Gene expression changes linked to antimicrobial resistance, oxidative stress, iron depletion and retained motility are observed when Burkholderia cenocepacia grows in cystic fibrosis sputum

<p>Abstract</p> <p>Background</p> <p>Bacteria from the <it>Burkholderia cepacia </it>complex (Bcc) are the only group of cystic fibrosis (CF) respiratory pathogens that may cause death by an invasive infection known as cepacia syndrome. Their large genome (> 7000 genes) and multiple pathways encoding the same putative functions make virulence factor identification difficult in these bacteria.</p> <p>Methods</p> <p>A novel microarray was designed to the genome of <it>Burkholderia cenocepacia </it>J2315 and transcriptomics used to identify genes that were differentially regulated when the pathogen was grown in a CF sputum-based infection model. Sputum samples from CF individuals infected with the same <it>B. cenocepacia </it>strain as genome isolate were used, hence, other than a dilution into a minimal growth medium (used as the control condition), no further treatment of the sputum was carried out.</p> <p>Results</p> <p>A total of 723 coding sequences were significantly altered, with 287 upregulated and 436 downregulated; the microarray-observed expression was validated by quantitative PCR on five selected genes. <it>B. cenocepacia </it>genes with putative functions in antimicrobial resistance, iron uptake, protection against reactive oxygen and nitrogen species, secretion and motility were among the most altered in sputum. Novel upregulated genes included: a transmembrane ferric reductase (BCAL0270) implicated in iron metabolism, a novel protease (BCAL0849) that may play a role in host tissue destruction, an organic hydroperoxide resistance gene (BCAM2753), an oxidoreductase (BCAL1107) and a nitrite/sulfite reductase (BCAM1676) that may play roles in resistance to the host defenses. The assumptions of growth under iron-depletion and oxidative stress formulated from the microarray data were tested and confirmed by independent growth of <it>B. cenocepacia </it>under each respective environmental condition.</p> <p>Conclusion</p> <p>Overall, our first full transcriptomic analysis of <it>B. cenocepacia </it>demonstrated the pathogen alters expression of over 10% of the 7176 genes within its genome when it grows in CF sputum. Novel genetic pathways involved in responses to antimicrobial resistance, oxidative stress, and iron metabolism were revealed by the microarray analysis. Virulence factors such as the cable pilus and Cenocepacia Pathogenicity Island were unaltered in expression. However, <it>B. cenocepacia </it>sustained or increased expression of motility-associated genes in sputum, maintaining a potentially invasive phenotype associated with cepacia syndrome.</p

Tracking sustainability: co-evolution of economic and ecological activities in the industrialization of the United Kingdom and China

The co-evolution of economic and ecological activities represents one of the fundamental challenges in the realm of sustainable development. This study on the word trends in mainstream newspapers from the UK and China reveals that both early-industrialised countries and latecomers follow three modes of economic and ecological co-evolution. First, both economic and ecological words demonstrate an S-shaped growth trajectory, and the mode underscores the importance of information propagation, whilst also highlighting the crucial role of self-organisation in the accept society. Second, the co-occurrence of these two type words exhibits a Z-shaped relationship: for two-thirds of the observed period, they display synergistic interactions, while the remaining time shows trade-offs. Lastly, the words related to ecological degradation follow M-shaped trajectories in parallel with economic growth, suggesting periodic disruptions and reconstructions in their interrelationships. Our findings contribute to a more nuanced understanding of the co-evolutionary mechanisms that govern collective behaviours in human society

Studying the distribution patterns, dynamics and influencing factors of city functional components by gradient analysis

Understanding the spatial distribution characteristics and formation mechanism of urban facilities (city functional components) constitutes the basis of urban layout optimization. Currently, research on the overall distribution of the various types of city functional components is lacking. In this study, by applying the gradient analysis method common in ecology, we considered 13 types of city functional components (80,214 individuals in total) in large, medium and small Chinese cities (9 cities in total) to carry out quantitative analysis of the distribution of components along urban–rural gradients through density distribution curves. The results indicated that: (1) a higher density of city functional components near the city centre revealed an obvious aggregated distribution; (2) the spatial distribution dynamics of city functional components were related to the city size, providing a reference for the rational distribution of components in cities of different sizes; (3) the distribution of city functional components was affected by their ecosystem services. This study offers a new perspective for the application of ecological methods in the examination of the distribution of city functional components

Profiling of the BRCA1 transcriptome through microarray and ChIP-chip analysis

A role for BRCA1 in the direct and indirect regulation of transcription is well established. However, a comprehensive view of the degree to which BRCA1 impacts transcriptional regulation on a genome-wide level has not been defined. We performed genome-wide expression profiling and ChIP-chip analysis, comparison of which revealed that although BRCA1 depletion results in transcriptional changes in 1294 genes, only 44 of these are promoter bound by BRCA1. However, 27% of these transcripts were linked to transcriptional regulation possibly explaining the large number of indirect transcriptional changes observed by microarray analysis. We show that no specific consensus sequence exists for BRCA1 DNA binding but rather demonstrate the presence of a number of known and novel transcription factor (TF)- binding sites commonly found on BRCA1 bound promoters. Co-immunoprecipitations confirmed that BRCA1 interacts with a number of these TFs including AP2-α, PAX2 and ZF5. Finally, we show that BRCA1 is bound to a subset of promoters of genes that are not altered by BRCA1 loss, but are transcriptionally regulated in a BRCA1-dependent manner upon DNA damage. These data suggest a model, whereby BRCA1 is present on defined promoters as part of an inactive complex poised to respond to various genotoxic stimuli

Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial.

