Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis.

BACKGROUND: Currently, sepsis induced cardiotoxicity is among the major causes of sepsis-related death. The specific molecular mechanisms of sepsis induced cardiotoxicity are currently unknown. Therefore, the purpose of this paper is to identify the key molecule mechanisms for sepsis induced cardiotoxicity. METHODS: Original data of sepsis induced cardiotoxicity was derived from Gene Expression Omnibus (GEO; GSE63920; GSE44363; GSE159309) dataset. Functional enrichment analysis was used to analysis sepsis induced cardiotoxicity related signaling pathways. Our findings also have explored the relationship of cuproptosis and N6-Methyladenosine (m6A) in sepsis induced cardiotoxicity. Mice are randomly assigned to 3 groups: saline treatment control group, LPS group administered a single 5 mg/kg dose of LPS for 24 h, LPS + CD274 inhibitor group administered 10 mg/kg CD274 inhibitor for 24 h. RESULTS: Overall, expression of cuproptosis-related genes (CRGs) CD274, Ceruloplasmin (CP), Vascular endothelial growth factor A (VEGFA), Copper chaperone for cytochrome c oxidase 11 (COX11), chemokine C-C motif ligand 8 (CCL8), Mitogen-activated protein kinase kinase 1(MAP2K1), Amine oxidase 3 (AOC3) were significantly altered in sepsis induced cardiotoxicity. The results of spearman correlation analysis was significant relationship between differentially regulated genes (DEGs) of CRGs and the expression level of m6A methylation genes. GO and KEGG showed that these genes were enriched in response to interferon-beta, MHC class I peptide loading complex, proteasome core complex, chemokine receptor binding, TAP binding, chemokine activity, cytokine activity and many more. These findings suggest that cuproptosis is strongly associated with sepsis induced cardiotoxicity. CONCLUSION: In the present study, we found that cuproptosis were associated with sepsis induced cardiotoxicity. The CD274, CP, VEGFA, COX11, CCL8, MAP2K1, AOC3 genes are showing a significant difference expression in sepsis induced cardiotoxicity. Our studies have found significant correlations between CRGs and m6A methylation related genes in sepsis induced cardiotoxicity. These results provide insight into mechanism for sepsis induced cardiotoxicity.

Correlation of Blood and Intestinal Mucosa miR-34a Expressions with Disease Severity in Ulcerative Colitis Patients.

BACKGROUND: miR-34a has been implicated in many autoimmune diseases and gastrointestinal diseases. However, the expression of miR-34 in ulcerative colitis (UC) patients were not fully studied. This study was performed to in-vestigate the association of blood and intestinal tissue miR-34a expression of patients with disease severity in UC patients. METHODS: Our study enrolled 82 patients with UC and 80 age- and gender- matched healthy individuals. Blood miR-34a expressions were detected using reverse transcription-polymerase chain reaction (RT-PCR). Local intestinal miR-34a, STAT3 mRNA and IL-23 mRNA expressions were also detected in the lesioned area and adjacent non-affected intestinal tissue in patients. Disease severity of UC was assessed by Mayo score. The diagnostic value of both blood and local miR-34a expression for UC patients was assessed by receiver operating characteristic (ROC) curve. RESULTS: Blood miR-34a was increased in UC patients in contrast with healthy individuals with statistical significance. In UC patients, local intestinal miR-34a expressions were markedly upregulated compared to adjacent non-affected intestinal tissue. Local intestinal miR-34a expressions were positively correlated with STAT3 mRNA and IL-23 mNRA. Both blood and local miR-34a expressions were significantly and positively related to Mayo scores. ROC curve analysis indicated that both blood and local miR-34a expressions may act as decent marker for Mayo grade. CONCLUSIONS: Blood and intestinal tissue miR-34a expressions are correlated with disease severity in UC patients. Both blood and intestinal tissue miR-34a expressions may serve as potential diagnostic and prognostic makers for UC. Therapeutic methods targeting miR-34a may act as potential ways for UC treatment.

