seasonal changes in gut microbiome composition have been reported in several species under natural environments. Dietary content significantly affects the composition of the microbiome, and, in the natural environment, the diet varies between different seasons. Therefore, understanding the seasonal regulatory mechanisms of the gut microbiome is important for understanding the seasonal adaptation strategies of animals. Herein, we examined the effects of changing day length and temperature, which mimic summer and winter conditions, on the gut microbiome of laboratory mice. Principal coordinate analysis and analysis of the composition of microbiomes of 16S rRNA sequencing data demonstrated that the microbiomes of the cecum and large intestine showed significant differences between summer and winter mimicking conditions. Similar to previous studies, a daily rhythm was observed in the composition of the microbiome. Furthermore, the phylogenetic investigation of communities by reconstruction of unobserved states predicted seasonal changes in several metabolic pathways. Changing day length and temperature can affect the composition of the gut microbiome without changing dietary contents., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Matsumoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: China's economy has been transitioning from a phase of rapid growth to high-quality development. The high-quality development of industry is the foundation of a sustainable and healthy growth of national economy, and is of great significance to improve people's living standards, and to meet people's needs for a better life., Methods: We develop an evaluation index system of high-quality development of industry from the perspectives of industrial benefit, innovation ability, coordination ability, green ability, opening ability and sharing ability. Based on a panel data of 30 provinces in China during 1999-2018, we evaluate the level of high-quality development of industry using the entropy-weight method and Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS) method. Meanwhile we select six specific years and adopt the Natural Breaks method to classify the provinces according to their levels. At last, Moran's I index is used to analyze the spatial correlation among the provinces., Results: Opening ability and innovation ability are found to have greater impacts on industrial high-quality development than other indices, and their influence has been increasing in recent years. There are large spatial and temporal differences among different provinces. Municipalities and coastal provinces are found to be at constantly high levels. The levels in the central region dropped first and then increased, however it was the opposite in the western region. In the northeast region, the levels fluctuated greatly. Overall, the high-quality development of industry among China's provinces shows positive spatial correlation. Most provinces in China are in High-High and Low-Low clustering States. The High-High clustering type is mainly distributed in the eastern region and the Low-Low clustering type is mainly distributed in the western and central regions., Conclusion: (1) Innovation ability and open ability are the most important factors. (2) Green ability has not sufficiently contributed to China's industrial development. (3) Regional and time evolution differences are significant. (4) There is a significant and stable spatial clustering effect in the high-quality development of industry among China's provinces., Competing Interests: The authors have declared that no competing interests exist.

The aims are to explore the construction of the knowledge management model for engineering cost consulting enterprises, and to expand the application of data mining techniques and machine learning methods in constructing knowledge management model. Through a questionnaire survey, the construction of the knowledge management model of construction-related enterprises and engineering cost consulting enterprises is discussed. First, through the analysis and discussion of ontology-based data mining (OBDM) algorithm and association analysis (Apriori) algorithm, a data mining algorithm (ML-AR algorithm) on account of ontology-based multilayer association and machine learning is proposed. The performance of the various algorithms is compared and analyzed. Second, based on the knowledge management level, analysis and statistics are conducted on the levels of knowledge acquisition, sharing, storage, and innovation. Finally, according to the foregoing, the knowledge management model based on engineering cost consulting enterprises is built and analyzed. The results show that the reliability coefficient of this questionnaire is above 0.8, and the average extracted value is above 0.7, verifying excellent reliability and validity. The efficiency of the ML-AR algorithm at both the number of transactions and the support level is better than the other two algorithms, which is expected to be applied to the enterprise knowledge management model. There is a positive correlation between each level of knowledge management; among them, the positive correlation between knowledge acquisition and knowledge sharing is the strongest. The enterprise knowledge management model has a positive impact on promoting organizational innovation capability and industrial development. The research work provides a direction for the development of enterprise knowledge management and the improvement of innovation ability., Competing Interests: The authors have declared that no competing interests exist.

