BioPhysConnectoR: Connecting Sequence Information and Biophysical Models

<p>Abstract</p> <p>Background</p> <p>One of the most challenging aspects of biomolecular systems is the understanding of the coevolution in and among the molecule(s).</p> <p>A complete, theoretical picture of the selective advantage, and thus a functional annotation, of (co-)mutations is still lacking. Using sequence-based and information theoretical inspired methods we can identify coevolving residues in proteins without understanding the underlying biophysical properties giving rise to such coevolutionary dynamics. Detailed (atomistic) simulations are prohibitively expensive. At the same time reduced molecular models are an efficient way to determine the reduced dynamics around the native state. The combination of sequence based approaches with such reduced models is therefore a promising approach to annotate evolutionary sequence changes.</p> <p>Results</p> <p>With the <monospace>R</monospace> package <monospace>BioPhysConnectoR</monospace> we provide a framework to connect the information theoretical domain of biomolecular sequences to biophysical properties of the encoded molecules - derived from reduced molecular models. To this end we have integrated several fragmented ideas into one single package ready to be used in connection with additional statistical routines in <monospace>R</monospace>. Additionally, the package leverages the power of modern multi-core architectures to reduce turn-around times in evolutionary and biomolecular design studies. Our package is a first step to achieve the above mentioned annotation of coevolution by reduced dynamics around the native state of proteins.</p> <p>Conclusions</p> <p><monospace>BioPhysConnectoR</monospace> is implemented as an <monospace>R</monospace> package and distributed under GPL 2 license. It allows for efficient and perfectly parallelized functional annotation of coevolution found at the sequence level.</p

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Key Role of Mfd in the Development of Fluoroquinolone Resistance in Campylobacter jejuni

Campylobacter jejuni is a major food-borne pathogen and a common causative agent of human enterocolitis. Fluoroquinolones are a key class of antibiotics prescribed for clinical treatment of enteric infections including campylobacteriosis, but fluoroquinolone-resistant Campylobacter readily emerges under the antibiotic selection pressure. To understand the mechanisms involved in the development of fluoroquinolone-resistant Campylobacter, we compared the gene expression profiles of C. jejuni in the presence and absence of ciprofloxacin using DNA microarray. Our analysis revealed that multiple genes showed significant changes in expression in the presence of a suprainhibitory concentration of ciprofloxacin. Most importantly, ciprofloxacin induced the expression of mfd, which encodes a transcription-repair coupling factor involved in strand-specific DNA repair. Mutation of the mfd gene resulted in an approximately 100-fold reduction in the rate of spontaneous mutation to ciprofloxacin resistance, while overexpression of mfd elevated the mutation frequency. In addition, loss of mfd in C. jejuni significantly reduced the development of fluoroquinolone-resistant Campylobacter in culture media or chickens treated with fluoroquinolones. These findings indicate that Mfd is important for the development of fluoroquinolone resistance in Campylobacter, reveal a previously unrecognized function of Mfd in promoting mutation frequencies, and identify a potential molecular target for reducing the emergence of fluoroquinolone-resistant Campylobacter

Weight-loss intervention using implementation intentions and mental imagery: A randomised control trial study protocol

Background: Overweight and obesity are major health problems worldwide. This protocol describes the HEALTHI (Healthy Eating and Active LifesTyle Health Intervention) Program, a 12-week randomised-controlled weight-loss intervention that adopts two theory-based intervention techniques, mental imagery and implementation intentions, a behaviour-change technique based on planning that have been shown to be effective in promoting health-behaviour change in previous research. The effectiveness of goal-reminder text messages to augment intervention effects will also be tested. The trial will determine the effects of a brief, low cost, theory-based weight-loss intervention to improve dietary intake and physical activity behaviour and facilitate weight-loss in overweight and obese individuals. Methods/Design: Overweight or obese participants will be randomly allocated to one of three conditions: (1) a psycho-education plus an implementation intentions and mental imagery condition; (2) a psycho-education plus an implementation intentions and mental imagery condition with text messages; or (3) a psycho-education control condition. The intervention will be delivered via video presentation to increase the intervention's applicability in multiple contexts and keep costs low. We hypothesise that the intervention conditions will lead to statistically-significant changes in the primary and secondary outcome variables measured at 6 and 12 weeks post-intervention relative to the psycho-education control condition after controlling for baseline values. The primary outcome variable will be body weight and secondary outcome variables will be biomedical (body mass, body fat percentage, muscle mass, waist-hip circumference ratio, systolic and diastolic blood pressure, low-density lipoprotein, high-density lipoprotein, total cholesterol, triglycerides, blood glucose and insulin levels), psychological (quality of life, motivation, risk perception, outcome expectancy, intention, action self-efficacy, maintenance self-efficacy, goal setting and planning), and behavioural (self-reported diet intake, and physical activity involvement) measures. We also expect the intervention condition augmented with text messages to lead to statistically significant differences in the primary and secondary outcome variables at the follow up periods after controlling for baseline values. Discussion: The planned trial will test the effectiveness of the theory-based HEALTHI program intervention to reduce weight and salient psychological, biomedical, and behavioural outcomes in overweight and obese adults. The study has been designed to maximise applicability to real world settings and could be integrated into existing weight management practices

