Systemic inflammation response index predicts the postoperative recurrence of chronic rhinosinusitis with nasal polyps: a retrospective study in the Chinese population.

PURPOSE: Endoscopic sinus surgery (ESS) is now frequently used to treat chronic sinusitis with nasal polyps (CRSwNP), but postoperative recurrence plagues many patients. We aimed to assess the value of the systemic inflammation response index (SIRI) and the systemic immune-inflammatory index (SII) for the prediction of postoperative recurrence in patients with CRSwNP. METHODS: A total of 143 patients with CRSwNP and 76 age- and sex-matched healthy subjects were enrolled. Patients were divided into the recurrence group and the non-recurrence group according to the recurrence of CRSwNP. Univariate and multivariate analyses showed independent risk factors for the recurrence. A receiver operating characteristic curve analysis was conducted to assess the predictive accuracy of the variables and determine the optimal cut-off values. Finally, a survival analysis was conducted. RESULTS: Univariate analysis revealed that age, sex, CRP, EOS, SIRI, SII, NLR, ELR, and Lund-Mackay CT scores were significant predictors of the recurrence of CRSwNP. Multivariate analysis confirmed that SIRI (OR = 1.310, p < 0.001) and Lund-Mackay CT scores (OR = 1.396, p < 0.001) were independent predictors. SIRI (AUC = 0.761, 95% CI: 0.685-0.836) had a certain value in predicting the recurrence of CRSwNP. CONCLUSION: SIRI is a potential predictive marker of the postoperative recurrence of CRSwNP.

Construction and application of procedural pathways combined with information management in nursing staff skills training system.

OBJECTIVE: To explore the application effect of procedural pathways combined with information management in the construction of nursing staff skills training system. METHODS: This was a quasi-experimental study with a control group and an experimental group. A total of 300 newly admitted nurses or nurses who required training within three years of admission were selected as the experimental group, and 267 nurses who were trained in the same hospital during the same period in 2020 were selected as the control group. The experimental group received skills training using a system that combines procedural pathways with information management, while the control group received traditional teaching mode. The outcome measures included theoretical score, operation score, nurse competency, patient satisfaction, and nursing-related adverse events. The data were analyzed using t-test, chi-square test, and rank-sum test. RESULTS: The experimental group had higher scores in theoretical assessment, skills assessment, nurse competency, and patient satisfaction, and lower incidence of nursing-related adverse events than the control group (P < 0.05). CONCLUSION: The strategy of procedural pathways combined with information management provides a new perspective and method for nursing operation skills training, effectively improves clinical nursing quality and ensures patient safety.

Immune regulation and prognosis indicating ability of a newly constructed multi-genes containing signature in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common renal malignancy, although newly developing targeted therapy and immunotherapy have been showing promising effects in clinical treatment, the effective biomarkers for immune response prediction are still lacking. The study is to construct a gene signature according to ccRCC immune cells infiltration landscape, thus aiding clinical prediction of patients response to immunotherapy. METHODS: Firstly, ccRCC transcriptome expression profiles from Gene Expression Omnibus (GEO) database as well as immune related genes information from IMMPORT database were combine applied to identify the differently expressed meanwhile immune related candidate genes in ccRCC comparing to normal control samples. Then, based on protein-protein interaction network (PPI) and following module analysis of the candidate genes, a hub gene cluster was further identified for survival analysis. Further, LASSO analysis was applied to construct a signature which was in succession assessed with Kaplan-Meier survival, Cox regression and ROC curve analysis. Moreover, ccRCC patients were divided as high and low-risk groups based on the gene signature followed by the difference estimation of immune treatment response and exploration of related immune cells infiltration by TIDE and Cibersort analysis respectively among the two groups of patients. RESULTS: Based on GEO and IMMPORT databases, a total of 269 differently expressed meanwhile immune related genes in ccRCC were identified, further PPI network and module analysis of the 269 genes highlighted a 46 genes cluster. Next step, Kaplan-Meier and Cox regression analysis of the 46 genes identified 4 genes that were supported to be independent prognosis indicators, and a gene signature was constructed based on the 4 genes. Furthermore, after assessing its prognosis indicating ability by both Kaplan-Meier and Cox regression analysis, immune relation of the signature was evaluated including its association with environment immune score, Immune checkpoint inhibitors expression as well as immune cells infiltration. Together, immune predicting ability of the signature was preliminary explored. CONCLUSIONS: Based on ccRCC genes expression profiles and multiple bioinformatic analysis, a 4 genes containing signature was constructed and the immune regulation of the signature was preliminary explored. Although more detailed experiments and clinical trials are needed before potential clinical use of the signature, the results shall provide meaningful insight into further ccRCC immune researches.

