Draft genome sequence of isolate Staphylococcus aureus LHSKBClinical, isolated from an infected hip

We report here the genome sequence of a clinical isolate of <i>Staphylococcus aureus</i> from an orthopedic infection. Phenotypically diverse <i>Staphylococcus aureus</i> strains are associated with orthopedic infections and subsequent implant failure, and some are highly resistant to antibiotics. This genome sequence will support further analyses of strains causing orthopedic infections

Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells

Background: Neuroblastoma accounts for 7% of paediatric malignancies but is responsible for 15% of all childhood cancer deaths. Despite rigorous treatment involving chemotherapy, surgery, radiotherapy and immunotherapy, the 5-year overall survival rate of high-risk disease remains < 40%, highlighting the need for improved therapy. Since neuroblastoma cells exhibit aberrant metabolism, we determined whether their sensitivity to radiotherapy could be enhanced by drugs affecting cancer cell metabolism. Methods: Using a panel of neuroblastoma and glioma cells, we determined the radiosensitising effects of inhibitors of glycolysis (2-DG) and mitochondrial function (metformin). Mechanisms underlying radiosensitisation were determined by metabolomic and bioenergetic profiling, flow cytometry and live cell imaging and by evaluating different treatment schedules. Results: The radiosensitising effects of 2-DG were greatly enhanced by combination with the antidiabetic biguanide, metformin. Metabolomic analysis and cellular bioenergetic profiling revealed this combination to elicit severe disruption of key glycolytic and mitochondrial metabolites, causing significant reductions in ATP generation and enhancing radiosensitivity. Combination treatment induced G2/M arrest that persisted for at least 24 h post-irradiation, promoting apoptotic cell death in a large proportion of cells. Conclusion: Our findings demonstrate that the radiosensitising effect of 2-DG was significantly enhanced by its combination with metformin. This clearly demonstrates that dual metabolic targeting has potential to improve clinical outcomes in children with high-risk neuroblastoma by overcoming radioresistance

Integrating Candida albicans metabolism with biofilm heterogeneity by transcriptome mapping

This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z. We are grateful to microbiology colleagues throughout Scotland for clinical isolates collection.Peer reviewedPublisher PD

A novel metabolomic approach used for the comparison of Staphylococcus aureus planktonic cells and biofilm samples

Introduction: Bacterial cell characteristics change significantly during differentiation between planktonic and biofilm states. While established methods exist to detect and identify transcriptional and proteomic changes, metabolic fluctuations that distinguish these developmental stages have been less amenable to investigation. Objectives: The objectives of the study were to develop a robust reproducible sample preparation methodology for high throughput biofilm analysis and to determine differences between Staphylococcus aureus in planktonic and biofilm states. Methods: The method uses bead beating in a chloroform/methanol/water extraction solvent to both disrupt cells and quench metabolism. Verification of the method was performed using liquid-chromatography-mass spectrometry. Raw mass-spectrometry data was analysed using an in-house bioinformatics pipe-line incorporating XCMS, MzMatch and in-house R-scripts, with identifications matched to internal standards and metabolite data-base entries. Results: We have demonstrated a novel mechanical bead beating method that has been optimised for the extraction of the metabolome from cells of a clinical Staphylococcus aureus strain existing in a planktonic or biofilm state. This high-throughput method is fast and reproducible, allowing for direct comparison between different bacterial growth states. Significant changes in arginine biosynthesis were identified between the two cell populations. Conclusions: The method described herein represents a valuable tool in studying microbial biochemistry at a molecular level. While the methodology is generally applicable to the lysis and extraction of metabolites from Gram positive bacteria, it is particularly applicable to biofilms. Bacteria that exist as a biofilm are shown to be highly distinct metabolically from their ‘free living’ counterparts, thus highlighting the need to study microbes in different growth states. Metabolomics can successfully distinguish between a planktonic and biofilm growth state. Importantly, this study design, incorporating metabolomics, could be optimised for studying the effects of antimicrobials and drug modes of action, potentially providing explanations and mechanisms of antibiotic resistance and to help devise new antimicrobials

Instances and connectors : issues for a second generation process language

This work is supported by UK EPSRC grants GR/L34433 and GR/L32699Over the past decade a variety of process languages have been defined, used and evaluated. It is now possible to consider second generation languages based on this experience. Rather than develop a second generation wish list this position paper explores two issues: instances and connectors. Instances relate to the relationship between a process model as a description and the, possibly multiple, enacting instances which are created from it. Connectors refers to the issue of concurrency control and achieving a higher level of abstraction in how parts of a model interact. We believe that these issues are key to developing systems which can effectively support business processes, and that they have not received sufficient attention within the process modelling community. Through exploring these issues we also illustrate our approach to designing a second generation process language.Postprin

