Elevated Paracellular Glucose Flux across Cystic Fibrosis Airway Epithelial Monolayers Is an Important Factor for Pseudomonas aeruginosa Growth.

People with cystic fibrosis (CF) who develop related diabetes (CFRD) have accelerated pulmonary decline, increased infection with antibiotic-resistant Pseudomonas aeruginosa and increased pulmonary exacerbations. We have previously shown that glucose concentrations are elevated in airway surface liquid (ASL) of people with CF, particularly in those with CFRD. We therefore explored the hypotheses that glucose homeostasis is altered in CF airway epithelia and that elevation of glucose flux into ASL drives increased bacterial growth, with an effect over and above other cystic fibrosis transmembrane conductance regulator (CFTR)-related ASL abnormalities. The aim of this study was to compare the mechanisms governing airway glucose homeostasis in CF and non-CF primary human bronchial epithelial (HBE) monolayers, under normal conditions and in the presence of Ps. aeruginosa filtrate. HBE-bacterial co-cultures were performed in the presence of 5 mM or 15 mM basolateral glucose to investigate how changes in blood glucose, such as those seen in CFRD, affects luminal Ps. aeruginosa growth. Calu-3 cell monolayers were used to evaluate the potential importance of glucose on Ps. aeruginosa growth, in comparison to other hallmarks of the CF ASL, namely mucus hyperviscosity and impaired CFTR-dependent fluid secretions. We show that elevation of basolateral glucose promotes the apical growth of Ps. aeruginosa on CF airway epithelial monolayers more than non-CF monolayers. Ps. aeruginosa secretions elicited more glucose flux across CF airway epithelial monolayers compared to non-CF monolayers which we propose increases glucose availability in ASL for bacterial growth. In addition, elevating basolateral glucose increased Ps. aeruginosa growth over and above any CFTR-dependent effects and the presence or absence of mucus in Calu-3 airway epithelia-bacteria co-cultures. Together these studies highlight the importance of glucose as an additional factor in promoting Ps. aeruginosa growth and respiratory infection in CF disease

Evolutionary relationships between Rhynchosporium lolii sp. nov. and other Rhynchosporium species on grass.

Copyright: 2013 King et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThe fungal genus Rhynchosporium (causative agent of leaf blotch) contains several host-specialised species, including R. commune (colonising barley and brome-grass), R. agropyri (couch-grass), R. secalis (rye and triticale) and the more distantly related R. orthosporum (cocksfoot). This study used molecular fingerprinting, multilocus DNA sequence data, conidial morphology, host range tests and scanning electron microscopy to investigate the relationship between Rhynchosporium species on ryegrasses, both economically important forage grasses and common wild grasses in many cereal growing areas, and other plant species. Two different types of Rhynchosporium were found on ryegrasses in the UK. Firstly, there were isolates of R. commune that were pathogenic to both barley and Italian ryegrass. Secondly, there were isolates of a new species, here named R. lolii, that were pathogenic only to ryegrass species. R. lolii was most closely related to R. orthosporum, but exhibited clear molecular, morphological and host range differences. The species was estimated to have diverged from R. orthosporum ca. 5735 years before the present. The colonisation strategy of all of the different Rhynchosporium species involved extensive hyphal growth in the sub-cuticular regions of the leaves. Finally, new species-specific PCR diagnostic tests were developed that could distinguish between these five closely related Rhynchosporium species.Peer reviewedFinal Published versio

Is a cooperative approach to seaweed farming effectual? An analysis of the seaweed cluster project (SCP), Malaysia

Seaweed (Kappaphycus spp.) farming has been practised in Malaysia since the late 1970s following government policy incentives (training and farming inputs). However, numerous governance, economic, environmental, technological and sociocultural challenges have limited the industry from achieving its full potential. The Seaweed Cluster Project (SCP) was introduced in 2012 to address some of these challenges. We sought to evaluate the effectiveness of the SCP in delivering its central objectives of increasing seaweed production, optimising the farming area, improving seaweed quality and farming efficiency, raising farmers’ income, and reducing the environmental impact of seaweed farming. Community and industry perceptions of the SCP were obtained from seven communities using a mixed-methods approach based on face-to-face semi-structured interviews, focus group discussions, household surveys, observation and secondary data. Views on the SCP outcomes were generally negative, including low take-up rates by indigenous people, poor stakeholder participation in decision-making, limited acceptance of new technologies, economic vulnerability, a complex marketing system, and low social cohesion of seaweed farming communities. Positive perceptions included recognition that the SCP confers high social status upon a community, reduces operating costs, and facilitates the production of certified seaweed. The SCP’s problems are linked to poor multi-level governance, weak market mechanisms and unintegrated community development. The study concludes with five recommendations to improve the SCP: promote the participation of indigenous people; legalise existing migrant farmers; strengthen local seaweed cooperative organisations; provide entrepreneurship skills to farmers; and fully integrate stakeholders into decision-making

