Andrea Arena

Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: A new paradigm

Clinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Interestingly, post-mortem analyses of Alzheimer disease (AD) subjects demonstrated insulin resistance in the brain proposing a role for cognitive deficits observed in AD. However, the mechanisms responsible for the onset of brain insulin resistance (BIR) need further elucidations. Biliverdin reductase-A (BVR-A) emerged as a unique Ser/Thr/Tyr kinase directly involved in the insulin signaling and represents an up-stream regulator of the insulin signaling cascade. Because we previously demonstrated the oxidative stress (OS)-induced impairment of BVR-A in human AD brain, we hypothesize that BVR-A dysregulation could be associated with the onset of BIR in AD. In the present work, we longitudinally analyze the age-dependent changes of (i) BVR-A protein levels and activation, (ii) total oxidative stress markers levels (PC, HNE, 3-NT) as well as (iii) IR/IRS1 levels and activation in the hippocampus of the triple transgenic model of AD (3xTg-AD) mice. Furthermore, ad hoc experiments have been performed in SH-SY5Y neuroblastoma cells to clarify the molecular mechanism(s) underlying changes observed in mice. Our results show that OS-induced impairment of BVR-A kinase activity is an early event, which starts prior the accumulation of Aβ and tau pathology or the elevation of TNF-α, and that greatly contribute to the onset of BIR along the progression of AD pathology in 3xTg-Ad mice. Based on these evidence we, therefore, propose a new paradigm for which: OS-induced impairment of BVR-A is firstly responsible for a sustained activation of IRS1, which then causes the stimulation of negative feedback mechanisms (i.e. mTOR) aimed to turn-off IRS1 hyper-activity and thus BIR. Similar alterations characterize also the normal aging process in mice, positing BVR-A impairment as a possible bridge in the transition from normal aging to AD.

Flutter of an Arch Bridge via a Fully Nonlinear Continuum Formulation

A fully nonlinear parametric model for wind-excited arch bridges is proposed to carry out the flutter analysis of Ponte della Musica under construction in Rome. Within the context of an exact kinematic formulation, all of the deformation modes are considered (extensional, shear, torsional, in-plane, and out-of-plane bending modes) both in the deck and supporting arches. The nonlinear equations of motion are obtained via a total Lagrangian formulation while linearly elastic constitutive equations are adopted for all structural members. The parametric nonlinear model is employed to investigate the bridge limit states appearing either as a divergence bifurcation (limit point obtained by path following the response under an increasing multiplier of the vertical accidental loads) or as a Hopf bifurcation of a suitable eigenvalue problem (where the bifurcation parameter is the wind speed). The eigenvalue problem ensues from the governing equations of motion linearized about the in-service prestressed bridge con...

Bach1 overexpression in down syndrome correlates with the alteration of the HO-1/BVR-A system: Insights for transition to alzheimer's disease

Bach1, among the genes encoded on chromosome 21, is a transcription repressor, which binds to antioxidant response elements of DNA thus inhibiting the transcription of specific genes involved in the cell stress response including heme oxygenase-1 (HO-1). HO-1 and its partner, biliverdin reductase-A (BVR-A), are upregulated in response to oxidative stress in order to protect cells against further damage. Since oxidative stress is an early event in Down syndrome (DS) and might contribute to the development of multiple deleterious DS phenotypes, including Alzheimers disease (AD) pathology, we investigated the status of the Bach1/HO-1/BVR-A axis in DS and its possible implications for the development of AD. In the present study, we showed increased total Bach1 protein levels in the brain of all DS cases coupled with reduced induction of brain HO-1. Furthermore, increased oxidative stress could, on one hand, overcome the inhibitory effects of Bach1 and, on the other hand, promote BVR-A impairment. Our data show that the development of AD in DS subjects is characterized by (i) increased Bach1 total and poly-ubiquitination; (ii) increased HO-1 protein levels; and (iii) increased nitration of BVR-A followed by reduced activity. To corroborate our findings, we analyzed Bach1, HO-1, and BVR-A status in the Ts65Dn mouse model at 3 (young) and 15 (old) months of age. The above data support the hypothesis that the dysregulation of HO-1/BVR-A system contributes to the early increase of oxidative stress in DS and provide potential mechanistic paths involved in the neurodegenerative process and AD development.

