GADD45 alpha inhibition of DNMT1 dependent DNA methylation during homology directed DNA repair

In this work, we examine regulation of DNA methyltransferase 1 (DNMT1) by the DNA damage inducible protein, GADD45 alpha. We used a system to induce homologous recombination (HR) at a unique double-strand DNA break in a GFP reporter in mammalian cells. After HR, the repaired DNA is hypermethylated in recombinant clones showing low GFP expression (HR-L expressor class), while in high expressor recombinants (HR-H clones) previous methylation patterns are erased. GADD45 alpha, which is transiently induced by double-strand breaks, binds to chromatin undergoing HR repair. Ectopic overexpression of GADD45 alpha during repair increases the HR-H fraction of cells (hypomethylated repaired DNA), without altering the recombination frequency. Conversely, silencing of GADD45 alpha increases methylation of the recombined segment and amplifies the HR-L expressor (hypermethylated) population. GADD45 alpha specifically interacts with the catalytic site of DNMT1 and inhibits methylation activity in vitro. We propose that double-strand DNA damage and the resulting HR process involves precise, strand selected DNA methylation by DNMT1 that is regulated by GADD45 alpha. Since GADD45 alpha binds with high avidity to hemimethylated DNA intermediates, it may also provide a barrier to spreading of methylation during or after HR repair

A priori convergence of the Greedy algorithm for the parametrized reduced basis method

The convergence and efficiency of the reduced basis method used for the approximation of the solutions to a class of problems written as a parametrized PDE depends heavily on the choice of the elements that constitute the “reduced basis”. The purpose of this paper is to analyze the a priori convergence for one of the approaches used for the selection of these elements, the greedy algorithm. Under natural hypothesis on the set of all solutions to the problem obtained when the parameter varies, we prove that three greedy algorithms converge; the last algorithm, based on the use of an a posteriori estimator, is the approach actually employed in the calculations

Analyzing marker substances for Complex Regional Pain Syndrome (CRPS)

Weniger als 5% der Patienten entwickeln Komplex-Regionales Schmerzsyndrom (CRPS) nach einem Trauma, insbesondere nach Frakturen. Es ist ein schmerzhaftes Syndrom, dass durch eine Vielzahl von klinischen Merkmalen gekennzeichnet ist. Es kann chronisch werden, wenn es nicht in den ersten Monaten kuriert wird. Wahrscheinlich spielen mehrere pathophysiologische Mechanismen eine Rolle in CRPS. Es wird vermutet, dass Neuropeptide und anti-inflammatorische Lipid-Mediatoren involviert sind. In dieser Arbeit wurden diese Moleküle in Hautbiopsien und Serum mit dem Ziel der Korrelation ihrer Konzentration mit klinischen Parametern mittels Massenspektrometrie (MS) untersucht. Hochauflösende und insbesondere NanoMS identifizierte Peptide und Fettsäuren im niederen fmol-Bereich. Die Methodik zeigte aber auch wenig Toleranz gegenüber dem chemischen Untergrund, so dass vornehmlich die robustere Kapillarchromatography eingesetzt wurde. Die Serum-Proteaseaktivität mit einem Fokus auf Angiotensin-konvertierendem Enzym (ACE) wurde untersucht. Bradykinin (BK) wurde zügig zu BK1-8 und BK1-5 abgebaut. Niedrigere BK1-5 Levels waren in Übereinstimmung mit der Hypothese verringerter ACE-Aktivität in CRPS.Less than 5% of patients develop Complex Regional Pain Syndrome (CRPS) after trauma, mostly after fractures. It is a painful syndrome characterized by a variety of clinical features including classical signs of inflammation and it can become chronical if not cured in the first few months. Likely, a number of pathophysiological mechanisms play a role in CRPS. The involvement of neuropeptides and anti-inflammatory lipid mediators has been suggested. Here, mass spectrometry (MS) was used to investigate these molecules in skin biopsies and serum with the aim of correlating their concentration with clinical parameters. High-end and in particular nanoscale MS identified peptides as well as fatty acids at the low fmol level. However, it also showed little tolerance for the chemical background so that a more robust capillary chromatography approach was preferentially used. Serum protease activity with a focus on angiotensin converting enzyme (ACE) was studied. Bradykinin (BK) was rapidly degraded to BK1-8 and BK1-5. The formation of lower BK1-5 levels was indicated in agreement with the hypothesis of reduced ACE-activity in CRPS

