Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation

Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1-5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans and in mice. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.     

A conserved molecular pathway mediates myoblast fusion in insects and vertebrates

Skeletal muscles arise by fusion of precursor cells, myoblasts, into multinucleated fibers. In vertebrates, mechanisms controlling this essential step in myogenesis remain poorly understood. Here we provide evidence that Kirrel, a homolog of receptor proteins that organize myoblast fusion in Drosophila melanogaster, is necessary for muscle precursor fusion in zebrafish. Within developing somites, Kirrel expression localized to membranes of fusion-competent myoblasts of the fast-twitch lineage. Unlike wild-type myoblasts that form spatially arrayed syncytial (multinucleated) fast myofibers, those deficient in Kirrel showed a significant reduction in fusion capacity. Inhibition of Rac, a GTPase and the most downstream intracellular transducer of the fusion signal in D. melanogaster, also compromised fast-muscle precursor fusion in zebrafish. However, unlike in D. melanogaster, constitutive Rac activation in zebrafish led to hyperfused giant syncytia, highlighting an entirely new function for this protein in zebrafish for gating the number and polarity of fusion events. These findings uncover a substantial degree of evolutionary conservation in the genetic regulation of myoblast fusion.     

Tumor suppressor role of protein 4.1B/DAL-1

Protein 4.1B/DAL-1 is a membrane skeletal protein that belongs to the protein 4.1 family. Protein 4.1B/DAL-1 is localized to sites of cell–cell contact and functions as an adapter protein, linking the plasma membrane to the cytoskeleton or associated cytoplasmic signaling effectors and facilitating their activities in various pathways. Protein 4.1B/DAL-1 is involved in various cytoskeleton-associated processes, such as cell motility and adhesion. Moreover, protein 4.1B/DAL-1 also plays a regulatory role in cell growth, differentiation, and the establishment of epithelial-like cell structures. Protein 4.1B/DAL-1 is normally expressed in multiple human tissues, but loss of its expression or prominent down-regulation of its expression is frequently observed in corresponding tumor tissues and tumor cell lines, suggesting that protein 4.1B/DAL-1 is involved in the molecular pathogenesis of these tumors and acts as a potential tumor suppressor. This review will focus on the structure of protein 4.1B/DAL-1, 4.1B/DAL-1-interacting molecules, 4.1B/DAL-1 inactivation and tumor progression, and anti-tumor activity of the 4.1B/DAL-1.     

Protein–protein interactions: switch from classical methods to proteomics and bioinformatics-based approaches

Following the sequencing of the human genome and many other organisms, research on protein-coding genes and their functions (functional genomics) has intensified. Subsequently, with the observation that proteins are indeed the molecular effectors of most cellular processes, the discipline of proteomics was born. Clearly, proteins do not function as single entities but rather as a dynamic network of team players that have to communicate. Though genetic (yeast two-hybrid Y2H) and biochemical methods (co-immunoprecipitation Co-IP, affinity purification AP) were the methods of choice at the beginning of the study of protein–protein interactions (PPI), in more recent years there has been a shift towards proteomics-based methods and bioinformatics-based approaches. In this review, we first describe in depth PPIs and we make a strong case as to why unraveling the interactome is the next challenge in the field of proteomics. Furthermore, classical methods of investigation of PPIs and structure-based bioinformatics approaches are presented. The greatest emphasis is placed on proteomic methods, especially native techniques that were recently developed and that have been shown to be reliable. Finally, we point out the limitations of these methods and the need to set up a standard for the validation of PPI experiments.     

