2,7-Pyrrolo[2,1-f][1,2,4]triazines as JAK2 inhibitors: modification of target structure to minimize reactive metabolite formation

The JAK2/STAT pathway has important roles in hematopoiesis. With the discovery of the JAK2 V617F mutation and its presence in many patients with myeloproliferative neoplasms, research in the JAK2 inhibitor arena has dramatically increased. We report a novel series of potent JAK2 inhibitors containing a 2,7-pyrrolotriazine core. To minimize potential drug-induced toxicity, targets were analyzed for the ability to form a glutathione adduct. Glutathione adduct formation was decreased by modification of the aniline substituent at C2.     

Repeated landmass reformation limits diversification in the widespread littoral zone mosquito Anopheles sundaicus sensu lato in the Indo‐Oriental Region

Southeast Asia harbours abundant biodiversity, hypothesized to have been generated by Pliocene and Pleistocene climatic and environmental change. Vicariance between the island of Borneo, the remaining Indonesian archipelago and mainland Southeast Asia caused by elevated sea levels during interglacial periods has been proposed to lead to diversification in the littoral zone mosquito Anopheles (Cellia) sundaicus (Rodenwaldt) sensu lato. To test this biogeographical hypothesis, we inferred the population history and assessed gene flow of A. sundaicus s.l. sampled from 18 populations across its pan‐Asian species range, using sequences from mitochondrial cytochrome c oxidase subunit 1 (CO1), the internal transcribed spacer 2 (ITS2) and the mannose phosphate isomerase (Mpi) gene. A hypothesis of ecological speciation for A. sundaicus involving divergent adaptation to brackish and freshwater larval habitats was also previously proposed, based on a deficiency of heterozygotes for Mpi allozyme alleles in sympatry. This hypothesis was not supported by Mpi sequence data, which exhibited no fixed differences between brackish and freshwater larval habitats. Mpi and CO1 supported the presence of up to eight genetically distinct population groupings. Counter to the hypothesis of three allopatric species, divergence was often no greater between Borneo, Sumatra/Java and the Southeast Asian mainland than it was between genetic groupings within these landmasses. An isolation‐with‐migration (IM) model indicates recurrent gene flow between the current major landmasses. Such gene flow would have been possible during glacial periods when the current landmasses merged, presenting opportunities for dispersal along expanding and contracting coastlines. Consequently, Pleistocene climatic variation has proved a homogenizing, rather than diversifying, force for A. sundaicus diversity.     

Identification process based on shear wave propagation within a phantom using finite element modelling and magnetic resonance elastography

Magnetic resonance elastography (MRE), based on shear wave propagation generated by a specific driver, is a non-invasive exam performed in clinical practice to improve the liver diagnosis. The purpose was to develop a finite element (FE) identification method for the mechanical characterisation of phantom mimicking soft tissues investigated with MRE technique. Thus, a 3D FE phantom model, composed of the realistic MRE liver boundary conditions, was developed to simulate the shear wave propagation with the software ABAQUS. The assumptions of homogeneity and elasticity were applied to the FE phantom model. Different ranges of mesh size, density and Poisson's ratio were tested in order to develop the most representative FE phantom model. The simulated wave displacement was visualised with a dynamic implicit analysis. Subsequently, an identification process was performed with a cost function and an optimisation loop provided the optimal elastic properties of the phantom. The present identification process was validated on a phantom model, and the perspective will be to apply this method on abdominal tissues for the set-up of new clinical MRE protocols that could be applied for the follow-up of the effects of treatments.     

Extracellular signal-regulated kinase 1/2 plays a pro-life role in experimental brain stem death via MAPK signal-interacting kinase at rostral ventrolateral medulla

Background  

As the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this fatal phenomenon. The present study assessed the hypothesis that extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinases (MAPKs) that is important for cell survival and is activated specifically by MAPK kinase 1/2 (MEK1/2), plays a pro-life role in RVLM during brain stem death. We further delineated the participation of MAPK signal-interacting kinase (MNK), a novel substrate of ERK in this process.     

Sensitivity analysis of ultrasonic guided waves propagating in trilayered bone models: a numerical study

The fundamental ultrasonic guided modes are consistently observed in long bones ex vivo and in vivo. However, the responses of ultrasonic guided waves to the changes of cortical thickness, cortical elastic parameters, and thickness of the overlying soft tissues are not comprehensively understood. This paper systematically presents a sensitivity analysis of leaky Lamb modes to the geometry and material characteristics of layered bone model by means of semi-analytical finite element modeling. The stratified bone model is consisted of a transversely isotropic cortex with an overlying soft tissue and underlying marrow. The study is important as it offers guidance to the parameter inversion process about the optimal selection of guided modes and regions of sensitivity for better inversion results.     

Synthesis of 53 tissue and cell line expression QTL datasets reveals master eQTLs

Background

Gene expression genetic studies in human tissues and cells identify cis- and trans-acting expression quantitative trait loci (eQTLs). These eQTLs provide insights into regulatory mechanisms underlying disease risk. However, few studies systematically characterized eQTL results across cell and tissues types. We synthesized eQTL results from >50 datasets, including new primary data from human brain, peripheral plaque and kidney samples, in order to discover features of human eQTLs.

Results

We find a substantial number of robust cis-eQTLs and far fewer trans-eQTLs consistent across tissues. Analysis of 45 full human GWAS scans indicates eQTLs are enriched overall, and above nSNPs, among positive statistical signals in genetic mapping studies, and account for a significant fraction of the strongest human trait effects. Expression QTLs are enriched for gene centricity, higher population allele frequencies, in housekeeping genes, and for coincidence with regulatory features, though there is little evidence of 5′ or 3′ positional bias. Several regulatory categories are not enriched including microRNAs and their predicted binding sites and long, intergenic non-coding RNAs. Among the most tissue-ubiquitous cis-eQTLs, there is enrichment for genes involved in xenobiotic metabolism and mitochondrial function, suggesting these eQTLs may have adaptive origins. Several strong eQTLs (CDK5RAP2, NBPFs) coincide with regions of reported human lineage selection. The intersection of new kidney and plaque eQTLs with related GWAS suggest possible gene prioritization. For example, butyrophilins are now linked to arterial pathogenesis via multiple genetic and expression studies. Expression QTL and GWAS results are made available as a community resource through the NHLBI GRASP database [http://apps.nhlbi.nih.gov/grasp/].

Conclusions

Expression QTLs inform the interpretation of human trait variability, and may account for a greater fraction of phenotypic variability than protein-coding variants. The synthesis of available tissue eQTL data highlights many strong cis-eQTLs that may have important biologic roles and could serve as positive controls in future studies. Our results indicate some strong tissue-ubiquitous eQTLs may have adaptive origins in humans. Efforts to expand the genetic, splicing and tissue coverage of known eQTLs will provide further insights into human gene regulation.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-532) contains supplementary material, which is available to authorized users.