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Few studies have examined the long-term prognosis of Chinese patients with intracerebral hemorrhage (ICH). This study assessed the clinical characteristics and predictors of vascular events occurring within 5 years after ICH. We included consecutive patients diagnosed with first-ever ICH between June 2013 and December 2014. Based on follow-up data (collected until December 2019), we used multivariable logistic regression to examine the clinical characteristics and long-term predictors of vascular events (including recurrent ICH, ischemic stroke, and acute coronary syndrome) in patients who survived more than 30 days after ICH. Across the 307 patients in our analysis, the 5-year mortality rate was 28.01%. Within 5 years after ICH, major vascular events were observed in 62 patients (17.82%, 95% CI 13.78–21.82%). We observed high incidence of recurrent ICH (8.91%) and ischemic stroke (10.06%), but low incidence of acute coronary syndrome (1.15%). Most cases of recurrent ICH (80.65%) occurred within 3 years after ICH. Age ≥56 years and history of ischemic stroke or transient ischemic attack (TIA) were identified as predictors of cardiovascular and cerebrovascular events. ICH survivors are at high risk of both cardiovascular and cerebrovascular events, especially older patients (≥56 years) and those who experienced ischemic stroke or TIA prior to their first ICH. Recurrent ICH is more likely to occur within the first three years after first ICH than at later times. Clinicians should monitor patients closely for adverse events, particularly during the first three years after initial ICH.

Environmental factors in time and space play a critical role in advancing the sustainable development of the fresh agricultural product supply chain. This paper, availing the panel data of 31 Chinese provinces from 2008 to 2019, constructs a system of indicators assessing the development of the fresh agricultural product supply chain, and obtains the comprehensive development level in the Entropy Weight Method (EWM). Furthermore, it establishes a comparison between optimal solutions generated by the Instrumental Variables Method (IVM) and the Generalized Method of Moments (GMM) over the endogeneity issue of variables, creates the comparison between the weighted regression methods of Geographically Weighted Regression (GWR) and Multi-scale Geographic Weighted Regression (MGWR), and obtains the relationship among the 14 environmental factors in their spatio-temporal impacts on the development of the fresh agricultural product supply chain. The results indicate that: (1) the environmental influencing factors in this paper have significant endogenous problems and various environmental factors impact on the fresh agricultural product supply chain in different trends and to different degrees. (2) With different bandwidths, the environmental factors could impact the fresh agricultural product supply chain to greatly varied degrees, demonstrating a strong attribute of regional correlation.

Background Pseudomonas aeruginosa is a notorious opportunistic pathogen causing various types of biofilm-related infections. Biofilm formation is a unique microbial strategy that allows P. aeruginosa to survive adverse conditions such as antibiotic treatment and human immune clearance. Results In this study, we experimentally evolved P. aeruginosa PAO1 biofilms for cyclic treatment in the presence of high dose of imipenem, and enriched hyperbiofilm mutants within six cycles in two independent lineages. The competition assay showed that the evolved hyperbiofilm mutants can outcompete the ancestral strain within biofilms but not in planktonic cultures. Whole-genome sequencing analysis revealed the hyperbiofilm phenotype is caused by point mutations in rpoS gene in all independently evolved mutants and the same mutation was found in P. aeruginosa clinical isolates. We further showed that mutation in rpoS gene increased the intracellular c-di-GMP level by turning on the expression of the diguanylate cyclases. Mutation in rpoS increased pyocyanin production and virulence in hyperbiofilm variants. Conclusion Here, our study revealed that antibiotic treatment of biofilm-related P. aeruginosa infections might induce a hyperbiofilm phenotype via rpoS mutation, which might partially explain antimicrobial treatment failure of many P. aeruginosa biofilm-related infections.

BackgroundPseudomonas aeruginosa is a notorious opportunistic pathogen causing various biofilm-related infections. Biofilm formation is a unique microbial strategy that allows P. aeruginosa to survive adverse conditions such as antibiotic treatment and human immune responses. ResultsIn this study, we experimentally evolved P. aeruginosa PAO1 biofilms for cyclic treatment in the presence of high dose of imipenem, and enriched hyperbiofilm mutants within six cycles in two independent lineages. The competition assay showed the evolved hyperbiofilm mutants can outcompete the ancestral strain within biofilm by prolonging the biofilm mode of growth but not in planktonic cultures. Whole-genome sequencing analysis revealed the hyperbiofilm phenotype is caused by point mutations in rpoS gene in all independently evolved mutants and the same mutation was found in P. aeruginosa clinical isolates. We further showed that mutation in rpoS enhanced biofilm formation by prolonging the biofilm mode of growth and elevating the intracellular c-di-GMP level. Mutation in rpoS increased pyocyanin production and virulence in both P. aeruginosa laboratory strains and clinical isolates. ConclusionHere, our study revealed that antibiotic treatment of biofilm-related P. aeruginosa infections might induce a hyperbiofilm phenotype via rpoS mutation, which might partially explain antimicrobial treatment failure of many P. aeruginosa biofilm-related infections.