Nonlinear aeroelastic formulation for flexible high-aspect ratio wings via geometrically exact approach

The nonlinear aeroelastic modeling and behavior of HALE wings, undergoing large deformations and exhibiting dynamic stall, are presented. A fully nonlinear three-dimensional structural model, based on an exact kinematic approach, is coupled with the incompressible unsteady aerodynamic model obtained via a reduced-order indicial formulation accounting for viscous effects, in term of dynamic stall and flow separation. To this end, a modified Beddoes-Leishman model is employed. Aeroelastic simulations are performed by reducing the governing equations to a form amenable to numerical integration. Space and time integrations are conducted using a numerical scheme that includes PDE, associated with the equation of motion of the flexible wing, and ODEs, associated with the lag-state formulation pertinent to the unsteady aerodynamic loads, in a hybrid solution form. The numerical investigations show that the proposed approach is suitable for studying the aeroelastic behavior of highly nonlinear wings, for an improved understanding of the nonlinear phenomena occurring particularly in the neighborhood of the flutter boundary and in the post-critical regime.

Increased mammalian target of rapamycin signaling contributes to the accumulation of protein oxidative damage in a mouse model of down's syndrome

Background: Neurodegenerative diseases are characterized by increased levels of oxidative stress and an altered mammalian target of rapamycin (mTOR)/autophagy axis; however, the mutual relationship between these two events is controversial. Previous studies in Downs syndrome (DS) and Alzheimers disease (AD) suggested that the accumulation of protein oxidative damage results from the increased free radical production, mainly related to metabolic alterations, mitochondrial degeneration and amyloid-β deposition, and aberrant activity of protein degradative systems. Summary: This study analyzed mTOR signaling in Ts65Dn mice, a model of DS, at 6 and 12 months of age compared with euploid mice showing the early aberrant hyperphosphorylation of mTOR coupled with the reduction of autophagosome formation. Moreover, the evaluation of protein oxidation shows an increase in protein nitration and protein-bound 4-hydroxynonenal in 12-month-old Ts65Dn mice suggesting the potential involvement of altered autophagy in the buildup of protein oxidative damage. In addition, data obtained on cell culture support the protective role of autophagy in reducing protein oxidation. Key Messages: Overall, this study provides further evidence for the role of mTOR hyperactivation and reduced autophagy in the accumulation of protein oxidative damage during DS and AD pathologies.

Nonlinear aeroelastic formulation and postflutter analysis of flexible high-aspect-ratio wings

The nonlinear aeroelastic modeling and the post-flutter behavior of high-altitude long-endurance wings are discussed. A parametric structural model of wings based on an exact kinematic approach is formulated and coupled with an incompressible unsteady aerodynamic model that is obtained via an indicial formulation accounting for viscous effects, including dynamic stall and flow separation. To this end, a modified Beddoes-Leishman model is employed, and the equations of motion, together with the equations governing the aerodynamic states, are obtained via a total Lagrangian formulation. The critical and post-critical dynamic aeroelastic response is evaluated, and the limit cycles occurring in the post-flutter condition past the Hopf bifurcation are studied. Together, with comparisons from the available data of an experimental wing model with tip store, the effects of the unsteady loads and dynamic stall are evaluated and compared with predictions obtained from a model using a classical quasi-steady aerodyna...

Unsteady aerodynamic modeling and flutter analysis of long-span suspension bridges

