A stochastic model of Escherichia coli AI-2 quorum signal circuit reveals alternative synthesis pathways

Quorum sensing (QS) is an important determinant of bacterial phenotype. Many cell functions are regulated by intricate and multimodal QS signal transduction processes. The LuxS/AI-2 QS system is highly conserved among Eubacteria and AI-2 is reported as a ‘universal' signal molecule. To understand the hierarchical organization of AI-2 circuitry, a comprehensive approach incorporating stochastic simulations was developed. We investigated the synthesis, uptake, and regulation of AI-2, developed testable hypotheses, and made several discoveries: (1) the mRNA transcript and protein levels of AI-2 synthases, Pfs and LuxS, do not contribute to the dramatically increased level of AI-2 found when cells are grown in the presence of glucose; (2) a concomitant increase in metabolic flux through this synthesis pathway in the presence of glucose only partially accounts for this difference. We predict that ‘high-flux' alternative pathways or additional biological steps are involved in AI-2 synthesis; and (3) experimental results validate this hypothesis. This work demonstrates the utility of linking cell physiology with systems-based stochastic models that can be assembled de novo with partial knowledge of biochemical pathways

Vitamin D supplementation and breast cancer prevention : a systematic review and meta-analysis of randomized clinical trials

In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L

Investigating the effectiveness and feasibility of exercise on microvascular reactivity and quality of life in systemic sclerosis patients: study protocol for a feasibility study

Background: Raynaud’s phenomenon is one of the first clinical manifestations observed in systemic sclerosis (SSc). This microvasculature disorder affects mostly the digits in over 95% of SSc patients, significantly affecting their healthrelated quality of life (HRQoL) and incurring higher hospital admissions and other healthcare costs. Exercise is known to improve both micro- and macrovascular function – aerobic exercise and resistance training, separately or combined, have been demonstrated to lead to significant vasculo-physiological improvements in conditions that present vasculopathy. However, the effects of a combined exercise programme on microcirculation in SSc patients has yet to be investigated. Therefore, the purpose of this study is to assess the effects of high-intensity interval training (HIIT) combined with circuit resistance training on the microvascular function in the digital area of SSc patients. Methods: This will be a randomised controlled, feasibility trial with two arms, wherein 30 patients with SSc in receipt of medical treatment will be randomly assigned to usual care (medical treatment) or to a 12-week supervised exercise programme. Patients in the exercise group will undertake two, 45-min sessions each week consisting of 30 min HIIT (30 s 100% peak power output/30 s passive recovery) on the arm crank ergometer and 15 min of upper body circuit resistance training. Patients will be assessed before as well as at 3 and 6 months following randomisation. Primary outcomes of the study will be recruitment and retention rate, intervention acceptability and adherence to the exercise programme. Secondary outcomes include the digital area cutaneous microvascular function (laser Doppler fluximetry combined with iontophoresis), physical fitness, functional ability, upper back transcutaneous oxygen tension, body composition and quality of life (EQ-5D-5L). Selected interviews with a subsample of patients will be undertaken to explore their experiences of having Raynaud’s phenomenon and the acceptability of the exercise intervention and study procedures. Discussion: Data from this study will be used to identify the feasibility of a combined exercise programme to be implemented in SSc patients, the acceptability of the intervention and the study design, and to determine the effects of exercise on the microvasculature. Overall, this study will provide sufficient data to inform and support a full multicentre clinical trial

Survival of Escherichia coli in the environment: fundamental and public health aspects

In this review, our current understanding of the species Escherichia coli and its persistence in the open environment is examined. E. coli consists of six different subgroups, which are separable by genomic analyses. Strains within each subgroup occupy various ecological niches, and can be broadly characterized by either commensalistic or different pathogenic behaviour. In relevant cases, genomic islands can be pinpointed that underpin the behaviour. Thus, genomic islands of, on the one hand, broad environmental significance, and, on the other hand, virulence, are highlighted in the context of E. coli survival in its niches. A focus is further placed on experimental studies on the survival of the different types of E. coli in soil, manure and water. Overall, the data suggest that E. coli can persist, for varying periods of time, in such terrestrial and aquatic habitats. In particular, the considerable persistence of the pathogenic E. coli O157:H7 is of importance, as its acid tolerance may be expected to confer a fitness asset in the more acidic environments. In this context, the extent to which E. coli interacts with its human/animal host and the organism's survivability in natural environments are compared. In addition, the effect of the diversity and community structure of the indigenous microbiota on the fate of invading E. coli populations in the open environment is discussed. Such a relationship is of importance to our knowledge of both public and environmental health. The ISME Journal (2011) 5, 173-183; doi:10.1038/ismej.2010.80; published online 24 June 2010NATO [ESP.EAP.CLG 981785]; The Soil Biotechnology Foundationinfo:eu-repo/semantics/publishedVersio

