Investigating the DNA-Binding Site for VirB, a Key Transcriptional Regulator of Shigella Virulence Genes, Using an In Vivo Binding Tool

The transcriptional anti-silencing and DNA-binding protein, VirB, is essential for the virulence of Shigella species and, yet, sequences required for VirB-DNA binding are poorly understood. While a 7-8 bp VirB-binding site has been proposed, it was derived from studies at a single VirB-dependent promoter, icsB. Our previous in vivo studies at a different VirB-dependent promoter, icsP, found that the proposed VirB-binding site was insufficient for regulation. Instead, the required site was found to be organized as a near-perfect inverted repeat separated by a single nucleotide spacer. Thus, the proposed 7-8 bp VirB-binding site needed to be re-evaluated. Here, we engineer and validate a molecular tool to capture protein-DNA binding interactions in vivo. Our data show that a sequence organized as a near-perfect inverted repeat is required for VirB-DNA binding interactions in vivo at both the icsB and icsP promoters. Furthermore, the previously proposed VirB-binding site and multiple sites found as a result of its description (i.e., sites located at the virB, virF, spa15, and virA promoters) are not sufficient for VirB to bind in vivo using this tool. The implications of these findings are discussed

Adolescent dietary patterns in Fiji and their relationships with standardized body mass index

BACKGROUND: Obesity has been increasing in adolescents in Fiji and obesogenic dietary patterns need to be assessed to inform health promotion. The objective of this study was to identify the dietary patterns of adolescents in peri-urban Fiji and determine their relationships with standardized body mass index (BMI-z). METHODS: This study analysed baseline measurements from the Pacific Obesity Prevention In Communities (OPIC) Project. The sample comprised 6,871 adolescents aged 13-18 years from 18 secondary schools on the main island of Viti Levu, Fiji. Adolescents completed a questionnaire that included diet-related variables; height and weight were measured. Descriptive statistics and regression analyses were conducted to examine the associations between dietary patterns and BMI-z, while controlling for confounders and cluster effect by school. RESULTS: Of the total sample, 24% of adolescents were overweight or obese, with a higher prevalence among Indigenous Fijians and females. Almost all adolescents reported frequent consumption of sugar sweetened beverages (SSB) (90%) and low intake of fruit and vegetables (74%). Over 25% of participants were frequent consumers of takeaways for dinner, and either high fat/salt snacks, or confectionery after school. Nearly one quarter reported irregular breakfast (24%) and lunch (24%) consumption on school days, while fewer adolescents (13%) ate fried foods after school. IndoFijians were more likely than Indigenous Fijians to regularly consume breakfast, but had a high unhealthy SSB and snack consumption.Regular breakfast (p<0.05), morning snack (p<0.05) and lunch (p<0.05) consumption were significantly associated with lower BMI-z. Consumption of high fat/salt snacks, fried foods and confectionery was lower among participants with higher BMI-z. CONCLUSIONS: This study provides important information about Fijian adolescents' dietary patterns and associations with BMI-z. Health promotion should target reducing SSB, increasing fruit and vegetables consumption, and increasing regularity of meals among adolescents. Future research is needed to investigate moderator(s) of inverse associations found between BMI-z and consumption of snacks, fried foods and confectionery to assess for potential reverse causality

ENDURALIFE - powered cardiac resynchronisation therapy defibrillator devices for treating heart failure: A NICE Medical Technology Guidance

ENDURALIFE™-powered cardiac resynchronisation therapy defibrillator (CRT-D) devices were the subject of an evaluation by the National Institute for Health and Care Excellence, through its Medical Technologies Evaluation Programme, for the treatment of heart failure. Boston Scientific (manufacturer) submitted a case for the adoption of the technology, claiming that it has a longer battery life resulting in a longer time to CRT-D replacement. Other claimed benefits were fewer complications associated with replacement procedures, fewer hospital admissions, less time spent in hospital and reduced demand on cardiology device implantation rooms. The submission was critiqued by Cedar, an external assessment centre. The submitted clinical evidence showed that ENDURALIFE-powered devices implanted during the period 2008–2010 were superior, in terms of longevity, to other devices at that time. Submitted economic evidence indicated that, because of a reduction in the need for replacement procedures, ENDURALIFE-powered devices were cost saving when compared to comparator devices. Cedar highlighted uncertainty of the applicability of the clinical evidence to devices marketed today. The Medical Technologies Advisory Committee noted that this was unavoidable due to the follow-up time required to study battery life. Clinical experts noted that increased battery life is an important patient benefit. However, centres use devices from multiple manufacturers to negate pressure on clinical services in the event of a major device recall. The clinical and economic evidence showed benefits to the patient, and further analysis requested by the committee suggested that ENDURALIFE-powered CRT-Ds may save between £2120 and £5627 per patient over 15 years through a reduction in the need for replacement procedures. ENDURALIFE-powered CRT-D devices received a positive recommendation in Medical Technologies Guidance 3

Supported self-management in community stroke rehabilitation: what is it and how does it work? A protocol for a realist evaluation study

No abstract available

Effects of a multicomponent resistance-based exercise program with protein, vitamin D and calcium supplementation on cognition in men with prostate cancer treated with ADT: Secondary analysis of a 12-month randomised controlled trial

OBJECTIVES: The aim of this preplanned secondary analysis of a 12-month randomised controlled trial was to investigate the effects of a multicomponent exercise programme combined with daily whey protein, calcium and vitamin D supplementation on cognition in men with prostate cancer treated with androgen deprivation therapy (ADT). DESIGN: 12-month, two-arm, randomised controlled trial. SETTING: University clinical exercise centre. PARTICIPANTS: 70 ADT-treated men were randomised to exercise-training plus supplementation (Ex+ Suppl, n=34) or usual care (control, n=36). INTERVENTION: Men allocated to Ex + Suppl undertook thrice weekly resistance training with weight-bearing exercise training plus daily whey protein (25 g), calcium (1200 mg) and vitamin D (2000 IU) supplementation. PRIMARY AND SECONDARY OUTCOME MEASURES: Cognition was assessed at baseline, 6 and 12 months via a computerised battery (CogState), Trail-making test, Rey auditory-verbal learning test and Digit span. Data were analysed with linear mixed models and an intention-to-treat and prespecified per-protocol approach (exercise-training: ≥ 66%, nutritional supplement: ≥ 80%). RESULTS: Sixty (86%) men completed the trial (Ex + Suppl, n = 31; control, n = 29). Five (7.1%) men were classified as having mild cognitive impairment at baseline. Median (IQR) adherence to the exercise and supplement was 56% (37%-82%) and 91% (66%-97%), respectively. Ex + Suppl had no effect on cognition at any time. CONCLUSIONS: A 12-month multicomponent exercise training and supplementation intervention had no significant effect on cognition in men treated with ADT for prostate cancer compared with usual care. Exercise training adherence below recommended guidelines does not support cognitive health in men treated with ADT for prostate cancer. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registry (ACTRN12614000317695, registered 25/03/2014) and acknowledged under the Therapeutic Goods Administration Clinical Trial Notification Scheme (CT-2015-CTN-03372-1 v1)

Multiscale digital Arabidopsis predicts individual organ and whole-organism growth

Understanding how dynamic molecular networks affect wholeorganism physiology, analogous to mapping genotype to phenotype, remains a key challenge in biology. Quantitative models that represent processes at multiple scales and link understanding from several research domains can help to tackle this problem. Such integrated models are more common in crop science and ecophysiology than in the research communities that elucidate molecular networks. Several laboratories have modeled particular aspects of growth in Arabidopsis thaliana, but it was unclear whether these existing models could productively be combined. We test this approach by constructing a multiscale model of Arabidopsis rosette growth. Four existing models were integrated with minimal parameter modification (leaf water content and one flowering parameter used measured data). The resulting framework model links genetic regulation and biochemical dynamics to events at the organ and whole-plant levels, helping to understand the combined effects of endogenous and environmental regulators on Arabidopsis growth. The framework model was validated and tested with metabolic, physiological, and biomass data from two laboratories, for five photoperiods, three accessions, and a transgenic line, highlighting the plasticity of plant growth strategies. The model was extended to include stochastic development. Model simulations gave insight into the developmental control of leaf production and provided a quantitative explanation for the pleiotropic developmental phenotype caused by overexpression of miR156, which was an open question. Modular, multiscale models, assembling knowledge from systems biology to ecophysiology, will help to understand and to engineer plant behavior from the genome to the field. (Résumé d'auteur

Facile synthesis and proposed mechanism of α,ω‐oxetanyl-telechelic poly(3-nitratomethyl-3-methyl oxetane) by an SN2(i) nitrato displacement method in basic media

The synthesis of a novel heterocyclic–telechelic polymer, α,ω-oxetanyl-telechelic poly(3-nitratomethyl-3-methyl oxetane), is described. Infrared spectroscopy (IR), gel permeation chromatography (GPC), and nuclear magnetic resonance (NMR) spectroscopy have been used to confirm the successful synthesis, demonstrating the presence of the telechelic-oxetanyl moieties. Synthesis of the terminal functionalities has been achieved via displacement of nitrato groups, in a manner similar to that employed with other leaving groups such as azido, bromo, and nitro, initiated by nucleophiles. In the present case, displacement occurs on the ends of a nitrato-functionalized polymer driven by the formation of sodium nitrate, which is supported by the polar aprotic solvent N,N-dimethyl formamide. The formation of an alkoxide at the polymer chain ends is favored and allows internal back-biting to the nearest carbon bearing the nitrato group, intrinsically in an SN2(i) reaction, leading to α,ω-oxetanyl functionalization. The telechelic-oxetanyl moieties have the potential to be cross-linked by chemical (e.g., acidic) or radiative (e.g., ultraviolet) curing methods without the use of high temperatures, usually below 100°C. This type of material was designed for future use as a contraband simulant, whereby it would form the predominant constituent of elastomeric composites comprising rubbery polymer with small quantities of solids, typically crystals of contraband substances, such as explosives or narcotics. This method also provides an alternative approach to ring closure and synthesis of heterocycles