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Polyphenylene sulfide (PPS) fiber is widely used in the fields of high-temperature filtration, protective clothing, electronics, automobile, and aircrafts sectors relying on its excellent heat and chemical resistance. However, PPS fiber is easily oxidized under high temperature, which vastly restricts its applications. In this study, using the copper nanoparticles loaded halloysite nanotubes (HNTs@Cu) as a nanofiller, we prepared a PPS composite fiber with improved oxidation resistance. The successful loading of copper nanoparticles into HNTs was demonstrated through TEM and elemental analysis. The crystallinity, orientation, thermal and mechanical properties of PPS nanocomposite fibers were investigated via DSC, XRD, WXRD, TGA and mechanical test. While the mechanical performance of the composite fibers was slightly decreased, the thermal stability was improved when comparing to the neat PPS fiber. The composite fiber with 1.0 wt.% loading of HNTs@Cu showed an over 100% retention rate of breaking strength after thermal oxidative aging, suggesting an improvement in oxidation resistance of PPS fiber. This work provides an effective and accessible method for improving the thermal stability and oxidation resistance of PPS fibers, which thereby helps to extend the applications of PPS fibers in high temperature environment.

Cryptococcal meningitis (CM) is increasingly recognised in human immunodeficiency virus (HIV)-uninfected patients with high mortality. The efficacy and safety profiles of induction therapy with high-dose fluconazole plus flucytosine remain unclear.HIV-uninfected CM patients who received high-dose fluconazole (800 mg/d) for initial therapy in Huashan Hospital were included in this retrospective study from January 2013 to December 2018. Efficacy and safety of initial therapy, clinical outcomes and risk factors were evaluated.Twenty-seven (71.1%) patients who received high-dose fluconazole with flucytosine combination therapy and 11 (28.9%) having fluconazole alone for induction therapy were included. With a median duration of 42 days (IQR, 28-86), the successful response rate of initial therapy was 76.3% (29/38), while adverse drug reactions occurred in 14 patients (36.8%). The rate of persistently positive cerebrospinal fluid (CSF) culture results was 30.6% at 2 weeks, which was significantly associated with CSF CrAg titre1:1280 (OR 9.56; 95% CI 1.40-103.65; p = .010) and CSF culture of Cryptococcus 3.9 logInduction therapy with high-dose fluconazole (800 mg/d), combined with flucytosine, effectively treated HIV-uninfected CM and was well tolerated. Long-term fluconazole treatment with continued monitoring is beneficial for patients with persistent infection.

Congenital heart disease (CHD) is the most common type of birth defect and the main noninfectious cause of death during the neonatal stage. The non-POU domain containing, octamer-binding gene, NONO, performs a variety of roles involved in DNA repair, RNA synthesis, transcriptional and post-transcriptional regulation. Currently, hemizygous loss-of-function mutation of NONO have been described as the genetic origin of CHD. However, essential effects of NONO during cardiac development have not been fully elucidated. In this study, we aim to understand role of Nono in cardiomyocytes during development by utilizing the CRISPR/Cas9 gene editing system to deplete Nono in the rat cardiomyocytes H9c2. Functional comparison of H9c2 control and knockout cells showed that Nono deficiency suppressed cell proliferation and adhesion. Furthermore, Nono depletion significantly affected the mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis, resulting in H9c2 overall metabolic deficits. Mechanistically we demonstrated that the Nono knockout impeded the cardiomyocyte function by attenuating phosphatidyl inositol 3 kinase-serine/threonine kinase (Pi3k/Akt) signaling via the assay for transposase-accessible chromatin using sequencing in combination with RNA sequencing. From these results we propose a novel molecular mechanism of Nono to influence cardiomyocytes differentiation and proliferation during the development of embryonic heart. We conclude that NONO may represent an emerging possible biomarkers and targets for the diagnosis and treatment of human cardiac development defects.

There are concerns on avoiding diagnostic delay and misdiagnosis for chronic pulmonary aspergillosis due to its high morbidity and mortality. A proportion of CPA patients test negative for Aspergillus IgG.

AA could decrease TGF-β1 secretion and suppress tubulointerstitial fibrosis by directly inhibiting TGF-βR1 and activate the autophagy–lysosome system in DN fibrosis.

Central nervous system (CNS) aspergillosis is an uncommon but fatal disease, the diagnosis of which is still difficult.We aim to explore the diagnositic performance of non-cultural methods for CNS aspergillosis.In this retrospective study, all pathologically confirmed rhinosinusitis patients in whom cerebrospinal fluid (CSF) galactomannan (GM) test and metagenomic next-generation sequencing (mNGS) had been performed were included. We evaluated the diagnostic performances of CSF GM optical density indexes (ODI) at different cut-off values and compared performance with mNGS in patients with and without CNS aspergillosis, as well as in patients with different manifestations of CNS aspergillosis.Of the 21 proven and probable cases, 1 had positive culture result, 5 had positive mNGS results and 10 had a CSF GM ODI of 0.7. Sample concordance between mNGS and GM test was poor, but best diagnostic performance was achieved by combination of GM test (ODI of 0.7) and mNGS, which generated a sensitivity of 61.9% and specificity of 82.6%. Further investigation of combination diagnostic performances in different kind of CNS aspergillosis was also conducted. Lowest sensitivity (42.9%) was identified in abscess group, while increased sensitivity (60.0%) were achieved in abscess with encephalitis groups. Combination test exhibited the best performance for encephalitis patients who had only CSF abnormalities, in whom the sensitivity and specificity were 77.8% and 82.6%, respectively.In conclusion, combination of these 2 tests might be useful for diagnosis of CNS aspergillosis associated with fungal rhinosinusitis, especially in encephalitis patients.