A parametric one-dimensional model of suspension bridges is employed to investigate their static and dynamic aeroelastic behavior in response to a gust load and at the onset of flutter. The equilibrium equations are obtained via a direct total Lagrangian formulation where the kinematics for the deck, assumed to be linear, feature the vertical and the chord-wise displacements of the deck mean axis and the torsional rotations of the deck cross sections, while preserving their shape during rotation. The cables elasto-geometric stiffness contribution is obtained by condensing the equilibrium in the longitudinal direction assuming small horizontal displacements and neglecting the cable kinematics along the bridge chord-wise direction. The equations of motion are linearized about the prestressed static aeroelastic configuration and are obtained via an updated Lagrangian formulation.The equations of motion governing the structural dynamics of the bridge are coupled with the incompressible unsteady aero-dynamic model obtained by a set of reduced-order indicial functions developed for the cross section of a suspension bridge, here represented by a rectangular cross-section. The space dependence of the governing equations is treated using the Galerkin approach borrowing as set of trial functions, the eigenbasis of the modal space. The time integration is subsequently performed by using a numerical scheme that includes the modal reduced dynamic aeroelastic Ordinary Differential Equations (ODEs) and the added aerodynamic states also represented in ODE form, the latter being associated with the lag-state formulation pertinent to the unsteady wind-induced loads.The model is suitable to analyze the effect of a time and space non uniform gust load distributed on the bridge span. The obtained aeroelastic system is also suitable to study the onset of flutter and to investigate the sensitivity of the flutter condition on geometrical and aerodynamic parameters. The flutter instability is evaluated using appropriate frequency and time domain characteristics. The parametric continuum model is exploited to perform dynamic aeroelastic flutter analysis and gust response of the Runyang Suspension Bridge over the Yangtze river in China.Copyright

Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype

Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimers disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1α) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl-p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS.

Nonlinear finite element-based path following of periodic solutions

A computational framework is proposed to path follow the periodic solutions of nonlinear spatially continuous systems and more general coupled multiphysics problems represented by systems of partial differential equations with time-dependent excitations. The set of PDEs is cast in first order differential form (in time) u = f (u ,s,t;c ) where u (s,t) is the vector collecting all state variables including the velocities/time rates, s is a space coordinate (here, one-dimensional systems are considered without lack of generality for the space dependence) and t denotes time. The vector field f depends, in general, not only on the classical state variables (such as positions and velocities) but also on the space gradients of the leading unknowns. The space gradients are introduced as part of the state variables. This is justified by the mathematical and computational requirements on the continuity in space up to the proper differential order of the space gradients associated with the unknown position vector field. The path following procedure employs, for the computation of the periodic solutions, only the evaluation of the vector field f . This part of the path following procedure within the proposed combined scheme was formerly implemented by Dankowicz and coworkers in a MATLAB software package called COCO. The here proposed procedure seeks to discretize the space dependence of the variables using finite elements based on Lagrangian polynomials which leads to a discrete form of the vector field f . A concurrent bifurcation analysis is carried out by calculating the eigenvalues of the monodromy matrix. A hinged-hinged nonlinear beam subject to a primary-resonance harmonic transverse load or to a parametric-resonance horizontal end displacement is considered as a case study. Some primary-resonance frequency-response curves are calculated along with their stability to assess the convergence of the discretization scheme. The frequency-response curves are shown to be in close agreement with those calculated by direct integration of the PDEs through the FE software called COMSOL Multiphysics. Besides primary-resonance direct forcing conditions, also parametric forcing causing the principal parametric resonance of the lowest two bending modes is considered through construction of the associated transition curves. The proposed approach integrates algorithms from the finite element and bifurcation domains thus enabling an accurate and effective unfolding of the bifurcation and post-bifurcation scenarios of nonautonomous PDEs with the underlying structures.Copyright

Modulation of GLP-1 signaling as a novel therapeutic approach in the treatment of Alzheimer’s disease pathology

ABSTRACT Introduction: Clinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Post-mortem analyses of Alzheimer disease (AD) subjects revealed insulin resistance in the brain, suggesting a role of this condition in cognitive deficits observed in AD. In this review, we focus on the glucagon-like peptide-1 (GLP-1) signaling pathway, whose role in the brain is collecting increasing attention because of its association with insulin signaling activation. Areas covered: The role of GLP-1-mediated effects in the brain and how they are affected along the progression of AD pathology is discussed. Furthermore, we provide a comprehensive discussion about the use of GLP-1 mimetics drugs, which have been developed as a treatment for T2DM but seem to possess a number of other physiological properties, including neuroprotective and anti-inflammatory effects, that may be useful to slow AD progression. Expert commentary: The repurposing of antidiabetic drugs for the modulation of brain insulin resistance in AD appears to be of great interest. The beneficial effects on synaptogenesis, neurogenesis, and cell repair as well as the reduction of the chronic inflammatory response, and most importantly the reduction of amyloid plaques in the brain indicate that these drugs have promise as novel treatments for AD.