Tissue specificity in DNA repair: lessons from trinucleotide repeat instability.

DNA must constantly be repaired to maintain genome stability. Although it is clear that DNA repair reactions depend on cell type and developmental stage, we know surprisingly little about the mechanisms that underlie this tissue specificity. This is due, in part, to the lack of adequate study systems. This review discusses recent progress toward understanding the mechanism leading to varying rates of instability at expanded trinucleotide repeats (TNRs) in different tissues. Although they are not DNA lesions, TNRs are hotspots for genome instability because normal DNA repair activities cause changes in repeat length. The rates of expansions and contractions are readily detectable and depend on cell identity, making TNR instability a particularly convenient model system. A better understanding of this type of genome instability will provide a foundation for studying tissue-specific DNA repair more generally, which has implications in cancer and other diseases caused by mutations in the caretakers of the genome

Explicit approximate controllability of the Schr\"odinger equation with a polarizability term

We consider a controlled Schr\"odinger equation with a dipolar and a polarizability term, used when the dipolar approximation is not valid. The control is the amplitude of the external electric field, it acts non linearly on the state. We extend in this infinite dimensional framework previous techniques used by Coron, Grigoriu, Lefter and Turinici for stabilization in finite dimension. We consider a highly oscillating control and prove the semi-global weak $H^2$ stabilization of the averaged system using a Lyapunov function introduced by Nersesyan. Then it is proved that the solutions of the Schr\"odinger equation and of the averaged equation stay close on every finite time horizon provided that the control is oscillating enough. Combining these two results, we get approximate controllability to the ground state for the polarizability system

Minimizing carry-over PCR contamination in expanded CAG/CTG repeat instability applications.

Expanded CAG/CTG repeats underlie the aetiology of 14 neurological and neuromuscular disorders. The size of the repeat tract determines in large part the severity of these disorders with longer tracts causing more severe phenotypes. Expanded CAG/CTG repeats are also unstable in somatic tissues, which is thought to modify disease progression. Routine molecular biology applications involving these repeats, including quantifying their instability, are plagued by low PCR yields. This leads to the need for setting up more PCRs of the same locus, thereby increasing the risk of carry-over contamination. Here we aimed to reduce this risk by pre-treating the samples with a Uracil N-Glycosylase (Ung) and using dUTP instead of dTTP in PCRs. We successfully applied this method to the PCR amplification of expanded CAG/CTG repeats, their sequencing, and their molecular cloning. In addition, we optimized the gold-standard method for measuring repeat instability, small-pool PCR (SP-PCR), such that it can be used together with Ung and dUTP-containing PCRs, without compromising data quality. We performed SP-PCR on myotonic-dystrophy-derived samples containing an expansion as large as 1000 repeats, demonstrating the applicability to clinically-relevant material. Thus, we expect the protocols herein to be applicable for molecular diagnostics of expanded repeat disorders

St. Athanasius' two treatises contra apollinarem

Since the closing years of the19th century the two treatises of St Athanasius against Apollinaris have been regarded by some scholars as spurious. This view has been a matter of considerable debate because of its implications for the interpretation of St Athanasius' Christology. The first part of this dissertation examines the history of criticism from the end of the nineteenth century to the present, and outlines the major points of research which has to be undertaken in a re-examination of the case. Accordingly the dissertation proceeds with the examination of the External Witnesses (Part II), the Internal Evidence (Part III), the Style (Part IV), the doctrine of the Death of Christ (Part V), the doctrine of the Soul of Christ (Part VI) and finally the Christology of Athanasius and the two disputed treatises (Part VII). Particular emphasis is placed on the theological issues raised in this connection. Part V contains a re-examination of all the Athanasian texts on the Death of Christ, as well as in the two works under investigation. Part VI contains a full critical analysis of the modem scholarly debate on the Soul of Christ in Athanasius. Finally Part VII (the longest section of the dissertation) re-examines all the works of Athanasius on Christology with particular reference to the doctrine and terminology of the Incarnation. The above researches establish the conclusion that there are no fundamental problems to the traditional Athanasian paternity of the two Contra Apollinarem. The external Witnesses are many and important. The internal evidence shows that Athanasius is the possible author. The Style presents no divergencies. As for the doctrine it has been shown that it is Athanasian in outline and in many significant details

