Diverse function and regulation of CmSnf1 in entomopathogenic fungus Cordyceps militaris.

SNF1/AMPK protein kinases play important roles in fungal development and activation of catabolite-repressed genes. In this study, we characterized the role of SNF1 ortholog in Cordyceps militaris (CmSnf1). The vegetative growth of a CmSnf1 deletion mutant was (ΔCmSnf1) reduced by 42.2% with arabinose as a sole carbon source. Most strikingly, the ΔCmSnf1 produced only a few conidia and exhibited delayed conidial germination. We found that CmSnf1 was necessary for mycelium to penetrate the insect cuticle to form the fruiting body on silkworm pupae, consistent with the down-regulation of chitinase- and protease-encoding genes in ΔCmSnf1. However, cordycepin content increased by more than 7 times in culture supernatants. Correspondingly, the relative expression levels of cordycepin gene cluster members were also elevated. In particular, the expression of cns4 associated with cordycepin transfer was up-regulated >10-fold. Furthermore, transcriptional analysis showed that CmSnf1 regulated the expression of genes involved in cell autophagy and oxidative stress tolerance. We speculated that under environmental stress, both the ATG and SNF1 pathways might collaborate to sustain adverse environments. Our study provides an initial framework to probe the diverse function and regulation of CmSnf1 in C. militaris, which will shed more light on the direction of molecular improvement of medicinal fungi.

Discovery and Characterization of the Highly Active Fungal Immunomodulatory Protein Fip-vvo82.

Volvaria volvacea (Bull. ex Fr.) Sing, an important edible and medicinal macro-fungus, has been used to remedy various diseases for hundreds of years in East Asia. To identify key proteins with the unique therapeutic activity in V. volvacea, we conducted a genomewide comparison of V. volvacea protein families and those of other edible fungi that lack therapeutic functions and identified seven fungal immunomodulatory proteins (FIPs) in V. volvacea. On the basis of the predicted physiological and biochemical characteristics of the seven FIPs, the novel Fip-vvo82 was inferred to have high immunomodulatory activity; this was confirmed by molecular and immunological experiments and further characterized by modeling the three-dimensional structure and protein-protein docking. This is the first study to show that V. volvacea has more than one FIP.

Family caregivers and outcome of people with schizophrenia in rural China: 14-year follow-up study.

OBJECTIVE: This study examined the differences in 14-year outcomes of persons with schizophrenia with and without family caregiver(s) in a rural community in China. METHODS: All participants with schizophrenia (n = 510) aged 15 years and older were identified in a 1994 epidemiological investigation of 123,572 people and followed up in 2004 and 2008 in Xinjin County, Chengdu, China. RESULTS: Individuals without family caregiver in 1994 had significantly higher rate of homelessness (23.8 %) and lower rate of survival (47.5 %) in 2008 than those with family caregivers (5.1 and 70.9 %). Compared with individuals with family caregivers, those without family caregivers were more likely to be male, live alone, have fewer family members, lower family economic status, lower rates of marriage and complete remission, higher mean scores on PANSS and lower mean score on GAF in 2008. The predictors of participants without family caregiver in 2008 included having a small number of family members at baseline and being male. CONCLUSIONS: The absence of a family caregiver is a predictive factor of poorer long-term outcome of persons with schizophrenia in the rural community. The critical role of family caregiving should be incorporated in the planning and delivering of mental health policies and community-based mental health services.

Gender differences in outcomes in people with schizophrenia in rural China: 14-year follow-up study.

BACKGROUND: Little is known about gender differences in the long-term outcomes of people with schizophrenia living in the community. AIMS: To explore gender differences in the 14-year outcome of people with schizophrenia in rural China. METHOD: A 14-year follow-up study among a 1994 cohort (n = 510) of participants with schizophrenia was conducted in Xinjin County, Chengdu, China. All participants and their informants were followed up in 2004 and 2008 using the Patients Follow-up Schedule. RESULTS: Compared with female participants, male participants were significantly younger, had significantly higher rates of mortality, suicide and homelessness, and poorer family and social support. There was no significant gender difference in Positive and Negative Syndrome Scale scores, previous suicide attempts, those never treated, previous hospital admission or inability to work. Longer duration of illness was associated with functional decline and comparatively poorer family economic status. CONCLUSIONS: The long-term outcomes of men with schizophrenia is worse than those of women with the disorder in rural China. Higher mortality, suicide and homelessness rates in men may contribute partly to the higher prevalence of schizophrenia in women in China. Policies on social and family support and gender-specific intervention strategies for improving long-term outcomes should be developed for people with this disorder.

