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| Jan. 7, 2009 | Telomeres and Aging | |||||||||||
| Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must "cap" each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or "uncapped" telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many "uncapped" telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed. | ||||||||||||
| Jan. 6, 2009 | Circular reasoning: microRNAs and cell-cycle control | |||||||||||
| MicroRNAs (miRNAs) have attracted considerable attention because of their important roles in development, normal physiology, and disease states including cancer. Recent studies have identified specific miRNAs that regulate the cell cycle and have documented that the loss or gain of miRNA-mediated cell-cycle control contributes to malignancy. miRNAs regulate classic cell-cycle control pathways by directly targeting proteins such as E2F transcription factors, cyclin-dependent kinases (Cdks), cyclins and Cdk inhibitors. Moreover, from recent findings, it has been suggested that miRNAs themselves might be subject to cell-cycle dependent regulation. Together, these observations indicate that the reciprocal control of RNA silencing and the metazoan cell cycle impacts cellular behavior and disease. | ||||||||||||
| Jan. 5, 2009 | Functional genomics of cancer | |||||||||||
| Cancer genomics has focused on the discovery of genetic mutations and chromosomal structural rearrangements that either increase susceptibility to cancer or support the cancer phenotype. Though each individual mutation may induce specific cancer phenotypes, it is the interaction of the functional changes in transcription and proteins that give the characteristics of cancer. Whereas molecular biology focuses on the impact of individual genes on the cancer state, functional genomics assesses the comprehensive genetic alterations in a cancer cell and seeks to integrate the dynamic changes in these networks so that cancer phenotypes can be explained. Most commonly, the transcriptome is the target of analysis because of the maturity, completeness, and speed of the technologies, but progressively the proteome is being studied in the same comprehensive manner. The focus of this review, however, will be on the functional consequences of cancer genomic alterations with special reference to the transcriptome and in the perturbed gene expression found in cancer states. The developments in the past two years (which is our time horizon) have been heavily driven by the applications of the new ultra high-throughput sequencing approaches assisted by computational discovery strategies. The precision and comprehensiveness of the analyses are astonishing. The collective results, when taken together, suggest that despite the large range of mutational and epigenetic events, there is a convergence onto a finite number of pathways that drive cancer behavior. Moreover, the interconnectivity of regulatory control mechanisms suggest that the earlier concepts distinguishing driver from passenger abnormalities may undervalue the contribution of the numerous aberrations that have small but additive effects on cancer virulence. | ||||||||||||
| Jan. 4, 2009 | Cell Delivery Mechanisms for Tissue Repair | |||||||||||
| Many cell populations, derived from both adult tissues and embryonic stem cells, show promise for the treatment of a variety of diseases. Although the major effort in stem cell therapies in the past has been identifying potentially therapeutic cells, it is now clear that developing systems to deliver these cells and promote their efficient engraftment will provide an equally challenging task. More sophisticated pretransplantation manipulations and material carriers may dramatically improve the survival, engraftment, and fate control of transplanted stem cells and their ultimate clinical utility. | ||||||||||||
| Jan. 3, 2009 | Stem Cells for Spinal Cord Repair | |||||||||||
| Spinal cord injury typically results in permanent disability. Many studies have indicated that transplantation of several different types of stem cells promotes functional recovery in animal models of spinal cord injury. A conceptually different approach to utilize stem cells for regenerative therapies may be recruitment of endogenous neural stem cells resident in the adult spinal cord. We discuss the possibilities, risks, and mechanisms for stem cells in spinal cord repair. | ||||||||||||
| Jan. 2, 2009 | Nature, Nurture, or Chance: Stochastic Gene Expression and Its Consequences | |||||||||||
| Gene expression is a fundamentally stochastic process, with randomness in transcription and translation leading to cell-to-cell variations in mRNA and protein levels. This variation appears in organisms ranging from microbes to metazoans, and its characteristics depend both on the biophysical parameters governing gene expression and on gene network structure. Stochastic gene expression has important consequences for cellular function, being beneficial in some contexts and harmful in others. These situations include the stress response, metabolism, development, the cell cycle, circadian rhythms, and aging. | ||||||||||||
| Jan. 1, 2009 | Mechanisms and Consequences of Dendritic Cell Migration | |||||||||||
| Dendritic cells (DCs) are critical for adaptive immunity and tolerance. Most DCs are strategically positioned as immune sentinels poised to respond to invading pathogens in tissues throughout the body. Differentiated DCs and their precursors also circulate in blood and can get rapidly recruited to sites of challenge. Within peripheral tissues, DCs collect antigenic material and then traffic to secondary lymphoid organs, where they communicate with lymphocytes to orchestrate adaptive immune responses. Hence, the migration and accurate positioning of DCs is indispensable for immune surveillance. Here, we review the molecular traffic signals that govern the migration of DCs throughout their life cycle. |
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