Interrelationships between sarcopenia, bone turnover markers and low bone mineral density in patients on hemodialysis.

BACKGROUND: Hemodialysis (HD) patients are at risk for sarcopenia (SP) and bone loss, which may impact falls and bone fragility and lead to poor prognosis. Patients with HD and those with osteoporosis (OP) are still underdiagnosed and untreated. The aims of the present study were to evaluate the factors that affect bone mineral density (BMD) loss in HD patients, and explore traditional and novel approaches to manage chronic kidney disease-mineral-bone disorder (CKD-MBD). METHODS: Patients who underwent regular HD at the First Affiliated Hospital of Soochow University were retrospectively evaluated. According to the WHO osteoporosis criteria, patients were categorized into three groups: normal BMD, osteopenia, and osteoporosis. Demographic and clinical data, skeletal muscle mass, and bone turnover markers(BTM) were compared between the three groups. The correlation between bone density and muscle mass was calculated, and related risk factors were analyzed. RESULTS: This study enrolled 130 HD patients, 36 patients were diagnosed with sarcopenia (27.7%), 44 patients were diagnosed with osteopenia (33.8%), 19 patients were diagnosed with osteoporosis (14.6%), and 23 patients were diagnosed with osteosarcopenia (17.7%). The SMI was positively correlated with the BMD of the lumbar spine (r = 0.23, p < 0.01) and femoral neck (r = 0.22, p < 0.05). In ordinal logistic regression analysis, the odds ratio (OR) for low BMD was high for patients with sarcopenia (OR = 5.894, 95% CI 1.592-21.830, p < 0.01), older age (OR = 1.095, 95% CI 1.041-1.153, p < 0.001), higher TRACP-5b levels (OR = 1.597, 95% CI 1.230-2.072, p < 0.01), and lower 25-OH vitamin D levels (OR = 0.631, 95% CI 0.544-0.733, p < 0.001). CONCLUSION: The preservation of skeletal muscle mass could be important to prevent a BMD decrease in HD patients. Adequate intake of vitamin D and control of TRACP-5b levels will help reduce the occurrence and progression of osteopenia/sarcopenia in HD patients.

Ablation of Sam68 in adult mice increases thermogenesis and energy expenditure.

Genetic deletion of Src associated in mitosis of 68kDa (Sam68), a pleiotropic adaptor protein prevents high-fat diet-induced weight gain and insulin resistance. To clarify the role of Sam68 in energy metabolism in the adult stage, we generated an inducible Sam68 knockout mice. Knockout of Sam68 was induced at the age of 7-10 weeks, and then we examined the metabolic profiles of the mice. Sam68 knockout mice gained less body weight over time and at 34 or 36 weeks old, had smaller fat mass without changes in food intake and absorption efficiency. Deletion of Sam68 in mice elevated thermogenesis, increased energy expenditure, and attenuated core-temperature drop during acute cold exposure. Furthermore, we examined younger Sam68 knockout mice at 11 weeks old before their body weights deviate, and confirmed increased energy expenditure and thermogenic gene program. Thus, Sam68 is essential for the control of adipose thermogenesis and energy homeostasis in the adult.

Hepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity.

