Multi-Objective Big Data Optimization with jMetal and Spark

Big Data Optimization is the term used to refer to optimization problems which have to manage very large amounts of data. In this paper, we focus on the parallelization of metaheuristics with the Apache Spark cluster computing system for solving multi-objective Big Data Optimization problems. Our purpose is to study the influence of accessing data stored in the Hadoop File System (HDFS) in each evaluation step of a metaheuristic and to provide a software tool to solve these kinds of problems. This tool combines the jMetal multi-objective optimization framework with Apache Spark. We have carried out experiments to measure the performance of the proposed parallel infrastructure in an environment based on virtual machines in a local cluster comprising up to 100 cores. We obtained interesting results for computational e ort and propose guidelines to face multi-objective Big Data Optimization problems.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

In silico labeling reveals the time-dependent label half-life and transit-time in dynamical systems

Background: Mathematical models of dynamical systems facilitate the computation of characteristic properties that are not accessible experimentally. In cell biology, two main properties of interest are (1) the time-period a protein is accessible to other molecules in a certain state - its half-life - and (2) the time it spends when passing through a subsystem - its transit-time. We discuss two approaches to quantify the half-life, present the novel method of in silico labeling, and introduce the label half-life and label transit-time. The developed method has been motivated by laboratory tracer experiments. To investigate the kinetic properties and behavior of a substance of interest, we computationally label this species in order to track it throughout its life cycle. The corresponding mathematical model is extended by an additional set of reactions for the labeled species, avoiding any double-counting within closed circuits, correcting for the influences of upstream fluxes, and taking into account combinatorial multiplicity for complexes or reactions with several reactants or products. A profile likelihood approach is used to estimate confidence intervals on the label half-life and transit-time. Results: Application to the JAK-STAT signaling pathway in Epo-stimulated BaF3-EpoR cells enabled the calculation of the time-dependent label half-life and transit-time of STAT species. The results were robust against parameter uncertainties. Conclusions: Our approach renders possible the estimation of species and label half-lives and transit-times. It is applicable to large non-linear systems and an implementation is provided within the PottersWheel modeling framework (http://www.potterswheel.de)

DAPK3 participates in the mRNA processing of immediate early genes in Chronic Lymphocytic Leukaemia

Cross‐linking of the B cell receptor (BCR) induces transcriptional activation of immediate early genes (IEGs) including EGR1 and DUSP2 in chronic lymphocytic leukaemia (CLL). Here, we have shown that this transcriptional activation correlated with histone H3 threonine 6 and 11 phosphorylation. Both transcription and histone post‐translational modifications are repressed by ibrutinib, a small molecule inhibitor used in CLL treatment. Moreover, we have identified the Death‐Associated Protein Kinase 3 (DAPK3), as the kinase mediating these histone phosphorylation marks in response to activation of the BCR signalling pathway with this kinase being recruited to RNA polymerase II in an anti‐IgM‐dependent manner. DAPK inhibition mimics ibrutinib‐induced repression of both IEG mRNA and histone H3 phosphorylation and has anti‐proliferative effect comparable to ibrutinib in CLL in vitro. DAPK inhibitor (DAPKi) does not repress transcription itself but impacts on mRNA processing and has a broader anti‐tumour effect than ibrutinib, by repressing both anti‐IgM‐ and CD40L‐dependent activation

Lipid Adjustment in the Analysis of Environmental Contaminants and Human Health Risks

The literature on exposure to lipophilic agents such as polychlorinated biphenyls (PCBs) is conflicting, posing challenges for the interpretation of potential human health risks. Laboratory variation in quantifying PCBs may account for some of the conflicting study results. For example, for quantification purposes, blood is often used as a proxy for adipose tissue, which makes it necessary to model serum lipids when assessing health risks of PCBs. Using a simulation study, we evaluated four statistical models (unadjusted, standardized, adjusted, and two-stage) for the analysis of PCB exposure, serum lipids, and health outcome risk (breast cancer). We applied eight candidate true causal scenarios, depicted by directed acyclic graphs, to illustrate the ramifications of misspecification of underlying assumptions when interpreting results. Statistical models that deviated from underlying causal assumptions generated biased results. Lipid standardization, or the division of serum concentrations by serum lipids, was observed to be highly prone to bias. We conclude that investigators must consider biology, biologic medium (e.g., nonfasting blood samples), laboratory measurement, and other underlying modeling assumptions when devising a statistical plan for assessing health outcomes in relation to environmental exposures