Checkpoint Signaling, Base Excision Repair, and PARP Promote Survival of Colon Cancer Cells Treated with 5-Fluorodeoxyuridine but Not 5-Fluorouracil

The fluoropyrimidines 5-fluorouracil (5-FU) and FdUrd (5-fluorodeoxyuridine; floxuridine) are the backbone of chemotherapy regimens for colon cancer and other tumors. Despite their widespread use, it remains unclear how these agents kill tumor cells. Here, we have analyzed the checkpoint and DNA repair pathways that affect colon tumor responses to 5-FU and FdUrd. These studies demonstrate that both FdUrd and 5-FU activate the ATR and ATM checkpoint signaling pathways, indicating that they cause genotoxic damage. Notably, however, depletion of ATM or ATR does not sensitize colon cancer cells to 5-FU, whereas these checkpoint pathways promote the survival of cells treated with FdUrd, suggesting that FdUrd exerts cytotoxicity by disrupting DNA replication and/or inducing DNA damage, whereas 5-FU does not. We also found that disabling the base excision (BER) repair pathway by depleting XRCC1 or APE1 sensitized colon cancer cells to FdUrd but not 5-FU. Consistent with a role for the BER pathway, we show that small molecule poly(ADP-ribose) polymerase 1/2 (PARP) inhibitors, AZD2281 and ABT-888, remarkably sensitized both mismatch repair (MMR)-proficient and -deficient colon cancer cell lines to FdUrd but not to 5-FU. Taken together, these studies demonstrate that the roles of genotoxin-induced checkpoint signaling and DNA repair differ significantly for these agents and also suggest a novel approach to colon cancer therapy in which FdUrd is combined with a small molecule PARP inhibitor

Low-mass and sub-stellar eclipsing binaries in stellar clusters

We highlight the importance of eclipsing double-line binaries in our understanding on star formation and evolution. We review the recent discoveries of low-mass and sub-stellar eclipsing binaries belonging to star-forming regions, open clusters, and globular clusters identified by ground-based surveys and space missions with high-resolution spectroscopic follow-up. These discoveries provide benchmark systems with known distances, metallicities, and ages to calibrate masses and radii predicted by state-of-the-art evolutionary models to a few percent. We report their density and discuss current limitations on the accuracy of the physical parameters. We discuss future opportunities and highlight future guidelines to fill gaps in age and metallicity to improve further our knowledge of low-mass stars and brown dwarfs.Comment: 30 pages, 5 figures, no table. Review pape

WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis

Acute appendicitis (AA) is among the most common cause of acute abdominal pain. Diagnosis of AA is challenging; a variable combination of clinical signs and symptoms has been used together with laboratory findings in several scoring systems proposed for suggesting the probability of AA and the possible subsequent management pathway. The role of imaging in the diagnosis of AA is still debated, with variable use of US, CT and MRI in different settings worldwide. Up to date, comprehensive clinical guidelines for diagnosis and management of AA have never been issued. In July 2015, during the 3rd World Congress of the WSES, held in Jerusalem (Israel), a panel of experts including an Organizational Committee and Scientific Committee and Scientific Secretariat, participated to a Consensus Conference where eight panelists presented a number of statements developed for each of the eight main questions about diagnosis and management of AA. The statements were then voted, eventually modified and finally approved by the participants to The Consensus Conference and lately by the board of co-authors. The current paper is reporting the definitive Guidelines Statements on each of the following topics: 1) Diagnostic efficiency of clinical scoring systems, 2) Role of Imaging, 3) Non-operative treatment for uncomplicated appendicitis, 4) Timing of appendectomy and in-hospital delay, 5) Surgical treatment 6) Scoring systems for intra-operative grading of appendicitis and their clinical usefulness 7) Non-surgical treatment for complicated appendicitis: abscess or phlegmon 8) Pre-operative and post-operative antibiotics.Peer reviewe