Cytoophidia Influence Cell Cycle and Size in Schizosaccharomyces pombe.

Cytidine triphosphate synthase (CTPS) forms cytoophidia in all three domains of life. Here we focus on the function of cytoophidia in cell proliferation using Schizosaccharomyces pombe as a model system. We find that converting His359 of CTPS into Ala359 leads to cytoophidium disassembly. By reducing the level of CTPS protein or specific mutation, the loss of cytoophidia prolongs the G2 phase and expands cell size. In addition, the loss-filament mutant of CTPS leads to a decrease in the expression of genes related to G2/M transition and cell growth, including histone chaperone slm9. The overexpression of slm9 alleviates the G2 phase elongation and cell size enlargement induced by CTPS loss-filament mutants. Overall, our results connect cytoophidia with cell cycle and cell size control in Schizosaccharomyces pombe.

Enhancing physically-based hydrological modeling with an ensemble of machine-learning reservoir operation modules under heavy human regulation using easily accessible data.

Dams and reservoirs have significantly altered river flow dynamics worldwide. Accurately representing reservoir operations in hydrological models is crucial yet challenging. Detailed reservoir operation data is often inaccessible, leading to relying on simplified reservoir operation modules in most hydrological models. To improve the capability of hydrological models to capture flow variability influenced by reservoirs, this study proposes a hybrid hydrological modeling framework, which combines a process-based hydrological model with a machine-learning-based reservoir operation module designed to simulate runoff under reservoir operations. The reservoir operation module employs an ensemble of three machine learning models: random forest, support vector machine, and AutoGluon. These models predict reservoir outflows using precipitation and temperature data as inputs. The Soil and Water Assessment Tool (SWAT) then integrates these outflow predictions to simulate runoff. To evaluate the performance of this hybrid approach, the Xijiang Basin within the Pearl River Basin, China, is used as a case study. The results highlight the superiority of the SWAT model coupled with machine learning-based reservoir operation models compared to alternative modeling approaches. This hybrid model effectively captures peak flows and dry period runoff. The Nash-Sutcliffe Efficiency (NSE) in daily runoff simulations shows substantial improvement, ranging from 0.141 to 0.780, with corresponding enhancements in the coefficient of determination (R2) by 0.098-0.397 when compared to the original reservoir operation modules in SWAT. In comparison to parameterization techniques lacking a dedicated reservoir module, NSE enhancements range from 0.068 to 0.537, and R2 improvements range from 0.027 to 0.139. The proposed hybrid modeling approach effectively characterizes the impact of reservoir operations on river flow dynamics, leading to enhanced accuracy in runoff simulation. These findings offer valuable insights for hydrological forecasting and water resources management in regions influenced by reservoir operations.

Titanium dioxide nanoparticles enhance photocurrent generation of cyanobacteria.

Photosynthetic microorganisms such as cyanobacteria can convert photons into electrons, providing ideal eco-friendly materials for converting solar energy into electricity. However, the electrons are hardly transported outside the cyanobacterial cells due to the insulation feature of the cell wall/membrane. Various nanomaterials have been reported to enhance extracellular electron transfer of heterotrophic electroactive microorganisms, but its effect on intact photosynthetic microorganisms remains unclear. In this study, we investigated the effect of six different nanomaterials on the photocurrent generation of cyanobacterium Synechocystis sp. PCC 6803. Among the nanomaterials tested, titanium dioxide (TiO2) nanoparticles increased the photocurrent generation of Synechocystis sp. PCC 6803 up to four-fold at the optimum concentration of 2 mg/mL. Transmission electron microscopy and scanning electron microscopy showed that TiO2 bound to cyanobacterial cells and likely penetrated inside of cell membrane. Photochemical analyses for photosystems showed that TiO2 blocked the electrons transfer downstream in PS I, implying a possible extracellular electron pathway mediated by TiO2. This study provides an alternative approach for enhancing the photocurrent generation of cyanobacteria, showing the potential of photosynthetic-nanomaterial hybrids.

Association of cardio-renal biomarkers and mortality in the U.S.: a prospective cohort study.