Different outcomes of never-treated and treated patients with schizophrenia: 14-year follow-up study in rural China.

BACKGROUND: The long-term outcome of never-treated patients with schizophrenia is unclear. AIMS: To compare the 14-year outcomes of never-treated and treated patients with schizophrenia and to establish predictors for never being treated. METHOD: All participants with schizophrenia (n = 510) in Xinjin, Chengdu, China were identified in an epidemiological investigation of 123 572 people and followed up from 1994 to 2008. RESULTS: The results showed that there were 30.6%, 25.0% and 20.4% of patients who received no antipsychotic medication in 1994, 2004 and 2008 respectively. Compared with treated patients, those who were never treated in 2008 were significantly older, had significantly fewer family members, had higher rates of homelessness, death from other causes, being unmarried, living alone, being without a caregiver and poor family attitudes. Partial and complete remission in treated patients (57.3%) was significantly higher than that in the never-treated group (29.8%). Predictors of being in the never-treated group in 2008 encompassed baseline never-treated status, being without a caregiver and poor mental health status in 1994. CONCLUSIONS: Many patients with schizophrenia still do not receive antipsychotic medication in rural areas of China. The 14-year follow-up showed that outcomes for the untreated group were worse. Community-based mental healthcare, health insurance and family intervention are crucial for earlier diagnosis, treatment and rehabilitation in the community.

Salvage surgery and conversion surgery for patients with non-small cell lung cancer: A narrative review.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths. With the development of screening, patient selection and treatment strategies, patients' survival outcomes and living quality significantly improved. However, some patients still have local recurrence or residual tumors after receiving definitive therapies. Salvage surgery has been regarded as an effective option for recurrent or residual NSCLC, but its effectiveness remains undetermined. Furthermore, conversion surgery is a special type of salvage surgery for tumors converted from "initially unresectable" to "potentially resectable" status due to a favorable response to systemic treatments. Although conversion surgery is a promising curative procedure for advanced NSCLC, its concept and clinical value remain unfamiliar to clinicians. In this narrative review, we provided an overview of the safety and efficacy of salvage surgery, especially salvage surgery after sublobar resection in early-stage NSCLC. More importantly, we highlighted the concept and value of conversion surgery after systemic treatment in advanced NSCLC to gain some insights into its role in the treatment of lung cancer.

Preoperative Clinical Characteristics Predict Recurrent Laryngeal Nerve Lymph Node Metastasis and Overall Survival in Esophageal Squamous Cell Carcinoma: A Retrospective Study With External Validation.

Background: Recurrent laryngeal nerve (RLN) lymph node metastasis (LNM) is not rare in patients with esophageal squamous cell carcinoma (ESCC). We aimed to develop and externally validate a preoperative nomogram using clinical characteristics to predict RLN LNM in patients with ESCC and evaluate its prognostic value. Methods: A total of 430 patients with ESCC who underwent esophagectomy with lymphadenectomy of RLN LNs at two centers between May 2015 and June 2019 were reviewed and divided into training (center 1, n = 283) and external validation cohorts (center 2, n = 147). Independent risk factors for RLN LNM were determined by multivariate logistic regression, and a nomogram was developed. The performance of the nomogram was assessed in terms of discrimination, calibration, clinical usefulness, and prognostic value. The nomogram was internally validated by the bootstrap method and externally validated by the external validation cohort. Results: Multivariate analysis indicated that clinical T stage (P <0.001), endoscopic tumor length (P = 0.003), bioptic tumor differentiation (P = 0.004), and preoperative carcinoembryonic antigen level (P = 0.001) were significantly associated with RLN LNM. The nomogram had good discrimination with the area under the curve of 0.770 and 0.832 after internal and external validations. The calibration curves and decision curve analysis confirmed the good calibration and clinical usefulness of this model. High-risk of RLN LNM predicted by the nomogram was associated with worse overall survival in the external validation cohort (P <0.001). Conclusion: A nomogram developed by preoperative clinical characteristics demonstrated a good performance to predict RLN LNM and prognosis for patients with ESCC.

Risk factors for poor work functioning of persons with schizophrenia in rural China.

