Homology modelling of transferrin-binding protein A from Neisseria meningitidis

Neisseria meningitidis, a causative agent of bacterial meningitis, obtains transferrin-bound iron by expressing two outer membrane located transferrin-binding proteins, TbpA and TbpB. TbpA is thought to be an integral outer membrane pore that facilitates iron uptake. Evidence suggests that TbpA is a useful antigen for inclusion in a vaccine effective against meningococcal disease, hence the identification of regions involved in ligand binding is of paramount importance to design strategies to block uptake of iron. The protein shares sequence and functional similarities to the Escherichia coli siderophore receptors FepA and FhuA, whose structures have been determined. These receptors are composed of two domains, a 22-stranded b-barrel and an N-terminal plug region that sits within the barrel and occludes the transmembrane pore. A three-dimensional TbpA model was constructed using FepA and FhuA structural templates, hydrophobicity analysis and homology modelling. TbpA was found to possess a similar architecture to the siderophore receptors. In addition to providing insights into the highly immunogenic nature of TbpA and allowing the prediction of potentially important ligandbinding epitopes, the model also reveals a narrow channel through its entire length. The relevance of this channel and the spatial arrangement of external loops, to the mechanism of iron translocation employed by TbpA is discussed

Trichloroethylene-induced formic aciduria: effect of dose, sex and strain of rat.

The industrial solvent trichloroethylene (TCE) has been reported to increase the excretion of formic acid in the urine of male Fischer 344 (F-344) rats following large oral doses. We have examined the dose–response relationship for formic aciduria in male and female Fischer 344 rats, the effect of some known metabolites of TCE and examined the response in male Wistar rats to help understand its relevance to renal toxicity. We report that doses of TCE as low as 8 mg/kg for 3 days to both male and female F344 rats produced formic aciduria. The formic aciduria was time-dependent being more marked after 3 doses compared to one dose in male F344 rats and to a lesser extent in female F344 rats. TCE administration to male Wistar rats produced less formic aciduria than in male F344 rats, indicating a strain difference in response. As TCE is primarily metabolised by cytochrome P450 2E1, Wistar rats were administered inducers of cytochrome P450 2E1 followed by TCE, this increased formic acid excretion to a concentration similar to that observed in male F344 rats, indicating a role for P450. Administration of the major metabolites of TCE, trichloroethanol and trichloroacetic acid to male F344 rats also produced a marked and sustained formic aciduria, while the metabolite of TCE formed via glutathione conjugation had no effect on formic acid excretion. The mechanism whereby this response occurs is currently not understood, but the formic acid excreted is not a metabolite of TCE, but appears to be due to interference with the metabolic utilisation of formate by a down stream metabolite of TCE. Over the three days of the studies no histopathological evidence of kidney toxicity was observed in F344 rats given TCE, indicating that the perturbation of formate metabolism does not lead to acute renal injury

Quality assessment of nutrition coverage in the media: A 6 week survey of five popular UK newspapers

Objectives: To investigate the quality of nutrition articles in popular national daily newspapers in the UK and to identify important predictors of article quality. Setting: Newspapers are a primary source of nutrition information for the public. Design: Newspaper articles were collected on 6 days of the week (excluding Sunday) for 6 weeks in summer 2014. Predictors included food type and health outcome, size of article, whether the journalist was named and day of the week. Outcome measures: A validated quality assessment tool was used to assess each article, with a minimum possible score of −12 and a maximum score of 17. Newspapers were checked in duplicate for relevant articles. The association of each predictor on article quality score was analysed adjusting for remaining predictors. A logistic regression model was implemented with quality score as the binary outcome, categorised as poor (score less than zero) or satisfactory (score of zero or more). Results: Over 6 weeks, 141 nutrition articles were included across the five newspapers. The median quality score was 2 (IQR −2–6), and 44 (31%) articles were poor quality. There was no substantial variation in quality of reporting between newspapers once other factors such as anonymous publishing, health outcome, aspect of diet covered and day of the week were taken into account. Particularly low-quality scores were obtained for anonymously published articles with no named journalist, articles that focused on obesity and articles that reported on high fat and processed foods. Conclusions: The general public are regularly exposed to poor quality information in newspapers about what to eat to promote health, particularly articles reporting on obesity. Journalists, researchers, university press officers and scientific journals need to work together more closely to ensure clear, consistent nutrition messages are communicated to the public in an engaging way

Glucose transporter Glut-1 is detectable in pen-necrotic regions in many human tumor types but not normal tissues: Study using tissue microarrays

