Targeting the ubiquitin proteasome pathway for the treatment of septic shock in patients

Endotoxic shock is a serious systemic inflammatory response to an external biological stressor. The responsiveness of NF-κB is built upon rapid protein modification and degradation involving the ubiquitin proteasome pathway. Using transgenic mice, we have obtained in vivo evidence that interference with this pathway can alleviate the symptoms of toxic shock. We posit that administration of proteasome inhibitors may enhance the survival of patients with septic shock

A Unifying Hypothesis for Familial and Sporadic Alzheimer's Disease

Alzheimer's disease (AD) is characterised by the aggregation of two quite different proteins, namely, amyloid-beta (Aβ), which forms extracellular plaques, and tau, the main component of cytoplasmic neurofibrillary tangles. The amyloid hypothesis proposes that Aβ plaques precede tangle formation but there is still much controversy concerning the order of events and the linkage between Aβ and tau alterations is still unknown. Mathematical modelling has become an essential tool for generating and evaluating hypotheses involving complex systems. We have therefore used this approach to discover the most probable pathway linking Aβ and tau. The model supports a complex pathway linking Aβ and tau via GSK3β, p53, and oxidative stress. Importantly, the pathway contains a cycle with multiple points of entry. It is this property of the pathway which enables the model to be consistent with both the amyloid hypothesis for familial AD and a more complex pathway for sporadic forms

Research on Reform in Mathematics Education, 1993-2000

Proponents and opponents of reform of mathematics education all cite the research base in support of their positions. This article reports the results of a review of studies that contained empirical evidence of the effects of reform or the difficulty of implementing reform that were published between 1993 and 2000. The studies reviewed indicate that implementation of math reform contributes to student achievement, but evidence abounds of superficial implementation and barriers to enactment. There are well-documented strategies for reducing these barriers, the most promising strategies being inservice that simultaneously focuses on teachers' practice and their cognition about mathematics teaching.Promoteurs et adversaires d'une réforme en enseignement des mathématiques puisent tous dans la recherche pour appuyer leurs points de vue. Cet article présente le résultat d'une analyse d'études empiriques publiées entre 1993 et 2000 et qui évoquent les effets d'une réforme ou la difficulté d'en mettre une en application. Selon les études analysées, la mise en œuvre d'une réforme en enseignement des mathématiques contribue aux réalisations des élèves. Toutefois, énormément d'articles évoquent une mise en œuvre superficielle et des obstacles à la réforme. Parmi les stratégies bien documentées pour minimiser ces obstacles, celles qui promettent le plus impliquent une formation pour enseignants en cours d'emploi qui touche à la fois les méthodes des enseignants et leurs connaissances sur l'enseignement des mathématiques

Yukawa Textures From Heterotic Stability Walls

A holomorphic vector bundle on a Calabi-Yau threefold, X, with h^{1,1}(X)>1 can have regions of its Kahler cone where it is slope-stable, that is, where the four-dimensional theory is N=1 supersymmetric, bounded by "walls of stability". On these walls the bundle becomes poly-stable, decomposing into a direct sum, and the low energy gauge group is enhanced by at least one anomalous U(1) gauge factor. In this paper, we show that these additional symmetries can strongly constrain the superpotential in the stable region, leading to non-trivial textures of Yukawa interactions and restrictions on allowed masses for vector-like pairs of matter multiplets. The Yukawa textures exhibit a hierarchy; large couplings arise on the stability wall and some suppressed interactions "grow back" off the wall, where the extended U(1) symmetries are spontaneously broken. A number of explicit examples are presented involving both one and two stability walls, with different decompositions of the bundle structure group. A three family standard-like model with no vector-like pairs is given as an example of a class of SU(4) bundles that has a naturally heavy third quark/lepton family. Finally, we present the complete set of Yukawa textures that can arise for any holomorphic bundle with one stability wall where the structure group breaks into two factors.Comment: 53 pages, 4 figures and 13 table