BACKGROUND: The long-term work performance of persons with schizophrenia in the community is unclear. This study examined the status of long-term work functioning and the predictors of poor work status among patients with schizophrenia in a Chinese rural area. METHODS: A 10-year follow-up investigation (1994-2004) of a cohort (n = 510) of persons with schizophrenia was conducted in Xinjin County, Chengdu, China. RESULTS: Compared with baseline data, work functioning of patients with schizophrenia deteriorated after 10 years. The rates of not working increased significantly from 12.0% in 1994 to 23.0% in 2004. Bivariate analyses showed that the poor work functioning in 2004 was significantly associated with male gender, older age, older age of first onset, higher level of education, longer duration of illness, lower family economic status, lack of caregivers, poor work status in 1994, living in shabby or unstable house, marked symptoms, and higher score on the Social Disability Screening Schedule (SDSS). In multiple logistic regression analyses, higher score of SDSS and poor work status in 1994 were identified as unique predictors of poor work status in 2004. CONCLUSION: The status of work functioning of persons with schizophrenia decreased over the course of the illness. The risk factors for poor work functioning and specific socio-cultural environment should be considered in planning community mental health services and rehabilitation for these patients.

[Comparing the therapeutic effect of lung transplantation with the therapeutic effect of whole lung lavage for the patients with end-stage pneumoconiosis].

OBJECTIVE: To explore the therapeutic effects of lung transplantation (LTx) and whole lung lavage (WLL) for patients with end-stage pneumoconiosis. METHODS: From June 2002 to February 2011, 5 cases with end-stage pneumoconiosis were treated with LTx and 12 cases with end-stage pneumoconiosis were treated with WLL. The clinical symptoms, pulmonary functions, pulmonary artery pressures, blood gas analysis, imagings of chest and survival status were retrospectively analyzed. RESULTS: In LTx group, the clinical symptoms (cough, sense of suppression in the chest), pulmonary functions and blood gas indicators were improved, pulmonary artery pressures decreased to normal levels, the imaging of chest showed that the implanted lung inflated well and was with clear lung markings. But the contralateral lungs without treatment appeared the progression of disease in the imaging of chest. In WLL group, the clinical symptoms in a half year after treatment were improved but the symptomatic relief rate declined with time, the pulmonary functions in half year after treatment were improved but decreased after 2 years, the pulmonary artery hypertension enhanced generally, as compared with that prior to WLL. The disease progression in the chest imaging examination was not found in a half year after WLL, but appeared in 1 ∼ 2 years after WLL. During following-up. the mean survival times in LTx and WLL groups were 40.5 and 21.4 months, respectively. In LTx group, one patient died of multiple organ dysfunctions (MODS) caused by primary graft dysfunction (PGD), one case died of severe infection in seven months after LTx. Up to now, other 3 cases have survived for 65, 41 and 29 months, respectively. In WLL group, 3 cases died of pulmonary infection, 2 cases died of respiratory failure, one case died of heart failure and one case died of encephalon vascular accident, the mean survival time of these 7 patients was (19.0 ± 8.7) months. So far other 5 cases have survived for 7, 9, 13, 18 and 26 months, respectively. CONCLUSION: LTx has greater risk of death during preoperative period, but patients after LTx may have long survival times with good quality of life. The clinical symptoms and pulmonary functions of patients can be improved temporarily after WLL, but the survival time of WLL is inferior to that of LTx.

[Lung transplantation for silicosis: a report of 5 cases].

OBJECTIVE: To investigate the selection of recipients, operative technique, and perioperative management of lung transplantation for silicosis. METHODS: Lung transplantations (LTx) were performed for five end-stage silicosis in our hospital who were diagnosed in accordance with recommendations of the local Prophylactic Therapeutic Institution for Occupational Diseases. The chest roentgenogram and high resolution CT showed somewhat pulmonary interstitial fibrosis, pulmonary emphysema and massive opacities. The mean pulmonary artery pressure (mPAP) was > 30mmHg, NYHA III or IV. Two patients received thoracic surgery prior to LTx, one patient was ventilator-dependent. One patient received bilateral sequence lung transplantation (BSLT) under extracorporeal membrane oxygenation (ECMO) support. Four patients received single lung transplantation (SLT), 3 under ECMO support. RESULTS: Patient five died of multiple organ failure on postoperative day 8, the remaining four patients were discharged from hospital. During follow up, patient three died of severe infection 7 month postoperatively, the remaining three patients were alive for 5 years, 3 years and 2 years respectively, and lived good quality of life, especially with lower mPAP and improved lung function. Although our patients suffered low-grade chronic rejection with the manifestation of bronchiolitis obliterative syndrome (BOS). CONCLUSION: Lung transplantation is a viable option for patients with end-stage silicosis, providing acceptable quality of life and survival. Both SLT and BSLT are satisfactory approach for end-stage silicosis,and long-term survival requires further investigations.