In the medical system, the verification, preservation and synchronization of electronic medical records has always been a difficult problem, and the random dissemination of patient records will bring various risks to patient privacy. Therefore, how to achieve secure data sharing on the basis of ensuring users' personal privacy becomes the key. In recent years, blockchain has been proposed to be a promising solution to achieve data sharing with security and privacy preservation due to its advantages of immutability. So, a distributed electronic medical records searchable scheme was proposed by leveraging blockchain and smart contract technology. Firstly, we perform a hash calculation on the electronic medical data and store the corresponding value on the blockchain to ensure its integrity and authenticity. Then, we encrypt the electronic medical data and store it in the interplanetary file system which is a distributed storage protocol. These operations not only can solve centralized data store of servers of several medical institutions, but also be good at lowering stress from data store and high-frequency access to blockchain. Secondly, the encrypted keyword index information of electronic medical records was stored on the Ethereum blockchain, meanwhile a smart contract deployed in the Ethereum blockchain is used to realize keyword search instead of depending on a centralized third party. Furthermore, we use attribute-based encryption scheme to ensure that only the attributes meeting the access policy can decrypt the encrypted electronic medical records. Finally, our performance analysis and security analysis show that the scheme is secure and efficient., Competing Interests: The authors have declared that no competing interests exist.

Postoperative sore throat is one of the most common complications following endotracheal intubation. Nebulization therapy, a preferable and safety method of drug delivery, has been shown to be effective in postoperative sore throat prevention in many studies. However, the relative efficacy of various nebulized agents remains unknown. In this review, we aimed to quantify and rank order the efficacy of available nebulized agents for various postoperative sore throat-related outcomes. A comprehensive literature search of PubMed, EMBASE, CENTRAL and Google Scholar was conducted to identify eligible studies from inception to 25 May 2020. Incidence of postoperative sore throat 1hour and 24hours postoperatively and severity of postoperative sore throat 24 hours postoperatively were the primary outcomes. We conducted a Bayesian network meta-analysis to combine direct and indirect evidence to estimate the relative effects between treatments as well as the probabilities of ranking for treatments based on their protective effects. We identified 32 trials assessing 6 interventions. Overall inconsistency and heterogeneity were acceptable. Nebulized corticosteroids, magnesium, and ketamine differed from non-analgesic methods on the three primary outcomes. Based on the surface under the cumulative ranking curve, nebulized corticosteroids ranked first in almost all outcomes among the nebulized drugs. Considering only high-quality and 2-arm design studies, nebulized corticosteroids still seemed best. In conclusion, prophylactic use of nebulized corticosteroids, magnesium, and ketamine can effectively prevent postoperative sore throat, and nebulized corticosteroids appears to be the overall best approach., Competing Interests: The authors have declared that no competing interests exist.

Securinega suffruticosa (Pall.) Rehd is an excellent natural secondary shrub in the Shell Islands of Yellow River Delta. The roots of S. suffruticosa have high medicinal value and are used to treat diseases, such as neurasthenia and infant malnutrition. Any organism that is isolated from this species is of immense interest due to its potential novel bioactive compounds. In this research, the distribution and diversity of culturable endophytic fungi in S. suffruticosa were studied, and the endophytic fungi with antimicrobial activity were screened. A total of 420 endophytic fungi isolates were obtained from the S. suffruticosa grown in Shell Islands, from which 20 genera and 35 species were identified through morphological and internal transcribed spacer (ITS) sequence analyses. Chaetomium, Fusarium, Cladosporium, and Ceratobasidium were the dominant genera. The high species richness S (42), Margalef index D' (5.6289), Shannon-Wiener index H' (3.1000), Simpson diversity index Ds (0.9459), PIE index (0.8670), and evenness Pielou index J (0.8719) and a low dominant index λ (0.0541) indicated the high diversity of endophytic fungi in S. suffruticosa, the various species of endophytic fungi with obvious tissue specificity. The inhibition percentages of the 12 species of such endophytic fungi against Colletotrichum siamense were 3.6%-26.3%. C. globosum, Fusarium sp.3, and C. ramotenellum had a high antibacterial activity against Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The Minimum Inhibitory Concentration (MIC) and the Minimum Bactericidal Concentration (MBC) were between 0.5 mg/mL and 2 mg/mL. Alkaloid content detection indicated that endophytic fungi had a high alkaloid content, whereas the alkaloid contents of C. globosum and Fusarium sp.3 reached 0.231% and 0.170%, respectively. Members belonging to the endophytic fungal community in the S. suffruticosa of Shell Islands that may be used as antagonists and antibacterial agents for future biotechnology applications were identified for the first time., Competing Interests: The authors have declared that no competing interests exist.