The hypoxic tumor microenvironment is associated with malignant progression and poor treatment response. The glucose transporter Glut-1 is a prognostic factor and putative hypoxia marker. So far, studies of Glut-1 in cancer have utilised conventional immunohistochemical analysis in a series of individual biopsy or surgical specimens. Tissue microarrays, however, provide a rapid, inexpensive means of profiling biomarker expression. To evaluate hypoxia markers, tissue cores must show architectural features of hypoxia, i.e. viable tissue surrounding necrotic regions. Glut-1 may be a useful biomarker to validate tissue microarrays for use in studies of hypoxia-regulated genes in cancer. In this study, we carried out immunohistochemical detection of Glut-1 protein in many tumor and normal tissue types in a range of tissue microarrays. Glut-1 was frequently found in peri-necrotic regions, occurring in 9/34 lymphomas, 6/12 melanomas, and 5/16 glioblastomas; and in 43/54 lung, 22/84 colon, and 23/60 ovarian tumors. Expression was rare in breast (6/40) and prostate (1/57) tumors, and in normal tissue, was restricted to spleen, tongue and CNS endothelium. In conclusion, tissue microarrays enable the observation of Glut-1 expression in peri-necrotic regions, which may be linked to hypoxia, and reflect previous studies showing differential Glut-1 expression across tumor types and non malignant tissue

Molecular gas in nearby powerful radio galaxies

We report the detection of CO(1-0) and CO(2-1) emission from the central region of nearby 3CR radio galaxies (z$<$ 0.03). Out of 21 galaxies, 8 have been detected in, at least, one of the two CO transitions. The total molecular gas content is below 10$^9$ \msun. Their individual CO emission exhibit, for 5 cases, a double-horned line profile that is characteristic of an inclined rotating disk with a central depression at the rising part of its rotation curve. The inferred disk or ring distributions of the molecular gas is consistent with the observed presence of dust disks or rings detected optically in the cores of the galaxies. We reason that if their gas originates from the mergers of two gas-rich disk galaxies, as has been invoked to explain the molecular gas in other radio galaxies, then these galaxies must have merged a long time ago (few Gyr or more) but their remnant elliptical galaxies only recently (last 10$^7$ years or less) become active radio galaxies. Instead, we argue the the cannibalism of gas-rich galaxies provide a simpler explanation for the origin of molecular gas in the elliptical hosts of radio galaxies (Lim et al. 2000). Given the transient nature of their observed disturbances, these galaxies probably become active in radio soon after the accretion event when sufficient molecular gas agglomerates in their nuclei.Comment: 6 pages, including 2 figures,in "QSO Hosts and Their Environments", ed. I. Marquez, in pres

Trichloroethylene and trichloroethanol-induced formic aciduria and renal injury in male F-344 rats following 12 weeks exposure

Trichloroethylene (TCE) is widely used as a cleaning and decreasing agent and has been shown to cause liver tumours in rodents and a small incidence of renal tubule tumours in male rats. The basis for the renal tubule injury is believed to be related to metabolism of TCE via glutathione conjugation to yield the cysteine conjugate that can be activated by the enzyme cysteine conjugate β-lyase in the kidney. More recently TCE and its major metabolite trichloroethanol (TCE-OH) have been shown to cause formic aciduria which can cause renal injury after chronic exposure in rats. In this study we have compared the renal toxicity of TCE and TCE-OH in rats to try and ascertain whether the glutathione pathway or formic aciduria can account for the toxicity. Male rats were given TCE (500 mg/kg/day) or TCE-OH at (100 mg/kg/day) for 12 weeks and the extent of renal injury measured at several time points using biomarkers of nephrotoxicity and prior to termination assessing renal tubule cell proliferation. The extent of formic aciduria was also determined at several time points, while renal pathology and plasma urea and creatinine were determined at the end of the study. TCE produced a very mild increase in biomarkers of renal injury, total protein, and glucose over the first two weeks of exposure and increased Kim-1 and NAG in urine after 1 and 5 weeks exposure, while TCE-OH did not produce a consistent increase in these biomarkers in urine. However, both chemicals produced a marked and sustained increase in the excretion of formic acid in urine to a very similar extent. The activity of methionine synthase in the liver of TCE and TCE-OH treated rats was inhibited by about 50% indicative of a block in folate synthesis. Both renal pathology and renal tubule cell proliferation were reduced after TCE and TCE-OH treatment compared to controls. Our findings do not clearly identify the pathway which is responsible for the renal toxicity of TCE but do provide some support for metabolism via glutathione conjugation

Photoactive organic-inorganic hybrid polymer waveguides for optical device technologies