Hypothyroidism among military infants born in countries of varied iodine nutrition status

<p>Abstract</p> <p>Background</p> <p>Iodine deficiency is a global problem representing the most common preventable cause of mental retardation. Recently, the impact of subtle deficiencies in iodine intake on children and pregnant women has been questioned. This study was designed to compare hypothyroidism among infants born to US military families in countries of varied iodine nutrition status.</p> <p>Methods</p> <p>A cohort design was used to analyze data from the Department of Defense Birth and Infant Health Registry for infants born in 2000-04 (<it>n </it>= 447,691). Hypothyroidism was defined using ICD-9-CM codes from the first year of life (<it>n </it>= 698). The impact of birth location on hypothyroidism was assessed by comparing rates in Germany, Japan, and US territories with the United States, while controlling for infant gender, plurality, gestational age, maternal age, maternal military status, and military parent's race/ethnicity.</p> <p>Results</p> <p>Hypothyroidism did not vary by birth location with adjusted odds ratios (OR) as follows: Germany (OR 0.82, [95% CI 0.50, 1.35]), Japan (OR 0.67, [95% CI 0.37, 1.22]), and US territories (OR 1.29, [95% CI 0.57, 2.89]). Hypothyroidism was strongly associated with preterm birth (OR 5.44, [95% CI 4.60, 6.42]). Hypothyroidism was also increased among infants with civilian mothers (OR 1.24, [95% CI 1.00, 1.54]), and older mothers, especially ages 40 years and older (OR 2.09, [95% CI 1.33, 3.30]).</p> <p>Conclusions</p> <p>In this study, hypothyroidism in military-dependent infants did not vary by birth location, but was associated with other risk factors, including preterm birth, civilian maternal status, and advanced maternal age.</p

Catheter Related Bloodstream Infection (CR-BSI) in ICU Patients: Making the Decision to Remove or Not to Remove the Central Venous Catheter

Background Approximately 150 million central venous catheters (CVC) are used each year in the United States. Catheter-related bloodstream infections (CR-BSI) are one of the most important complications of the central venous catheters (CVCs). Our objective was to compare the in-hospital mortality when the catheter is removed or not removed in patients with CR-BSI. Methods We reviewed all episodes of CR-BSI that occurred in our intensive care unit (ICU) from January 2000 to December 2008. The standard method was defined as a patient with a CVC and at least one positive blood culture obtained from a peripheral vein and a positive semi quantitative (\u3e15 CFU) culture of a catheter segment from where the same organism was isolated. The conservative method was defined as a patient with a CVC and at least one positive blood culture obtained from a peripheral vein and one of the following: (1) differential time period of CVC culture versus peripheral culture positivity of more than 2 hours, or (2) simultaneous quantitative blood culture with 5:1 ratio (CVC versus peripheral). Results 53 CR-BSI (37 diagnosed by the standard method and 16 by the conservative method) were diagnosed during the study period. There was a no statistically significant difference in the in-hospital mortality for the standard versus the conservative method (57% vs. 75%, p = 0.208) in ICU patients. Conclusion In our study there was a no statistically significant difference between the standard and conservative methods in-hospital mortality

Quantifying culture gaps between physicians and managers in Dutch hospitals: a survey

Background: The demands in hospitals for safety and quality, combined with limitations in financing health care require effective cooperation between physicians and managers. The complex relationship between both groups has been described in literature. We aim to add a perspective to literature, by developing a questionnaire which provides an opportunity to quantitatively report and elaborate on the size and content of differences between physicians and managers. Insight gained from use of the questionnaire might enable us to reflect on these differences and could provide practical tools to improve cooperation between physicians and managers, with an aim to enhance hospital performance.\ud \ud Methods: The CG-Questionnaire was developed by adjusting, pre-testing, and shortening Kralewski's questionnaire, and appeared suitable to measure culture gaps. It was shortened by exploratory factor analysis, using principal-axis factoring extraction with Varimax rotation. The CG-Questionnaire was sent to all physicians and managers within 37 Dutch general hospitals. ANOVA and paired sample T-tests were used to determine significant differences between perceptions of daily work practices based in both professional cultures; culture gaps. The size and content of culture gaps were determined with descriptive statistics.\ud \ud Results: The total response (27%) consisted of 929 physicians and 310 managers. The Cronbachs alpha's were 0.70 - 0.79. Statistical analyses showed many differences; culture gaps were found in the present situation; they were even larger in the preferred situation. Differences between both groups can be classified into three categories: (1) culture gaps in the present situation and not in the preferred, (2) culture gaps in the preferred situation and not in the present, and (3) culture gaps in both situations.\ud \ud Conclusions: With data from the CG-Questionnaire it is now possible to measure the size and content of culture gaps between physicians and managers in hospitals. Results gained with the CG-Questionnaire enables hospitals to reflect on these differences. Combining the results, we distinguished three categories of increasing complexity. We linked these three categories to three methods from intergroup literature (enhanced information, contact and ultimately meta cognition) which could help to improve the cooperation between physicians and managers