Influence of obesity-related risk factors in the aetiology of glioma

BACKGROUND: Obesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: Genetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity-related traits was used to infer evidence for a causal relationship. RESULTS: No convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma-glioblastoma (GBM) or non-GBM tumours. CONCLUSIONS: This study provides no evidence to implicate obesity-related factors as causes of glioma

High connectivity of the Crocodile Shark between the Atlantic and Southwest Indian Oceans: highlights for conservation

Among the various shark species that are captured as bycatch in commercial fishing operations, the group of pelagic sharks is still one of the least studied and known. Within those, the crocodile shark, Pseudocarcharias kamoharai, a small-sized lamnid shark, is occasionally caught by longline vessels in certain regions of the tropical oceans worldwide. However, the population dynamics of this species, as well as the impact of fishing mortality on its stocks, are still unknown, with the crocodile shark currently one of the least studied of all pelagic sharks. Given this, the present study aimed to assess the population structure of P. kamoharai in several regions of the Atlantic and Indian Oceans using genetic molecular markers. The nucleotide composition of the mitochondrial DNA control region of 255 individuals was analyzed, and 31 haplotypes were found, with an estimated diversity Hd = 0.627, and a nucleotide diversity pi = 0.00167. An analysis of molecular variance (AMOVA) revealed a fixation index phi(ST) = -0.01118, representing an absence of population structure among the sampled regions of the Atlantic Ocean, and between the Atlantic and Indian Oceans. These results show a high degree of gene flow between the studied areas, with a single genetic stock and reduced population variability. In panmictic populations, conservation efforts can be concentrated in more restricted areas, being these representative of the total biodiversity of the species. When necessary, this strategy could be applied to the genetic maintenance of P. kamoharai.Foundation for Research Support of the Sao Paulo State - FAPESP [2011/23787-0, 2010/51903-2]; Portuguese Foundation for Science and Technology (FCT) [SFRH/BPD/93936/2013]; Foundation for Research Support of the Sao Paulo State - FAPESP [2011/23787-0, 2010/51903-2]; Portuguese Foundation for Science and Technology (FCT) [SFRH/BPD/93936/2013]info:eu-repo/semantics/publishedVersio

Microfoundations

The paper argues that the microfoundations programme can be understood as an implementation of an underlying methodological principle, methodological individualism, and that it therefore shares a fundamental ambiguity with that principle, viz, whether the macro must be derived from and therefore reducible to, or rather consistent with micro-level behaviours. The pluralist conclusion of the paper is not that research guided by the principle of microfoundations is necessarily wrong, but that the exclusion of approaches not guided by that principle is indeed necessarily wrong. The argument is made via an examination of the advantages claimed for dynamic stochastic general equilibrium models, the relationship between parts and wholes in social science, and the concepts of reduction, substrate neutrality, the intentional stance, and hypostatisation

Microfoundations

This paper argues that the microfoundations programme can be understood as an implementation of an underlying methodological principle—methodological individualism—and that it therefore shares a fundamental ambiguity with that principle, viz, whether the macro must be derived from and therefore reducible to, or rather consistent with, micro-level behaviours. The pluralist conclusion of the paper is not that research guided by the principle of microfoundations is necessarily wrong, but that the exclusion of approaches not guided by that principle is indeed necessarily wrong. The argument is made via an examination of the advantages claimed for dynamic stochastic general equilibrium models, the relationship between parts and wholes in social science, and the concepts of reduction, substrate neutrality, the intentional stance, and hypostatisation

Case-control study on uveal melanoma (RIFA): rational and design

BACKGROUND: Although a rare disease, uveal melanoma is the most common primary intraocular malignancy in adults, with an incidence rate of up to 1.0 per 100,000 persons per year in Europe. Only a few consistent risk factors have been identified for this disease. We present the study design of an ongoing incident case-control study on uveal melanoma (acronym: RIFA study) that focuses on radiofrequency radiation as transmitted by radio sets and wireless telephones, occupational risk factors, phenotypical characteristics, and UV radiation. METHODS/DESIGN: We conduct a case-control study to identify the role of different exposures in the development of uveal melanoma. The cases of uveal melanoma were identified at the Division of Ophthalmology, University of Essen, a referral centre for tumours of the eye. We recruit three control groups: population controls, controls sampled from those ophthalmologists who referred cases to the Division of Ophthalmology, University of Duisburg-Essen, and sibling controls. For each case the controls are matched on sex and age (five year groups), except for sibling controls. The data are collected from the study participants by short self-administered questionnaire and by telephone interview. During and at the end of the field phase, the data are quality-checked. To estimate the effect of exposures on uveal melanoma risk, we will use conditional logistic regression that accounts for the matching factors and allows to control for potential confounding