β-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency.

ObjectiveThe islet in type 2 diabetes is characterized by β-cell apoptosis, β-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in β-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum-associated degradation/ubiquitin/proteasome system.Research design and methodsWe used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832/13 cells and apoptosis was evaluated.ResultsWe report accumulation of polyubiquinated proteins and UCH-L1 deficiency in β-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in β-cells induced endoplasmic reticulum stress leading to apoptosis.ConclusionsOur results indicate that defective protein degradation in β-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises β-cell viability

Metabolic aspects of cardiovascular diseases: Is FoxO1 a player or a target?

The O subfamily of forkhead (FoxO) 1 is a crucial regulator of cell metabolism in several tissues, including the heart, where it is involved in cardiac regulation of glucose and lipid metabolic pathways, and endothelium, controlling the levels of some relevant biomarkers in atherosclerotic process. Despite the growing understanding of FoxO1 biology, the metabolic consequences of FoxO1 modifications and its implication in CVD, atherosclerosis and T2DM are still not incompletely described. In this review we discuss how FoxO1 affects cardiovascular pathophysiology and which of its effects should be restrained or enhanced to preserve endothelial and heart functions

Diabetes influences cancer risk in patients with increased carotid atherosclerosis burden

Background and aims: Atherosclerosis and cancer share several risk factors suggesting that at least in part their pathogenesis is sustained by common mechanisms. To investigate this relation we followed a group of subjects with carotid atherosclerosis at baseline up for malignancy development.Methods and results: we carried out an observational study exploring cancer incidence (study endpoint) in subjects with known carotid atherosclerosis at baseline (n = 766) without previous cancer or carotid vascular procedures. During the follow-up (160 +/- 111 weeks) 24 cancer occurred, corresponding to an overall annual incidence rate of 0.11%. 10 diagnosis of cancer occurred in individuals with a carotid stenosis >50% (n = 90) whereas 14 in patients with a carotid stenosis <50% patients (n = 676) (p < 0.001). Respect to patients without cancer, diabetes was markedly more common in subjects with cancer diagnosis during the FU (37.3%vs75.0%, p < 0.001). After controlling for classic risk factors, carotid stenosis >50% (HR = 2.831, 95%CI = 1.034-5.714; p = 0.036) and diabetes (HR = 4.831, 95%CI = 1.506-15.501; p = 0.008) remained significantly associated with cancer diagnosis.Conclusions: to our knowledge this is the first study reporting a significant risk of cancer development in subjects with diabetes and high risk of cerebrovascular events, highlighting the need of a carefully clinical screening for cancer in diabetic patients with overt carotid atherosclerosis. (C) 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved

Why early tactile speech aids may have failed: no perceptual integration of tactile and auditory signals

Tactile speech aids, though extensively studied in the 1980s and 90s, never became a commercial success. A hypothesis to explain this failure might be that it is difficult to obtain true perceptual integration of a tactile signal with information from auditory speech: exploitation of tactile cues from a tactile aid might require cognitive effort and so prevent speech understanding at the high rates typical of everyday speech. To test this hypothesis, we attempted to create true perceptual integration of tactile with auditory information in what might be considered the simplest situation encountered by a hearing-impaired listener. We created an auditory continuum between the syllables BA and VA, and trained participants to associate BA to one tactile stimulus VA to another tactile stimulus. After training, we tested if auditory discrimination along the continuum between the two syllables could be biased by incongruent tactile stimulation. We found that such a bias occurred only when the tactile stimulus was above its previously measured tactile discrimination threshold. Such a pattern is compatible with the idea that the effect is due to a cognitive or decisional strategy, rather than to truly perceptual integration. We therefore ran a further study, where we created a tactile version of the McGurk effect. We extensively trained two Subjects over six days to associate four recorded auditory syllables with four corresponding apparent motion tactile patterns. In a subsequent test, we presented stimulation that was either congruent or incongruent with the learnt association, and asked Subjects to report the syllable they perceived. We found no analog to the McGurk effect. These findings strengthen our hypothesis according to which tactile aids failed because integration of tactile cues with auditory speech occurred at a cognitive or decisional level, rather than truly at a perceptual leve