We aim to assess the efficacy and safety profiles of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer using a meta-analysis.We extracted and examined data from phase I, II and III clinical trials from PubMed, Embase, Web of Science, and Cochrane Library, which included patients with metastatic castration-resistant prostate cancer who were treated with immune checkpoint inhibitors. We performed a meta-analysis to investigate several indexes of efficacy and safety, including the objective response rate, 1-year overall survival (OS) rate, prostate-specific antigen response rate, and adverse event rate of immune checkpoint inhibitors. The material data were calculated and pooled using The R Project for Statistical Computing and STATA 12.0 software.We identified 12 clinical trials in our study. We assessed the pooled frequencies of all-grade AEs and grade ≥ 3 AEs first and showed 0.82 (95% CI: 0.74-0.91, I2 = 94%, P.01) and 0.42 (95% CI: 0.33-0.54, I2 = 96%, P.01), respectively. The objective response rate was 0.10 (95% CI: 0.04-0.19, I2 = 70%, P.01), and the 1-year OS and prostate-specific antigen response rate were 0.55 (95% CI: 0.45-0.67, I2 = 93%, P.01) and 0.18 (95% CI: 0.16-0.20, I2 = 43%, P = .03), respectively.The immune checkpoint inhibitors therapy was well tolerated and showed potential to improve tumor responses in patients with metastatic castration-resistant prostate cancer.

The cerebrospinal fluid (CSF) immune responses in HIV-uninfected cryptococcal meningitis (CM) have not been well studied. In this study, we aimed to explore the phenotype of CSF immune response during the course of disease and to examine relationships between phenotypes and disease severity. We profiled the CSF immune response in 128 HIV-uninfected CM and 30 pulmonary cryptococcosis patients using a 27-plex Luminex cytokine kit. Principal component analyses (PCA) and logistic regression model were performed. Concentrations of 23 out of 27 cytokines and chemokines in baseline CSF were significantly elevated in CM patients compared with pulmonary cryptococcosis cases. In CM patients with Cryptococcus neoformans infection, IL-1ra, IL-9, and VEGF were significantly elevated in immunocompetent cases. Cytokine levels usually reached peaks within the first 2 weeks of antifungal treatment and gradually decreased over time. PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting of Th1, Th2, and Th17 type cytokines. Prognostic analysis showed that higher scores for the PCs loading pro-inflammatory cytokines, IFN-γ, TNF-α, and IL-12; and anti-inflammatory cytokine, IL-4; and chemokines, Eotaxin, FGF-basis, and PDGF-bb; as well as lower scores for the PCs loading RANTES were associated with disease severity, as defined by a Glasgow Coma Scale of

Diabetic nephropathy (DN) fibrosis is a major cause of end-stage renal disease with unsatisfactory therapy drugs and a low 5-year survival rate. There is a lack of specific and effective treatment drugs. In the present study, we report that asiatic acid (AA), a triterpenic acid found in

Bepridil is a commonly used medication for arrhythmia and heart failure. It primarily exerts hemodynamic effects by inhibiting Na

Our aim was to study whether radial pulse wave signals can improve the risk prediction of incident hypertension and are associated with its concomitant metabolic risk factors beyond the traditional cardiovascular risk factor Ba-PWV. By enrolling 523 Chinese subjects in this study, linear and stepwise regression analysis was performed to assess the association of radial artery pulse wave signals and Ba-PWV with blood pressure and its related metabolic risk factors such as fasting plasma glucose (FPG), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and uric acid (UA). The area under the receiver-operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated by risk assessment plot to compare the discriminative ability among models with and without radial artery pulse wave signals. After adjusting related confounding factors, radial artery pulse wave variable h3/h1 was selected as the sensitive influential factor for blood pressure. Moreover, a new model with h3/h1 had a higher AUC than the reference model without it (0.86 vs 0.84; P=0.030). And the NRI and IDI for the new model was 50.0% (P=0.017) and 3.16% (P=0.044), respectively. In addition to Ba-PWV, we found that the decrease of t4, t5, and h5 might be associated with higher FPG, TC, LDL-C, and UA and lower HDL-C. This research might provide a valuable additional tool for remote wearable monitoring of radial artery pulse wave signals in hypertension risk evaluation and management.

Background Causes of voriconazole-related visual adverse events (VVAE) remained controversial. Objectives We aimed to explore the relationship between voriconazole serum concentrations and VVAE as well as the potential influence of transient receptor potential melastatin 1 (TRPM1) on VVAE. Patients/methods This prospective observational cohort study was done in two stages. Patients who received voriconazole for invasive fungal diseases were consecutively enrolled. Correlations between voriconazole trough levels and VVAE were explored in 76 patients. Genotyping was further conducted for 17 tag SNPs of TRPM1 in a larger population of 137 patients. Genotype distributions were compared between patients with and without VVAE. Result Of the 76 patients, a total of 229 steady-state voriconazole trough levels were evaluated, 69.9% of which were within the target range (1-5.5 mg/L). No correlations were found between voriconazole trough levels and VVAE. Of the total 137 patients, VVAE occurred in 37 (27.0%) patients, including visual hallucination (13.9%, 19/137) and visual disturbances (19.0%, 26/137). Significant difference in TRPM1 genotype distribution was only observed in patients with visual hallucination but not with visual disturbances. We found that rs890160 G/T genotype was under-presented (OR, 0.11; 95% CI, 0.01-0.84; P = .011) and rs1378847 C/C genotype was more frequently detected (OR, 8.89; 95% CI, 1.14-69.02; P = .013) in patients with visual hallucination when compared with those without. Conclusion Transient receptor potential melastatin 1 was genetically associated with voriconazole-related visual hallucination. The correlation was failed to found between voriconazole trough levels and VVAE.