Paraquat (PQ), one of the most widely used herbicides worldwide, causes severe toxic effects in humans and animals. 1-methylhydantoin (MH) is an active ingredient of Ranae Oviductus, which has broad pharmacological activities, e.g., eliminating reactive oxygen species and inhibiting inflammation. This study investigated the effects of MH on lung injury induced by PQ. A PQ poisoning model was established by intragastric infusion of PQ (25 mg/kg), and the control group was simultaneously gavaged with the same dose of saline. The MH group was intraperitoneally injected with 100 mg/kg once per day after intragastric infusion of PQ (25 mg/kg) for five consecutive days. All animals were sacrificed on the sixth day, and the lung tissues were dissected for metabolomics analysis. The lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, TNF-α and malondialdehyde (MDA) content were determined according to the instructions of the detection kit. Compared with that in the control group, the content of LDH, TNF-α and MDA in the lung tissue of the PQ group was significantly higher, and the activity of SOD in the lung tissue was significantly lower (all p<0.05). Compared with that in the control group, the content of LDH, TNF-α and MDA in the MH group was significantly higher, and the activity of SOD was significantly lower (all p<0.05). However, the differences in SOD activity, LDH activity between the PQ and MH groups were not statistically significant (all p > 0.05). There were significant differences in MDA and TNF-α content between the PQ group and MH group (all p<0.05). MH decreased the production of malondialdehyde and TNF-α to protect against the lung injury caused by PQ poisoning, but it had no significant effect on the activity of LDH and SOD. There were significant differences in metabolomics between the MH group and the PQ poisoning group, primarily in bile acid biosynthesis and metabolism of cholesterol, nicotinate, nicotinamide, alanine, aspartate, glutamate, glycine, threonine, serine, phenylalanine and histidine. Therefore, this study highlights that MH has non-invasive mechanisms and may be a promising tool to treat lung injury induced by PQ poisoning., Competing Interests: The authors have declared that no competing interests exist.

Temperature can be a major factor for the distribution of insects, especially among invasive insects. Sirex noctilio (Hymenoptera: Siricidae) has invaded many regions in China, causing enormous ecological and economic losses. We aimed to explore the trend and potential of diffusion by researching the thermal survival limits of S. noctilio. We measured the supercooling point (SCP), critical thermal temperature (CTmax), high lethal temperature (HLT) and low lethal temperature (LLT) for S. noctilio population in China and assessed life stage-related variation in thermal tolerance. Moreover, we determined the temperature tolerance range of S. noctilio and identified the temperature parameters for its potential invasive distribution risk analysis. The SCP of adults was -11.78 ± 0.67 (mean ± SEM), the CTmax was 37.67 ± 0.54, and those of larvae were -20.77 ± 0.44 and 40.53 ± 0.27, respectively. The LLT increased with exposure time, and the HLT was generally near 43°C. S. noctilio adults can tolerate higher temperatures than larvae, and the larvae showed high resistance to cold temperature. We calculated several temperature indexes based on our results, such as the lower temperature threshold (DV0) at -2.7°C, the upper temperature threshold (DV3) at 31°C, the temperature threshold for both heat stress (TTHS) at 35°C and cold stress (TTCS) at -32.5°C. We observed that, S. noctilio was not resistant to high temperatures, its CTmax is slightly lower than the lethal temperature, and the adults were more tolerant than larvae. Our next goal was to combine the temperature tolerance of symbiotic fungi, information on climate change and the current distribution of this species to predict its potential global distribution., Competing Interests: The authors have declared that no competing interests exist.