COVID-19 pandemic has caused millions of death globally and caused huge impact on the health of infected patients. Shift in the lung microbial ecology upon such viral infection often worsens the disease and increases host susceptibility to secondary infections. Recent studies have indicated that bacterial coinfection is an unignorable factor contributing to the aggravation of COVID-19 and posing great challenge to clinical treatments. However, there is still a lack of in-depth investigation on the coinfecting bacteria in COVID-19 patients for better treatment of bacterial coinfection. With the knowledge thatPseudomonas aeruginosais one of the top coinfecting pathogens, we analyzed the adaptation and convergent evolution of nosocomialP. aeruginosaisolated from two critical COVID-19 patients in this study. We sequenced and compared the genomes and transcriptomes ofP. aeruginosaisolates longitudinally and parallelly for its evolutionary traits.P. aeruginosaoverexpressed alginate and attenuated Type VI secretion system (T6SS) during coinfection for excessive biofilm formation and suppressed virulence. Results of bacterial competition assay and macrophage cytotoxicity test indicated thatP. aeruginosareduced its virulence towards both prokaryotic competitors and eukaryotic host through inhibiting its T6SS during evolution.P. aeuginosaT6SS is thus one of the reasons for its advantage to cause coinfection in COVID-19 patients while the attenuation of T6SS could cause a shift in the microecological composition in the lung. Our study will contribute to the development of therapeutic measures and the discovery of novel drug target to eliminateP. aeruginosacoinfection in COVID-19 patient.

Acute inflammatory response needs to be tightly regulated for promoting the elimination of pathogens and preveting the risk of tumorigenesis, but the mechanism has not been fully elucidated. Here, we report that Ras guanine nucleotide releasing protein 1 (RasGRP1) plays a bifunctional regulator that promotes acute inflammation and inhibits inflammation-associated cancer. At the mRNA level, RasGRP1 strengthens the inflammatory response by functioning as a competing endogenous RNA to specifically promote IL-6 expression by sponging let-7a. In vivo overexpression of the RasGRP1 3’ untranslated region significantly aggravated lipopolysaccharide-induced systemic inflammation and dextran sulphate sodium-induced colitis in IL-6+/+ mice but not in IL-6-/- mice. At the protein level, RasGRP1 restricts the growth of inflammation-contributed cancer cells by impairing EGFR-SOS1-Ras-AKT signalling. Tumour patients with high RasGRP1 expression showed a better clinical outcome than those with low expression. Considering acute inflammation rarely leads to tumorigenesis, this work reveals that RasGRP1 is an essential bifunctional regulator for acute inflammatory response.

Pseudomonas aeruginosa is a biofilm-forming opportunistic pathogen which causes chronic infections in immunocompromised patients and leads to high mortality rate. It is identified as a common coinfecting pathogen in COVID-19 patients causing exacerbation of illness. In our hospital, P. aeruginosa is one of the top coinfecting bacteria identified among COVID-19 patients. We collected a strong biofilm-forming P. aeruginosa strain displaying small colony variant morphology from a severe COVID-19 patient. Genomic and transcriptomic sequencing analyses were performed with phenotypic validation to investigate its adaptation in SARS-CoV-2 infected environment. Genomic characterization predicted specific genomic islands highly associated with virulence, transcriptional regulation, and DNA restriction-modification systems. Epigenetic analysis revealed a specific N6-methyl adenine (m6A) methylating pattern including methylation of alginate, flagellar and quorum sensing associated genes. Differential gene expression analysis indicated that this isolate formed excessive biofilm by reducing flagellar formation (7.4 to 1,624.1 folds) and overproducing extracellular matrix components including CdrA (4.4 folds), alginate (5.2 to 29.1 folds) and Pel (4.8–5.5 folds). In summary, we demonstrated that P. aeuginosa clinical isolates with novel epigenetic markers could form excessive biofilm, which might enhance its antibiotic resistance and in vivo colonization in COVID-19 patients.

