Tissue engineering: creation of long-lasting blood vessels

The construction of stable blood vessels is a fundamental challenge for tissue engineering in regenerative medicine. Although certain genes can be introduced into vascular cells to enhance their survival and proliferation, these manipulations may be oncogenic. We show here that a network of long-lasting blood vessels can be formed in mice by co-implantation of vascular endothelial cells and mesenchymal precursor cells, by-passing the need for risky genetic manipulations. These networks are stable and functional for one year in vivo.     

TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex

Telomere length in humans is partly controlled by a feedback mechanism in which telomere elongation by telomerase is limited by the accumulation of the TRF1 complex at chromosome ends. TRF1 itself can be inhibited by the poly(ADP-ribose) polymerase (PARP) activity of its interacting partner tankyrase 1, which abolishes its DNA binding activity in vitro and removes the TRF1 complex from telomeres in vivo. Here we report that the inhibition of TRF1 by tankyrase is in turn controlled by a second TRF1-interacting factor, TIN2 (ref. 6). Partial knockdown of TIN2 by small hairpin RNA in a telomerase-positive cell line resulted in telomere elongation, which is typical of reduced TRF1 function. Transient inhibition of TIN2 with small interfering RNA led to diminished telomeric TRF1 signals. This effect could be reversed with the PARP inhibitor 3-aminobenzamide and did not occur in cells overexpressing a PARP-dead mutant of tankyrase 1. TIN2 formed a ternary complex with TRF1 and tankyrase 1 and stabilized their interaction, an effect also observed with the PARP-dead mutant of tankyrase 1. In vitro, TIN2 protected TRF1 from poly(ADP-ribosyl)ation by tankyrase 1 without affecting tankyrase 1 automodification. These data identify TIN2 as a PARP modulator in the TRF1 complex and can explain how TIN2 contributes to the regulation of telomere length.     

The harlequin mouse mutation downregulates apoptosis-inducing factor

Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. We have identified the Hq mutation as a proviral insertion in the apoptosis-inducing factor (Aif) gene, causing about an 80% reduction in AIF expression. Mutant cerebellar granule cells are susceptible to exogenous and endogenous peroxide-mediated apoptosis, but can be rescued by AIF expression. Overexpression of AIF in wild-type granule cells further decreases peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice show oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice re-enter the cell cycle before undergoing apoptosis. Our results provide a genetic model of oxidative stress-mediated neurodegeneration and demonstrate a direct connection between cell cycle re-entry and oxidative stress in the ageing central nervous system.     

Dodecahedral space topology as an explanation for weak wide-angle temperature correlations in the cosmic microwave background

The current 'standard model' of cosmology posits an infinite flat universe forever expanding under the pressure of dark energy. First-year data from the Wilkinson Microwave Anisotropy Probe (WMAP) confirm this model to spectacular precision on all but the largest scales. Temperature correlations across the microwave sky match expectations on angular scales narrower than 60 degrees but, contrary to predictions, vanish on scales wider than 60 degrees. Several explanations have been proposed. One natural approach questions the underlying geometry of space--namely, its curvature and topology. In an infinite flat space, waves from the Big Bang would fill the universe on all length scales. The observed lack of temperature correlations on scales beyond 60 degrees means that the broadest waves are missing, perhaps because space itself is not big enough to support them. Here we present a simple geometrical model of a finite space--the Poincaré dodecahedral space--which accounts for WMAP's observations with no fine-tuning required. The predicted density is Omega(0) approximately 1.013 > 1, and the model also predicts temperature correlations in matching circles on the sky.