CRANKITE: a fast polypeptide backbone conformation sampler

Background: CRANKITE is a suite of programs for simulating backbone conformations of polypeptides and proteins. The core of the suite is an efficient Metropolis Monte Carlo sampler of backbone conformations in continuous three-dimensional space in atomic details. Methods: In contrast to other programs relying on local Metropolis moves in the space of dihedral angles, our sampler utilizes local crankshaft rotations of rigid peptide bonds in Cartesian space. Results: The sampler allows fast simulation and analysis of secondary structure formation and conformational changes for proteins of average length

Airports at Risk: The Impact of Information Sources on Security Decisions

Security decisions in high risk organizations such as airports involve obtaining ongoing and frequent information about potential threats. Utilizing questionnaire survey data from a sample of airport employees in European Airports across the continent, we analyzed how both formal and informal sources of security information affect employee's decisions to comply with the security rules and directives. This led us to trace information network flows to assess its impact on the degree employees making security decisions comply or deviate with the prescribed security rules. The results of the multivariate analysis showed that security information obtained through formal and informal networks differentially determine if employee will comply or not with the rules. Information sources emanating from the informal network tends to encourage employees to be more flexible in their security decisions while formal sources lead to be more rigid with complying with rules and protocols. These results suggest that alongside the formal administrative structure of airports, there exists a diverse and pervasiveness set of informal communications networks that are a potent factor in determining airport security levels

Interpreting 16S metagenomic data without clustering to achieve sub-OTU resolution

The standard approach to analyzing 16S tag sequence data, which relies on clustering reads by sequence similarity into Operational Taxonomic Units (OTUs), underexploits the accuracy of modern sequencing technology. We present a clustering-free approach to multi-sample Illumina datasets that can identify independent bacterial subpopulations regardless of the similarity of their 16S tag sequences. Using published data from a longitudinal time-series study of human tongue microbiota, we are able to resolve within standard 97% similarity OTUs up to 20 distinct subpopulations, all ecologically distinct but with 16S tags differing by as little as 1 nucleotide (99.2% similarity). A comparative analysis of oral communities of two cohabiting individuals reveals that most such subpopulations are shared between the two communities at 100% sequence identity, and that dynamical similarity between subpopulations in one host is strongly predictive of dynamical similarity between the same subpopulations in the other host. Our method can also be applied to samples collected in cross-sectional studies and can be used with the 454 sequencing platform. We discuss how the sub-OTU resolution of our approach can provide new insight into factors shaping community assembly.Comment: Updated to match the published version. 12 pages, 5 figures + supplement. Significantly revised for clarity, references added, results not change

Changes in multimodality functional imaging parameters early during chemoradiation predict treatment response in patients with locally advanced head and neck cancer.

Objective To assess the optimal timing and predictive value of early intra-treatment changes in multimodality functional and molecular imaging (FMI) parameters as biomarkers for clinical remission in patients receiving chemoradiation for head and neck squamous cell carcinoma (HNSCC).Methods Thirty-five patients with stage III-IVb (AJCC 7th edition) HNSCC prospectively underwent 18F-FDG-PET/CT, and diffusion-weighted (DW), dynamic contrast-enhanced (DCE) and susceptibility-weighted MRI at baseline, week 1 and week 2 of chemoradiation. Patients with evidence of persistent or recurrent disease during follow-up were classed as non-responders. Changes in FMI parameters at week 1 and week 2 were compared between responders and non-responders with the Mann-Whitney U test. The significance threshold was set at a p value of 40%; p = 0.007) and maximum standardized uptake value (SUVmax; p = 0.034) after week 1 than non-responders but these differences were absent by week 2. In contrast, it was not until week 2 that MRI-derived parameters were able to discriminate between the two groups: larger fractional increases in primary tumor apparent diffusion coefficient (ADC; p trans; p = 0.012) and interstitial space volume fraction (Ve; p = 0.047) were observed in responders versus non-responders. ADC was the most powerful predictor (∆ >17%, AUC 0.937).Conclusion Early intra-treatment changes in FDG-PET, DW and DCE MRI-derived parameters are predictive of ultimate response to chemoradiation in HNSCC. However, the optimal timing for assessment with FDG-PET parameters (week 1) differed from MRI parameters (week 2). This highlighted the importance of scanning time points for the design of FMI risk-stratified interventional studies

Effects of Perfluorocarbons on surfactant exocytosis and membrane properties in isolated alveolar type II cells

<p>Abstract</p> <p>Background</p> <p>Perfluorocarbons (PFC) are used to improve gas exchange in diseased lungs. PFC have been shown to affect various cell types. Thus, effects on alveolar type II (ATII) cells and surfactant metabolism can be expected, data, however, are controversial.</p> <p>Objective</p> <p>The study was performed to test two hypotheses: (I) the effects of PFC on surfactant exocytosis depend on their respective vapor pressures; (II) different pathways of surfactant exocytosis are affected differently by PFC.</p> <p>Methods</p> <p>Isolated ATII cells were exposed to two PFC with different vapor pressures and spontaneous surfactant exocytosis was measured. Furthermore, surfactant exocytosis was stimulated by either ATP, PMA or Ionomycin. The effects of PFC on cell morphology, cellular viability, endocytosis, membrane permeability and fluidity were determined.</p> <p>Results</p> <p>The spontaneous exocytosis was reduced by PFC, however, the ATP and PMA stimulated exocytosis was slightly increased by PFC with high vapor pressure. In contrast, Ionomycin-induced exocytosis was decreased by PFC with low vapor pressure. Cellular uptake of FM 1-43 - a marker of membrane integrity - was increased. However, membrane fluidity, endocytosis and viability were not affected by PFC incubation.</p> <p>Conclusions</p> <p>We conclude that PFC effects can be explained by modest, unspecific interactions with the plasma membrane rather than by specific interactions with intracellular targets.</p

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis.