Direct X-ray photoconversion in flexible organic thin film devices operated below 1 v

The application of organic electronic materials for the detection of ionizing radiations is very appealing thanks to their mechanical flexibility, low-cost and simple processing in comparison to their inorganic counterpart. In this work we investigate the direct X-ray photoconversion process in organic thin film photoconductors. The devices are realized by drop casting solution-processed bis-(triisopropylsilylethynyl)pentacene (TIPS-pentacene) onto flexible plastic substrates patterned with metal electrodes; they exhibit a strong sensitivity to X-rays despite the low X-ray photon absorption typical of low-Z organic materials. We propose a model, based on the accumulation of photogenerated charges and photoconductive gain, able to describe the magnitude as well as the dynamics of the X-ray-induced photocurrent. This finding allows us to fabricate and test a flexible 2 × 2 pixelated X-ray detector operating at 0.2 V, with gain and sensitivity up to 4.7 × 10 4 and 77,000 nC mGy 1 cm 3, respectively

Impact of Sex and Gender on Clinical Management of Patients with Advanced Chronic Liver Disease and Type 2 Diabetes

Gender differences in the epidemiology, pathophysiological mechanisms and clinical features in chronic liver diseases that may be associated with type 2 diabetes (T2D) have been increasingly reported in recent years. This sexual dimorphism is due to a complex interaction between sex- and gender-related factors, including biological, hormonal, psychological and socio-cultural variables. However, the impact of sex and gender on the management of T2D subjects with liver disease is still unclear. In this regard, sex-related differences deserve careful consideration in pharmacology, aimed at improving drug safety and optimising medical therapy, both in men and women with T2D; moreover, low adherence to and persistence of long-term drug treatment is more common among women. A better understanding of sex- and gender-related differences in this field would provide an opportunity for a tailored diagnostic and therapeutic approach to the management of T2D subjects with chronic liver disease. In this narrative review, we summarized available data on sex- and gender-related differences in chronic liver disease, including metabolic, autoimmune, alcoholic and virus-related forms and their potential evolution towards cirrhosis and/or hepatocarcinoma in T2D subjects, to support their appropriate and personalized clinical management

Quantum states of elementary three-geometry

We introduce a quantum volume operator $K$ in three--dimensional Quantum Gravity by taking into account a symmetrical coupling scheme of three SU(2) angular momenta. The spectrum of $K$ is discrete and defines a complete set of eigenvectors which is alternative with respect to the complete sets employed when the usual binary coupling schemes of angular momenta are considered. Each of these states, that we call quantum bubbles, represents an interference of extended configurations which provides a rigorous meaning to the heuristic notion of quantum tetrahedron. We study the generalized recoupling coefficients connecting the symmetrical and the binary basis vectors, and provide an explicit recursive solution for such coefficients by analyzing also its asymptotic limit.Comment: 15 pages, LaTe

Glass transition in the quenched and annealed version of the frustrated lattice gas model

In this paper we study the 3d frustrated lattice gas model in the annealed version, where the disorder is allowed to evolve in time with a suitable kinetic constraint. Although the model does not exhibit any thermodynamic transition it shows a diverging peak at some characteristic time in the dynamical non-linear susceptibility, similar to the results on the p-spin model in mean field and Lennard-Jones mixture recently found by Donati et al. [cond-mat/9905433]. Comparing these results to those obtained in the model with quenched interactions, we conclude that the critical behavior of the dynamical susceptibility is reminiscent of the thermodynamic transition present in the quenched model, and signaled by the divergence of the static non-linear susceptibility, suggesting therefore a similar mechanism also in supercooled glass-forming liquids.Comment: 8 pages, 14 figure

Abiraterone acetate in metastatic castration-resistant prostate cancer after chemotherapy. A retrospective “Real Life” analysis of activity and safety

Abiraterone acetate (AA) is a potent, selective androge (CYP17) biosynthesis inhibitor, which showed to improve overall survival (HR = 0.646) in mCRPC patients progressing after docetaxel. In this retrospective analysis we assessed the safety and efficacy of AA in patients affected with mCRPC progressing after chemotherapy, treated in the normal clinical practice, in several Italian Oncologic Units, after the approval of the drug from the Italian Drug Agency (AIFA)