Paleoseismology of a major crustal seismogenic source near Mexico City. The southern border of the Acambay Graben

The Trans-Mexican Volcanic Belt is an active continental volcanic arc related to subduction along the Middle America trench. It is characterized by intra-arc extension resulting into several major arc-parallel active fault systems and tectonic basins. The Acambay graben, one of the largest of these basins, is located near Mexico City, in the central part of this province. In 1912, a M 6.9 earthquake ruptured the surface along the northern border of the graben together with at least two other faults. In this paper, we analyze the paleoseismic history of the southern border of the Acambay Graben, with new observations made in one natural outcrop and four paleoseismological trenches excavated across branches of the Venta de Bravo Fault at the site where it overlaps with the Pastores Fault. We present evidence of at least two paleo-earthquakes that occurred between 12,190 +/- 175 and 5,822 +/- 87 cal year BP and between 647 +/- 77 and 250 cal year BP. On one of these branches, we estimate a minimum slip-rate value between 0.1 and 0.23 mm/year for the last 12 ka and a mean recurrence interval of 8.5 +/- 3 ka. By considering several likely rupture lengths along the Venta de Bravo and Pastores faults, we calculated a maximum possible magnitude of M-w 7.01 +/- 0.27. Finally, by correlating events recorded along different faults within the Acambay Graben, we discuss several possible rupture coalescent scenarios and related consequences for Mexico City

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

A general process for the development of peptide-based immunoassays for monoclonal antibodies

Monoclonal antibodies (mAb) are an important and growing class of cancer therapeutics, but pharmacokinetic analyses have in many cases been constrained by the lack of standard and robust pharmacologic assays. The goal of this project was to develop a general method for the production of immunoassays that can measure the levels of therapeutic monoclonal antibodies in biologic samples at relevant concentrations. Alemtuzumab and rituximab are monoclonal approved for the treatment of B-cell malignancies and were used as a model system. Phage-displayed peptide libraries were screened for peptide sequences recognized by alemtuzumab (anti-CD52) or rituximab (anti-CD20). Synthetic biotinylated peptides were used in enzyme-linked immunosorbent assays (ELISA). Peptides directly synthesized on polymer resin beads were used in an immunofluorescent-based assay. Peptide mimetope sequences were recovered for both mAb and confirmed by competitive staining and kinetic measurements. A peptide-based ELISA method was developed for each. The assay for rituximab had a limit of detection of 4 μg/ml, and the assay for alemtuzumab had a limit of detection of 1 μg/ml. Antibody-specific staining of peptide conjugated beads could be seen in a dose-dependent manner. Phage-displayed peptide libraries can be a source of highly specific mimetopes for therapeutic mAb. The biotinylated forms of those peptides are compatible with conventional ELISA methods with sensitivities comparable to other assay methods and sufficient for pharmacological studies of those mAb given at high dose. The process outlined here can be applied to any mAb to enable improved pharmacokinetic analysis during the development and clinical use of this class of therapies

Reversibility of liver fibrosis

Liver fibrosis, and its end stage cirrhosis are a major cause of morbidity and mortality and therapeutic options are limited. However, the traditional view of liver disease as an irreversible process is obsolete and it is now evident that the development of liver fibrosis is a dynamic and potentially bidirectional process. Spontaneous resolution of scarring is seen in animal models of liver fibrosis and in human trials in which the stimuli responsible for chronic or repeated hepatic inflammation is successfully removed. Key players in the process are hepatic stellate cells, macrophages, MMPs and their inhibitors Timps. It is also evident that in advanced fibrotic liver disease, specific histological features define what is currently described as "irreversible" fibrosis. This includes the development of paucicellular scars enriched in extensively cross-linked matrix components, such as fibrillar collagen and elastin. Our recent work has focused on the role of macrophage metalloelastase (MMP-12) in the turnover of elastin in reversible and irreversible models of fibrosis. We have shown that elastin turnover in liver injury and fibrosis is regulated by macrophages via Mmp-12 expression, activity and ratio to its inhibitor Timp-1. Failure of elastin degradation, together with increased deposition leads to accumulation of elastin in the fibrotic scars

Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking ELTD1

BACKGROUND: Epidermal growth factor (EGF), latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is developmentally upregulated in the heart. Little is known about the relationship between ELTD1 and cardiac diseases. Therefore, we aimed to clarify the role of ELTD1 in pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: C57BL/6J wild-type (WT) mice and ELTD1-knockout (KO) mice were subjected to left ventricular pressure overload by descending aortic banding (AB). KO mice exhibited more unfavorable cardiac remodeling than WT mice 28 days post AB; this remodeling was characterized by aggravated cardiomyocyte hypertrophy, thickening of the ventricular walls, dilated chambers, increased fibrosis, and blunted systolic and diastolic cardiac function. Analysis of signaling pathways revealed enhanced extracellular signal-regulated kinase (ERK) and the c-Jun amino-terminal kinase (JNK) phosphorylation in response to ELTD1 deletion. CONCLUSIONS: ELTD1 deficiency exacerbates cardiac hypertrophy and cardiac function induced by AB-induced pressure overload by promoting both cardiomyocyte hypertrophy and cardiac fibrosis. These effects are suggested to originate from the activation of the ERK and JNK pathways, suggesting that ELTD1 is a potential target for therapies that prevent the development of cardiac disease

L2-norm multiple kernel learning and its application to biomedical data fusion

<p>Abstract</p> <p>Background</p> <p>This paper introduces the notion of optimizing different norms in the dual problem of support vector machines with multiple kernels. The selection of norms yields different extensions of multiple kernel learning (MKL) such as <it>L</it>_∞, <it>L</it>₁, and <it>L</it>₂MKL. In particular, <it>L</it>₂MKL is a novel method that leads to non-sparse optimal kernel coefficients, which is different from the sparse kernel coefficients optimized by the existing <it>L</it>_∞MKL method. In real biomedical applications, <it>L</it>₂MKL may have more advantages over sparse integration method for thoroughly combining complementary information in heterogeneous data sources.</p> <p>Results</p> <p>We provide a theoretical analysis of the relationship between the <it>L</it>₂optimization of kernels in the dual problem with the <it>L</it>₂coefficient regularization in the primal problem. Understanding the dual <it>L</it>₂problem grants a unified view on MKL and enables us to extend the <it>L</it>₂method to a wide range of machine learning problems. We implement <it>L</it>₂MKL for ranking and classification problems and compare its performance with the sparse <it>L</it>_∞and the averaging <it>L</it>₁MKL methods. The experiments are carried out on six real biomedical data sets and two large scale UCI data sets. <it>L</it>₂MKL yields better performance on most of the benchmark data sets. In particular, we propose a novel <it>L</it>₂MKL least squares support vector machine (LSSVM) algorithm, which is shown to be an efficient and promising classifier for large scale data sets processing.</p> <p>Conclusions</p> <p>This paper extends the statistical framework of genomic data fusion based on MKL. Allowing non-sparse weights on the data sources is an attractive option in settings where we believe most data sources to be relevant to the problem at hand and want to avoid a "winner-takes-all" effect seen in <it>L</it>_∞MKL, which can be detrimental to the performance in prospective studies. The notion of optimizing <it>L</it>₂kernels can be straightforwardly extended to ranking, classification, regression, and clustering algorithms. To tackle the computational burden of MKL, this paper proposes several novel LSSVM based MKL algorithms. Systematic comparison on real data sets shows that LSSVM MKL has comparable performance as the conventional SVM MKL algorithms. Moreover, large scale numerical experiments indicate that when cast as semi-infinite programming, LSSVM MKL can be solved more efficiently than SVM MKL.</p> <p>Availability</p> <p>The MATLAB code of algorithms implemented in this paper is downloadable from <url>http://homes.esat.kuleuven.be/~sistawww/bioi/syu/l2lssvm.html</url>.</p

Genome of the facultative scuticociliatosis pathogen Pseudocohnilembus persalinus provides insight into its virulence through horizontal gene transfer

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Maintenance N-acetyl cysteine treatment for bipolar disorder : a double-blind randomised placebo controlled trial

Background N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder.Method The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of [greater than or equal to]12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes.Results There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures.Conclusions There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. Trial Registration The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493)