Due to the Expanded Program on Immunization (EPI) and supplementary immunization activities (SIAs) in China, the incidence of measles in China has decreased extensively. The incidence reached its lowest levels in contemporary history in 2012 and 2017, with incidence rates of 4.6 and 4.3 per million population, respectively. However, more than 147,000 measles cases were reported from 2013 to 2016. Furthermore, the proportions of cases in infants < 8 months and adults have been increasing since 2013, representing a considerable challenge for measles elimination in China. A total of 14,868 measles viruses were isolated from confirmed measles cases from 2011 to 2017, of which 14,631 were identified as the predominant endemic genotype, H1; 87 were identified as genotype A viruses that were vaccine associated strains; and 150 were identified as non-H1 genotype viruses. The non-H1 genotype viruses included 62 D8 viruses, 70 D9 viruses, 3 D11 viruses, 14 B3 viruses, and 1 G3 virus, which were identified as imported or import-related viruses that caused sporadic cases or small outbreaks. Most of the transmission chains detected during the period 2011-2012 were interrupted and were followed by many new transmission chains of unknown origin that spread, causing a large measles resurgence in China during 2013-2016. After 4 years of measles resurgence and continuous implementation of the routine immunization program and SIAs, the population immunity reached a sufficiently high level to interrupt most of the transmission chains; only a few strains survived, which continued to be sporadically detected in China in 2017. In the present study, the results from the combined epidemiological and molecular virological data demonstrated the great progress towards measles elimination in China by the further analysis of circulation dynamics for the endemic H1 genotype measles virus from 2011 to 2017. And this study accumulated critical baseline data on circulating wild-type measles viruses in China and provides comprehensive information to the world. These comprehensive baseline data provide evidence to support measles elimination in the future, not only in China but also in other countries worldwide. In addition, the information will be very useful to other countries for tracing their sources of measles cases and for identifying transmission links, which can help prevent potential measles outbreaks., Competing Interests: The authors have declared that no competing interests exist.

Background: Hand, foot and mouth disease (HFMD) is spread widely across Asia, and the hospitalization burden is currently not well understood. Here, we estimated serotype-specific and age-specific hospitalization rates of HFMD in Southern China., Methods: We enrolled pediatric HFMD patients admitted to 3/3 county-level hospitals, and 3/23 township-level hospitals in Anhua county, Hunan (CN). Samples were collected to identify enterovirus serotypes by RT-PCRs between October 2013 and September 2016. Information on other eligible, but un-enrolled, patients were retrospectively collected from the same six hospitals. Monthly numbers of all-cause hospitalizations were collected from each of the 23 township-level hospitals to extrapolate hospitalizations associated with HFMD among these., Results: During the three years, an estimated 3,236 pediatric patients were hospitalized with lab-confirmed HFMD, and among these only one case was severe. The mean hospitalization rate was 660 (95% CI: 638-684) per 100,000 person-years for lab-confirmed HFMD, with higher rates among CV-A16 and CV-A6 associated HFMD (213 vs 209 per 100,000 person-years), and lower among EV-A71, CV-A10 and other enterovirus associated HFMD (134, 39 and 66 per 100,000 person-years respectively, p<0.001). Children aged 12-23 months had the highest hospitalization rates (3,594/100,000 person-years), followed by those aged 24-35 months (1,828/100,000 person-years) and 6-11 months (1,572/100,000 person-years). Compared with other serotypes, CV-A6-associated hospitalizations were evident at younger ages., Conclusions: Our study indicates a substantial hospitalization burden associated with non-severe HFMD in a rural county in southern China. Future mitigation policies should take into account the disease burden identified, and optimize interventions for HFMD., Competing Interests: The authors have declared that no competing interests exist.