Hepatic glucose production (HGP) is an important component of glucose homeostasis, and deregulated HGP, particularly through gluconeogenesis, contributes to hyperglycemia and pathology of type-2 diabetes (T2D). It has been shown that the gluconeogenic gene expression is governed primarily by the transcription factor cAMP-response element (CRE)-binding protein (CREB) and its coactivator, CREB-regulated transcriptional coactivator 2 (CRTC2). Recently, we have discovered that Sam68, an adaptor protein and Src kinase substrate, potently promotes hepatic gluconeogenesis by promoting CRTC2 stability; however, the detailed mechanisms remain unclear. Here we show that in response to glucagon, Sam68 increases CREB/CRTC2 transactivity by interacting with CRTC2 in the CREB/CRTC2 complex and occupying the CRE motif of promoters, leading to gluconeogenic gene expression and glucose production. In hepatocytes, glucagon promotes Sam68 nuclear import, whereas insulin elicits its nuclear export. Furthermore, ablation of Sam68 in hepatocytes protects mice from high-fat diet (HFD)-induced hyperglycemia and significantly increased hepatic and peripheral insulin sensitivities. Thus, hepatic Sam68 potentiates CREB/CRTC2-mediated glucose production, contributes to the pathogenesis of insulin resistance, and may serve as a therapeutic target for T2D.

Application of New Energy Thermochromic Composite Thermosensitive Materials of Smart Windows in Recent Years.

Thermochromic smart windows technology can intelligently regulate indoor solar radiation by changing indoor light transmittance in response to thermal stimulation, thus reducing energy consumption of the building. In recent years, with the development of new energy-saving materials and the combination with practical technology, energy-saving smart windows technology has received more and more attention from scientific research. Based on the summary of thermochromic smart windows by Yi Long research groups, this review described the applications of thermal responsive organic materials in smart windows, including poly(N-isopropylacrylamide) (PNIPAm) hydrogels, hydroxypropyl cellulose (HPC) hydrogels, ionic liquids and liquid crystals. Besides, the mechanism of various organic materials and the properties of functional materials were also introduced. Finally, opportunities and challenges relating to thermochromic smart windows and prospects for future development are discussed.

Bioinformatic analysis identifying FGF1 gene as a new prognostic indicator in clear cell Renal Cell Carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) has been the commonest renal cell carcinoma (RCC). Although the disease classification, diagnosis and targeted therapy of RCC has been increasingly evolving attributing to the rapid development of current molecular pathology, the current clinical treatment situation is still challenging considering the comprehensive and progressively developing nature of malignant cancer. The study is to identify more potential responsible genes during the development of ccRCC using bioinformatic analysis, thus aiding more precise interpretation of the disease METHODS: Firstly, different cDNA expression profiles from Gene Expression Omnibus (GEO) online database were used to screen the abnormal differently expressed genes (DEGs) between ccRCC and normal renal tissues. Then, based on the protein-protein interaction network (PPI) of all DEGs, the module analysis was performed to scale down the potential genes, and further survival analysis assisted our proceeding to the next step for selecting a credible key gene. Thirdly, immunohistochemistry (IHC) and quantitative real-time PCR (QPCR) were conducted to validate the expression change of the key gene in ccRCC comparing to normal tissues, meanwhile the prognostic value was verified using TCGA clinical data. Lastly, the potential biological function of the gene and signaling mechanism of gene regulating ccRCC development was preliminary explored. RESULTS: Four cDNA expression profiles were picked from GEO database based on the number of containing sample cases, and a total of 192 DEGs, including 39 up-regulated and 153 down-regulated genes were shared in four profiles. Based on the DEGs PPI network, four function modules were identified highlighting a FGF1 gene involving PI3K-AKT signaling pathway which was shared in 3/4 modules. Further, both the IHC performed with ccRCC tissue microarray which contained 104 local samples and QPCR conducted using 30 different samples confirmed that FGF1 was aberrant lost in ccRCC. And Kaplan-Meier overall survival analysis revealed that FGF1 gene loss was related to worse ccRCC patients survival. Lastly, the pathological clinical features of FGF1 gene and the probable biological functions and signaling pathways it involved were analyzed using TCGA clinical data. CONCLUSIONS: Using bioinformatic analysis, we revealed that FGF1 expression was aberrant lost in ccRCC which statistical significantly correlated with patients overall survival, and the gene's clinical features and potential biological functions were also explored. However, more detailed experiments and clinical trials are needed to support its potential drug-target role in clinical medical use.