Characterization of biofilm formation and metabolic activities is critical to investigating biofilm interactions with environmental factors and illustrating biofilm regulatory mechanisms. An appropriate in vitro model that mimics biofilm in vivo habitats therefore demands accurate quantitation and investigation of biofilm-associated activities. Current methodologies commonly involve static biofilm setups (such as biofilm assays in microplates, bead biofilms, or biofilms on glass-slides) and fluidic flow biofilm systems (such as drip-flow biofilm reactors, 3-channel biofilm reactors, or tubing biofilm reactors). Continuous flow systems take into consideration the contribution of hydrodynamic shear forces, nutrient supply, and physical transport of dispersed cells, which define the habitat for biofilm development in most natural and engineered systems. This protocol describes the assembly of 3 flow-system setups to cultivate Pseudomonas aeruginosa PAO1 and Shewanella oneidensis MR-1 model biofilms, including the respective quantitation and observation approaches. The standardized flow systems promise productive and reproducible biofilm experimental results, which can be further modified according to specific research projects.

This study characterized a genetically adapted Pseudomonas aeruginosa small colony variant isolated from a COVID-19 patient who suffered persistent bacterial coinfection and eventually recovered from critical illness. Specification and modification of the isolates discovered at genomic and transcriptomic levels with aligned phenotypic observations indicated that these isolates formed excessive biofilm with elevated quorum sensing systems.

Polybrominated diphenyl ethers (PBDEs) are a group of brominated flame retardants that are ubiquitously detected in the environment and associated with adverse health outcomes. 6-OH-BDE-47 is a metabolite of the flame retardant, 2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47), and there is increasing concern regarding its developmental neurotoxicity and endocrine disrupting properties. In this study, we report that early life exposure in zebrafish (Danio rerio) embryos to 6-OH-BDE-47 (50 and 100 nM) resulted in higher coiling frequency and significantly increased apoptotic cells in the brain. These effects were partially rescued by overexpression of thyroid hormone receptor β (THRβ) mRNA. Moreover, exposure to 100 nM 6-OH-BDE-47 significantly reduced the number of hypothalamic 5-hydroxytryptamine (5-HT, serotonin)-immunoreactive (5-HT-ir) neurons and the mRNA expression of tryptophan hydroxylase 2 (TPH2). These results indicate that 6-OH-BDE-47 affected thyroid hormone regulation through THRβ and negatively impacted the nervous system, in turn, affecting coiling behavior. Correlations of these endpoints suggest that coiling frequency could be used as an indicator of neurotoxicity in embryos.

We report a facile and general strategy for enhancing the photostability of organic fluorophores for bioimaging applications. As a proof of concept, bright and robust fluorescence was observed in solid states of a well-defined synthetic polymer polycaprolactone consisting of di(thiophene-2-yl)-diketopyrrolopyrrole covalently linked in the middle of the polymer chain as a biocompatible and bioresorbable matrix. The nanoparticles prepared through a nanoprecipitation process of these polymers could be internalized by both tumor cells and stem cells with little cytotoxicity. Moreover, these highly fluorescent nanoparticles exhibited significantly enhanced photostability compared to commercial quantum dots or physical blends of dye/polymer complexes in cell imaging and long-term tracing.

Trantinterol, a selective β2-adrenoceptor agonist, is currently in Phase II clinical trials for the treatment of asthma and bronchitis. The synthesis of deuterium-labelled trantinterol is described. The labelled trantinterol is used as an internal standard for the analysis and metabolic studies. Copyright © 2010 John Wiley & Sons, Ltd.

At present, environmental issues are coming to the forefront in all parts of the global with increasing public concern. Coal is one of the most important primary energies in this world. Some pollutants such as SO2, NO x , Hg and other harmful matters are yielded during coal combustion. In china, coal holds up to 70% of consumption of the primary energy, and most of the power stations mainly adopt coal as the energy source, which induces much deterioration of the environment. To develop effective air pollution control techniques for coal-fired boilers is very important. Till now, scientists all around the world have developed various methods to reduce air pollution caused by coal combustion. Although the environmental situation has ameliorated, the pollutant emissions have not been completely eliminated. Some pilot projects have demonstrated that it is not economical to remove pollutants separately. There are several advantages to remove air pollutants simultaneously in a whole system, such as simplifying the controlling system, improving the operation characteristics, reducing the operating cost and so on. Many ways have been reported to remove the SO2, NO x and Hg from the flue gas, however, the combination control of air pollutants is rarely investigated. Besides introducing the hazards of air pollutants, and some techniques about desulfurization, denitration and mercury control methods, the paper summarizes the method to design the experimental devices of combination control, and the reasons to determine the experimental program and to select the adsorbents. The combination control scheme recommended in this paper is that spraying CMA (calcium magnesium acetate) into the furnace and increasing humidity at the end of the flue gas duct to take off SO2, NO x and Hg2+ simultaneously, applying the adsorption device of impregnating the zeolite with activated manganese dioxide as adsorbents to adsorb mercury, and using bag-house to capture fly ash to remove mercury.