All-optical active plasmonic devices with memory and power switching functionalities based on epsilon-near-zero nonlinear metamaterials

All-optical active plasmonic devices are of fundamental importance for designing efficient nanophotonic circuits. We theoretically propose and numerically investigate an active plasmonic device made up of a nonlinear epsilon-near-zero metamaterial slab of thickness smaller than 100 nanometers lying on a linear epsilon-near-zero metamaterial substrate. We predict that, in free-space coupling configuration, the device, operating at low-intensity, would display plasmon mediated hysteresis behavior since the phase difference between the reflected and the incident optical waves turns out to be multi-valued and dependent on the history of the excitation process. Such an hysteresis behavior would allow to regard the proposed device as a compact memory unit whose state is accessible by measuring either the mentioned phase difference or the power, which is multi-valued as well, carried by the nonlinear plasmon wave. Since multiple plasmon powers comprise both positive and negative values, the device would also operate as a switch of the plasmon power direction at each jump along an hysteresis loop.Comment: 9 pages, 4 figure

Zonal shear and super-rotation in a magnetized spherical Couette flow experiment

We present measurements performed in a spherical shell filled with liquid sodium, where a 74 mm-radius inner sphere is rotated while a 210 mm-radius outer sphere is at rest. The inner sphere holds a dipolar magnetic field and acts as a magnetic propeller when rotated. In this experimental set-up called DTS, direct measurements of the velocity are performed by ultrasonic Doppler velocimetry. Differences in electric potential and the induced magnetic field are also measured to characterize the magnetohydrodynamic flow. Rotation frequencies of the inner sphere are varied between -30 Hz and +30 Hz, the magnetic Reynolds number based on measured sodium velocities and on the shell radius reaching to about 33. We have investigated the mean axisymmetric part of the flow, which consists of differential rotation. Strong super-rotation of the fluid with respect to the rotating inner sphere is directly measured. It is found that the organization of the mean flow does not change much throughout the entire range of parameters covered by our experiment. The direct measurements of zonal velocity give a nice illustration of Ferraro's law of isorotation in the vicinity of the inner sphere where magnetic forces dominate inertial ones. The transition from a Ferraro regime in the interior to a geostrophic regime, where inertial forces predominate, in the outer regions has been well documented. It takes place where the local Elsasser number is about 1. A quantitative agreement with non-linear numerical simulations is obtained when keeping the same Elsasser number. The experiments also reveal a region that violates Ferraro's law just above the inner sphere.Comment: Phys Rev E, in pres

Weak Lensing Mass Reconstruction of the Galaxy Cluster Abell 209

Weak lensing applied to deep optical images of clusters of galaxies provides a powerful tool to reconstruct the distribution of the gravitating mass associated to these structures. We use the shear signal extracted by an analysis of deep exposures of a region centered around the galaxy cluster Abell 209, at redshift z=0.2, to derive both a map of the projected mass distribution and an estimate of the total mass within a characteristic radius. We use a series of deep archival R-band images from CFHT-12k, covering an area of 0.3 deg^2. We determine the shear of background galaxy images using a new implementation of the modified Kaiser-Squires-Broadhurst pipeline for shear determination, which we has been tested against the ``Shear TEsting Program 1 and 2'' simulations. We use mass aperture statistics to produce maps of the 2 dimensional density distribution, and parametric fits using both Navarro-Frenk-White (NFW) and singular-isothermal-sphere profiles to constrain the total mass. The projected mass distribution shows a pronounced asymmetry, with an elongated structure extending from the SE to the NW. This is in general agreement with the optical distribution previously found by other authors. A similar elongation was previously detected in the X-ray emission map, and in the distribution of galaxy colours. The circular NFW mass profile fit gives a total mass of M_{200} = 7.7^{+4.3}_{-2.7} 10^{14} solar masses inside the virial radius r_{200} = 1.8\pm 0.3 Mpc. The weak lensing profile reinforces the evidence for an elongated structure of Abell 209, as previously suggested by studies of the galaxy distribution and velocities.Comment: accepted by A&A, 15 pages, 11 figure