Distributed all-atom simulations of intrinsically unstructured proteins

The Computational Biophysics Group at the Universitat Pompeu Fabra (GRIB-UPF) hosts two unique computational resources dedicated to the execution of large scale molecular dynamics (MD) simulations: (a) the ACMD molecular-dynamics software, used on standard personal computers with graphical processing units (GPUs); and (b) the GPUGRID. net computing network, supported by users distributed worldwide that volunteer GPUs for biomedical research. We leveraged these resources and developed studies, protocols and open-source software to elucidate energetics and pathways of a number of biomolecular systems, with a special focus on flexible proteins with many degrees of freedom. First, we characterized ion permeation through the bactericidal model protein Gramicidin A conducting one of the largest studies to date with the steered MD biasing methodology. Next, we addressed an open problem in structural biology, the determination of drug-protein association kinetics; we reconstructed the binding free energy, association, and dissaciociation rates of a drug like model system through a spatial decomposition and a Makov-chain analysis. The work was published in the Proceedings of the National Academy of Sciences and become one of the few landmark papers elucidating a ligand-binding pathway. Furthermore, we investigated the unstructured Kinase Inducible Domain (KID), a 28-peptide central to signalling and transcriptional response; the kinetics of this challenging system was modelled with a Markovian approach in collaboration with Frank Noe’s group at the Freie University of Berlin. The impact of the funding includes three peer-reviewed publication on high-impact journals; three more papers under review; four MD analysis components, released as open-source software; MD protocols; didactic material, and code for the hosting group.

A targeted association study of immunity genes and networks suggests novel associations with placental malaria infection

A large proportion of the death toll associated with malaria is a consequence of malaria infection during pregnancy, causing up to 200,000 infant deaths annually. We previously published the first extensive genetic association study of placental malaria infection, and here we extend this analysis considerably, investigating genetic variation in over 9,000 SNPs in more than 1,000 genes involved in immunity and inflammation for their involvement in susceptibility to placental malaria infection. We applied a new approach incorporating results from both single gene analysis as well as gene-gene interactionson a protein-protein interaction network. We found suggestive associations of variants in the gene KLRK1 in the single geneanalysis, as well as evidence for associations of multiple members of the IL-7/IL-7R signalling cascade in the combined analysis. To our knowledge, this is the first large-scale genetic study on placental malaria infection to date, opening the door for follow-up studies trying to elucidate the genetic basis of this neglected form of malaria.

@neurIST infrastructure for advanced disease management through integration of heterogeneous data, computing, and complex processing services

The increasing volume of data describing humandisease processes and the growing complexity of understanding, managing, and sharing such data presents a huge challenge for clinicians and medical researchers. This paper presents the@neurIST system, which provides an infrastructure for biomedical research while aiding clinical care, by bringing together heterogeneous data and complex processing and computing services. Although @neurIST targets the investigation and treatment of cerebral aneurysms, the system’s architecture is generic enough that it could be adapted to the treatment of other diseases.Innovations in @neurIST include confining the patient data pertaining to aneurysms inside a single environment that offers cliniciansthe tools to analyze and interpret patient data and make use of knowledge-based guidance in planning their treatment. Medicalresearchers gain access to a critical mass of aneurysm related data due to the system’s ability to federate distributed informationsources. A semantically mediated grid infrastructure ensures that both clinicians and researchers are able to seamlessly access andwork on data that is distributed across multiple sites in a secure way in addition to providing computing resources on demand forperforming computationally intensive simulations for treatment planning and research.

La quête du consentement éclairé en médecine comme construction sociale [The application of informed consent in medicine as social construction].

The aim of this article is to propose an anthropological point of view about informed consent in medicine. This quest for legitimacy should be read as a relational and social construction. In the heart of clinical complexity we find on one side various techniques employed by the medical community to validate research and to obtain the consent of patients. On the other side patients offer plural and subjective answers due to the doctor patient hierarchical and long relationship. Between constraints and freedoms, informed consent brings to light social relation.

Efficacy of brief motivational intervention at army conscription to address alcohol use and related problems: a randomized controlled trial