OBJECTIVE: Diabetes poses a significant threat to human health. There is a lack of large-scale cohort studies to explore the association between mortality risk and indicators beyond blood glucose monitoring in diabetic populations. METHODS: Multivariable Cox proportional hazards regression models were performed to investigate the association of 13 blood biomarkers with mortality risk in the National Health and Nutrition Examination Survey (NHANES) and biomarker levels were log-transformed and correlated with mortality. RESULTS: During a median follow-up of 7.42 years, 1783 diabetic patients were enrolled. Compared to traditional risk factors, the addition of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and ß-2 microglobulin biomarkers increased the predictive ability for all-cause mortality by 56.4%, 29.5%, 38.1%, 18.8%, 35.7%, and 41.3%, respectively. However, the inclusion of blood glucose monitoring had no impact on the prediction of all-cause mortality. Compared with the 1st quartiles of creatinine and Cystatin C, the risk of diabetes mortality were higher in the highest quartiles (HR: 5.16, 95% CI: 1.87-14.22; HR: 10.06, 95% CI: 4.20-24.13). CONCLUSIONS: In the diabetic population, elevated plasma levels of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and ß-2 microglobulin serve as robust and straightforward predictors of long-term mortality compared to blood glucose levels and HbA1c values. Creatinine and cystatin C stand out as more precise markers for predicting diabetes mortality prior to blood glucose monitoring.

SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium-glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated. METHODS: Isoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-ß1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs). RESULTS: Both our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT. CONCLUSIONS: Our study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF.

P38 MAPK activated ADAM17 mediates ACE2 shedding and promotes cardiac remodeling and heart failure after myocardial infarction.

BACKGROUND: Heart failure (HF) after myocardial infarction (MI) is a prevalent disease with a poor prognosis. Relieving pathological cardiac remodeling and preserving cardiac function is a critical link in the treatment of post-MI HF. Thus, more new therapeutic targets are urgently needed. The expression of ADAM17 is increased in patients with acute MI, but its functional role in post-MI HF remains unclear. METHODS: To address this question, we examined the effects of ADAM17 on the severity and prognosis of HF within 1 year of MI in 152 MI patients with or without HF. In mechanistic studies, the effects of ADAM17 on ventricular remodeling and systolic function were extensively assessed at the tissue and cellular levels by establishing animal model of post-MI HF and in vitro hypoxic cell model. RESULTS: High levels of ADAM17 predicted a higher incidence of post-MI HF, poorer cardiac function and higher mortality. Animal studies demonstrated that ADAM17 promoted the occurrence of post-MI HF, as indicated by increased infarct size, cardiomyocyte hypertrophy, myocardial interstitial collagen deposition and cardiac failure. ADAM17 knock down significantly improved pathological cardiac remodeling and cardiac function in mice with MI. Mechanistically, activated ADAM17 inhibited the cardioprotective effects of ACE2 by promoting hydrolytic shedding of the transmembrane protein ACE2 in cardiomyocytes, which subsequently mediated the occurrence of cardiac remodeling and the progression of heart failure. Moreover, the activation of ADAM17 in hypoxic cardiomyocytes was dependent on p38 MAPK phosphorylation at threonine 735. CONCLUSIONS: These data highlight a novel and important mechanism for ADAM17 to cause post-MI HF, which will hopefully be a new potential target for early prediction or intervention of post-MI HF. Video abstract.

Isotopic Constraints on Sources and Transformations of Nitrate in the Mount Everest Proglacial Water.