Non-chiral current algebras for deformed supergroup WZW models

We study deformed WZW models on supergroups with vanishing Killing form. The deformation is generated by the isotropic current-current perturbation which is exactly marginal under these assumptions. It breaks half of the global isometries of the original supergroup. The current corresponding to the remaining symmetry is conserved but its components are neither holomorphic nor anti-holomorphic. We obtain the exact two- and three-point functions of this current and a four-point function in the first two leading orders of a 1/k expansion but to all orders in the deformation parameter. We further study the operator product algebra of the currents, the equal time commutators and the quantum equations of motion. The form of the equations of motion suggests the existence of non-local charges which generate a Yangian. Possible applications to string theory on Anti-de Sitter spaces and to condensed matter problems are briefly discussed.Comment: 43 pages, Latex, one eps figure; v.2: minor corrections, a reference adde

Failure of erythromycin to eliminate airway colonization with ureaplasma urealyticum in very low birth weight infants

BACKGROUND: Airway colonization of mechanically ventilated very low birth weight infants (birth weight < 1500 grams) by Ureaplasma urealyticum (Uu) is associated with an increased risk of bronchopulmonary dysplasia (BPD). While Uu is sensitive to erythromycin in vitro, the efficacy of intravenous (IV) erythromycin to eliminate Uu from the airways has not been studied. METHODS: 17 very low birth weight infants with Uu positive tracheal aspirate (TA) cultures were randomized to either 5 (8 infants) or 10 days (9 infants) of IV erythromycin lactobionate (40 mg/kg/day in 3 divided doses). Tracheal aspirate cultures for Uu were performed on days 0, 5, 10 and 15. RESULTS: Intravenous erythromycin failed to eliminate airway colonization in a large proportion of infants regardless of whether they received 5 or 10 days of treatment. Ureaplasma urealyticum was isolated from 4/15 (27%) of TAs obtained at 5 days, 5/12 TAs (42%) obtained at 10 days and 6/11(55%) TAs obtained at 15 days (combined group data). CONCLUSIONS: Erythromycin administered IV does not eliminate Uu from the airways in a large proportion of infants. Failure of erythromycin to eliminate Uu from the airways may contribute to the lack of efficacy of this drug in reducing the incidence of BPD in very low birth weight infants

An approach to trial design and analysis in the era of non-proportional hazards of the treatment effect

Background: Most randomized controlled trials with a time-to-event outcome are designed and analysed under the proportional hazards assumption, with a target hazard ratio for the treatment effect in mind. However, the hazards may be non-proportional. We address how to design a trial under such conditions, and how to analyse the results. Methods: We propose to extend the usual approach, a logrank test, to also include the Grambsch-Therneau test of proportional hazards. We test the resulting composite null hypothesis using a joint test for the hazard ratio and for time-dependent behaviour of the hazard ratio. We compute the power and sample size for the logrank test under proportional hazards, and from that we compute the power of the joint test. For the estimation of relevant quantities from the trial data, various models could be used; we advocate adopting a pre-specified flexible parametric survival model that supports time-dependent behaviour of the hazard ratio. Results: We present the mathematics for calculating the power and sample size for the joint test. We illustrate the methodology in real data from two randomized trials, one in ovarian cancer and the other in treating cellulitis. We show selected estimates and their uncertainty derived from the advocated flexible parametric model. We demonstrate in a small simulation study that when a treatment effect either increases or decreases over time, the joint test can outperform the logrank test in the presence of both patterns of non-proportional hazards. Conclusions: Those designing and analysing trials in the era of non-proportional hazards need to acknowledge that a more complex type of treatment effect is becoming more common. Our method for the design of the trial retains the tools familiar in the standard methodology based on the logrank test, and extends it to incorporate a joint test of the null hypothesis with power against non-proportional hazards. For the analysis of trial data, we propose the use of a pre-specified flexible parametric model that can represent a time-dependent hazard ratio if one is present

Male reproductive health and environmental xenoestrogens

EHP is a publication of the U.S. government. Publication of EHP lies in the public domain and is therefore without copyright. Research articles from EHP may be used freely; however, articles from the News section of EHP may contain photographs or figures copyrighted by other commercial organizations and individuals that may not be used without obtaining prior approval from both the EHP editors and the holder of the copyright. Use of any materials published in EHP should be acknowledged (for example, "Reproduced with permission from Environmental Health Perspectives") and a reference provided for the article from which the material was reproduced.Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.Supported by EU Contract BMH4-CT96-0314