Excessive proliferation and migration of airway smooth muscle cell (ASMC) contribute to asthma pathogenesis. Long noncoding RNAs (lncRNAs) are reported to take part in asthma pathogenesis. This study is targeted at deciphering the role of the lncRNA antisense noncoding RNA in the INK4 locus (ANRIL) in ASMC proliferation, migration and extracellular matrix (ECM) deposition. qRT-PCR was performed to determine ANRIL, miR-98-5p, and cyclin D1 (CCND1) mRNA expression levels in transforming growth factor-β1 (TGF-β1)-treated ASMCs. CCK-8 and Transwell assays were employed to examine ASMC proliferation and migration, respectively. Dual-luciferase reporter gene assay and RNA immunoprecipitation assay were carried out for analyzing the targeted relationship of miR-98-5p with ANRIL or CCND1 mRNA 3'-UTR. The levels of CCND1 and ECM proteins (such as fibronectin, COL3A1, and COL1A2) in ASMCs were detected through Western blot. In this work, we found that ANRIL and CCND1 were up-regulated in TGF-β1-treated ASMCs, whereas miR-98-5p was down-regulated. ANRIL overexpression facilitated the proliferation, ECM deposition and migration of TGF-β1-induced ASMCs, while knocking down ANRIL had the opposite effect. Furthermore, ANRIL targeted miR-98-5p directly, and CCND1 was miR-98-5p's downstream target. ANRIL indirectly increased CCND1 expression in ASMCs via competitively binding to miR-98-5p. MiR-98-5p inhibition or CCND1 overexpression counteracted the inhibiting effect that ANRIL knockdown had on TGF-β1-stimulated ASMC proliferation, migration and ECM deposition. In conclusion, ANRIL indirectly up-regulates CCND1 expression by targeting miR-98-5p to promote ASMC proliferation, migration and ECM deposition, thus facilitating the pathogenesis of asthma.

Active control algorithms are widely used in enclosed-space noise control with the nonlinearities of secondary-source loudspeakers ignored. Inspired by nonlinear energy transfer resulting from nonlinear stiffness, this work concerns using a nonlinear loudspeaker to improve enclosed-space noise control. An enclosed-space active noise control system with a nonlinear loudspeaker is modeled. Based on the model, an approximate frequency response function of the noise control system is derived analytically via the harmonic balance method and verified using numerical methods. A globally consistent and bounded Lyapunov function is derived. The effects of the mass, nonlinear stiffness, volume, and area ratio on the noise reduction are also explored. Both analytical and numerical results demonstrate that the improved nonlinear loudspeaker is effective in improving the low-power characteristics of the loudspeaker, increasing noise reduction and improving fault-tolerant and robustness of the active noise control system.

Cyclocarya paliurus, a Chinese herbal medicine and new food resource, contains a triterpenic-acid-rich extract that demonstrated ameliorative effect on diabetic nephropathy (DN). A more in-depth discovery of functional components led to the isolation of seven new triterpenoids including two pentacyclic triterpenes, 1α,2α,3β,23-tetrahydroxyolean-12-en-28-oic acid and 2α,3β,22α-tirhydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside, and five tetracyclic triterpenoid glycosides (cypaliurusides N-R), together with twelve known compounds from the leaves of C. paliurus. Their structures were determined using a comprehensive analysis of chemical and spectroscopic data. Partial compounds were assessed for anti-fibrotic activities in high-glucose and TGF-β1 induced HK-2 cells. Compound 16 remarkably decreased the level of fibronectin with an inhibition rate of 37.1%. Furthermore, 16 effectively alleviated the epithelial-mesenchymal transformation (EMT) process by upregulating E-cadherin expression and downregulating α-SMA expression, and it significantly decreased the level of the transcriptional inhibitors (Snail and Twist) of E-cadherin. The discovery of anti-fibrotic compounds from C. paliurus provides the potential utilization and functional candidates for the DN prevention.

Cryptococcosis is a potentially lethal disease that is primarily caused by the fungus Cryptococcus neoformans, treatment options for cryptococcosis are limited. Here, we show glucuronoxylomannan, the major polysaccharide component of C. neoformans, induces the recruitment of neutrophilic myeloid-derived suppressor cells in mice and patients with cryptococcosis. Depletion of neutrophilic myeloid-derived suppressor cells enhances host defense against C. neoformans infection. We identify C-type lectin receptor-2d recognizes glucuronoxylomannan to potentiate the immunosuppressive activity of neutrophilic myeloid-derived suppressor cells by initiating p38-mediated production of the enzyme arginase-1, which inhibits T-cell mediated antifungal responses. Notably, pharmacological inhibition of arginase-1 expression by a specific inhibitor of p38, SB202190, or an orally available receptor tyrosine kinase inhibitor, vandetanib, significantly enhances T-cell mediated antifungal responses against cryptococcosis. These data reveal a crucial suppressive role of neutrophilic myeloid-derived suppressor cells during cryptococcosis and highlight a promising immunotherapeutic application by inhibiting arginase-1 production to combat infectious diseases.