Glacier melting exports a large amount of nitrate to downstream aquatic ecosystems. Glacial lakes and glacier-fed rivers in proglacial environments serve as primary recipients and distributors of glacier-derived nitrate (NO3-), yet little is known regarding the sources and cycling of nitrate in these water bodies. To address this knowledge gap, we conducted a comprehensive analysis of nitrate isotopes (δ15NNO3, δ18ONO3, and Δ17ONO3) in waters from the glacial lake and river of the Rongbuk Glacier-fed Basin (RGB) in the mountain Everest region. The concentrations of NO3- were low (0.43 ± 0.10 mg/L), similar to or even lower than those observed in glacial lakes and glacier-fed rivers in other high mountain regions, suggesting minimal anthropogenic influence. The NO3- concentration decreases upon entering the glacial lake due to sedimentation, and it increases gradually from upstream to downstream in the river as a soil source is introduced. The analysis of Δ17ONO3 revealed a substantial contribution of unprocessed atmospheric nitrate, ranging from 34.29 to 56.43%. Denitrification and nitrification processes were found to be insignificant in the proglacial water of RGB. Our study highlights the critical role of glacial lakes in capturing and redistributing glacier-derived NO3- and emphasizes the need for further investigations on NO3- transformation in the fast-changing proglacial environment over the Tibetan Plateau and other high mountain regions.

Treated wastewater and weak removal mechanisms enhance nitrate pollution in metropolitan rivers.

The focus of urban water environment renovation has shifted to high nitrate (NO3-) load. Nitrate input and nitrogen conversion are responsible for the continuous increase in nitrate levels in urban rivers. This study utilized nitrate stable isotopes (δ15N-NO3- and δ18O-NO3-) to investigate NO3- sources and transformation processes in Suzhou Creek, located in Shanghai. The results demonstrated that NO3- was the most common form of dissolved inorganic nitrogen (DIN), accounting for 66 ± 14% of total DIN with a mean value of 1.86 ± 0.85 mg L-1. The δ15N-NO3- and δ18O-NO3- values ranged from 5.72 to 12.42‰ (mean value: 8.38 ± 1.54‰) and -5.01 to 10.39‰ (mean value: 0.58 ± 1.76‰), respectively. Based on isotopic evidence, the river received a significant amount of nitrate through direct exogenous input and sewage ammonium nitrification, while nitrate removal (denitrification) was insignificant, resulting in nitrate accumulation. Analysis using the MixSIAR model revealed that treated wastewater (68.3 ± 9.7%), soil nitrogen (15.7 ± 4.8%) and nitrogen fertilizer (15.5 ± 4.9%) were the main sources of NO3- in rivers. Despite the fact that Shanghai's urban domestic sewage recovery rate has reached 92%, reducing nitrate concentrations in treated wastewater is crucial for addressing nitrogen pollution in urban rivers. Additional efforts are needed to upgrade urban sewage treatment during low flow periods and/or in the main stream, and to control non-point sources of nitrate, such as soil nitrogen and nitrogen fertilizer, during high flow periods and/or tributaries. This research provides insights into NO3- sources and transformations, and serves as a scientific basis for controlling NO3- in urban rivers.

Style and influencing factors of tutors-postgraduates' interactions in Chinese medical colleges: a cross-sectional survey in Heilongjiang Province.

OBJECTIVES: This study assesses the style of tutor-postgraduate interactions in Chinese medical colleges and explores the association between postgraduates' demographic factors and tutors' demographic characteristics. METHODS: With the stratified sampling method, a cross-sectional online survey was used. A total of 813 medical postgraduates were recruited as participants, with an effective response rate of 85.49%. The two dimensions of "Professional Ability Interaction" and "Comprehensive Cultivation Interaction" in the self-developed "Instructor-Graduate Interaction Scale for Medical Colleges" were used as dependent variables. And tutors' demographic characteristics and postgraduates' demographic characteristics were taken as independent variables. Logistic regression analysis was used to explore the influencing factors of Tutor-Postgraduates Interactions in medical colleges. RESULTS: The Tutor-Postgraduates Interaction scale consists of 14 items from the two dimensions of "Professional Ability Interaction" and "Comprehensive Cultivation Interaction". The results of the logistic regression analysis show the reasons for selecting the mentor students (industry recognition, the tutor's research direction, charm in attracting mentors, and recommendations for mentor selection); student to mentor satisfaction; student to study life satisfaction; and regular academic seminars. Indirect guidance and a high postgraduate grade high are the protective factors of interaction between tutors and postgraduates of medical colleges and universities postgraduates. Older mentors and more graduate tutors are the risk factors for Tutor-Postgraduates Interaction in medical colleges (P < 0.05). CONCLUSION: The current study proposes that managers should pay more attention to the double-track promotion of "Professional Ability Interaction" and "Comprehensive Cultivation Interaction". We should not only pay attention to the cultivation of postgraduates' professional ability but also pay more attention to the comprehensive cultivation including postgraduates' mental and psychological aspects. The interaction between tutors and postgraduates in medical colleges is generally good, but much attention should be given to the dual-track promotion mentioned above. Regular academic seminars play an important role in the process of postgraduate training. The research findings, including the influencing factors regarding tutor-postgraduate interactions, the Professional Ability Interaction and Comprehensive Cultivation Interaction, are very informative and can contribute to strategies for postgraduate management systems that enhance this relationship.

