Data-driven reverse engineering of signaling pathways using ensembles of dynamic models

Signaling pathways play a key role in complex diseases such as cancer, for which the development of novel therapies is a difficult, expensive and laborious task. Computational models that can predict the effect of a new combination of drugs without having to test it experimentally can help in accelerating this process. In particular, network-based dynamic models of these pathways hold promise to both understand and predict the effect of therapeutics. However, their use is currently hampered by limitations in our knowledge of the underlying biochemistry, as well as in the experimental and computational technologies used for calibrating the models. Thus, the results from such models need to be carefully interpreted and used in order to avoid biased predictions. Here we present a procedure that deals with this uncertainty by using experimental data to build an ensemble of dynamic models. The method incorporates steps to reduce overfitting and maximize predictive capability. We find that by combining the outputs of individual models in an ensemble it is possible to obtain a more robust prediction. We report results obtained with this method, which we call SELDOM (enSEmbLe of Dynamic lOgic-based Models), showing that it improves the predictions previously reported for several challenging problems.JRB and DH acknowledge funding from the EU FP7 project NICHE (ITN Grant number 289384). JRB acknowledges funding from the Spanish MINECO project SYNBIOFACTORY (grant number DPI2014-55276-C5-2-R). AFV acknowledges funding from the Galician government (Xunta de Galiza) through the I2C postdoctoral fellowship ED481B2014/133-0. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Axillary artery compromise in a minimally displaced proximal humerus fracture: a case report

Minimally displaced fractures of the surgical neck of the humerus are rarely associated with axillary artery injury. The innocuous appearance of the x-rays can be misleading and a missed arterial injury in these fractures could potentially lead to disastrous consequences. We report the case of a patient who sustained a minimally displaced fracture of the proximal humerus with vascular compromise requiring immediate investigation and referral to vascular surgeons. Despite spontaneous resolution of the vascular insult, it is important to remember the association of such fractures with vascular injuries in order to diagnose them early and prevent serious complications including amputation

Estimating the Fitness Cost of Escape from HLA Presentation in HIV-1 Protease and Reverse Transcriptase

Human immunodeficiency virus (HIV-1) is, like most pathogens, under selective pressure to escape the immune system of its host. In particular, HIV-1 can avoid recognition by cytotoxic T lymphocytes (CTLs) by altering the binding affinity of viral peptides to human leukocyte antigen (HLA) molecules, the role of which is to present those peptides to the immune system. It is generally assumed that HLA escape mutations carry a replicative fitness cost, but these costs have not been quantified. In this study, we assess the replicative cost of mutations which are likely to escape presentation by HLA molecules in the region of HIV-1 protease and reverse transcriptase. Specifically, we combine computational approaches for prediction of in vitro replicative fitness and peptide binding affinity to HLA molecules. We find that mutations which impair binding to HLA-A molecules tend to have lower in vitro replicative fitness than mutations which do not impair binding to HLA-A molecules, suggesting that HLA-A escape mutations carry higher fitness costs than non-escape mutations. We argue that the association between fitness and HLA-A binding impairment is probably due to an intrinsic cost of escape from HLA-A molecules, and these costs are particularly strong for HLA-A alleles associated with efficient virus control. Counter-intuitively, we do not observe a significant effect in the case of HLA-B, but, as discussed, this does not argue against the relevance of HLA-B in virus control. Overall, this article points to the intriguing possibility that HLA-A molecules preferentially target more conserved regions of HIV-1, emphasizing the importance of HLA-A genes in the evolution of HIV-1 and RNA viruses in general

Relativistic Binaries in Globular Clusters

Galactic globular clusters are old, dense star systems typically containing 10\super{4}--10\super{7} stars. As an old population of stars, globular clusters contain many collapsed and degenerate objects. As a dense population of stars, globular clusters are the scene of many interesting close dynamical interactions between stars. These dynamical interactions can alter the evolution of individual stars and can produce tight binary systems containing one or two compact objects. In this review, we discuss theoretical models of globular cluster evolution and binary evolution, techniques for simulating this evolution that leads to relativistic binaries, and current and possible future observational evidence for this population. Our discussion of globular cluster evolution will focus on the processes that boost the production of hard binary systems and the subsequent interaction of these binaries that can alter the properties of both bodies and can lead to exotic objects. Direct {\it N}-body integrations and Fokker--Planck simulations of the evolution of globular clusters that incorporate tidal interactions and lead to predictions of relativistic binary populations are also discussed. We discuss the current observational evidence for cataclysmic variables, millisecond pulsars, and low-mass X-ray binaries as well as possible future detection of relativistic binaries with gravitational radiation.Comment: 88 pages, 13 figures. Submitted update of Living Reviews articl

Working passionately does not always pay off : the negative moderating role of passion on the relationship between deliberate practice and venture performance

Deliberate practice, an iterative process that leads to expertise, is found to be positively associated with superior performance in domains such as sports, education, and entrepreneurship. At the same time, deliberate practice is also seen as being less than enjoyable and difficult to pursue consistently. As such, passion is considered to be a vital motivator of engagement in and maintenance of deliberate practice. Despite the evident importance of passion, the relationship between passion and deliberate practice in entrepreneurship has not been subject to sufficient empirical evaluation. Therefore, in this study, we consider the way in which passion moderates the relationship between deliberate practice and venture performance. We hypothesize that deliberate practice is positively related to venture performance and that passion positively moderates this relationship. We find support for our first hypothesis, in line with previous studies. However, contrary to our second hypothesis, we find that entrepreneurial passion negatively moderates the deliberate practice-venture performance relationship. In response to this finding, we provide possible explanations as to why this negative moderation effect was observed by drawing on Kolb’s experiential learning cycle

Prevalence of over-the-counter drug-related overdoses at Accident and Emergency departments in Northern Ireland--a retrospective evaluation.

Background and objectives: One major concern associated with misuse/abuse of over-the-counter (OTC) products is the potential for over-dosage. The aim of this research study was to evaluate, over a 3-month period, OTC medicine-related overdoses (those involving OTC drugs only and OTC drugs in combination with other drugs) that led to patients presenting at the Accident and Emergency (A & E) departments in four Belfast hospitals. Methods: A data collection sheet was designed to capture the information required from the A & E records in each hospital. A retrospective week-by-week data collection, reviewing A & E records, took place over a 3-month period (starting on 1 December 2002). All data related to cases presenting at the A & E departments because of drug overdoses (either accidental or deliberate according to Read Clinical Classification) were included in the study. Data were coded and entered into a custom designed SPSS© database for analysis, using Chi square and Fisher exact tests. Results: OTC drug-related overdoses comprised 40.1% of all overdoses, of which 24.0% were OTC-only overdoses. Those who overdosed on OTC drugs (solely or combined with other drugs) were mainly female (62.3%) and in the age category 31-50 years (44.9%;