Cell migration is a highly integrated multistep process that orchestrates embryonic morphogenesis; contributes to tissue repair and regeneration; and drives disease progression in cancer, mental retardation, atherosclerosis, and arthritis. The migrating cell is highly polarized with complex regulatory pathways that spatially and temporally integrate its component processes. This review describes the mechanisms underlying the major steps of migration and the signaling pathways that regulate them, and outlines recent advances investigating the nature of polarity in migrating cells and the pathways that establish it.

/pdf/cell-migration-integrating-signals-from-front-to-back-g0h3q2xs5i.pdf

Cell migration: integrating signals from front to back.

Slowly but surely, Alzheimer's disease (AD) patients lose their memory and their cognitive abilities, and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. Although drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise may soon help in developing effective preventative and therapeutic strategies.

/pdf/pathways-towards-and-away-from-alzheimer-s-disease-1j591hguge.pdf

Pathways towards and away from Alzheimer's disease

Epstein-Barr virus.

The ability of a eukaryotic cell to resist deformation, to transport intracellular cargo and to change shape during movement depends on the cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins. Recent work has demonstrated that both internal and external physical forces can act through the cytoskeleton to affect local mechanical properties and cellular behaviour. Attention is now focused on how cytoskeletal networks generate, transmit and respond to mechanical signals over both short and long timescales. An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.

/pdf/cell-mechanics-and-the-cytoskeleton-4jmvbqe21g.pdf

Cell mechanics and the cytoskeleton

Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.

Sirtuin activators mimic caloric restriction and delay ageing in metazoans

The actin cytoskeleton is a complex structure that performs a wide range of cellular functions. In 2001, significant advances were made to our understanding of the structure and function of actin m...

Actin Binding Proteins: Regulation of Cytoskeletal Microfilaments

Analysis of global microRNA (miRNA) expression in postmortem cortical grey matter from the superior temporal gyrus, revealed significant up-regulation of miR-181b expression in schizophrenia. This finding was supported by quantitative real-time RT-PCR analysis of miRNA expression in a cohort of 21 matched pairs of schizophrenia and non-psychiatric controls. The implications of this finding are substantial, as this miRNA is predicted to regulate many target genes with potential significance to the development of schizophrenia. They include the calcium sensor gene visinin-like 1 (VSNL1) and the ionotropic AMPA glutamate receptor subunit (GRIA2), which were found to be down-regulated in the same cortical tissue from the schizophrenia group. Both of these genes were also suppressed in miR-181b transfected cells and shown to contain functional miR-181b miRNA recognition elements by reporter gene assay. This study suggests altered miRNA levels could be a significant factor in the dysregulation of cortical gene expression in schizophrenia.

Dysregulation of miRNA 181b in the temporal cortex in schizophrenia

The Anterior Cingulate Cortex (ACC, Brodmans Area 24) is implicated in the pathogenesis of schizophrenia due to its normal functions and connectivity together with reports of structural, morphological and neurotransmitter aberrations within this brain area in the disease state. Two-dimensional gel electrophoresis (2DE) was employed to scan and compare the ACC gray matter proteomes between schizophrenia (n=10) and control (n=10) post-mortem human tissue. This proteomic approach has detected 42 protein spots with altered levels in the schizophrenia cohort, which to our knowledge is the first proteomic analysis of the ACC in schizophrenia. Thirty nine of these proteins were subsequently identified using mass spectrometry and functionally classified into metabolism and oxidative stress, cytoskeletal, synaptic, signalling, trafficking and glial-specific groups. Some of the identified proteins have previously been implicated in the disease pathogenesis and some offer new insights into schizophrenia. Investigating these proteins, the genes encoding these proteins, their functions and interactions may shed light on the molecular mechanisms underlying the heterogeneous symptoms characteristic of schizophrenia.

A proteome analysis of the anterior cingulate cortex gray matter in schizophrenia

Objective: In order to conduct postmortem human brain research into the neuropatho-logical basis of schizophrenia, it is critical to establish cohorts that are well-characterized and well-matched. ...

/pdf/selection-of-reference-gene-expression-in-a-schizophrenia-2iy7xk1diy.pdf

Selection of reference gene expression in a schizophrenia brain cohort

Abnormalities within the corpus callosum (CC) have been identified in schizophrenia brains and are thought to affect inter-hemispheric communication, which in-turn is postulated to underlie some schizophrenia symptoms Furthermore, hemisphere asymmetry of fractional anisotropy, detected by diffusion tensor imaging, left-higher-than-right- has been observed in normal individuals in the CC genu This asymmetry is significantly reduced in the left CC genu of first-episode and chronic schizophrenia subjects We examined the protein expression profile of the CC genu, including the profiles from the left and right hemisphere, in schizophrenia brains compared to controls using two-dimensional gel electrophoresis and mass spectrometry techniques Proteins involved in cytoskeletal structure and function, neuroprotective function and energy metabolism were identified as differentially expressed, suggesting these proteins may underlie abnormal CC genu structure and function Proteins in these functional categories also displayed different expression levels in the left CC genu compared to the right in both control and schizophrenia brains and therefore may be involved in normal CC asymmetry and reduced asymmetry in schizophrenia individuals This initial pool of protein candidates and abnormal functional pathways opens up avenues for further investigation of molecular mechanisms involving the CC in schizophrenia pathogenesis and symptoms

Irina Dedova

Papers

Actin Binding Proteins: Regulation of Cytoskeletal Microfilaments

Dysregulation of miRNA 181b in the temporal cortex in schizophrenia

A proteome analysis of the anterior cingulate cortex gray matter in schizophrenia

Selection of reference gene expression in a schizophrenia brain cohort

Abnormal pathways in the genu of the corpus callosum in schizophrenia pathogenesis: a proteome study