BACKGROUND Cryptococcal meningitis (CM)-associated immune reconstitution inflammatory syndrome (IRIS) is associated with high mortality, the epidemiology and pathophysiology of which is poorly understood, especially in non-HIV populations. OBJECTIVES We aim to explore the incidence, clinical risk factors, immunological profiles and potential influence of leukotriene A4 hydroxylase (LTA4H) on non-HIV CM IRIS populations. METHODS In this observational cohort study, 101 previously untreated non-HIV CM patients were included. We obtained data for clinical variables, 27 cerebrospinal fluid (CSF) cytokines levels and LTA4H genotype frequencies. Changes of CSF cytokines levels before and at IRIS occurrence were compared. RESULTS Immune reconstitution inflammatory syndrome was identified in 11 immunocompetent males, generating an incidence of 10.9% in non-HIV CM patients. Patients with higher CrAg titres (> 1:160) were more likely to develop IRIS, and titre of 1:1280 is the optimum level to predict IRIS occurrence. Baseline CSF cytokines were significantly higher in IRIS group, which indicated a severe host immune inflammation response. Four LTA4H SNPs (rs17525488, rs6538697, rs17525495 and rs1978331) exhibited significant genetic susceptibility to IRIS in overall non-HIV CM, while five cytokines were found to be associated with rs1978331, and baseline monocyte chemotactic protein 1 (MCP-1) became the only cytokine correlated with both IRIS and LTA4H SNPs. CONCLUSIONS Our study suggested that non-HIV CM patients with high fungal burden and severe immune inflammation response were more likely to developed IRIS. LTA4H polymorphisms may affect the pathogenesis of IRIS by regulating the level of baseline CSF MCP-1.

Background Cirrhosis is an end-stage liver disease and is reported as an independent risk factor for cryptococcosis. Information about cryptococcosis in patients with cirrhosis remains sparse. Methods Human immunodeficiency virus–uninfected patients with cryptococcosis and cirrhosis admitted to Huashan Hospital from July 2005 to June 2020 were reviewed. Efficacy and safety of antifungal treatments, clinical outcome, and prognostic factors of mortality were evaluated. Results A total of 49 cryptococcosis patients with cirrhosis were included. Sites of infection involved central nervous system (n = 38), lung (n = 21), bloodstream (n = 11), skin (n = 1), and bone (n = 1). Nine patients (18.4%) had pulmonary cryptococcosis alone. Viral hepatitis B infection (57.1%) was the most common cause of cirrhosis. Patients with decompensated cirrhosis (Child-Pugh class B and C) were more likely to have extrapulmonary cryptococcosis than those with compensated cirrhosis (90.7% vs 64.7%; P = .049). In patients with cryptococcal meningitis (CM), 7 were treated with amphotericin B with/without flucytosine, 5 with amphotericin B plus fluconazole with/without flucytosine, and 12 with fluconazole with/without flucytosine. Fluconazole (>400 mg/day) was well tolerated and only 1 patient had a mild adverse drug reaction. At 1-year follow-up, all patients treated with fluconazole with or without flucytosine survived, whereas the mortality rate was 14.3%–20.0% in the remaining groups. In addition, Child-Pugh class C cirrhosis (hazard ratio [HR], 7.555 [95% confidence interval {CI}, 1.393–40.971]) and time to diagnosis >120 days (HR, 18.619 [95% CI, 2.117–163.745]) were independent factors for 1-year mortality in patients with CM. Conclusions Severity of cirrhosis was associated with developing extrapulmonary cryptococcosis and mortality in CM. Early diagnosis and intervention of cryptococcosis are key for outcome., This study shows a higher rate of extrapulmonary cryptococcosis and higher mortality of cryptococcal meningitis in patients with more advanced cirrhosis, which calls on early recognition and timely intervention of cryptococcosis in patients with cirrhosis.

AIM Genetic tools are a prerequisite for engineering cell factories for synthetic biology and biotechnology. Methylorubrum extorquens is an important platform for a future one-carbon (C1) bioeconomy, but its application is currently limited by the availability of genetic tools. Small regulatory RNA (sRNA) is an important regulatory factor in bacteria and has been applied for gene repression in several strains. This study aimed to construct a synthetic sRNA system based on the MicC scaffold and the chaperone Hfq to control gene expression in M. extorquens. METHODS AND RESULTS Initially, the exogenous lacZ gene was transposed into the M. extorquens chromosome as a reporter, and corresponding β-galactosidase was measured to assess the knockdown efficiency of lacZ. A synthetic sRNA containing a 24-nt antisense RNA targeting lacZ and an Escherichia coli MicC scaffold were constructed, and different Hfqs from E. coli, M. extorquens AM1 and PA1 were further identified. The results showed that the expression of endogenous hfqs from the chromosome in M. extorquens strains was inadequate, and only when it was overexpressed via the plasmid did the colonies show a colour change and a corresponding decrease in β-galactosidase expression. More specifically, M. extorquens strains with overexpressing their own Hfq showed the best gene repression efficiency. Furthermore, this E. coli MicC scaffold and AM1 Hfq system were combined to knock down crtI gene expression in AM1, leading to an 86% decrease in carotenoid production (0·09 mg g-1 ) compared to that (0·65 mg g-1 ) in the wild-type strain. CONCLUSION A functional synthetic sRNA system combined with E. coli MicC and endogenous Hfq was constructed in M. extorquens strains, which was able to interfere with the target crtI gene and reduce carotenoid production. SIGNIFICANCE AND IMPACT OF THE STUDY The synthetic sRNA system reported in this study provides a genetic tool for the manipulation of M. extorquens. The present findings might be helpful for achieving high-throughput gene knockdown expression.

Four new cytochalasans, arbuschalasins A-D (1-4), along with thirteen known analogues (5-17), were isolated from the solid rice medium of endophytic fungus Xylaria arbuscula. Arbuschalasins A-B feature a rare 5/6/6/6 fused ring system while arbuschalasin D was characterized as the first example of natural cytochalasans that possesses a 5/5/11 fused scaffold. The structures of 1-4 were assigned by spectroscopic data, with their absolute structures being determined by electronic circular dichroism (ECD) calculations. All of the isolates were evaluated against the human colorectal adenocarcinoma cell lines (HCT15). Compounds 6 and 7 showed significant inhibitory effects (IC

Contains fulltext : 235737.pdf (Publisher’s version ) (Closed access) Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.