IMUP and GPRC5A: two newly identified risk score indicators in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic cancer has been a threateningly lethal malignant tumor worldwide. Despite the promising survival improvement in other cancer types attributing to the fast development of molecular precise medicine, the current treatment situation of pancreatic cancer is still woefully challenging since its limited response to neither traditional radiotherapy and chemotherapy nor emerging immunotherapy. The study is to explore potential responsible genes during the development of pancreatic cancer, thus identifying promising gene indicators and probable drug targets. METHODS: Different bioinformatic analysis were used to interpret the genetic events in pancreatic cancer development. Firstly, based on multiple cDNA microarray profiles from Gene Expression Omnibus (GEO) database, the genes with differently mRNA expression in cancer comparing to normal pancreatic tissues were identified, followed by being grouped based on the difference level. Then, GO and KEGG were performed to separately interpret the multiple groups of genes, and further Kaplan-Meier survival and Cox Regression analysis assisted us to scale down the candidate genes and select the potential key genes. Further, the basic physicochemical properties, the association with immune cells infiltration, mutation or other types variations besides expression gap in pancreatic cancer comparing to normal tissues of the selected key genes were analyzed. Moreover, the aberrant changed expression of key genes was validated by immunohistochemistry (IHC) experiment using local hospital tissue microarray samples and the clinical significance was explored based on TCGA clinical data. RESULTS: Firstly, a total of 22,491 genes were identified to express differently in cancer comparing to normal pancreatic tissues based on 5 cDNA expression profiles, and the difference of 487/22491 genes was over eightfold, and 55/487 genes were shared in multi profiles. Moreover, after genes interpretation which showed the > eightfold genes were mainly related to extracellular matrix structural constituent regulation, Kaplan-Meier survival and Cox-regression analysis were performed continually, and the result indicated that of the 55 extracellular locating genes, GPRC5A and IMUP were the only two independent prognostic indicators of pancreatic cancer. Further, detailed information of IMUP and GPRC5A were analyzed including their physicochemical properties, their expression and variation ratio and their association with immune cells infiltration in cancer, as well as the probable signaling pathways of genes regulation on pancreatic cancer development. Lastly, local IHC experiment performed on PAAD tissue array which was produced with 62 local hospital patients samples confirmed that GPRC5A and IMUP were abnormally up-regulated in pancreatic cancer, which directly associated with worse patients both overall (OS) and recurrence free survival (RFS). CONCLUSIONS: Using multiple bioinformatic analysis as well as local hospital samples validation, we revealed that GPRC5A and IMUP expression were abnormally up-regulated in pancreatic cancer which associated statistical significantly with patients survival, and the genes' biological features and clinical significance were also explored. However, more detailed experiments and clinical trials are obligatory to support their further potential drug-target role in clinical medical treatment.

Neddylation mediates ventricular chamber maturation through repression of Hippo signaling.

During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling.

The inhibitory effect of volatile organic compounds produced by Bacillus subtilis CL2 on pathogenic fungi of wolfberry.