Constraining Scalar Leptoquarks from the K and B Sectors

Upper bounds at the weak scale are obtained for all $\lambda_{ij}\lambda_{im}$ type product couplings of the scalar leptoquark model which may affect K-K(bar), B_d-B_d(bar), and B_s-B_s(bar)$ mixing, as well as leptonic and semileptonic K and B decays. Constraints are obtained for both real and imaginary parts of the couplings. We also discuss the role of leptoquarks in explaining the anomalously large CP-violating phase in B_s-B_s(bar) mixing.Comment: 16 pages, 5 figures, more constraints analyzed, added a number of reference

Regulation of recombination at yeast nuclear pores controls repair and triplet repeat stability.

Secondary structure-forming DNA sequences such as CAG repeats interfere with replication and repair, provoking fork stalling, chromosome fragility, and recombination. In budding yeast, we found that expanded CAG repeats are more likely than unexpanded repeats to localize to the nuclear periphery. This positioning is transient, occurs in late S phase, requires replication, and is associated with decreased subnuclear mobility of the locus. In contrast to persistent double-stranded breaks, expanded CAG repeats at the nuclear envelope associate with pores but not with the inner nuclear membrane protein Mps3. Relocation requires Nup84 and the Slx5/8 SUMO-dependent ubiquitin ligase but not Rad51, Mec1, or Tel1. Importantly, the presence of the Nup84 pore subcomplex and Slx5/8 suppresses CAG repeat fragility and instability. Repeat instability in nup84, slx5, or slx8 mutant cells arises through aberrant homologous recombination and is distinct from instability arising from the loss of ligase 4-dependent end-joining. Genetic and physical analysis of Rad52 sumoylation and binding at the CAG tract suggests that Slx5/8 targets sumoylated Rad52 for degradation at the pore to facilitate recovery from acute replication stress by promoting replication fork restart. We thereby confirmed that the relocation of damage to nuclear pores plays an important role in a naturally occurring repair process

Multidimensional Instability and Dynamics of Spin Avalanches in Crystals of Nanomagnets

We obtain a fundamental instability of the magnetization-switching fronts in superparamagnetic and ferromagnetic materials such as crystals of nanomagnets, ferromagnetic nanowires, and systems of quantum dots with large spin. We develop the instability theory for both linear and nonlinear stages. By using numerical simulations we investigate the instability properties focusing on spin avalanches in crystals of nanomagnets. The instability distorts spontaneously the fronts and leads to a complex multidimensional front dynamics. We show that the instability has a universal physical nature, with a deep relationship to a wide variety of physical systems, such as the Darrieus-Landau instability of deflagration fronts in combustion, inertial confinement fusion, and thermonuclear supernovae, and the instability of doping fronts in organic semiconductors

Vulnerability analysis of satellite-based synchronized smart grids monitoring systems

The large-scale deployment of wide-area monitoring systems could play a strategic role in supporting the evolution of traditional power systems toward smarter and self-healing grids. The correct operation of these synchronized monitoring systems requires a common and accurate timing reference usually provided by a satellite-based global positioning system. Although these satellites signals provide timing accuracy that easily exceeds the needs of the power industry, they are extremely vulnerable to radio frequency interference. Consequently, a comprehensive analysis aimed at identifying their potential vulnerabilities is of paramount importance for correct and safe wide-area monitoring system operation. Armed with such a vision, this article presents and discusses the results of an experimental analysis aimed at characterizing the vulnerability of global positioning system based wide-area monitoring systems to external interferences. The article outlines the potential strategies that could be adopted to protect global positioning system receivers from external cyber-attacks and proposes decentralized defense strategies based on self-organizing sensor networks aimed at assuring correct time synchronization in the presence of external attacks