We conducted a systematic literature review to obtain risk population-based fungal disease incidence or prevalence data from China. Data were categorized by risk factors and extrapolated by using most recent demographic figures. A total of 71,316,101 cases (5.0% of the population) were attributed to 12 risk factors and 17 fungal diseases. Excluding recurrent Candida vaginitis (4,057/100,000 women) and onychomycosis (2,600/100,000 persons), aspergillosis (317/100,000 persons) was the most common problem; prevalence exceeded that in most other countries. Cryptococcal meningitis, an opportunistic infection, occurs in immunocompetent persons almost twice as often as AIDS. The pattern of fungal infections also varies geographically; Talaromyces marneffei is distributed mainly in the Pearl River Basin, and the Yangtze River bears the greatest histoplasmosis burden. New host populations, new endemic patterns, and high fungal burdens in China, which caused a huge impact on public health, underscore the urgent need for building diagnostic and therapeutic capacity.

Ethnopharmacological relevance Cyclocarya paliurus (CP) is a traditional Chinese herb and possesses a variety of biological activities including anti-hyperglycemia, anti-hyperlipidemia, antioxidant and anti-inflammation. Arjunolic acid (AA) is an abundant and bioactive ingredient in CP that shows significant protection against many metabolic diseases such as diabetic complication. Diabetic retinopathy (DR) is a serious complication of diabetes and may lead to vision loss. However, the protective effects and underlying mechanisms of AA against DR is not still understood. Aim of the study We aimed to investigate whether AA activates AMPK/mTOR/HO-1 regulated autophagy pathway to alleviate DR. Materials and methods In the study, the STZ-induced diabetic model of rats was established, and AA with 10 and 30 mg/kg dosages was given orally for ten weeks to investigate their effect on retinal injury of DR. H2O2-induced ARPE-19 cells were applied to evaluate anti-apoptosis and anti-oxidant effect of AA. Results The results revealed that AA could prevent STZ-induced weight loss and increase the retinal thickness and nuclei counts. The level of HO-1 protein was upregulated both in vivo and in vitro. In addition, AA prevented retinal damage and cell apoptosis through the AMPK-mTOR-regulated autophagy pathway. Furthermore, anti-apoptosis capacity, as well as the expression of HO-1 and LC3 protein, were effectively locked by AMPK inhibitor dorsomorphin dihydrochloride (compound C). Conclusions This finding implies that AA may be a promising candidate drug by protecting retinal cells from STZ-induced oxidative stress and inflammation through the AMPK/mTOR/HO-1 regulated autophagy pathway.

Background Cryptococcal meningitis (CM) is a significant source of mortality, the pathogenesis of which has not been fully understood, especially in non-HIV infected populations. We aimed to compare single nucleotide polymorphisms (SNPs) of Toll-like receptor (TLR) in non-HIV CM patients with those of healthy controls, and to assess the links among TLR SNPs, cytokine concentrations in cerebrospinal fluid (CSF), and clinical severity. Methods This observational cohort study was done in 2 stages: a discovery stage and a validation stage. We conducted a case-control genetic association study between 159 non-HIV CM patients and 468 healthy controls. TLR SNPs significantly related to susceptibility were further validated in a second cohort of 583 subjects from a certain district. Cytokine concentrations in CSF were used to evaluate the in situ immune response of CNS after infection. Correlations among TLR SNPs, CSF cytokine concentrations, and clinical severity were validated in a third prospective cohort of 99 previously untreated non-HIV CM patients. Logistic regression model was used to determine the independent predictors for disease severity. Findings In the discovery stage, the genotype distributions of 8 TLR SNPs in non-HIV CM patients exhibited a significant difference in comparison with controls, of which 3 SNPs remained statistically significant in patients without predisposing factors. In the validation stage, 5 of the 8 nominated TLR SNPs were found to influence CSF cytokine expression. Eighteen cytokines were significantly up-regulated in severely ill patients, among which 12 were affected by TLR2 rs3804099. The rs3804099 was also found in relation to disease severity. High IL-10 levels in CSF (OR 2*97, 95% CI 1*49-5*90; p=0*002) was suggested as an independent predictor for severity after adjusted for possible confounders. Interpretation TLR participate in both the occurrence and the pathogenesis of non-HIV CM. The in situ immune responses of CM were under genetic influence of TLR and contributed to disease severity. Our findings inform of an opportunity for early evaluation and treatment of non-HIV CM. TLR might also become a potential target on which to base host-directed immunotherapy. Funding: National Natural Science Foundation of China and National Key Basic Research Program of China (973 Program). Declaration of Interest: We declare no competing interests. Ethical Approval: Ethical approval was obtained from the medical ethics committee of Huashan Hospital, Mengchao Hepatobiliary Hospital, Fujian HIV/AIDS Diagnosis and Treatment Center, and No. 476 Hospital of Fuzhou General Hospital.

Four new C-11 monosaccharide attached dammarane triterpenoid glycosides cypaliurusides S V (1–4), along with nine known dammarane triterpenoid glycosides (5–13) were isolated from a CHCl3-soluble extract of the leaves of Cyclocarya paliurus. All characterized compounds were assayed for their cytotoxicities against HepG2 cells and 10 compounds were evaluated for the agonistic effects on sirtuin1 (SIRT1). The results showed that compounds 1, 5 and 6 were strongly cytotoxic in HepG2 cell line. Two dammarane triterpenoid glycosides 3 and 10 exhibited agonistic activities on SIRT1 with IC50 of 10 μM and 20 μM, respectively.

