Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing

Cancer is both a genetic and an epigenetic disease. Inactivation of tumour-suppressor genes by epigenetic changes is frequently observed in human cancers, particularly as a result of the modifications of histones and DNA methylation. It is therefore important to understand how these damaging changes might come about. By studying tumorigenesis in the Drosophila eye, here we identify two Polycomb group epigenetic silencers, Pipsqueak and Lola, that participate in this process. When coupled with overexpression of Delta, deregulation of the expression of Pipsqueak and Lola induces the formation of metastatic tumours. This phenotype depends on the histone-modifying enzymes Rpd3 (a histone deacetylase), Su(var)3-9 and E(z), as well as on the chromodomain protein Polycomb. Expression of the gene Retinoblastoma-family protein (Rbf) is downregulated in these tumours and, indeed, this downregulation is associated with DNA hypermethylation. Together, these results establish a mechanism that links the Notch-Delta pathway, epigenetic silencing pathways and cell-cycle control in the process of tumorigenesis.     

On Modeling Bio-Scaffolds: Structural and Fluid Transport Characterization Based on 3-D Imaging Data

Bio-scaffolds which are most commonly open celled porous structures are increasingly used for tissue engineering and regenerative medicine. A number of studies have shown that the bulk properties of such irregular structures are poorly modeled using idealized unit cell approaches. The paper therefore uses novel image based meshing techniques to explore both fluid flow and bulk structural properties of a bone scaffold, as accurate modeling of bio-scaffolds with non-uniform cellular structures is very important for the development of optimal scaffolds for tissue engineering application. In this study, a porous hydroxyapatite/tricalcium phosphate (HA/TCP) bone scaffold has been scanned in a Micro-CT scanner, and converted into a volumetric mesh using image processing software developed by the authors. The resulting mesh was then exported to commercial FEA and CFD solvers for analysis. Initial FEA and CFD studies have shown promising results and have highlighted the importance of accurate modeling to understand how microstructures influence the mechanical property of the scaffold, and to analyze flow regimes through the sample. The work highlights the potential use of image based meshing for the ad hoc characterization of scaffolds as well as for assisting in the design of scaffolds with tailored strength, stiffness, and transport properties.     

Ongoing therapeutic trials and outcome measures for Duchenne muscular dystrophy

Muscular dystrophy is a heterogeneous group of genetic disorders characterised by progressive muscle tissue degeneration. No effective treatment has been discovered for these diseases. Preclinical and clinical studies aimed at the development of new therapeutic approaches have been carried out, primarily in subjects affected with dystrophinopathies (Duchenne and Becker muscular dystrophy). In this review, we outline the current therapeutic approaches and past and ongoing clinical trials, highlighting both the advantages and limits of each one. The experimental designs of these trials were based on different rationales, including immunomodulation, readthrough strategies, exon skipping, gene therapy, and cell therapy. We also provide an overview of available outcome measures, focusing on their reliability in estimating meaningful clinical improvement in order to aid in the design of future trials. This perspective is extremely relevant to the field considering the recent development of novel therapeutic approaches that will result in an increasing number of clinical studies over the next few years.     

Mineral lick use by GPS radio-collared mountain goats in southeastern British Columbia

In most populations of mountain goats ( Oreamnos americanus ), mineral lick use is an essential part of the ecology of the species. In many areas, the distribution and use of licks in the landscape is poorly known, rendering planning for resource development difficult. We examined lick use by 28 GPS radio-collared mountain goats in 2 study areas in southeastern British Columbia during 2004–2005. Viewing collar-location movements on digital orthophotos, we assumed goat use of 6 previously known and 10 suspected mineral licks. Field visits verified that 9 of the 10 suspected sites were mineral licks. Thirteen of the 15 licks used by collared goats were within forests with commercial harvesting potential. All but 3 of the licks were ≤600 m from the closest logging block, and 5 licks were <100 m away. Number of annual visits to licks by individual goats ranged from 0 to 9. Goats often moved considerable distances (up to 17.3 km) to visit licks. Most visits by males occurred between early May and late June (median 9 June), and most visits by females occurred between early June and mid-July (median 21 June). Mean time spent at licks on each visit was 1.5 days for females and 1.6 days for males. Most of the licks were characterized by numerous cavities dug under trees (which we term “lick trees”). Using GPS collars, we were able to collect data on lower-elevation mineral licks not previously known to researchers.     

Analysis of <Emphasis Type="Italic">Dictyostelium</Emphasis> TACC reveals differential interactions with CP224 and unusual dynamics of <Emphasis Type="Italic">Dictyostelium</Emphasis> microtubules

We have localized TACC to the microtubule-nucleating centrosomal corona and to microtubule plus ends. Using RNAi we proved that Dictyostelium TACC promotes microtubule growth during interphase and mitosis. For the first time we show in vivo that both TACC and XMAP215 family proteins can be differentially localized to microtubule plus ends during interphase and mitosis and that TACC is mainly required for recruitment of an XMAP215-family protein to interphase microtubule plus ends but not for recruitment to centrosomes and kinetochores. Moreover, we have now a marker to study dynamics and behavior of microtubule plus ends in living Dictyostelium cells. In a combination of live cell imaging of microtubule plus ends and fluorescence recovery after photobleaching (FRAP) experiments of GFP-α-tubulin cells we show that Dictyostelium microtubules are dynamic only in the cell periphery, while they remain stable at the centrosome, which also appears to harbor a dynamic pool of tubulin dimers.     

Participative Methodology for Local Development: The Contribution of Engineers Without Borders from Italy and Colombia: Towards the Improvement of Water Quality in Vulnerable Communities

This paper presents a systemic methodology by which engineering is put to use in vulnerable communities through applied technological research and the main results of its application. The methodology presented corresponds to one implemented and designed by two groups of Engineers without Borders in Europe and Latin America, to integrate technical know-how with local context in communities with water problems in Colombia and the Democratic Republic of Congo. The main results of this methodology are related to the improvement of the living conditions of vulnerable groups thanks to the integration of the communities?? knowledge with engineering know-how, leading to autonomous communities and engineering professors and students learning from real life problems to enrich applied sciences.     

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.     

De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome

Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.     

Common variants at CD40 and other loci confer risk of rheumatoid arthritis

To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).