In addition to high vaccination coverage, timely and accurate laboratory confirmation of measles cases is critical to interrupt measles transmission. To evaluate the role of real-time reverse transcription-polymerase chain reaction (RT-PCR) in the diagnosis of measles cases, 46,363 suspected measles cases with rash and 395 suspected measles cases without rash were analyzed in this study; the cases were obtained from the Chinese measles surveillance system (MSS) during 2014-2017 and simultaneously detected by measles-specific IgM enzyme-linked immunosorbent assay (ELISA) and real-time RT-PCR. However, some IgM-negative measles cases were identified by real-time RT-PCR. The proportion of these IgM-negative and viral nucleic acid-positive measles cases was high among measles cases with measles vaccination history, cases without rash symptoms, and cases within 3 days of specimen collection after onset. The proportion of IgM-negative and viral nucleic acid-positive measles cases in the 0-3 day group was up to 14.4% for measles cases with rash and 40% for measles cases without rash. Moreover, the proportions of IgM-negative and nucleic acid-positive measles cases gradually increased with the increase in the measles vaccination dose. Therefore, integrated with IgM ELISA, real-time RT-PCR would greatly improve the accurate diagnosis of measles cases and avoid missing the measles cases, especially for measles cases during the first few days after onset when the patients were highly contagious and for measles cases with secondary vaccine failure. In conclusion, our study reconfirmed that IgM ELISA is the gold-standard detection assay for measles cases confirmation. However, real-time RT-PCR should be introduced and used to supplement the laboratory diagnosis, especially in the setting of pre-elimination and/or elimination wherever appropriate., Competing Interests: The authors have declared that no competing interests exist.

Fog computing can extend cloud computing to the edge of the network so as to reduce latency and network congestion. However, existing encryption schemes were rarely used in fog environment, resulting in high computational and storage overhead. Aiming at the demands of local information for terminal device and the shortcomings of cloud computing framework in supporting mobile applications, by taking the hospital scene as an example, a searchable personal health records framework with fine-grained access control in cloud-fog computing is proposed. The proposed framework combines the attribute-based encryption (ABE) technology and search encryption (SE) technology to implement keyword search function and fine-grained access control ability. When keyword index and trapdoor match are successful, the cloud server provider only returns relevant search results to the user, thus achieving a more accurate search. At the same time, the scheme is multi-authority, and the key leakage problem is solved by dividing the user secret key distribution task. Moreover, in the proposed scheme, we securely outsource part of the encryption and decryption operations to the fog node. It is effective both in local resources and in resource-constrained mobile devices. Based on the decisional q-parallel bilinear Diffie-Hellman exponent (q-DBDHE) assumption and decisional bilinear Diffie-Hellman (DBDH) assumption, our scheme is proven to be secure. Simulation experiments show that our scheme is efficient in the cloud-fog environment., Competing Interests: The authors have declared that no competing interests exist.

Notch signaling is conserved in most multicellular organisms and plays critical roles during animal development. The core components and major signal transduction mechanism of Notch signaling have been extensively studied. However, our understanding of how Notch signaling activity is regulated in diverse developmental processes still remains incomplete. Here, we report a genetic mosaic screen in Drosophila melanogaster that leads to identification of Notch signali ng modulators during wing development. We discovered a group of genes required for the formation of the fly wing margin, a developmental process that is strictly dependent on the balanced Notch signaling activity. These genes encode transcription factors, protein phosphatases, vacuolar ATPases and factors required for RNA transport, stability, and translation. Our data support the view that Notch signaling is controlled through a wide range of molecular processes. These results also provide foundations for further study by showing that Me31B and Wdr62 function as two novel modulators of Notch signaling activity., Competing Interests: The authors have declared that no competing interests exist.

Although numerous studies have described the relationship between HPA axis dysregulation and internalizing symptoms among adolescents, research using hair cortisol concentrations in pre- and young adolescent samples has not been reported. We investigated the association of self-reported internalizing symptoms with cortisol concertration in hair among pre- and young adolescents aged 10-12 years. Forty-six boys and 39 girls supplied a hair sample of at least 3 cm in length for an analysis of this period (3 months) cortisol excretion. Saliva cortisol reactivity to the Trier Social Stress Test for Children (TSST-C) also was assessed. The study found a positive association between ratings of depressive symptoms and cumulative levels of hair cortisol only in boys. Furthermore, higher ratings of anxiety symptoms were associated with lower hair cortisol concertration and lower saliva cortisol reactivity among girls. This study provides the first evidence for the notion that depressive symptoms in boys are associated with long-term cortisol concertration in hair, whereas anxiety symptoms in girls are associated with HPA-axis hypoactivity, when hair cortisol concentrations and saliva cortisol reactivity to acute stress are assessed concurrently.