ResumoObjetivosO aumento da prevalência da obesidade é um problema sério de saúde e econômico. A obesidade tem sido relatada como um dos principais contribuintes para uma variedade de doenças crônicas. A obesidade infantil tem aumentado nas últimas décadas e levado a complicações de saúde. Milhões de bebês e crianças são submetidos a cirurgia todos os anos por diversos motivos de saúde. O presente estudo foi feito para avaliar o efeito da raquianestesia com doses equipotentes de ropivacaína e bupivacaína em ratos recém‐nascidos com sobrepeso.MétodosAs crias de ratos Sprague‐Dawley foram alimentadas em excesso com dieta rica em gordura para induzir obesidade. Avaliações comportamentais para bloqueio sensorial e motor foram feitas por meio da avaliação das latências de retirada térmicas e mecânicas em vários intervalos de tempo após injeções por via intratecal de bupivacaína (5,0mg·kg−1) e ropivacaína (7,5mg·kg−1) em ratos P14. Tecido medular foi analisado para apoptose por determinação da caspase‐3 ativada, com o uso de anticorpo monoclonal anti‐caspase 3 ativada e ecoloração com Fluoro‐Jade C. A função da coluna vertebral em longo prazo em filhotes de ratos P30 foi avaliada.ResultadosA exposição à anestesia intratecal em P14 aumentou as latências térmicas e mecânicas e observamos aumento da apoptose, como apresentado pelo aumento da caspase‐3 ativada e células positivas para Fluro‐Jade C. Alterações significativas da função da coluna vertebral foram observadas em filhotes alimentados com dieta rica em gordura versus filhotes controles não obesos em dieta padrão. Bupivacaína produziu efeitos apoptóticos mais pronunciados sobre os filhotes P14; ropivacaína, entretanto, produziu efeitos duradouros, como evidenciado nos testes de função motora em P30.ConclusãoRopivacaína e bupivacaína induziram toxicidade medular mais pronunciada nos filhotes de ratos sobrealimentados do que nos controles normais.AbstractObjectivesThe increase in the prevalence of obesity presents a significant health and economic problem. Obesity has been reported to be a major contributor to variety of chronic diseases. Childhood obesity has been rising over the past decades leading to various complications in health. Millions of infants and children undergo surgery every year on various health grounds. The present investigation was undertaken to evaluate the effect of spinal anesthesia of equipotent doses of ropivacaine and bupivacaine on over‐weight neonatal rats.MethodsThe Sprague‐Dawley rat pups were overfed on high fat diet to induce obesity. Behavioral assessments for sensory and motor blockade was made by evaluating thermal and mechanical withdrawal latencies at various time intervals following intrathecal injections of bupivacaine (5.0mg·kg−1) and ropivacaine (7.5mg·kg−1) in P14 rats. Spinal tissue was analyzed for apoptosis by determination of activated caspase‐3 using monoclonal anti‐activated caspase‐3 and Fluoro‐Jade C staining. Long‐term spinal function in P30 rat pups was evaluated.ResultsExposure to intrathecal anesthesia in P14 increased thermal and mechanical latencies and was observed to increase apoptosis as presented by increase in activated caspase‐3 and Fluro‐Jade C positive cells. Significant alterations in spinal function were observed in high fat diet‐fed pups as against non‐obese control pups that were on standard diet. Bupivacaine produced more pronounced apoptotic effects on P14 pups; ropivacaine however produced long lasting effects as evidenced in motor function tests at P30.ConclusionRopivacaine and bupivacaine induced spinal toxicity that was more pronounced in over‐fed rat pups as against normal controls.

Background: This study aims to evaluate the risk factors of retinal re-detachment and visual outcome after silicone oil removal (SOR) in silicone oil-filled eyes.Methods: A total of 57 patients who underwent pars plana vitrectomy (PPV) and silicone oil injection for retinal detachment (RD), and subsequently underwent a silicone oil removal procedure. Pre-operative examinations were performed to determine the best-corrected visual acuity (BCVA) using the Snellen chart, while Icare was used to determine the intraocular pressure (IOP). In addition, slit-lamp examination of the anterior segment and lens, fundus pre-set lens examination for the posterior segment, color fundus photography, anterior segment photography and type B-ultrasonic scans were performed.Results: In five of 57 patients (8.77%), the retina re-detached following the removal of silicone oil. The factors for re-detachment were proliferative vitreoretinopathy (PVR) (two cases), the formation of new retinal breaks (two cases), and incomplete membrane peeling (one case). The rate of retinal re-detachment (reRD) was statistically independent of the duration of silicone oil endotamponade (P = .810). BCVA significantly improved following the removal of silicone oil (P = .001). The duration of the silicone oil tamponade was significant in the development of cataract (27 eyes, 47.3%; P = .0008), emulsified oil in the anterior chamber (13 eyes, 22.8%; P = .009), and glaucoma (seven eyes, 12.2%).Conclusion: The improvement of visual acuity was discovered following the removal of the intraocular silicone oil. Although the duration of the intraocular silicone oil endotamponade had no effect on the rate of retinal attachment, a longer duration of silicone oil endotamponade can lead to the development of complications, such as cataract, emulsified oil in the anterior chamber and glaucoma, suggesting that the earlier removal of oil should be performed.

