Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5' splice site selection

Alternative splicing (AS) modulates many physiological and pathological processes. For instance, AS of the BCL-X gene balances cell survival and apoptosis in development and cancer. Herein, we identified the polypyrimidine tract binding protein (PTBP1) as a direct regulator of BCL-X AS. Overexpression of PTBP1 promotes selection of the distal 5' splice site in BCL-X exon 2, generating the pro-apoptotic BCL-Xs splice variant. Conversely, depletion of PTBP1 enhanced splicing of the anti-apoptotic BCL-XL variant. In vivo cross-linking experiments and site-directed mutagenesis restricted the PTBP1 binding site to a polypyrimidine tract located between the two alternative 5' splice sites. Binding of PTBP1 to this site was required for its effect on splicing. Notably, a similar function of PTBP1 in the selection of alternative 5' splice sites was confirmed using the USP5 gene as additional model. Mechanistically, PTBP1 displaces SRSF1 binding from the proximal 5' splice site, thus repressing its selection. Our study provides a novel mechanism of alternative 5' splice site selection by PTBP1 and indicates that the presence of a PTBP1 binding site between two alternative 5' splice sites promotes selection of the distal one, while repressing the proximal site by competing for binding of a positive regulator

CURVED PLANFORM WINGS WITH A HIGH ASPECT RATIO FOR AIRCRAFTS OPERATING IN THE TRANSONIC REGIME

The present invention concerns an innovative wing (1) specific for an aircraft operating in the transonic regime and comprising: - A root section ; - A tip section and; - A leading edge for connecting the root section to the tip section. In accordance with the invention, the curved leading edge is configured according to a line by which locally the angle (Λ) formed by the forwarding direction of the wing and the perpendicular to the tangent of the leading edge increases progressively from the root section to the tip section of the wing. In such a way, the speed component (Vu) of the asymptotic flow orthogonal to the leading edge decreases progressively from the root section to the tip section, thus reducing the local Mach number progressively

Replica symmetry breaking in mean field spin glasses trough Hamilton-Jacobi technique

During the last years, through the combined effort of the insight, coming from physical intuition and computer simulation, and the exploitation of rigorous mathematical methods, the main features of the mean field Sherrington-Kirkpatrick spin glass model have been firmly established. In particular, it has been possible to prove the existence and uniqueness of the infinite volume limit for the free energy, and its Parisi expression, in terms of a variational principle, involving a functional order parameter. Even the expected property of ultrametricity, for the infinite volume states, seems to be near to a complete proof. The main structural feature of this model, and related models, is the deep phenomenon of spontaneous replica symmetry breaking (RSB), discovered by Parisi many years ago. By expanding on our previous work, the aim of this paper is to investigate a general frame, where replica symmetry breaking is embedded in a kind of mechanical scheme of the Hamilton-Jacobi type. Here, the analog of the "time" variable is a parameter characterizing the strength of the interaction, while the "space" variables rule out quantitatively the broken replica symmetry pattern. Starting from the simple cases, where annealing is assumed, or replica symmetry, we build up a progression of dynamical systems, with an increasing number of space variables, which allow to weaken the effect of the potential in the Hamilton-Jacobi equation, as the level of symmetry braking is increased. This new machinery allows to work out mechanically the general K-step RSB solutions, in a different interpretation with respect to the replica trick, and lightens easily their properties as existence or uniqueness.Comment: 24 pages, no figure

Notes on the p-spin glass studied via Hamilton-Jacobi and Smooth-Cavity techniques

In these notes, we continue our investigation of classical toy models of disordered statistical mechanics through various techniques recently developed and tested mainly on the paradigmatic SK spin glass. Here we consider the p-spin-glass model with Ising spins and interactions drawn from a normal distribution N[0,1]. After a general presentation of its properties (e.g. self-averaging of the free energy, existence of a suitable thermodynamic limit), we study its equilibrium behavior within the Hamilton-Jacobi framework and the smooth cavity approach. Through the former we find both the RS and the 1RSB expressions for the free energy, coupled with their self-consistent relations for the overlaps. Through the latter, we recover these results as irreducible expression, and we study the generalization of the overlap polynomial identities suitable for this model; a discussion on their deep connection with the structure of the internal energy and the entropy closes the investigation.Comment: To appear on JM