Bacillus subtilis strain CL2 is antagonistic to wolfberry postharvest pathogenic fungi. In this study, we isolated and screened this strain for in vitro experiments. The result of the two-sealed-base-plates method revealed that volatile organic compounds (VOCs) emitted from the strain CL2 inhibited the hyphal growth of four pathogenic fungi Mucor circinelloides LB1, Fusarium arcuatisporum LB5, Alternaria iridiaustralis LB7, and Colletotrichum fioriniae LB8. After exposure to VOCs for 5 days, the hyphal growth of the pathogen C. fioriniae LB8 was inhibited by 73%. Scanning electron microscopy revealed that the VOCs produced by B. subtilis CL2 caused the mycelium morphology of the pathogenic fungi to deform, twist, fold, and shrink. In the in vivo experiments, we noticed that VOCs could significantly reduce the weight loss rate of wolfberry fruits caused by the pathogenic fungus M. circinelloides LB1 and that the decay incidence rate were caused by the pathogenic fungi F. arcuatisporum LB5, A. iridiaustralis LB7, and C. fioriniae LB8. On the basis of the headspace-gas chromatography-ion mobility spectrometry analysis, seven VOCs produced by strain CL2 were identified. Among them, 2,3-butanedione and 3-methylbutyric acid are the main antifungal active substances. This study investigated the antifungal properties of VOCs produced by the strain CL2 on postharvest pathogenic fungi isolated from wolfberry fruits both in vivo and in vitro, thereby providing the theoretical basis for its future applications.

Risk factors for incorrect surgical count during surgery: An observational study.

BACKGROUND: Incorrect surgical counts are closely related to retained surgical items, which pose a threat to patients. However, the risk factors for incorrect surgical counts have not been identified yet. AIM: To identify the risk factors associated with incorrect surgical counts during surgery in a tertiary hospital. DESIGN: An observational case-control study. METHODS: Seventy cases of incorrect surgical counts were reviewed in this study. Data were collected from January 1, 2014, to April 4, 2019. For each case, we included four randomly selected control cases involving the same surgical procedures by the same surgeon within a 6-month period for comparison. The medical data of these cases were extracted for further statistical analysis. RESULTS: A higher incidence of incorrect surgical counts was observed among surgical counts performed between 8:00 a.m. to 12:00 a.m., emergency operations, prolonged procedures, and/or after addition of surgical items. CONCLUSION: Prolonged surgical procedures, emergency operations, time of occurrence, and addition of surgical items were the risk factors related to incorrect surgical counts during surgery.

MitoQ regulates redox-related noncoding RNAs to preserve mitochondrial network integrity in pressure-overload heart failure.

Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of HF (e.g., pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for posttranscriptional regulation via long noncoding RNAs (lncRNAs). We hypothesized that MitoQ preserves mitochondrial fusion proteins (i.e., mitofusin), likely through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in failing hearts. To test this hypothesis, 8-wk-old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and remarkable contractile dysfunction in 1 wk. Transmission electron microscopy and immunostaining revealed defective intermitochondrial and mitochondrial-sarcoplasmic reticulum ultrastructure in AAC mice compared with sham-operated animals, which was accompanied by elevated oxidative stress and suppressed mitofusin (i.e., Mfn1 and Mfn2) expression. MitoQ (1.36 mg·day-1·mouse-1, 7 consecutive days) significantly ameliorated LV dysfunction, attenuated Mfn2 downregulation, improved interorganellar contact, and increased metabolism-related gene expression. Moreover, our data revealed that MitoQ alleviated the dysregulation of an Mfn2-associated lncRNA (i.e., Plscr4). In summary, the present study supports a unique mechanism by which MitoQ improves myocardial intermitochondrial and mitochondrial-sarcoplasmic reticulum (SR) ultrastructural remodeling in HF by maintaining Mfn2 expression via regulation by an lncRNA. These findings underscore the important role of lncRNAs in the pathogenesis of HF and the potential of targeting them for effective HF treatment.NEW & NOTEWORTHY We have shown that MitoQ improves cardiac mitochondrial network integrity and mitochondrial-SR alignment in a pressure-overload mouse heart-failure model. This may be occurring partly through preventing the dysregulation of a redox-sensitive lncRNA-microRNA pair (i.e., Plscr4-miR-214) that results in an increase in mitofusin-2 expression.