© 2020 SPIE. Organic-inorganic hybrid polymers based on ureasils have found application as waveguides in luminescent solar concentrators and visible light communications. The mechanical properties, and thus processability of ureasils, has previously been qualitatively linked to the chemical structure, but has not yet been studied in detail. In this study, a series of low molecular weight ureasil polymers has been synthesised, and the correlation between the chemical structure and the optical and mechanical properties investigated. A wide-range of techniques are employed to investigate this relationship, including steady-state photoluminescence and Fourier-transform infrared spectroscopy, 4-point flexural testing, and uniaxial tensile testing.This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 818762 - SPECTRACON). T. J. F. S. thanks the EPSRC (EP/N509620/1) for financial support

Natural ventilation for the prevention of airborne contagion.

BACKGROUND: Institutional transmission of airborne infections such as tuberculosis (TB) is an important public health problem, especially in resource-limited settings where protective measures such as negative-pressure isolation rooms are difficult to implement. Natural ventilation may offer a low-cost alternative. Our objective was to investigate the rates, determinants, and effects of natural ventilation in health care settings. METHODS AND FINDINGS: The study was carried out in eight hospitals in Lima, Peru; five were hospitals of "old-fashioned" design built pre-1950, and three of "modern" design, built 1970-1990. In these hospitals 70 naturally ventilated clinical rooms where infectious patients are likely to be encountered were studied. These included respiratory isolation rooms, TB wards, respiratory wards, general medical wards, outpatient consulting rooms, waiting rooms, and emergency departments. These rooms were compared with 12 mechanically ventilated negative-pressure respiratory isolation rooms built post-2000. Ventilation was measured using a carbon dioxide tracer gas technique in 368 experiments. Architectural and environmental variables were measured. For each experiment, infection risk was estimated for TB exposure using the Wells-Riley model of airborne infection. We found that opening windows and doors provided median ventilation of 28 air changes/hour (ACH), more than double that of mechanically ventilated negative-pressure rooms ventilated at the 12 ACH recommended for high-risk areas, and 18 times that with windows and doors closed (p < 0.001). Facilities built more than 50 years ago, characterised by large windows and high ceilings, had greater ventilation than modern naturally ventilated rooms (40 versus 17 ACH; p < 0.001). Even within the lowest quartile of wind speeds, natural ventilation exceeded mechanical (p < 0.001). The Wells-Riley airborne infection model predicted that in mechanically ventilated rooms 39% of susceptible individuals would become infected following 24 h of exposure to untreated TB patients of infectiousness characterised in a well-documented outbreak. This infection rate compared with 33% in modern and 11% in pre-1950 naturally ventilated facilities with windows and doors open. CONCLUSIONS: Opening windows and doors maximises natural ventilation so that the risk of airborne contagion is much lower than with costly, maintenance-requiring mechanical ventilation systems. Old-fashioned clinical areas with high ceilings and large windows provide greatest protection. Natural ventilation costs little and is maintenance free, and is particularly suited to limited-resource settings and tropical climates, where the burden of TB and institutional TB transmission is highest. In settings where respiratory isolation is difficult and climate permits, windows and doors should be opened to reduce the risk of airborne contagion

A re-appraisal of the proposed rapid Matuyama–Brunhes geomagnetic reversal in the Sulmona Basin, Italy

An extremely sharp magnetic reversal observed in lacustrine sediments in central Italy has been interpreted as a record of the Matuyama-Brunhes geomagnetic polarity reversal that may represent less than a decade (Sagnotti et al., 2014. 2016). Here, we report new results from the same Sulmona Basin outcrop that question this interpretation. In particular, we find evidence of reversed (Matuyama) directions well above the proposed Matuyama-Brunhes Boundary (MBB). Coercivity spectra of anhysteretic remanent magnetization (ARM) imply a 3-component magnetic mineralogy: low-, intermediate-, and high-coercivity. The low-coercivity component is found in all but one of the samples and carries a strong modern overprint seen throughout the section. The high-coercivity component is dominated by volcanic material which is prone to remagnetization. Since it is much more magnetic than the surrounding lacustrine sediments, it may influence the remanence signal even when present at very low concentrations. The intermediate-coercivity component is the main carrier of any true primary remanence, but whether or not this can be isolated depends on the blocking-temperature and coercivity spectra of individual samples, and on the demagnetization method used. The complexity of the magnetization, the reversed zones above the proposed MBB, and the normal zones that Sagnotti and 2 colleagues found below it, lead to the conclusion that this section does not carry a reliable high-resolution record of the geomagnetic field. Thus, we feel that inferences about the stratigraphic position and duration of the MBB are premature