Efficacy and safety of colchicine for the treatment of myopericarditis

Objective Clinical trials have evaluated the efficacy and safety of colchicine only in simple pericarditis, excluding cases of concomitant myocarditis. The aim of this paper is to evaluate the efficacy and safety of colchicine for the treatment of the first attack of acute pericarditis with concomitant myocardial involvement. Methods Double-centre retrospective cohort study analysing consecutive patients admitted for first attack of pericarditis with myocarditis and treated with or without colchicine. The primary efficacy end point was the time to the first recurrence. Propensity score matching was used to generate two groups of patients with similar baseline characteristics. Colchicine-associated side effects were analysed as safety end-point. Results A total of 175 patients (mean age 46.2±20.1 years, 25.1% females, 88.6% with idiopathic/viral aetiology) were included. Seventy-nine (45.1%) patients were treated with colchicine. After a median follow-up of 25.3 (IQR 8.3-45.6) months, 58 (33.1%) patients had recurrences. The propensity score generated two groups of 73 patients with similar baseline characteristics but the use of colchicine. Patients treated with colchicine had a lower incidence of recurrences (respectively, 19.2% vs 43.8%; p=0.001) and a longer event-free survival (p=0.005). In multivariable analysis, women (HR 1.97, 95% CI 1.04 to 3.73; p=0.037) and corticosteroid use (HR 2.27, 95% CI 1.15 to 4.47; p=0.018) were independent risk factors for recurrences. Colchicine-associated side effects were mild and occurred in 3 (1.7%) patients. Conclusion In patients with first attack of pericarditis associated with myocardial involvement, colchicine was safe and efficacious for the reduction of recurrences

Light--like Wilson loops and gauge invariance of Yang--Mills theory in 1+1 dimensions

A light-like Wilson loop is computed in perturbation theory up to ${\cal O} (g^4)$ for pure Yang--Mills theory in 1+1 dimensions, using Feynman and light--cone gauges to check its gauge invariance. After dimensional regularization in intermediate steps, a finite gauge invariant result is obtained, which however does not exhibit abelian exponentiation. Our result is at variance with the common belief that pure Yang--Mills theory is free in 1+1 dimensions, apart perhaps from topological effects.Comment: 10 pages, plain TeX, DFPD 94/TH/

Diginyc partial hydatidiform mole with increased fetal nuchal translucency and ovarian hyperstimulation syndrome.

PURPOSE OF INVESTIGATION Hydatidiform mole (HM) is an abnormal pregnancy characterized by proliferation of cytotrophoblast and syncytiotrophoblast and vesicular swelling of placental villi. The fetus or embryo can be absent or abnormal. HMs can be complete or partial. CASE REPORT A case of diginyc partial HM at 12 weeks of gestational age was referred to the present center of prenatal diagnosis. The patient showed ovarian hyperstimulation syndrome. At ultrasonography, increased fetal nuchal translucency (NT) with fetal anomaly was evident, without sonographic signs of placental mole. Pregnancy was terminated with legal abortion. RESULTS Partial HM (PHM) was suspected by ultrasonographic fetal markers with ovarian hyperstimulation syndrome, but the diagnosis was performed only with fluorescent in situ hybridization. In particular fetal NT appeared increased also in diginyc mole. CONCLUSION In order to improve the detection rate of PHM, routine histological examinations may be associated to fluorescent in situ hybridization in all cases of fetal anomalies

BILATERAL RENAL ARTERY STENOSIS IN A HYPERTENSIVE LUPUS PATIENT WITHOUT RENAL DYSFUNCTION: A CASE REPORT

Systemic lupus erythematosus (SLE) is associated with a high prevalence of atherosclero-sis and an enhanced cardiovascular mortality. In adult subjects, several studies have shown the coexistence of SLE and renal artery stenosis, most of them with unilateral in-volvement or with renal dysfunction. We observed a 62-year-old man with SLE and a 10-year history of moderate-to-severe hy-pertension who was admitted to our hospital because of uncontrolled blood pressure val-ues (152/95 mmHg), despite drug therapy. No signs of renal impairment were evident. After an initial physical examination, which presented a periumbilical bruit, a renal ultra-sound was performed with evidence of bilateral renal artery stenosis. An angio-MR study also confirmed the diagnosis and showed a double renal artery on the right side. Many different factors can contribute to the bilateral renal artery stenosis in this patient. Chronic inflammatory state associated to SLE, metabolic alterations with dyslipidemia and steroid therapy may all be involved in the development of the renal atherosclerotic le-sions

Virtopsy in conjoined ischiopagus twins.

PURPOSE OF INVESTIGATION To propose a multidisciplinary protocol for postmortem disclosure of complex fetal malformations, comparing ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and autopsy in a case of conjoined ischiopagus twins. MATERIALS AND METHODS A screening second-trimester ultrasound diagnosed ischiopagus twins at 20 gestational weeks in a 31-year-old woman without any previous ultrasound examination. The couple decided for pregnancy termination. The formalin-fixed fetuses underwent full-body CT, MRI, and autopsy. RESULTS ultrasound accurately diagnosed ischiopagus twins. CT was very accurate in the description of bone components. MRI allowed better visualization of the visceral organs than CT. Only autopsy could disclose the aspect of the two gastrointestinal tracts and the external genitalia. CONCLUSIONS Prenatal ultrasound represents the standard diagnostic exam for conjoined twins. CT-MRI virtual autopsy (virtopsy) may be an option if the couple refuses to authorize necropsy or may be useful to plan a minimally invasive autopsy preserving the external phenotype