Cisatracurium inhibits the proliferation, migration and invasion of breast cancer cells by regulating the expression of miR-3174.

Breast cancer is a type of cancer that begins in the breast tissue. Being a woman is the most important factor in the risk of breast cancer. Although men also get the cancer, women are much more likely to get it. This experiment was founded to investigate the effect and mechanism of Cisatracurium on breast cancer cell proliferation, migration and invasion. Breast cancer cells MDA-MB-231 were cultured in vitro. MDA-MB-231 cells were treated with cisatracurium of different concentrations for 48 h. CCK-8method detected cell proliferation, Transwell detected cell migration and invasion, Western Blot method detected the expression levels of CyclinD1, p21, MMP-2andMMP-9protein in cells, RT-qPCR) detected the expression level of miR-3174in cells. After miR-3174 inhibitor was transfected into MDA-MB-231 in order to down-regulate the expression of miR-3174, the same methods as above were used to observe the effect of the down-regulating miR-3174 expression on MDA-MB-231 cell proliferation, migration and invasion as well as the expression levels of CyclinD1, p21, MMP -2 andMMP-9 protein. After different concentrations of Cisatracurium acted on MDA-MB-231 cells, the cell inhibition rate and p21 protein expression were significantly increased (p<0.05), the number of cell migration and invasion and the expression levels of CyclinD1, MMP-2 and MMP-9 were significantly reduced (p<0.05), and the expression of miR-3174 in cells was significantly reduced (p<0.05). After down-regulating the expression of miR-3174, the cell inhibition rate and p21 protein expression were significantly increased (p<0.05), the number of cell migration and invasion and the expression levels of CyclinD1, MMP-2 and MMP-9 were significantly reduced (p<0.05). Up-regulating miR-3174 expression could reverse the effect of Cisatracurium on the proliferation, migration and invasion of MDA-MB-231 cells. Cisatracurium can inhibit the proliferation, migration and invasion of breast cancer MDA-MB-231 cells, and its mechanism is related to the down-regulation of miR-3174 expression in cells.

A potentially important resource: endophytic yeasts.

Recent advancements in the research on endophytes isolated from plants and crops have greatly broadened its application in various fields. Endophytic bacteria and endophytic fungi are known to promote the growth of various plants. Besides, the secondary metabolites such as alcohol and xylitol secreted by the endophytic yeast also help their hosts to resist microbial invasion. This makes them a potential substitute for chemical-based control methods. Moreover, the plant hosts can also provide nutrients for the growth of endophytic yeasts. To achieve the symbiotic relationship, yeasts must colonize most parts of the plant tissues, including intercellular spaces, cytoplasm, stomata of seeds, roots, stems, leaves, and fruits as well. Conventionally, isolation of endophytic yeasts from different plant tissues and understanding their interior plants colonization mechanism have remainedkey strategies to exploit their key potentials. In this review, we will elaborate on the diversity, characteristics of colonization, and the factors that influence the distribution of endophytic yeasts. This review also lays a theoretical foundation for the application of endophytic yeasts in various industrial and agricultural practices.

Sam68 impedes the recovery of arterial injury by augmenting inflammatory response.