Experimental and Computational Analysis of Polyglutamine-Mediated Cytotoxicity

Expanded polyglutamine (polyQ) proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. PolyQ tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestration of polyQ into inclusion bodies can reduce the proteasomal burden and promote cell survival, at least in the short term. The presence of misfolded protein also leads to activation of stress kinases such as p38MAPK, which can be cytotoxic. The relationships of these systems are not well understood. We have used fluorescent reporter systems imaged in living cells, and stochastic computer modeling to explore the relationships of polyQ, p38MAPK activation, generation of reactive oxygen species (ROS), proteasome inhibition, and inclusion body formation. In cells expressing a polyQ protein inclusion, body formation was preceded by proteasome inhibition but cytotoxicity was greatly reduced by administration of a p38MAPK inhibitor. Computer simulations suggested that without the generation of ROS, the proteasome inhibition and activation of p38MAPK would have significantly reduced toxicity. Our data suggest a vicious cycle of stress kinase activation and proteasome inhibition that is ultimately lethal to cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supporting a central role for proteasome inhibition and p38MAPK activation in inclusion body formation and ROS-mediated cell death

Regulation of PCNA polyubiquitination in human cells

<p>Abstract</p> <p>Background</p> <p>The ubiquitin-based molecular switch dictating error free versus error prone repair has been conserved throughout eukaryotic evolution. A central component of this switch is the homotrimeric clamp PCNA, which is ubiquitinated in response to genotoxic stress allowing recovery of replication forks blocked at sites of DNA damage. The particulars of PCNA ubiquitination have been elucidated in yeast and to a further extent recently in human cells. However, gaps in the detailed mechanism and regulation of PCNA polyubiquitination still persist in human cells.</p> <p>Findings</p> <p>We expand upon several studies and show that PCNA is polyubiquitnated in normal skin fibroblasts, and that this ubiquitination is dependant on RAD18. Furthermore we define the types of DNA damage that induce ubiquitination on PCNA. Cisplatin, methylmethane sulphonate and benzo(a)pyrene-diol-epoxide induce the polyubiquitination of PCNA to the same extent as UV while polyubiquitination is not detected after X-ray treatment. Moreover, we show that ubiquitination of PCNA is not regulated by cell cycle checkpoint kinases ATM-Chk2 or ATR-Chk1. Significantly, we report that PCNA polyubiquitination is negatively regulated by USP1.</p> <p>Conclusions</p> <p>Our results demonstrate the importance of PCNA polyubiquitination in human cells and define the key regulator of this ubiquitination.</p

Stability Walls in Heterotic Theories

We study the sub-structure of the heterotic Kahler moduli space due to the presence of non-Abelian internal gauge fields from the perspective of the four-dimensional effective theory. Internal gauge fields can be supersymmetric in some regions of the Kahler moduli space but break supersymmetry in others. In the context of the four-dimensional theory, we investigate what happens when the Kahler moduli are changed from the supersymmetric to the non-supersymmetric region. Our results provide a low-energy description of supersymmetry breaking by internal gauge fields as well as a physical picture for the mathematical notion of bundle stability. Specifically, we find that at the transition between the two regions an additional anomalous U(1) symmetry appears under which some of the states in the low-energy theory acquire charges. We compute the associated D-term contribution to the four-dimensional potential which contains a Kahler-moduli dependent Fayet-Iliopoulos term and contributions from the charged states. We show that this D-term correctly reproduces the expected physics. Several mathematical conclusions concerning vector bundle stability are drawn from our arguments. We also discuss possible physical applications of our results to heterotic model building and moduli stabilization.Comment: 37 pages, 4 figure

Loss of UCHL1 promotes age-related degenerative changes in the enteric nervous system.

UCHL1 (ubiquitin carboxyterminal hydrolase 1) is a deubiquitinating enzyme that is particularly abundant in neurons. From studies of a spontaneous mutation arising in a mouse line it is clear that loss of function of UCHL1 generates profound degenerative changes in the central nervous system, and it is likely that a proteolytic deficit contributes to the pathology. Here these effects were found to be recapitulated in mice in which the Uchl1 gene had been inactivated by homologous recombination. In addition to the previously documented neuropathology associated with loss of UCHL1 function, axonal swellings were detected in the striatum. In agreement with previously reported findings the loss of UCHL1 function was accompanied by perturbations in ubiquitin pools, but glutathione levels were also significantly depleted in the brains of the knockout mice, suggesting that oxidative defense mechanisms may be doubly compromised. To determine if, in addition to its role in the central nervous system, UCHL1 function is also required for homeostasis of the enteric nervous system the gastrointestinal tract was analyzed in UCHL1 knockout mice. The mice displayed functional changes and morphological changes in gut neurons that preceded degenerative changes in the brain. The changes were qualitatively and quantitatively similar to those observed in wild type mice of much greater age, and strongly resemble changes reported for elderly humans. UCHL1 knockout mice should therefore serve as a useful model of gut aging