The effect of the α-glucosidase inhibitor acarbose on cardiovascular outcomes in patients with coronary heart disease and impaired glucose tolerance is unknown. We aimed to assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced. The Acarbose Cardiovascular Evaluation (ACE) trial was a randomised, double-blind, placebo-controlled, phase 4 trial, with patients recruited from 176 hospital outpatient clinics in China. Chinese patients with coronary heart disease and impaired glucose tolerance were randomly assigned (1:1), in blocks by site, by a centralised computer system to receive oral acarbose (50 mg three times a day) or matched placebo, which was added to standardised cardiovascular secondary prevention therapy. All study staff and patients were masked to treatment group allocation. The primary outcome was a five-point composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure, analysed in the intention-to-treat population (all participants randomly assigned to treatment who provided written informed consent). The secondary outcomes were a three-point composite outcome (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, development of diabetes, and development of impaired renal function. The safety population comprised all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513. Between March 20, 2009, and Oct 23, 2015, 6522 patients were randomly assigned and included in the intention-to-treat population, 3272 assigned to acarbose and 3250 to placebo. Patients were followed up for a median of 5·0 years (IQR 3·4-6·0) in both groups. The primary five-point composite outcome occurred in 470 (14%; 3·33 per 100 person-years) of 3272 acarbose group participants and in 479 (15%; 3·41 per 100 person-years) of 3250 placebo group participants (hazard ratio 0·98; 95% CI 0·86-1·11, p=0·73). No significant differences were seen between treatment groups for the secondary three-point composite outcome, death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function. Diabetes developed less frequently in the acarbose group (436 [13%] of 3272; 3·17 per 100 person-years) compared with the placebo group (513 [16%] of 3250; 3·84 per 100 person-years; rate ratio 0·82, 95% CI 0·71-0·94, p=0·005). Gastrointestinal disorders were the most common adverse event associated with drug discontinuation or dose changes (215 [7%] of 3263 patients in the acarbose group vs 150 [5%] of 3241 in the placebo group [p=0·0007]; safety population). Numbers of non-cardiovascular deaths (71 [2%] of 3272 vs 56 [2%] of 3250, p=0·19) and cancer deaths (ten [&lt;1%] of 3272 vs 12 [&lt;1%] of 3250, p=0·08) did not differ between groups. In Chinese patients with coronary heart disease and impaired glucose tolerance, acarbose did not reduce the risk of major adverse cardiovascular events, but did reduce the incidence of diabetes.</p

Early pregnancy peripheral blood gene expression and risk of preterm delivery: a nested case control study

<p>Abstract</p> <p>Background</p> <p>Preterm delivery (PTD) is a significant public health problem associated with greater risk of mortality and morbidity in infants and mothers. Pathophysiologic processes that may lead to PTD start early in pregnancy. We investigated early pregnancy peripheral blood global gene expression and PTD risk.</p> <p>Methods</p> <p>As part of a prospective study, ribonucleic acid was extracted from blood samples (collected at 16 weeks gestational age) from 14 women who had PTD (cases) and 16 women who delivered at term (controls). Gene expressions were measured using the GeneChip^®Human Genome U133 Plus 2.0 Array. Student's T-test and fold change analysis were used to identify differentially expressed genes. We used hierarchical clustering and principle components analysis to characterize signature gene expression patterns among cases and controls. Pathway and promoter sequence analyses were used to investigate functions and functional relationships as well as regulatory regions of differentially expressed genes.</p> <p>Results</p> <p>A total of 209 genes, including potential candidate genes (e.g. PTGDS, prostaglandin D2 synthase 21 kDa), were differentially expressed. A set of these genes achieved accurate pre-diagnostic separation of cases and controls. These genes participate in functions related to immune system and inflammation, organ development, metabolism (lipid, carbohydrate and amino acid) and cell signaling. Binding sites of putative transcription factors such as EGR1 (early growth response 1), TFAP2A (transcription factor AP2A), Sp1 (specificity protein 1) and Sp3 (specificity protein 3) were over represented in promoter regions of differentially expressed genes. Real-time PCR confirmed microarray expression measurements of selected genes.</p> <p>Conclusions</p> <p>PTD is associated with maternal early pregnancy peripheral blood gene expression changes. Maternal early pregnancy peripheral blood gene expression patterns may be useful for better understanding of PTD pathophysiology and PTD risk prediction.</p

A Staged Finite-Time Control Strategy for Formation of Underactuated Unmanned Surface Vehicles

The formation control issue for a group of underactuated unmanned surface vehicles (USVs) is discussed in the paper, and a staged finite-time control strategy for the USVs is proposed. Firstly, we try to steer each USV to its own starting point in the formation for a limited time, under the initial condition that each of these vehicles is parked at random. To deal with the nonholonomic behavior of the system, the dynamics of the USV is transformed into cascade systems. Then, the finite-time controller is designed for each vehicle based on homogeneity theory. After each USV reaches its own starting point with desired orientation, the model of the vehicle is decomposed into two subsystems under the Serret-Frenet frame. In order to maintain the formation pattern, two finite-time distributed controllers are developed for the surge subsystem and the yaw subsystem, respectively. The settling time for the staged control strategy is limited. Numerical simulations are carried out to illustrate the effectiveness of the proposed formation control strategy.</jats:p