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells

Mitochondria-dependent signalling pathway are involved in the early process of radiation-induced bystander effects

Bystander effects induced by cytoplasmic irradiation have been reported recently. However, the mechanism(s) underlying, such as the functional role of mitochondria, is not clear. In the present study, we used either mtDNA-depleted (ρ0) AL or normal (ρ+) AL cells as irradiated donor cells and normal human skin fibroblasts as receptor cells in a series of medium transfer experiments to investigate the mitochondria-related signal process. Our results indicated that mtDNA-depleted cells or normal AL cells treated with mitochondrial respiratory chain function inhibitors had an attenuated γ-H2AX induction, which indicates that mitochondria play a functional role in bystander effects. Moreover, it was found that treatment of normal AL donor cells with specific inhibitors of NOS, or inhibitor of mitochondrial calcium uptake (ruthenium red) significantly decreased γ-H2AX induction and that radiation could stimulate cellular NO and O2•− production in irradiated ρ+ AL cells, but not in ρ0 AL cells. These observations, together with the findings that ruthenium red treatment significantly reduced the NO and O2•− levels in irradiated ρ+ AL cells, suggest that radiation-induced NO derived from mitochondria might be an intracellular bystander factor and calcium-dependent mitochondrial NOS might play an essential role in the process

Discourses of conflict and collaboration and institutional context in the implementation of forest conservation policies in Soria, Spain

This article examines the emergence of conflict and collaboration in the implementation of forest conservation policies in Soria, Spain. We draw insights from discursive institutionalism and use a comparative case study approach to analyse and compare a situation of social conflict over the Natural Park declaration in the Sierra de Urbión, and a civil society led collaborative process to develop management plans for the “Sierra de Cabrejas” in Soria. The implementation of the EU Habitats Directive generated different outcomes in these two cases, which unfolded in the context of the same nature conservation legislation and national and provincial administrative structures but differed in terms of types of forests involved, property rights arrangements and forest use histories. We critically examine the influence of the institutional context and dominant discourses on the emergence of outcomes: conflict emerged where local institutions and discourses were threatened by the EU directive, while collaboration was possible where local institutions and counter-discourses were weak. We find that the institutional context plays an important part in determining local discourses in the implementation of forest conservation policies. Yet local counter-discourses have limited influence in the implementation and policy processes in the face of contestation by the discourses of regional civil servants conservation activists

Perceived need for mental health care and barriers to care in the Netherlands and Australia

This study of Australian and Dutch people with anxiety or depressive disorder aims to examine people's perceived needs and barriers to care, and to identify possible similarities and differences. Data from the Australian National Survey of Mental Health and Well-Being and the Netherlands Study of Depression and Anxiety were combined into one data set. The Perceived Need for Care Questionnaire was taken in both studies. Logistic regression analyses were performed to check if similarities or differences between Australia and the Netherlands could be observed. In both countries, a large proportion had unfulfilled needs and self-reliance was the most frequently named barrier to receive care. People from the Australian sample (N = 372) were more likely to perceive a need for medication (OR 1.8; 95% CI 1.3-2.5), counselling (OR 1.4; 95% CI 1.0-2.0) and practical support (OR 1.8; 95% CI 1.2-2.7), and people's overall needs in Australia were more often fully met compared with those of the Dutch sample (N = 610). Australians were more often pessimistic about the helpfulness of medication (OR 3.8; 95% CI 1.4-10.7) and skills training (OR 3.0; 95% CI 1.1-8.2) and reported more often financial barriers for not having received (enough) information (OR 2.4; 95% CI 1.1-5.5) or counselling (OR 5.9; 95% CI 2.9-11.9). In both countries, the vast majority of mental health care needs are not fulfilled. Solutions could be found in improving professionals' skills or better collaboration. Possible explanations for the found differences in perceived need and barriers to care are discussed; these illustrate the value of examining perceived need across nations and suggest substantial commonalities of experience across the two countries

A systematic review of dietary, nutritional, and physical activity interventions for the prevention of prostate cancer progression and mortality

PURPOSE: Given the long-term, although potentially fatal, nature of prostate cancer, there is increasing observational evidence for the reduction in disease progression and mortality through changes in lifestyle factors. METHODS: We systematically reviewed dietary, nutritional, and physical activity randomized interventions aimed at modifying prostate cancer progression and disease-specific mortality, including a detailed assessment of risk of bias and methodological quality. RESULTS: Forty-four randomized controlled trials of lifestyle interventions, with prostate cancer progression or mortality outcomes, were identified. Substantial heterogeneity of the data prevented a meta-analysis. The included trials involved 3,418 prostate cancer patients, median 64 men per trial, from 13 countries. A trial of a nutritional supplement of pomegranate seed, green tea, broccoli, and turmeric; a trial comparing flaxseed, low-fat diet, flaxseed, and low-fat diet versus usual diet; and a trial supplementing soy, lycopene, selenium, and coenzyme Q10, all demonstrated beneficial effects. These trials were also assessed as having low risk of bias and high methodological quality (as were seven other trials with no evidence of benefit). The remaining trials were either underpowered, at high or unclear risk of bias, inadequately reported, of short duration or measured surrogate outcomes of unproven relationship to mortality or disease progression, which precluded any benefits reported being reliable. CONCLUSION: Large, well-designed randomized trials with clinical endpoints are recommended for lifestyle modification interventions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10552-015-0659-4) contains supplementary material, which is available to authorized users