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Candida albicans and Cryptococcus neoformans, human-pathogenic fungi found worldwide, are receiving increasing attention due to high morbidity and mortality in immunocompromised patients. In the present work, 110 fungus pairs were constructed by coculturing 16 wood-decaying basidiomycetes, among which coculture of Trametes robiniophila Murr and Pleurotus ostreatus was found to strongly inhibit pathogenic fungi through bioactivity-guided assays. A combination of metabolomics and molecular network analysis revealed that 44 features were either newly synthesized or produced at high levels in this coculture system and that 6 of the features that belonged to a family of novel and unusual linear sesterterpenes contributed to high activity with MICs of 1 to 32 μg/ml against pathogenic fungi. Furthermore, dynamic 13C-labeling analysis revealed an association between induced features and the corresponding fungi. Unusual sesterterpenes were 13C labeled only in P. ostreatus in a time course after stimulation by the coculture, suggesting that these sesterterpenes were synthesized by P. ostreatus instead of T. robiniophila Murr. Sesterterpene compounds 1 to 3 were renamed postrediene A to C. Real-time reverse transcription-quantitative PCR (RT-qPCR) analysis revealed that transcriptional levels of three genes encoding terpene synthase, farnesyl-diphosphate farnesyltransferase, and oxidase were found to be 8.2-fold, 88.7-fold, and 21.6-fold higher, respectively, in the coculture than in the monoculture, indicating that biosynthetic gene cluster 10 was most likely responsible for the synthesis of these sesterterpenes. A putative biosynthetic pathway of postrediene A to postrediene C was then proposed based on structures of sesterterpenes and molecular network analysis. IMPORTANCE A number of gene clusters involved in biosynthesis of secondary metabolites are presumably silent or expressed at low levels under conditions of standard laboratory cultivation, resulting in a large gap between the pool of discovered metabolites and genome capability. This work mimicked naturally occurring competition by construction of an artificial coculture of basidiomycete fungi for the identification of secondary metabolites with novel scaffolds and excellent bioactivity. Unusual linear sesterterpenes of postrediene A to C synthesized by P. ostreatus not only were promising lead drugs against human-pathogenic fungi but also highlighted a distinct pathway for sesterterpene biosynthesis in basidiomycetes. The current work provides an important basis for uncovering novel gene functions involved in sesterterpene synthesis and for gaining insights into the mechanism of silent gene activation in fungal defense.

Cryptococcosis is one of the most common opportunistic infections in both immunocompetent and immunocompromised hosts. Although the cryptococcal antigen (CrAg) lateral flow assay (LFA) has been widely used in clinical settings due to its high sensitivity and specificity, the diagnostic value of a low CrAg LFA titers remains unclear. In this study, we performed a retrospective analysis of 149 HIV-negative patients with low CrAg LFA titers (≤1:10) in a Chinese tertiary hospital from January 2013 to December 2017, to evaluate the diagnostic value of low CrAg LFA titers in serum and cerebrospinal fluid (CSF) at different thresholds. Sensitivity and specificity of low CrAg LFA titers in patients with definitive diagnoses of cryptococcosis were 39.6% (95% CI, 29.7–50.1%) and 100% (95% CI, 69.2–100%), respectively, at a threshold of 1:10 in serum. A sensitivity of 72.9% (95% CI, 62.9–81.5%) and a decreased specificity of 70.0% (95% CI, 34.8–93.3%) were observed at a threshold of 1:5 in serum. No false-positive cases were identified in patients with low CrAg titers in CSF and all positive predictive values (PPVs) were 100%. Among the cases with low serum CrAg titers, lumbar puncture was performed in 97 patients and positive CSF CrAg titers were reported in 6 patients. In conclusion, the results of this study imply that low CrAg LFA titer, either in serum or CSF, is crucial for early diagnosis of cryptococcosis in HIV-negative patients, and lumbar puncture is recommended to be performed routinely for CSF testing when a positive low serum titer is reported. Cryptococcal meningitis should be considered seriously when the CSF CrAg titer is positive.

Candida albicans and Cryptococcus neoformans, human-pathogenic fungi found worldwide, are receiving increasing attention due to high morbidity and mortality in immunocompromised patients. In the present work, 110 fungus pairs were constructed by coculturing 16 wood-decaying basidiomycetes, among which coculture of Trametes robiniophila Murr and Pleurotus ostreatus was found to strongly inhibit pathogenic fungi through bioactivity-guided assays. A combination of metabolomics and molecular network analysis revealed that 44 features were either newly synthesized or produced at high levels in this coculture system and that 6 of the features that belonged to a family of novel and unusual linear sesterterpenes contributed to high activity with MICs of 1 to 32 μg/ml against pathogenic fungi. Furthermore, dynamic (13)C-labeling analysis revealed an association between induced features and the corresponding fungi. Unusual sesterterpenes were (13)C labeled only in P. ostreatus in a time course after stimulation by the coculture, suggesting that these sesterterpenes were synthesized by P. ostreatus instead of T. robiniophila Murr. Sesterterpene compounds 1 to 3 were renamed postrediene A to C. Real-time reverse transcription-quantitative PCR (RT-qPCR) analysis revealed that transcriptional levels of three genes encoding terpene synthase, farnesyl-diphosphate farnesyltransferase, and oxidase were found to be 8.2-fold, 88.7-fold, and 21.6-fold higher, respectively, in the coculture than in the monoculture, indicating that biosynthetic gene cluster 10 was most likely responsible for the synthesis of these sesterterpenes. A putative biosynthetic pathway of postrediene A to postrediene C was then proposed based on structures of sesterterpenes and molecular network analysis. IMPORTANCE A number of gene clusters involved in biosynthesis of secondary metabolites are presumably silent or expressed at low levels under conditions of standard laboratory cultivation, resulting in a large gap between the pool of discovered metabolites and genome capability. This work mimicked naturally occurring competition by construction of an artificial coculture of basidiomycete fungi for the identification of secondary metabolites with novel scaffolds and excellent bioactivity. Unusual linear sesterterpenes of postrediene A to C synthesized by P. ostreatus not only were promising lead drugs against human-pathogenic fungi but also highlighted a distinct pathway for sesterterpene biosynthesis in basidiomycetes. The current work provides an important basis for uncovering novel gene functions involved in sesterterpene synthesis and for gaining insights into the mechanism of silent gene activation in fungal defense.