OBJECTIVE: The role of Src-associated-in-mitosis-68-kDa (Sam68) in cardiovascular biology has not been studied. A recent report suggests that Sam68 promotes TNF-α-induced NF-κB activation in fibroblasts. Here we sought to dissect the molecular mechanism by which Sam68 regulates NF-κB signaling and its functional significance in vascular injury. APPROACH AND RESULTS: The endothelial denudation injury was induced in the carotid artery of Sam68-null (Sam68-/-) and WT mice. Sam68-/- mice displayed an accelerated re-endothelialization and attenuated neointima hyperplasia, which was associated with a reduced macrophage infiltration and lowered expression of pro-inflammatory cytokines in the injured vessels. Remarkably, the ameliorated vascular remodeling was recapitulated in WT mice after receiving transplantation of bone marrow (BM) from Sam68-/- mice, suggesting the effect was attributable to BM-derived inflammatory cells. In cultured Raw264.7 macrophages, knockdown of Sam68 resulted in a significant reduction in the TNF-α-induced expression of TNF-α, IL-1ß, and IL-6 and in the level of nuclear phospho-p65, indicating attenuated NF-κB activation; and these results were confirmed in peritoneal and BM-derived macrophages of Sam68-/- vs. WT mice. Furthermore, co-immunoprecipitation and mass-spectrometry identified Filamin A (FLNA) as a novel Sam68-interacting protein upon TNF-α treatment. Loss- and gain-of-function experiments suggest that Sam68 and FLNA are mutually dependent for NF-κB activation and pro-inflammatory cytokine expression, and that the N-terminus of Sam68 is required for TRAF2-FLNA interaction. CONCLUSIONS: Sam68 promotes pro-inflammatory response in injured arteries and impedes recovery by interacting with FLNA to stabilize TRAF2 on the cytoskeleton and consequently potentiate NF-κB signaling.

Transient inhibition of neddylation at neonatal stage evokes reversible cardiomyopathy and predisposes the heart to isoproterenol-induced heart failure.

Alterations in perinatal conditions (such as preterm birth) is linked to adult health and disease, in particular, the cardiovascular system. Neddylation, a novel posttranslational modification through which the ubiquitin-like protein NEDD8 is conjugated to protein substrates, has emerged as an important mechanism regulating embryonic cardiac chamber maturation. However, the importance of neddylation in postpartum cardiac development has not been investigated. Here, we aimed to determine whether transient, postnatal inhibition of neddylation has immediate and prolonged impact on the structure and function of the neonatal and adult hearts. Sprague-Dawley pups were given three intraperitoneal injections of MLN4924 (MLN), a specific neddylation inhibitor, at postnatal days (P)1, 3, and 5. Cardiac structure and function were temporally assessed during aging and after 2 wk of isoproterenol (ISO) infusion in adulthood. MLN treatment resulted in modest reduction of neddylated proteins in neonatal hearts. The MLN-treated rats developed cardiac hypertrophy and dysfunction by P7, which was accompanied by significantly reduced cardiomyocyte proliferation. At 3 mo of age, cardiac contractile function was restored in MLN-treated rats, but MLN-treated hearts displayed hypertrophic phenotype. Whereas ISO infusion triggered compensatory cardiac hypertrophy without impairing cardiac contractility in the control rats, the MLN-treated rats displayed a similar degree of hypertrophy, which quickly progressed to decompensation with ventricular wall thinning, chamber dilatation, and reduced ejection fraction as well as exacerbated pathological cardiac remodeling. Our findings suggest that neddylation is required for postnatal cardiac development and that perturbation of neddylation during development predisposes adult hearts to cardiac failure under stress conditions. NEW & NOTEWORTHY Our study demonstrates that perinatal perturbation of neddylation induces cardiomyopathy, impairs postnatal cardiac development, and increases susceptibility to catecholamine-induced cardiac dysfunction. The results reveal a previously unappreciated role of neddylation in postnatal cardiac maturation and call for close monitoring for the potential cardiotoxicity of MLN4924 (pevonedistat) and other agents that modify neddylation, especially in pregnant women and preadolescents.

Prognostic significance of TOP2A in non-small cell lung cancer revealed by bioinformatic analysis.

