Direct observation shows superposition and large scale flexibility within cytoplasmic dynein motors moving along microtubules

Cytoplasmic dynein is a dimeric AAA+ motor protein that performs critical roles in eukaryotic cells by moving along microtubules using ATP. Here using cryo-electron microscopy we directly observe the structure of Dictyostelium discoideum dynein dimers on microtubules at near-physiological ATP concentrations. They display remarkable flexibility at a hinge close to the microtubule binding domain (the stalkhead) producing a wide range of head positions. About half the molecules have the two heads separated from one another, with both leading and trailing motors attached to the microtubule. The other half have the two heads and stalks closely superposed in a front-to-back arrangement of the AAA+ rings, suggesting specific contact between the heads. All stalks point towards the microtubule minus end. Mean stalk angles depend on the separation between their stalkheads, which allows estimation of inter-head tension. These findings provide a structural framework for understanding dynein’s directionality and unusual stepping behaviour

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

Multicolor Tracking of Molecular Motors at Nanometer Resolution

Molecular motors move processively along cytoskeletal filaments through stepping of their catalytic head domains. Observation of the stepping movement of the heads reveals the mechanism of motor processivity and how they coordinate the cycles of the catalytic heads during processive motility. This chapter will discuss recent developments in simultaneous observation of the stepping motions of the two heads using multicolor single particle tracking microscopy

Qualidade de vida e saúde: aspectos conceituais e metodológicos Quality of life and health: conceptual and methodological issues

O conceito qualidade de vida tem suscitado pesquisas e cresce a sua utilização nas práticas desenvolvidas nos serviços de saúde, por equipes profissionais que atuam junto a usuários acometidos por enfermidades diversas. O presente artigo tem como objetivo descrever a evolução histórica e tecer algumas considerações sobre aspectos conceituais e metodológicos do conceito qualidade de vida (QV) no campo da saúde. Baseando-se na revisão da literatura, dois aspectos do termo são destacados no plano conceitual: subjetividade e multidimensionalidade. Quanto aos aspectos metodológicos, uma tendência significativa tem sido a construção e/ou adaptação de instrumentos de medida e de avaliação da QV. Conclui-se que os esforços teórico-metodológicos têm contribuído para a clarificação e relativa maturidade do conceito. Trata-se de um construto eminentemente interdisciplinar, o que implica a contribuição de diferentes áreas do conhecimento para o seu aprimoramento conceitual e metodológico. Sua utilização, portanto, pode contribuir para a melhoria da qualidade e da integralidade da assistência na perspectiva da saúde como direito de cidadania.<br>The quality of life (QL) concept has led to extensive scientific research and has been increasingly used by health care professionals treating a wide range of diseases. This paper addresses the historical use of the concept and specific issues linked to conceptual and methodological aspects of the QL construct within the health care context. Reviewing the literature, two aspects stand out: subjectivity and multidimensionality. In the methodological field, the construction and/or adaptation of QL measurement instruments appear as a significant trend. Theoretical and methodological efforts have helped clarify and improve the concept's adequacy. The QL construct is definitely interdisciplinary, encompassing contributions by different areas of knowledge and research, thereby improving its conceptual and methodological potential as a research instrument. Therefore, use of the concept can actually help improve both the quality and the integrated, multidimensional nature of health care from a perspective that views the latter as a basic citizen's right

A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues

Group A Streptococcus (GAS) causes the life-threatening infection in humans known as necrotizing fasciitis (NF). Infected subcutaneous tissues from an NF patient and mice challenged with the same GAS strain possessed high bacterial loads but a striking paucity of infiltrating polymorphonuclear leukocytes (PMNs). Impaired PMN recruitment was attributed to degradation of the chemokine IL-8 by a GAS serine peptidase. Here, we use bioinformatics approach coupled with target mutagenesis to identify this peptidase as ScpC. We show that SilCR pheromone downregulates scpC transcription via the two-component system—SilA/B. In addition, we demonstrate that in vitro, ScpC degrades the CXC chemokines: IL-8 (human), KC, and MIP-2 (both murine). Furthermore, using a murine model of human NF, we demonstrate that ScpC, but not the C5a peptidase ScpA, is an essential virulence factor. An ScpC-deficient mutant is innocuous for untreated mice but lethal for PMN-depleted mice. ScpC degrades KC and MIP-2 locally in the infected skin tissues, inhibiting PMN recruitment. In conclusion, ScpC represents a novel GAS virulence factor functioning to directly inactivate a key element of the host innate immune response