A reciprocal relationship between reactive oxygen species and mitochondrial dynamics in neurodegeneration

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Mechanics rules cell biology

Cells in the musculoskeletal system are subjected to various mechanical forces in vivo. Years of research have shown that these mechanical forces, including tension and compression, greatly influence various cellular functions such as gene expression, cell proliferation and differentiation, and secretion of matrix proteins. Cells also use mechanotransduction mechanisms to convert mechanical signals into a cascade of cellular and molecular events. This mini-review provides an overview of cell mechanobiology to highlight the notion that mechanics, mainly in the form of mechanical forces, dictates cell behaviors in terms of both cellular mechanobiological responses and mechanotransduction

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

Multidrug efflux pumps:structure, function and regulation

Infections arising from multidrug-resistant pathogenic bacteria are spreading rapidly throughout the world and threaten to become untreatable. The origins of resistance are numerous and complex, but one underlying factor is the capacity of bacteria to rapidly export drugs through the intrinsic activity of efflux pumps. In this Review, we describe recent advances that have increased our understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria. Clinical and laboratory data indicate that efflux pumps function not only in the drug extrusion process but also in virulence and the adaptive responses that contribute to antimicrobial resistance during infection. The emerging picture of the structure, function and regulation of efflux pumps suggests opportunities for countering their activities

Aggregation of the endoplasmic reticulum triggered by oligomeric beta-amyloid peptides could initiate autophagy

Poster Presentations - P2This journal supplement is the meeting abstracts of AAIC 2011BACKGROUND: Autophagic vacuoles have been demonstrated from postmortem human Alzheimer’s brains. However, the underlying mechanisms of initiating autophagic vacuoles or autophagosomes remain unclear. We have shown that oligomeric Abeta peptides trigger aggregation of the endoplasmic reticulum (ER). Following this event, the number of autophagosomes is increased. The aim of this study is to investigate the mechanisms of forming autophagosomes from the aggregated ER. METHODS: Primary cultures of hippocampal neurons were treated with oligomeric Abeta. Neurons were then transfected with different DNA constructs to express GFP-DFCP1 for protein docking to Phosphatidylinositol phosphate (PI(3)K), DsRed-KDEL for protein expressing in the ER, GFP/AsRed-Atg14L, mRFPVps34 and mCherryAmbra-1 for proteins involving in the nucleation of autophagosomes. RESULTS: With the use of live cell imaging by multiphoton microscopy, we found that Atg14L was localized on the ER. Aggregation of the ER facilitated them to be clustered which can then attract Vps34 together with Beclin-1 to form a nucleation complex. Ambra-1 is not the protein to initiate the nucleation complex. Consequently, an intermediate form of vesicles called omegasomes was formed and will be furthered matured to be autophagosomes. All these initiation steps were not triggered by mTOR signaling pathway. CONCLUSIONS: Our results are among the first to demonstrate the initiation factors for formation of autophagosomes. Aggregation of the ER may be the starting point for forming autophagosomes. In addition, the initiation processes for formation of autophagosomes are different to other systems which are regulated by mTOR. The results can answer a long-term question of how autophagy is initiated.The 2011 The Alzheimer's Association International Conference (AAIC), Paris, France, 16-21 July 2011. In Alzheimer's & Dementia, 2011, v. 7 n. 4, suppl., p. S406, abstract no. P2-29

Relationship between low molecular weight beta-amyloid peptide-induced fission/fusion imbalance and mitochondrial functions

Ref. No. 247.15/H61Poster Session 247 - Alzheimer's Disease: Abeta, Energy Metabolism, Cell Signaling, AutophagyMitochondria are involved in various vital cellular functions, ranging from bioenergetic metabolism, Ca2+ homeostasis to regulation of apoptosis. Dysfunction of mitochondria is a prominent feature in neurodegenerative diseases such as Alzheimer’s disease (AD); however the underlying mechanism of how the organelle becomes defected remains elusive. Mitochondria are dynamic organelles which continuously undergo fission and fusion to regulate their morphology and distribution. Recently, imbalance of fission/fusion has been suggested to be a novel mechanism of neurodegeneration. Nonetheless, the relationship between fission/fusion imbalance and functions of mitochondria is unclear. In the present study, we hypothesize that an imbalance of fission/fusion would result in mitochondrial dysfunction. We aim to investigate the temporal relationship between low molecular weight β-amyloid peptide (LMW Aβ)-induced impairment of mitochondrial dynamics and mitochondrial functions using different parameters. We found that LMW Aβ induced a time-dependent change in mitochondrial morphology. The length of mitochondria of hippocampal neurons treated with LMW Aβ was significantly shorter than that in control. Mitochondria changed from a long tubular network to rod-shaped and fragmented, implicating that the normal fission/fusion balance is disrupted. Different aspects of mitochondrial function were monitored at the corresponding Aβ treatment time-points using different parameters, e.g. mitochondrial superoxide production, mitochondrial Ca2+ concentration and mitochondrial membrane potential. The current study provides new insights of how mitochondrial dynamics is involved in neurodegeneration in AD.link_to_OA_fulltex