Stabilizing Ultrasmall Ceria-Cluster Nanozyme for Antibacterial and Antibiofouling Applications.

The generation of undesired biofouling in medical and engineering applications results in a reduction in function and durability. Copying functionalities of natural enzymes to combat biofouling by artificial nanomaterials is highly attractive but still challenged by the inferior catalytic activity and specificity principally because of low densities of active sites. Here, an innovate strategy is demonstrated to stabilize high-density ultrasmall ceria clusters on zirconia for biofouling prevention. Benefiting from the unique structure, CeO2 @ZrO2 nanozyme can significantly enhance the haloperoxidase-mimicking activity in catalyzing the oxidation of bromide with H2 O2 into biocidal hypobromous acid as a result of abundant defects and surface strong acidity sites, inducing impressive antibacterial and antibiofouling capacity compared with that of pristine CeO2 . This work is expected to open a new avenue for the rational design of cluster catalysts for various targeting catalytic applications.

Super-Resolution Imaging Reveals Dynamic Reticular Cytoophidia.

CTP synthase (CTPS) can form filamentous structures termed cytoophidia in cells in all three domains of life. In order to study the mesoscale structure of cytoophidia, we perform fluorescence recovery after photobleaching (FRAP) and stimulated emission depletion (STED) microscopy in human cells. By using an EGFP dimeric tag as a tool to explore the physical properties of cytoophidia, we find that cytoophidia are dynamic and reticular. The reticular structure of CTPS cytoophidia may provide space for other components, such as IMPDH. In addition, we observe CTPS granules with tentacles.

Surface Nanosieving Polyether Sulfone Particles with Graphene Oxide Encapsulation for the Negative Isolation toward Extracellular Vesicles.

Extracellular vesicles (EVs) contain specific biomarkers for disease diagnosis. Current EV isolation methods are hampered in important biological applications due to their low recovery and purity. Herein, we first present a novel EV negative isolation strategy based on surface nanosieving polyether sulfone particles with graphene oxide encapsulation (SNAPs) by which the coexisting proteins are irreversibly adsorbed by graphene oxide (GO) inside the particles, while EVs with large sizes are excluded from the outside due to the well-defined surface pore sizes (10-40 nm). By this method, the purity of the isolated EVs from urine could be achieved 4.91 ± 1.01e10 particles/µg, 40.9-234 times higher than those obtained by the ultracentrifugation (UC), size-exclusion chromatography (SEC), and PEG-based precipitation. In addition, recovery ranging from 90.4 to 93.8% could be obtained with excellent reproducibility (RSD < 6%). This was 1.8-4.3 times higher than those obtained via SEC and UC, comparable to that obtained by PEG-based precipitation. Taking advantage of this strategy, we further isolated urinary EVs from IgA nephropathy (IgAN) patients and healthy donors for comparative proteome analysis, by which significantly regulated EV proteins were found to distinguish IgAN patients from healthy donors. All of the results indicated that our strategy would provide a new avenue for highly efficient EV isolation to enable many important clinical applications.

Hypoosmolality impedes cytoophidium integrity during nitrogen starvation.