Objectives: The aim of this study was to evaluate the efficacy of brief motivational intervention (BMI) in reducing alcohol use and related problems among binge drinkers randomly selected from a census of 20 year-old French speaking Swiss men and to test the hypothesis that BMI contributes to maintain low-risk drinking among non-bingers. Methods: Randomized controlled trial comparing the impact of BMI on weekly alcohol use, frequency of binge drinking and occurrence of alcohol-related problems. Setting: Army recruitment center. Participants: A random sample of 622 men were asked to participate, 178 either refused, or missed appointment, or had to follow military assessment procedures instead, resulting in 418 men randomized into BMI or control conditions, 88.7% completing the 6-month follow-up assessment. Intervention: A single face-to-face BMI session exploring alcohol use and related problems in order to stimulate behaviour change perspective in a non-judgmental, empathic manner based on the principles of motivational interviewing (MI). Main outcome measures: Weekly alcohol use, binge drinking frequency and the occurrence of 12 alcohol-related consequences. Results: Among binge drinkers, we observed a 20% change in drinking induced by BMI, with a reduction in weekly drinking of 1.5 drink in the BMI group, compared to an increase of 0.8 drink per week in the control group (incidence rate ratio 0.8, 95% confidence interval 0,66 to 0,98, p = 0.03). BMI did not influence the frequency of binge drinking and the occurrence of 12 possible alcohol-related consequences. However, BMI induced a reduction in the alcohol use of participants who, after drinking over the past 12 months, experienced alcohol-related consequences, i.e., hangover (-20%), missed a class (-53%), got behind at school (-54%), argued with friends (-38%), engaged in unplanned sex (-45%) or did not use protection when having sex (-64%). BMI did not reduce weekly drinking in those who experienced the six other problems screened. Among non-bingers, BMI did not contribute to maintain low-risk drinking. Conclusions: At army conscription, BMI reduced alcohol use in binge drinkers, particularly in those who recently experienced alcohol-related adverse consequences. No preventive effect of BMI was observed among non-bingers. BMI is an interesting preventive option in young binge drinkers, particularly in countries with mandatory army recruitment.

Time-Lapse AFM Imaging of DNA Conformational Changes Induced by Daunorubicin.

Cancer is a major health issue that absorbs the attention of a large part of the biomedical research. Intercalating agents bind to DNA molecules and can inhibit their synthesis and transcription; thus, they are increasingly used as drugs to fight cancer. In this work, we show how atomic force microscopy in liquid can characterize, through time-lapse imaging, the dynamical influence of intercalating agents on the supercoiling of DNA, improving our understanding of the drug's effect.

In vivo fate mapping with SCL regulatory elements identifies progenitors for primitive and definitive hematopoiesis in mice.

One of the principal issues facing biomedical research is to elucidate developmental pathways and to establish the fate of stem and progenitor cells in vivo. Hematopoiesis, the process of blood cell formation, provides a powerful experimental system for investigating this process. Here, we employ transcriptional regulatory elements from the stem cell leukemia (SCL) gene to selectively label primitive and definitive hematopoiesis. We report that SCL-labelled cells arising in the mid to late streak embryo give rise to primitive red blood cells but fail to contribute to the vascular system of the developing embryo. Restricting SCL-marking to different stages of foetal development, we identify a second population of multilineage progenitors, proficient in contributing to adult erythroid, myeloid and lymphoid cells. The distinct lineage-restricted potential of SCL-labelled early progenitors demonstrates that primitive erythroid cell fate specification is initiated during mid gastrulation. Our data also suggest that the transition from a hemangioblastic precursors with endothelial and blood forming potential to a committed hematopoietic progenitor must have occurred prior to SCL-marking of definitive multilineage blood precursors.

Pansements bioactifs [Bioactive dressings]

Wound healing is a complex process involving several cell types (keratinocytes, fibroblasts, endothelial cells, etc.) as well as many growth factors (PDGF, TGF-betas, FGFs, VEGF, etc.). It can be challenging when wounds are deep or very large (third degree burn, ulceration after cutaneous tumor resection) or in presence of peripheral vascular disease, metabolic disturbances or peripheral neuropathy (chronic vascular or diabetic wounds). In order to promote skin regeneration, numerous bioactive dressings combining cells, matrices and growth factors are available on the market. This article provides a general overview of the various product categories and presents their main indications. The principal axes of the biomedical research in this area are also discussed.

Broadening the horizon--level 2.5 of the HUPO-PSI format for molecular interactions.

BACKGROUND: Molecular interaction Information is a key resource in modern biomedical research. Publicly available data have previously been provided in a broad array of diverse formats, making access to this very difficult. The publication and wide implementation of the Human Proteome Organisation Proteomics Standards Initiative Molecular Interactions (HUPO PSI-MI) format in 2004 was a major step towards the establishment of a single, unified format by which molecular interactions should be presented, but focused purely on protein-protein interactions. RESULTS: The HUPO-PSI has further developed the PSI-MI XML schema to enable the description of interactions between a wider range of molecular types, for example nucleic acids, chemical entities, and molecular complexes. Extensive details about each supported molecular interaction can now be captured, including the biological role of each molecule within that interaction, detailed description of interacting domains, and the kinetic parameters of the interaction. The format is supported by data management and analysis tools and has been adopted by major interaction data providers. Additionally, a simpler, tab-delimited format MITAB2.5 has been developed for the benefit of users who require only minimal information in an easy to access configuration. CONCLUSION: The PSI-MI XML2.5 and MITAB2.5 formats have been jointly developed by interaction data producers and providers from both the academic and commercial sector, and are already widely implemented and well supported by an active development community. PSI-MI XML2.5 enables the description of highly detailed molecular interaction data and facilitates data exchange between databases and users without loss of information. MITAB2.5 is a simpler format appropriate for fast Perl parsing or loading into Microsoft Excel.