Thermal fracture as a framework for quasi-static crack propagation

We address analytically and numerically the problem of crack path prediction in the model system of a crack propagating under thermal loading. We show that one can explain the instability from a straight to a wavy crack propagation by using only the principle of local symmetry and the Griffith criterion. We then argue that the calculations of the stress intensity factors can be combined with the standard crack propagation criteria to obtain the evolution equation for the crack tip within any loading configuration. The theoretical results of the thermal crack problem agree with the numerical simulations we performed using a phase field model. Moreover, it turns out that the phase-field model allows to clarify the nature of the transition between straight and oscillatory cracks which is shown to be supercritical.Comment: 19 pages, 8 figure

Determination of the prebiotic activity of wheat arabinogalactan peptide (AGP) using batch culture fermentation

Purpose To test the prebiotic activity of wheat arabinogalactan-peptide (AGP), which is a soluble dietary fibre composed of arabinogalactan polysaccharide linked to a 15-residue peptide, which accounts for up to 0.4% of the dry weight of wheat flour. Methods The prebiotic activity of AGP prepared from white wheat flour was tested using in-vitro fermentation by colonic bacteria in automated pH controlled anaerobic stirred batch cultures and compared to fructooligosaccharide (FOS) and wheat flour arabinoxylan (AX). Bacterial populations were measured using fluorescence in-situ hybridisation (flow-FISH) and short-chain fatty acid (SCFA) concentrations were measured using HPLC. Results Fermentation of AGP resulted in a significant bifidogenic activity and increased concentrations of SCFAs, mainly acetate after 24 h of fermentation. Conclusions These results were comparable to those obtained with AX and confirm the prebiotic potential of AGP. Furthermore, fermentation of a mixture of AGP and AX was faster compared to the single substrates and more similar to FOS, indicating that combinations of fermentable carbohydrates with different structures are potentially more effective as prebiotics than single substrates

Design of price incentives for adjunct policy goals in formula funding for hospitals and health services

Background. Hospital policy involves multiple objectives: efficiency of service delivery, pursuit of high quality care, promoting access. Funding policy based on hospital casemix has traditionally been considered to be only about promoting efficiency. Discussion. Formula-based funding policy can be (and has been) used to pursue a range of policy objectives, not only efficiency. These are termed 'adjunct' goals. Strategies to incorporate adjunct goals into funding design must, implicitly or explicitly, address key decision choices outlined in this paper. Summary. Policy must be clear and explicit about the behaviour to be rewarded; incentives must be designed so that all facilities with an opportunity to improve have an opportunity to benefit; the reward structure is stable and meaningful; and the funder monitors performance and gaming

Staging investigations for oesophageal cancer: a meta-analysis

The aim of the study was to compare the diagnostic performance of endoscopic ultrasonography (EUS), computed tomography (CT), and 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in staging of oesophageal cancer. PubMed was searched to identify English-language articles published before January 2006 and reporting on diagnostic performance of EUS, CT, and/or FDG-PET in oesophageal cancer patients. Articles were included if absolute numbers of true-positive, false-negative, false-positive, and true-negative test results were available or derivable for regional, celiac, and abdominal lymph node metastases and/or distant metastases. Sensitivities and specificities were pooled using a random effects model. Summary receiver operating characteristic analysis was performed to study potential effects of study and patient characteristics. Random effects pooled sensitivities of EUS, CT, and FDG-PET for regional lymph node metastases were 0.80 (95% confidence interval 0.75–0.84), 0.50 (0.41–0.60), and 0.57 (0.43–0.70), respectively, and specificities were 0.70 (0.65–0.75), 0.83 (0.77–0.89), and 0.85 (0.76–0.95), respectively. Diagnostic performance did not differ significantly across these tests. For detection of celiac lymph node metastases by EUS, sensitivity and specificity were 0.85 (0.72–0.99) and 0.96 (0.92–1.00), respectively. For abdominal lymph node metastases by CT, these values were 0.42 (0.29–0.54) and 0.93 (0.86–1.00), respectively. For distant metastases, sensitivity and specificity were 0.71 (0.62–0.79) and 0.93 (0.89–0.97) for FDG-PET and 0.52 (0.33–0.71) and 0.91 (0.86–0.96) for CT, respectively. Diagnostic performance of FDG-PET for distant metastases was significantly higher than that of CT, which was not significantly affected by study and patient characteristics. The results suggest that EUS, CT, and FDG-PET each play a distinctive role in the detection of metastases in oesophageal cancer patients. For the detection of regional lymph node metastases, EUS is most sensitive, whereas CT and FDG-PET are more specific tests. For the evaluation of distant metastases, FDG-PET has probably a higher sensitivity than CT. Its combined use could however be of clinical value, with FDG-PET detecting possible metastases and CT confirming or excluding their presence and precisely determining the location(s)