CTP synthase (CTPS) cytoophidia have been found in many species over domains of life in the past 10 years, implying the evolutionary conservation of these structures. However, there are differences in cytoophidia between species. The difference in CTPS cytoophidium properties between budding yeast (Saccharomyces cerevisiae) and fission yeast (Schizosaccharomyces pombe) inspires this research. We study the effects of culture environment on cytoophidia in S. cerevisiae by switching to the optimal medium for S. pombe. S. cerevisiae CTPS cytoophidium fragmentation and pseudohyphae formation are observed after treatment with S. pombe medium YES instead of S. cerevisiae medium YPD. By modifying the level of each ingredient of the media, we find that hypoosmolality impedes cytoophidium integrity during nitrogen starvation. Our study demonstrates the relationship between cytoophidium integrity and environmental stress, supporting the role of cytoophidia in stress resistance.

Psychological distress and self-management behaviours among patients with chronic hepatitis B receiving oral antiviral therapy.

AIMS: To assess the prevalence and associated factors of psychological distress among patients with chronic hepatitis B receiving oral antiviral therapy and explore the association between psychological distress and self-management behaviours among this population. DESIGN: A cross-sectional study. METHODS: A convenience sample of 188 patients with chronic hepatitis B receiving oral antiviral therapy was recruited from March-October 2018 to complete a self-report questionnaire including the Chinese version of Depression Anxiety Stress Scale-21 and Chronic Hepatitis B Self-Management Scale. Logistic regression analysis and hierarchical multiple regression analysis were used to determine the factors associated with psychological distress and the association between psychological distress and self-management behaviours respectively. RESULTS: The prevalence of depression, anxiety, and stress symptoms were 33.0%, 38.3% and 17.6% respectively. Depression was associated with older age, female gender, lower education level and longer treatment duration; anxiety was associated with female gender and longer treatment duration; and stress was associated with age of 31-40 years, female gender and unmarried status. There were significant associations between depression and anxiety symptoms and self-management behaviours. CONCLUSION: Psychological distress was prevalent among patients with chronic hepatitis B receiving oral antiviral therapy and had a negative impact on self-management. Interventions targeting depression and anxiety symptoms may be beneficial to improve self-management behaviours for this population. IMPACT: This study explored the factors associated with psychological distress in patients with chronic hepatitis B receiving oral antiviral therapy. The findings showed psychological distress was more common in patients who were with older age, female, less educated, unmarried and receiving longer duration of treatment and psychological distress was significantly associated with self-management behaviours. Nurses and other healthcare providers should provide interventions to reduce the risk of psychological distress and improve self-management behaviours for this population.

The association of functional polymorphisms in genes expressed in endothelial cells and smooth muscle cells with the myocardial infarction.

BACKGROUND: The association of platelet endothelial cell adhesion molecule 1 (PECAM1), hypoxia-inducible factor 1 subunit alpha (HIF1A), and KIAA1462 in myocardial infarction (MI) was investigated. The study included 401 Han Chinese MI patients and 409 controls. Three tag single-nucleotide polymorphisms (SNPs)-PECAM1 rs1867624, HIF1A rs2057482, and KIAA1462 rs3739998-were selected. SNP genotyping was performed by an improved multiplex ligation detection reaction assay. A systematic review and meta-analysis of studies including 3314 cases and 2687 controls on the association of 5 HIF1A SNPs and the overall risk of MI or coronary artery disease (CAD) was performed. RESULTS: The rs1867624 variants were associated with high TG concentrations (p = 0.040) and the rs2057482 variants were associated with decreased HDL-C in MI patients compared with the control group (p = 0.003). Rs2057482 SNP interacted with age to influence TC levels. The SNP of rs3739998 interacted with sex and hypertension to modulate CRE and TG levels, respectively (p < 3.04E-5-0.002). No association between the three SNPs and susceptibility to MI was found (p > 0.05 for all). In the meta-analysis of HIF1A, the rs11549465 C > T and rs10873142 T > C polymorphisms, but not rs2057482, rs11549467, and rs41508050, were correlated with overall MI or CAD risk. CONCLUSIONS: Taken together, this study provides additional evidence that genetic variation of the PECAM1 rs1867624 and HIF1A rs2057482 can mediate lipid levels in MI patients.