BACKGROUND: Lung cancer has been a common malignant tumor with a leading cause of morbidity and mortality, current molecular targets are woefully lacking comparing to the highly progressive cancer. The study is designed to identify new prognostic predictors and potential gene targets based on bioinformatic analysis of Gene Expression Omnibus (GEO) database. METHODS: Four cDNA expression profiles GSE19188, GSE101929, GSE18842 and GSE33532 were chosen from GEO database to analyze the differently expressed genes (DEGs) between non-small cell lung cancer (NSCLC) and normal lung tissues. After the DEGs functions were analyzed, the protein-protein interaction network (PPI) of DEGs were constructed, and the core gene in the network which has high connectivity degree with other genes was identified. We analyzed the association of the gene with the development of NSCLC as well as its prognosis. Lastly we explored the conceivable signaling mechanism of the gene regulation during the development of NSCLC. RESULTS: A total of 92 up regulated and 214 down regulated DEGs were shared in four cDNA expression profiles. Based on their PPI network, TOP2A was connected with most of other genes and was selected for further analysis. Kaplan-Meier overall survival analysis (OS) revealed that TOP2A was associated with worse NSCLC patients survival. And both GEPIA analysis and immunohistochemistry experiment (IHC) confirmed that TOP2A was aberrant gain of expression in cancer comparing to normal tissues. The clinical significance of TOP2A and probable signaling pathways it involved in were further explored, and a positive correlation between TOP2A and TPX2 expression was found in lung cancer tissues. CONCLUSION: Using bioinformatic analysis, we revealed that TOP2A could be adopted as a prognostic indicator of NSCLC and it potentially regulate cancer development through co-work with TPX2. However, more detailed experiments are needed to clarify its drug target role in clinical medical use.

Identification of Novel Endophytic Yeast Strains from Tangerine Peel.

Seven endophytic yeast strains were isolated from tangerine peel (Citrus reticulata Blanco) and genotyped through clustering with D1/D2 and ITS1-5.8S-ITS2 sequences from GenBank. Phenotypic characteristics were obtained through commercial kits and through assisted species identification. Indole-3-acetic acid (IAA) production by the yeast strains was assessed using Salkowski reagent and High-Performance Liquid chromatography (HPLC). The growth-promoting effects of the yeast were evaluated using the 'ragdoll' method. CRYb1, CRYb2 and CRYb7 isolates were identified as the closest species Hanseniaspora opuntiae. CRYb3 was identified as Pichia kluyveri. CRYb4, CRYb5 and CRYb6 were identified as Meyerozyma guilliermondii. CRYb1, CRYb5, CRYb6 and CRYb7 were found to be capable of IAA production. The most promising yeast strains now require further evaluation for their ability to promote plant growth in vitro and in vivo. These data increase our knowledge of the distribution and biological properties of endophytic yeast. This is important information that will be required to fully harness the growth-promoting properties of yeast strains.

Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy is a major risk factor in diabetic patients but its pathogenesis remains poorly understood. The ubiquitin-proteasome system (UPS) facilitates protein quality control by degrading unnecessary and damaged proteins in eukaryotic cells, and dysfunction of UPS is implicated in various cardiac diseases. However, the overall functional status of the UPS and its pathophysiological role in diabetic cardiomyopathy have not been determined. METHODS AND RESULTS: Type I diabetes was induced in wild-type and transgenic mice expressing a UPS functional reporter (GFPdgn) by injections of streptozotocin (STZ). STZ-induced diabetes progressively impaired cardiac UPS function as evidenced by the accumulation of GFPdgn proteins beginning two weeks after diabetes induction, and by a buildup of total and lysine (K) 48-linked polyubiquitinated proteins in the heart. To examine the functional role of the UPS in diabetic cardiomyopathy, cardiac overexpression of PA28α (PA28αOE) was used to enhance proteasome function in diabetic mouse hearts. PA28αOE diabetic mice displayed exhibited restoration of cardiac UPS function, as demonstrated by the diminished accumulation of GFPdgn and polyubiquitinated proteins. Moreover, PA28αOE diabetic mice exhibited reduced myocardial collagen deposition, decreased cardiomyocyte apoptosis, and improved cardiac systolic and diastolic function. CONCLUSION: Impairment of cardiac UPS function is an early event in STZ-induced diabetes. Overexpression of PA28α attenuates diabetes-induced proteotoxic stress and cardiomyopathy, suggesting a potential therapeutic role for enhancement of cardiac proteasome function in this disorder.