Discovery of 1H-benzo[d][1,2,3]triazol-1-yl 3,4,5-trimethoxybenzoate as a potential antiproliferative agent by inhibiting histone deacetylase.

Twenty-one benzotriazoles (3-16 and 18-24) were synthesized and half of them (5, 8-16, 20, and 21) were reported for the first time. Their antiproliferative activities against three human cancer cells were assayed. It revealed that 1H-benzo[d][1,2,3]triazol-1-yl 3,4,5-trimethoxybenzoate (9) showed considerable activity against three human cancer cell lines with the half maximal inhibitory concentration (IC(50)) values of 1.2-2.4 nM, which were close to the value of the positive control, doxorubicin. Further investigation indicated compound 9 was a potential histone deacetylase inhibitor (IC(50)=9.4 µM) and its binding mode was simulated using docking method.

Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors.

Two series of thiazolidinone derivatives designing for potential EGFR and HER-2 kinase inhibitors have been discovered. Some of them exhibited significant EGFR and HER-2 inhibitory activity. Compound 2-(2-(5-bromo-2-hydroxybenzylidene)hydrazinyl)thiazol-4(5H)-one (12) displayed the most potent inhibitory activity (IC(50)=0.09 microM for EGFR and IC(50)=0.42 microM for HER-2), comparable to the positive control erlotinib. Docking simulation was performed to position compound 12 into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicating that some of the thiazolidinone derivatives own high antiproliferative activity against MCF-7. Compound 12 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent.

Synthesis, molecular modeling and biological evaluation of dithiocarbamates as novel antitubulin agents.

A series of novel dithiocarbamate compounds with the chalcone scaffold have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and antitubulin polymerization inhibitors. Compound 2n showed the most potent biological activity in vitro, which inhibited the growth of MCF-7 cells with IC(50) of 0.04+/-0.01 microM and the polymerization of tubulin with IC(50) of 6.8+/-0.6 microM. To understand the tubulin-inhibitor interaction and the selectivity of the most active compound towards tubulin, molecular modeling studies were performed to dock compound 2n into the colchicine binding site, which suggested probable inhibition mechanism.

Novel depsides as potential anti-inflammatory agents with potent inhibitory activity against Escherichia coli-induced interleukin-8 production.

Sixteen novel depsides were synthesized for the first time. Their chemical structures were clearly determined by (1)H NMR, ESI mass spectra, and elemental analyses. All the compounds were assayed for antibacterial activities against three Gram-positive bacterial strains (Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538, and Streptococcus faecalis ATCC 9790) and three Gram-negative bacterial strains (Escherichia coli ATCC 35218, Pseudomonas aeruginosa ATCC 13525, and Enterobacter cloacae ATCC 13047) by the MTT method. Compound 2-(2-methoxy-2-oxoethyl)phenyl 5-bromonicotinate (5) exhibited significant antibacterial activities against E. coli ATCC 35218 with an MIC of 0.78 microg/mL, which was superior to the positive control kanamycin B. In addition, compound 5 showed potent inhibitory activity against E. coli-induced interleukin-8 production.

Differences in mortality and suicidal behaviour between treated and never-treated people with schizophrenia in rural China.

BACKGROUND: Many people with schizophrenia remain untreated in the community. Long-term mortality and suicidal behaviour among never-treated individuals with schizophrenia in the community are unknown. AIMS: To explore 10-year mortality and suicidal behaviour among never-treated individuals with schizophrenia. METHOD: We used data from a 10-year prospective follow-up study (1994-2004) among people with schizophrenia in Xinjin County, Chengdu, China. RESULTS: The mortality rate for never-treated individuals with schizophrenia was 2761 per 100 000 person-years during follow-up. There were no significant differences of rates of suicide and all-cause mortality between never-treated and treated individuals. The standardised mortality ratio (SMR) for never-treated people was 10.4 (95% CI 7.2-15.2) and for treated individuals 6.5 (95% CI 5.2-8.5). Compared with treated people, never-treated individuals were more likely to be older, poorer, have a longer duration of illness, marked symptoms and fewer family members. CONCLUSIONS: The never-treated individuals have similar mortality to and a higher proportion of marked symptoms than treated people, which may reflect the poor outcome of the individuals without treatment. The higher rates of mortality, homelessness and never being treated among people with schizophrenia in low- and middle-income nations might challenge presumed wisdom about schizophrenia outcomes in these countries.

Design, synthesis and biological evaluation of novel thiazole derivatives as potent FabH inhibitors.

Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram positive and negative bacteria. Three series of Schiff bases containing thiazole template were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 11 and 18 were potent inhibitors of E. coli FabH.

Synthesis, molecular docking and biological evaluation of metronidazole derivatives as potent Helicobacter pylori urease inhibitors.

Fourteen metronidazole derivatives (compounds 3a-f and 4b-h) have been synthesized by coupling of metronidazole and salicylic acid derivatives. All of them are reported for the first time. Their chemical structures are characterized by (1)H NMR, MS, and elemental analysis. The inhibitory activities against Helicobacter pylori urease have been investigated in vitro and many compounds have showed promising potential inhibitory activities of H. pylori urease. The effect of compounds 4b (IC(50)=26 microM) and 4 g (IC(50)=12 microM) was comparable with that of acetohydroxamic acid, a well known H. pylori urease inhibitor used as a positive control. The experimental values of IC(50) showed that inhibitor was potent urease inhibitor. A docking analysis using the autodock 4.0 program could explain the inhibitory activities of compound 4 g against H. pylori urease.

Mortality of geriatric and younger patients with schizophrenia in the community.

Little is known about the differences in mortality among non-institutionalized geriatric and younger patients with schizophrenia. In this study long-term mortality and suicidal behavior of all the geriatric (age > or = 65 years), middle-age (age 41-64 years), and young (age 15-40 years) subjects with schizophrenia living in a Chinese rural community were compared. A 10 year follow-up investigation among a 1994 cohort (n = 510) of patients with schizophrenia was conducted in Xinjin County, Chengdu, China. Compared with young subjects, geriatric subjects with schizophrenia were more likely to be female, have more previous physical illness, never accepted treatment, and practice religious (p < or = 0.01). There were no significant differences of suicide attempts among the three groups. Young subjects had a higher rate of suicide (1,033.8 per 100,000 person-years), and geriatric subjects had a higher rate of deaths due to other causes (accident and natural causes) (4,314.2 per 100,000 person-years). Standardized mortality ratios for both suicide and deaths due to other causes were highest in young subjects and the lowest in geriatric subjects. Patients with schizophrenia in all age groups had a marked increase in mortality and suicide. Specific intervention strategies for decreasing mortality and suicide should be developed for patients with schizophrenia in different age groups.

Family history of psychosis and outcome of people with schizophrenia in rural China: 14-year follow-up study.

OBJECTIVE: This study examined the differences in 14-year outcomes of persons with schizophrenia with and without family history of psychosis in a rural community in China. METHODS: All participants with schizophrenia (n=510) aged 15 years and older were identified in a 1994 epidemiological investigation of 123,572 people and followed up in 2004 and 2008 in Xinjin County, Chengdu, China. RESULTS: Individuals with positive family history of schizophrenia had significantly younger age of first onset than those with negative family history of schizophrenia in 1994 and 2004. Compared with individuals with negative family history of schizophrenia, those with positive family history of schizophrenia had significantly higher rate of homelessness and lower rate of death due to other reasons in 10-year (2004) and 14-year follow-up (2008). There were no significantly differences of mean scores on PANSS, SDSS and GAF in 2008 between positive and negative family history groups. CONCLUSIONS: The positive family history of schizophrenia is strongly related to younger age of onset, and may predict a poorer long-term outcome (e.g., higher rate of homelessness) in persons with schizophrenia in the rural community. The findings have implications for further studies on specific family-related mechanisms on clinical treatment and rehabilitation, as well as for planning and delivering of community-based mental health services.

Duration of untreated psychosis (DUP) and outcome of people with schizophrenia in rural China: 14-year follow-up study.

This study aims to examine the relationship between the duration of untreated psychosis (DUP) and 14-year outcomes of schizophrenia in a Chinese rural area. Participants with schizophrenia (n = 510) were identified in an epidemiological investigation of 123 572 people aged 15 years and older in 1994 and followed up in 2008 in Xinjin, Chengdu, China. Longer DUP (>6 months) was common in participants (27.3%). In 1994, participants with DUP ≤ 6 months were more likely to have a significantly lower rate of suicide attempts, shorter duration of illness and higher rate of full remission compared with those with DUP > 6 months. No significant differences were found regarding the rates of survival, suicide, death due to other causes and homelessness between individuals with shorter and longer DUP in 2008. Nevertheless, longer DUP (>6 months) of participants in 2008 was significantly associated with higher mean of PANSS total negative and general mental scores, longer duration of illness and higher rate of live alone in the logistic regression model. Earlier identification, treatment and rehabilitation, and family intervention should be addressed when developing mental health policies and delivering community mental health services.