Background Invasive aspergillosis is a complication in immunocompromised patients and commonly detected in patients with hematological malignancies, which mostly affect the lungs. Because of its high iodine content, rich blood supply and capsule, the thyroid is considered to be less prone to microbial invasion thus most infectious thyroiditis cases are caused by bacteria. However, a few case reports have described thyroid gland aspergilloses, most of which were due to disseminated invasive aspergillosis. Case presentation We first report a case of thyroid gland and subcutaneous labium majus aspergillosis in a Chinese patient who received long-term glucocorticoid treatment for systemic lupus erythematosus (SLE) and lupus nephritis, and then we reviewed 36 articles describing similar aspergillus infections in 41 patients. Conclusion We included 29 cases of diagnosed aspergillus thyroiditis and analyzed clinical findings, treatments and outcomes to provide clinical information for diagnosis and prognosis of thyroiditis caused by Aspergillus fumigatus.

Microarc oxidation(MAO) was used to prepare the coatings on the surface of Al-Si alloy. Besides, scanning electron microscope (SEM), energy dispersive spectrometer (EDS) and X-ray diffraction (XRD) were utilized to research the microstructure characteristics, the components distribution, and the phase compositions, for the microarc oxidation coatings on Al-Si alloys. Furthermore, the growth process and wear properties of the coatings were explored. Results indicated that:the phase compositions of microarc oxidized coating consisted of mullite (3Al2O3·2SiO2), α- Al2O3 and γ- Al2O3. With the increase of load, the friction coefficient of the coating decreased, however it was greater than that of Al-Si alloy substrate. The wear resistance of the coating were one time higher than that of the substrate.

BackgroundChronic and granulomatous invasive fungal rhinosinusitis are important causes of blindness and craniocerebral complications. However, the classification of these 2 diseases remains controversial.MethodsWe retrospectively analyzed patients with chronic and granulomatous invasive fungal rhinosinusitus in a Chinese tertiary hospital from 2009 to 2017, with a focus on classification and comparisons.ResultsAmong 55 patients enrolled in our study, 11 (11/55, 20%) had granulomatous invasive fungal rhinosinusitis (GIFRS) and 44 (44/55, 80%) had chronic invasive fungal rhinosinusitis (CIFRS). Aspergillus fumigatus and Dematiaceous hyphomycetes were identified in 2 patients with GIFRS. Compared with granulomatous type, CIFRS was more frequently encountered in immunocompromised patients (P = .022), and the time from onset to diagnosis was much shorter (P = .001). Proptosis and orbital apex syndrome showed no significant difference between granulomatous and CIFRS in our study. The treatment options and prognosis of both diseases also showed no significant difference.ConclusionsDespite the consensus on histopathology, the classification of the chronic and granulomatous types may need further evaluation in clinical considerations.

Background Community-acquired pneumonia (CAP) is a common condition with high mortality, morbidity and healthcare costs. This study aimed to determine whether clinical pathway (CP) implementation in different hospitals in China increased antibiotic compliance with the national CP in inpatients with CAP. Methods Chart reviews of CAP cases were conducted in 18 public hospitals from 3 different regions of China in 2015. Chi-square tests and the t-test were used to compare differences between hospitals that implemented CP (CP group) and those that did not (non-CP group). Multivariate logistic analysis was adopted to test whether CP implementation for CAP in hospitals affected their overall antibiotic use compliance rates with the national CP for CAP. Results The overall compliance rate with the national CP for inpatients with CAP was 43.69%. The compliance rates for timely initial antibiotic use, recommended antibiotic use and use of the recommended combination of antibiotics and the overall compliance rate were substantially higher in the CP group than in the non-CP group. A multivariate logistic model for overall compliance in inpatients with CAP showed that the hospitals in the CP group had greater overall compliance than those in the non-CP group (odds ratio [OR] = 1.76; 95% confidence interval [CI] = 1.16–2.71) after controlling for hospital and inpatient characteristics. Conclusion In China, the overall compliance rate with the national CP for inpatients with CAP was low, but inpatients with CAP in the hospitals in the CP group received antibiotics more concordantly with the national CP. Since adherence to evidence-based care has been shown to improve clinical outcomes, internal and external support from hospitals is required to facilitate CP implementation for inpatients with CAP. Additionally, governmental commitment, hospital input and population involvement are required to improve antibiotic utilization.

The co-culture of Trametes versicolor and Ganoderma applanatum is a model of intense basidiomycete interaction, which induces many newly synthesized or highly produced features. Currently, one of the major challenges is an identification of the origin of induced features during the co-culture. Herein, we report a 13C-dynamic labeling analysis used to determine an association of induced features and corresponding fungus even if the identities of metabolites were not available or almost nothing was known of biochemical aspects. After the co-culture of T. versicolor and G. applanatum for 10 days, the mycelium pellets of T. versicolor and G. applanatum were sterilely harvested and then mono-cultured in the liquid medium containing half fresh medium with 13C-labeled glucose as carbon source and half co-cultured supernatants collected on day 10. 13C-labeled metabolome analyzed by LC-MS revealed that 31 induced features including 3-phenyllactic acid and orsellinic acid were isotopically labeled in the mono-culture after the co-culture stimulation. Twenty features were derived from T. versicolor, 6 from G. applanatum, and 5 features were synthesized by both T. versicolor and G. applanatum. 13C-labeling further suggested that 12 features such as previously identified novel xyloside [N-(4-methoxyphenyl)formamide 2-O-beta-D-xyloside] were likely induced through the direct physical interaction of mycelia. Use of molecular network analysis combined with 13C-labeling provided an insight into the link between the generation of structural analogs and producing fungus. Compound 1 with m/z 309.0757, increased 15.4-fold in the co-culture and observed 13C incorporation in the mono-culture of both T. versicolor and G. applanatum, was purified and identified as a phenyl polyketide, 2,5,6-trihydroxy-4, 6-diphenylcyclohex-4-ene-1,3-dione. The biological activity study indicated that this compound has a potential to inhibit cell viability of leukemic cell line U937. The current work sets an important basis for further investigations including novel metabolites discovery and biosynthetic capacity improvement.