A germline mutation in Rab43 gene identified from a cancer family predisposes to a hereditary liver-colon cancer syndrome.

BACKGROUND: Hereditary cancer syndromes have inherited germline mutations which predispose to benign and malignant tumors. Understanding of the molecular causes in hereditary cancer syndromes has advanced cancer treatment and prevention. However, the causal genes of many hereditary cancer syndromes remain unknown due to their rare frequency of mutation. METHODS: A large Chinese family with a history of hereditary liver-colon cancer syndrome was studied. The genomic DNA was extracted from the blood samples of involved family members, whole-exome sequencing was performed to identify genetic variants. Functional validation of a candidate variant was carried out using gene expression, gene knockout and immunohistochemistry. RESULTS: The whole-exome of the proband diagnosed with colon cancer was sequenced in comparison with his mother. A total of 13 SNVs and 16 InDels were identified. Among these variants, we focused on a mutation of Rab43 gene, a GTPase family member involving in protein trafficking, for further validation. Sanger DNA sequencing confirmed a mutation (c: 128810106C > T, p: A158T) occurred in one allele of Rab43 gene from the proband, that heterozygous mutation also was verified in the genome of the proband's deceased father with liver cancer, but not in his healthy mother and sister. Ectopic expression of the Rab43 A158T mutant in Huh7 cells led to more enhanced cell growth, proliferation and migration compared to the expression of wild type Rab43. Conversely, knockout of Rab43 in HepG2 cells resulted in slow cell growth and multiple nuclei formation and impaired activation of Akt. Finally, a positive correlation between the expression levels of Rab43 protein and cancer development in that family was confirmed. CONCLUSIONS: A germline mutation of Rab43 gene is identified to be associated with the onset of a familial liver-colon cancer syndrome. Our finding points to a potential role of protein trafficking in the tumorigenesis of the familial cancer syndrome, and helps the genetic counseling to the affected family members.

The increasing menace of dengue in Guangzhou, 2001-2016: the most important epicenter in mainland China.

BACKGROUND: Dengue is the most prevalent mosquito-borne disease in the world, with China affected seriously in recent years. 65.8% of dengue cases identified in mainland China since 2005 were reported from the city of Guangzhou. METHODS: In this study, we described the incidence rate and distribution of dengue cases using data collected form National Notifiable Infectious Disease Reporting Information System data in Guangzhou for 2001 to 2016. All dengue cases were investigated using standardized questionnaire. RESULTS: A total of 42,469 dengue cases were reported, with an average annual incidence rate of 20.99 per 100,000 resident population. Over this time period, the incidence rate of indigenous cases increased. Dengue affected areas also expanded sharply geographically from 58.1% of communities affected during 2001-2005 to 96.4% of communities affected in 2011-2016. Overall 95.30% of the overseas imported cases were reported during March and December, while 99.79% of indigenous cases were reported during July and November. All four dengue virus serotypes were identified both in imported cases and indigenous cases. The Aedes albopictus mosquito was the only vector for dengue transmission in the area. CONCLUSIONS: Guangzhou has become the dengue epicenter in mainland China. Control strategies for dengue should be adjusted to the epidemiological characteristics above and intensive study need to be conducted to explore the factors that driving the rapid increase of dengue.

Advances in exosome isolation methods and their applications in proteomic analysis of biological samples.

Exosomes are membrane-bound vesicles secreted by cells, and contain various important biological molecules, such as lipids, proteins, messenger RNAs, microRNAs, and noncoding RNAs. Emerging evidence demonstrates that proteomic analysis of exosomes is of great significance in studying metabolic diseases, tumor metastasis, immune regulation, and so forth. However, exosome proteomic analysis has high requirements with regard to the purity of collected exosomes. Here recent advances in the methods for isolating exosomes and their applications in proteomic analysis are summarized. Graphical abstract.