Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Exercise induce hemoconcentration following spleen contraction in subjects with COPD

The blood-boosting spleen contraction represents a potential protective response to hypoxia by raising the blood gas storage capacity. Human spleen contraction has been observed during exercise, apnea and simulated altitude resulting in ejection of stored red blood cells into circulation. High-altitude exposure has been shown to increase spleen contraction suggesting that long-term hypoxia may improve the response in humans. Subjects with COPD are often exposed to hypoxia, which limits their physical performance. However, it is not known if spleen contraction occurs in subjects with COPD. Our aim was to reveal whether subjects with COPD recruit the spleen erythrocyte reserve during mild exercise. Methods SpO2, spleen volume and Hb were measured before and after 6 min walking test (6MWT) in 24 subjects with COPD. Results were analyzed for all subjects pooled and for subject groups with resting SpO2 above and below 90 % separated and expressed as mean. Results 6MWT reduced SpO2 from 91 to 83 % and spleen volume from 254 to 181 mL, while Hb increased from 150 to 154 g/L (p = 0.001 for all). Compared to subjects with SpO2 > 90 %, the group with SpO2 < 90 % displayed the largest resting spleen volume (339 vs 202 mL; p = 0.001) and the most pronounced spleen volume reduction (139 vs 40 mL; p = 0.007). Conclusion Exercise with hypoxia evokes spleen contraction in subjects with COPD and may represent a protective response during periods of hypoxia. The larger spleen volume and more pronounced contraction in the most hypoxic subjects may suggest long-term adaptation to hypoxia

Engaging students in paleontology: the design and implementation of an undergraduate-level blended course in Panama

Despite the fact that Latin-American countries present ideal environments to train young scientists, most of these countries lack local scientific capacity. Here I describe the design and implementation of an undergraduate-level blended course on paleontology. The course was taught in 2012 to 10 biology majors from the University of Panama and it had three main foci: (1) a design grounded in a theoretical framework that supports meaningful learning; (2) the application of concepts and skills to the region where the students live, making the learning experience relevant and authentic; and (3) a strong research and science-communication component that allowed students to experience real-life situations (i.e. those commonly faced by scientists throughout their careers). These components contributed synergistically to engage students with paleontology, a field not formally taught in their country. This work can be applied to different disciplines in science and to different levels in students’ scientific training