Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location

International audienceH-TWIST belongs to the family of basic helix-loop-helix (bHLH) transcription factors known to exert their activity through dimer formation. We have demonstrated recently that mutations in H-TWIST account for Saethre-Chotzen syndrome (SCS), an autosomal dominant craniosynostosis syndrome characterized by premature fusion of coronal sutures and limb abnormalities of variable severity. Although insertions, deletions, nonsense and missense mutations have been identified, no genotype-phenotype correlation could be found, suggesting that the gene alterations lead to a loss of protein function irrespective of the mutation. To assess this hypothesis, we studied stability, dimerization capacities and subcellular distribution of three types of TWIST mutant. Here, we show that: (i) nonsense mutations resulted in truncated protein instability; (ii) missense mutations involving the helical domains led to a complete loss of H-TWIST heterodimerization with the E12 bHLH protein in the two-hybrid system and dramatically altered the ability of the TWIST protein to localize in the nucleus of COS-transfected cells; and (iii) in-frame insertion or missense mutations within the loop significantly altered dimer formation but not the nuclear location of the protein. We conclude that at least two distinct mechanisms account for loss of TWIST protein function in SCS patients, namely protein degradation and subcellular mislocalization

A refined stable restriction theorem for vector bundles on quadric threefolds

Let E be a stable rank 2 vector bundle on a smooth quadric threefold Q in the projective 4-space P. We show that the hyperplanes H in P for which the restriction of E to the hyperplane section of Q by H is not stable form, in general, a closed subset of codimension at least 2 of the dual projective 4-space, and we explicitly describe the bundles E which do not enjoy this property. This refines a restriction theorem of Ein and Sols [Nagoya Math. J. 96, 11-22 (1984)] in the same way the main result of Coanda [J. reine angew. Math. 428, 97-110 (1992)] refines the restriction theorem of Barth [Math. Ann. 226, 125-150 (1977)].Comment: Ann. Mat. Pura Appl. 201

Influence of the confinement geometry on surface superconductivity

The nucleation field for surface superconductivity, $H_{c3}$, depends on the geometrical shape of the mesoscopic superconducting sample and is substantially enhanced with decreasing sample size. As an example we studied circular, square, triangular and wedge shaped disks. For the wedge the nucleation field diverges as $H_{c3}/H_{c2}=\sqrt{3}/\alpha$ with decreasing angle ($\alpha$) of the wedge, where $H_{c2}$ is the bulk upper critical field.Comment: 4 pages, 3 figures. Accepted for publication in Phys. Rev.

Compensated right ventricular function of the onset of pulmonary hypertension in a rat model depends on chamber remodeling and contractile augmentation.

Right-ventricular function is a good indicator of pulmonary arterial hypertension (PAH) prognosis; however, how the right ventricle (RV) adapts to the pressure overload is not well understood. Here, we aimed at characterizing the time course of RV early remodeling and discriminate the contribution of ventricular geometric remodeling and intrinsic changes in myocardial mechanical properties in a monocrotaline (MCT) animal model. In a longitudinal study of PAH, ventricular morphology and function were assessed weekly during the first four weeks after MCT exposure. Using invasive measurements of RV pressure and volume, heart performance was evaluated at end of systole and diastole to quantify contractility (end-systolic elastance) and chamber stiffness (end-diastolic elastance). To distinguish between morphological and intrinsic mechanisms, a computational model of the RV was developed and used to determine the level of prediction when accounting for wall masses and unloaded volume measurements changes. By four weeks, mean pulmonary arterial pressure and elastance rose significantly. RV pressures rose significantly after the second week accompanied by significant RV hypertrophy, but RV stroke volume and cardiac output were maintained. The model analysis suggested that, after two weeks, this compensation was only possible due to a significant increase in the intrinsic inotropy of RV myocardium. We conclude that this MCT-PAH rat is a model of RV compensation during the first month after treatment, where geometric remodeling on EDPVR and increased myocardial contractility on ESPVR are the major mechanisms by which stroke volume is preserved in the setting of elevated pulmonary arterial pressure. The mediators of this compensation might themselves promote longer-term adverse remodeling and decompensation in this animal model

Nanosized superconducting constrictions

Nanowires of lead between macroscopic electrodes are produced by means of an STM. Magnetic fields may destroy the superconductivity in the electrodes, while the wire remains in the superconducting state. The properties of the resulting microscopic Josephson junctions are investigated.Comment: 3 pages,3 eps figures include

Complete intersections: Moduli, Torelli, and good reduction

We study the arithmetic of complete intersections in projective space over number fields. Our main results include arithmetic Torelli theorems and versions of the Shafarevich conjecture, as proved for curves and abelian varieties by Faltings. For example, we prove an analogue of the Shafarevich conjecture for cubic and quartic threefolds and intersections of two quadrics.Comment: 37 pages. Typo's fixed. Expanded Section 2.

Mesoscopic superconductors in the London limit: equilibrium properties and metastability

We present a study of the behaviour of metastable vortex states in mesoscopic superconductors. Our analysis relies on the London limit within which it is possible to derive closed analytical expressions for the magnetic field and the Gibbs free energy. We consider in particular the situation where the vortices are symmetrically distributed along a closed ring. There, we obtain expressions for the confining Bean-Livingston barrier and for the magnetization which turns out to be paramagnetic away from thermodynamic equilibrium. At low temperature, the barrier is high enough for this regime to be observable. We propose also a local description of both thermodynamic and metastable states based on elementary topological considerations; we find structural phase transitions of vortex patterns between these metastable states and we calculate the corresponding critical fields.Comment: 24 pages, 20 figure

Subjective effects of the sleep position trainer on snoring outcomes in position-dependent non-apneic snorers

Purpose: To evaluate the effect of a new-generation positional device, the sleep position trainer (SPT), in non-apneic position-dependent snorers. Methods: Non-apneic position-dependent snorers with an apnea–hypopnea index (AHI) < 5 events/h were included between February 2015 and September 2016. After inclusion, study subjects used the SPT at home for 6 weeks. The Snore Outcome Survey (SOS) was filled out by the subjects at baseline and after 6 weeks, and at the same time, the Spouse/Bed Partner Survey (SBPS) was filled out by their bed partners. Results: A total of 36 participants were included and 30 completed the study. SOS score improved significantly after 6 weeks from 35.0 ± 13.5 to 55.3 ± 18.6, p < 0.001. SBPS score also improved significantly after 6 weeks from 24.7 ± 16.0 versus 54.5 ± 25.2, p < 0.001. The severity of snoring assessed with a numeric visual analogue scale (VAS) by the bed partner decreased significantly from a median of 8.0 with an interquartile range (IQR) of [7.0–8.5] to 7.0 [3.8–8.0] after 6 weeks (p = 0.004). Conclusions: Results of this study indicate that positional therapy with the SPT improved several snoring-related outcome measures in non-apneic position-dependent snorers. The results of this non-controlled study demonstrate that this SPT could be considered as an alternative therapeutic option to improve sleep-related health status of snorers and their bed partners