Medium-scale carbon nanotube thin-film integrated circuits on flexible plastic substrates

The ability to form integrated circuits on flexible sheets of plastic enables attributes (for example conformal and flexible formats and lightweight and shock resistant construction) in electronic devices that are difficult or impossible to achieve with technologies that use semiconductor wafers or glass plates as substrates. Organic small-molecule and polymer-based materials represent the most widely explored types of semiconductors for such flexible circuitry. Although these materials and those that use films or nanostructures of inorganics have promise for certain applications, existing demonstrations of them in circuits on plastic indicate modest performance characteristics that might restrict the application possibilities. Here we report implementations of a comparatively high-performance carbon-based semiconductor consisting of sub-monolayer, random networks of single-walled carbon nanotubes to yield small- to medium-scale integrated digital circuits, composed of up to nearly 100 transistors on plastic substrates. Transistors in these integrated circuits have excellent properties: mobilities as high as 80 cm(2) V(-1) s(-1), subthreshold slopes as low as 140 m V dec(-1), operating voltages less than 5 V together with deterministic control over the threshold voltages, on/off ratios as high as 10(5), switching speeds in the kilohertz range even for coarse (approximately 100-microm) device geometries, and good mechanical flexibility-all with levels of uniformity and reproducibility that enable high-yield fabrication of integrated circuits. Theoretical calculations, in contexts ranging from heterogeneous percolative transport through the networks to compact models for the transistors to circuit level simulations, provide quantitative and predictive understanding of these systems. Taken together, these results suggest that sub-monolayer films of single-walled carbon nanotubes are attractive materials for flexible integrated circuits, with many potential areas of application in consumer and other areas of electronics.     

Forecasting market impact costs and identifying expensive trades

Often, a relatively small group of trades causes the major part of the trading costs on an investment portfolio. Consequently, reducing the trading costs of comparatively few expensive trades would already result in substantial savings on total trading costs. Since trading costs depend to some extent on steering variables, investors can try to lower trading costs by carefully controlling these factors. As a first step in this direction, this paper focuses on the identification of expensive trades before actual trading takes place. However, forecasting market impact costs appears notoriously difficult and traditional methods fail. Therefore, we propose two alternative methods to form expectations about future trading costs. Applied to the equity trades of the world's second largest pension fund, both methods succeed in filtering out a considerable number of trades with high trading costs and substantially outperform no‐skill prediction methods. Copyright © 2008 John Wiley & Sons, Ltd.     

Eutrophication causes speciation reversal in whitefish adaptive radiations

Species diversity can be lost through two different but potentially interacting extinction processes: demographic decline and speciation reversal through introgressive hybridization. To investigate the relative contribution of these processes, we analysed historical and contemporary data of replicate whitefish radiations from 17 pre-alpine European lakes and reconstructed changes in genetic species differentiation through time using historical samples. Here we provide evidence that species diversity evolved in response to ecological opportunity, and that eutrophication, by diminishing this opportunity, has driven extinctions through speciation reversal and demographic decline. Across the radiations, the magnitude of eutrophication explains the pattern of species loss and levels of genetic and functional distinctiveness among remaining species. We argue that extinction by speciation reversal may be more widespread than currently appreciated. Preventing such extinctions will require that conservation efforts not only target existing species but identify and protect the ecological and evolutionary processes that generate and maintain species.     

Effect of vitamin E on post irradiation death in mice

Summary The 30-day survival after exposure to 800 Rad⁶⁰Co gamma radiation has been compared for female mice maintained on vitamin E deficient, vitamin E supplemented or regular lab rations before and/or after irradiation. Pre- or post-irradiation dietary supplementation had no effect on survival; however, injection ofa-tocopherol immediately after irradiation significantly reduced radiation lethality.Acknowledgments. This research was supported in part by a grant from the Committee in Aid of Scholarly Activities of Concordia University. The technical assistance of Miss Jocelyne Dagenais is gratefully acknowledged.     

Effect of cyproheptadine hydrochloride on spermatogenesis.

Administration of cyproheptadine hydrochloride (5 mg/kg/day) to old rats for 48 days stimulated spermatogenesis. It also initiated spermatogenesis in the abdominal testis of unilaterally cryptorchid rats after a 15-day treatment.