Graphene on hexagonal boron nitride as a tunable hyperbolic metamaterial

Hexagonal boron nitride (h-BN) is a natural hyperbolic material1, in which the dielectric constants are the same in the basal plane (ε[superscript t] ≡ ε[superscript x] = ε[superscript y]) but have opposite signs (ε[superscript t] ε[superscript z ]< 0) in the normal plane (ε[superscript z]). Owing to this property, finite-thickness slabs of h-BN act as multimode waveguides for the propagation of hyperbolic phonon polaritons—collective modes that originate from the coupling between photons and electric dipoles in phonons. However, control of these hyperbolic phonon polaritons modes has remained challenging, mostly because their electrodynamic properties are dictated by the crystal lattice of h-BN. Here we show, by direct nano-infrared imaging, that these hyperbolic polaritons can be effectively modulated in a van der Waals heterostructure composed of monolayer graphene on h-BN. Tunability originates from the hybridization of surface plasmon polaritons in graphene with hyperbolic phonon polaritons in h-BN so that the eigenmodes of the graphene/h-BN heterostructure are hyperbolic plasmon–phonon polaritons. The hyperbolic plasmon–phonon polaritons in graphene/h-BN suffer little from ohmic losses, making their propagation length 1.5–2.0 times greater than that of hyperbolic phonon polaritons in h-BN. The hyperbolic plasmon–phonon polaritons possess the combined virtues of surface plasmon polaritons in graphene and hyperbolic phonon polaritons in h-BN. Therefore, graphene/h-BN can be classified as an electromagnetic metamaterial as the resulting properties of these devices are not present in its constituent elements alone

Niclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 Degradation and Inhibiting the Wnt/β-Catenin Pathway

The Wnt/β-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/β-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/β-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced β-catenin accumulation, and inhibit Wnt/β-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/β-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC50 values less than 1 µM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC50 values are comparable to those shown to suppress the activities of Wnt/β-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/β-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer

Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism

Inflammasomes are cytosolic caspase-1-activation complexes that sense intrinsic and extrinsic danger signals, and trigger inflammatory responses and pyroptotic cell death. Homotypic interactions among Pyrin domains and caspase recruitment domains (CARDs) in inflammasome-complex components mediate oligomerization into filamentous assemblies. Several cytosolic proteins consisting of only interaction domains exert inhibitory effects on inflammasome assembly. In this study, we determined the structure of the human caspase-1 CARD domain (caspase-1[superscript CARD]) filament by cryo-electron microscopy and investigated the biophysical properties of two caspase-1-like CARD-only proteins: human inhibitor of CARD (INCA or CARD17) and ICEBERG (CARD18). Our results reveal that INCA caps caspase-1 filaments, thereby exerting potent inhibition with low-nanomolar K[subscript i] on caspase-1[superscript CARD] polymerization in vitro and inflammasome activation in cells. Whereas caspase-1[superscript CARD] uses six complementary surfaces of three types for filament assembly, INCA is defective in two of the six interfaces and thus terminates the caspase-1 filament

A method for assessing robustness of the results of a star-shaped network meta-analysis under the unidentifiable consistency assumption

Background In a star-shaped network, pairwise comparisons link treatments with a reference treatment (often placebo or standard care), but not with each other. Thus, comparisons between non-reference treatments rely on indirect evidence, and are based on the unidentifiable consistency assumption, limiting the reliability of the results. We suggest a method of performing a sensitivity analysis through data imputation to assess the robustness of results with an unknown degree of inconsistency. Methods The method involves imputation of data for randomized controlled trials comparing non-reference treatments, to produce a complete network. The imputed data simulate a situation that would allow mixed treatment comparison, with a statistically acceptable extent of inconsistency. By comparing the agreement between the results obtained from the original star-shaped network meta-analysis and the results after incorporating the imputed data, the robustness of the results of the original star-shaped network meta-analysis can be quantified and assessed. To illustrate this method, we applied it to two real datasets and some simulated datasets. Results Applying the method to the star-shaped network formed by discarding all comparisons between non-reference treatments from a real complete network, 33% of the results from the analysis incorporating imputed data under acceptable inconsistency indicated that the treatment ranking would be different from the ranking obtained from the star-shaped network. Through a simulation study, we demonstrated the sensitivity of the results after data imputation for a star-shaped network with different levels of within- and between-study variability. An extended usability of the method was also demonstrated by another example where some head-to-head comparisons were incorporated. Conclusions Our method will serve as a practical technique to assess the reliability of results from a star-shaped network meta-analysis under the unverifiable consistency assumption.This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C1178). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript