The prion-like properties of the mutant huntingtin protein : demonstration in in vitro and in vivo systems

La maladie de Huntington (MH) est une maladie neurodégénérative autosomique dominante qui affecte environ 3 à 8 personnes sur 100 000 dans le monde. La MH est causée par une mutation du gène HTT, lequel code pour la protéine huntingtine (HTT). Cette mutation consiste en une expansion de 35 répétitions CAG à même l'exon 1 du gène et aboutit à une répétition de la séquence polyglutamine (polyQ) au sein du segment N-terminal de la protéine HTT. Les personnes atteintes de MH développent des troubles moteurs, cognitifs et psychiatriques sévères, principalement à l'âge adulte. L'âge d’apparition des symptômes est généralement inversement proportionnel au nombre de répétitions CAG bien que la symptomatologie varie considérablement d'un patient à l'autre. L'origine de la MH est associée à l'expression de la protéine HTT mutée (mHTT) qui, en raison de son expansion polyQ, adopte une conformation pathogène et s'accumule en petits et/ou gros agrégats cytotoxiques. Bien que l'on suppose que ces événements soient responsables de la neurodégénérescence, le mécanisme sous-jacent aux voies physiopathologiques menant à l'apparition de la maladie et à la mort neuronale est toujours à l'étude. Un nombre croissant d'observations suggère que la mHTT possède des capacités de type prion, c’est-à-dire une aptitude à recruter des protéines endogènes normales et les corrompre afin de créer des agrégats toxiques; capacités qui sont également connues pour d'autres protéines, notamment l'amyloïde, la tau et la a-synucléine, associées à diverses maladies neurodégénératives. Nous avons émis l'hypothèse que le mHTT se propage de cellule en cellule et qu'elle se comporter tel un prion, contribuant à influencer le développement de la MH. Afin de tester cette hypothèse, des fibrilles synthétiques de mHTT ont été administrées à plusieurs lignées cellulaires ainsi qu'à des souris de différentes souches génétiques. Suite à une période d'incubation, les effets des fibrilles de mHTT sur la viabilité cellulaire, le comportement animal et les caractéristiques neuropathologiques ont été examiné. Nous avons ainsi observé que les fibrilles de mHTT provoquaient la mort cellulaire et des changements morphologiques des cellules cultivées, tandis qu’elles induisaient un phénotype comportemental transitoire de la maladie chez des souris saines. Les fibrilles de mHTT pouvaient également exacerber les déficits moteurs, anxieux et cognitifs de type MH dans un modèle de souris huntingtonien. Ainsi, notre étude suggère que la mHTT extracellulaire peut se propager de cellule à cellule et, une fois recrutée au sein de la cellule, provoquer des changements pathologiques. À la lumière de ces observations, nous croyons que la mHTT extracellulaire pourrait représenter une cible attrayante pour le développement de futures stratégies thérapeutiques. De surcroît, la plupart des traitements en études cliniques sont conçus pour cibler le gène HTT dans le but de diminuer l'expression de la protéine, ignorant la quantité importante de mHTT déjà présente dans le système à l'âge adulte. Par conséquent, une thérapie combinatoire ciblant, à la fois l'expression de mHTT et la mHTT extracellulaire préexistante, pourrait se révéler une voie prometteuse pour le traitement de la MH.Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that affects approximately 3 - 8 people in 100,000 individuals worldwide. HD is caused by a mutation in the HTT gene, which codes for the protein huntingtin (HTT), consisting of an expansion of 35 CAG repeats in the exon 1 of the gene and resulting in the elongated polyglutamine (polyQ) stretch at the N-terminal fragment of the protein HTT. Individuals who suffer from HD develop severe motor, cognitive and psychiatric impairments, which primarily manifest in adulthood. The onset of the disease is usually inversely proportional to the CAG repeat expansion, however, HD comes with a high variability of symptoms. HD is also associated with the expression of the mutated HTT (mHTT) protein. The mHTT protein adopts a pathogenic conformation, which accumulates in small and/or large cytotoxic aggregates. Although these events are suspected to contribute to neurodegeneration, the exact mechanisms underlying the pathophysiological pathways leading to disease onset and neuronal death are still under investigation. A growing body of evidence suggests that mHTT possesses prion-like capacities – the capacity to spread between cells and seed disease – a phenomenon associated with other proteins such as amyloid, tau and a-synuclein, all involved in various neurodegenerative diseases. We hypothesized that mHTT propagates in a non-autonomous manner and behaves in a prion-like fashion to influence the onset and severity of HD. To address this, exogenous synthetic mHTT fibrils were administered to several cell lines and to mice of different genetic backgrounds. Following an incubation period, the effects of mHTT fibrils on cellular viability, animal behavior and neuropathological features were examined. We observed that mHTT fibrils provoked cell death and morphological changes in cultured cells, induced transient HD-related behavioral phenotypes in healthy mice and exacerbated motor, anxiety-like and cognitive deficits in an HD mouse model. Our study suggests that extracellular mHTT can propagate between cellular elements and once uptaken, trigger pathological changes. In light of these observations, we believe that extracellular mHTT could represent an appealing target for future therapeutic strategies. Current disease-modifying treatments tested in the clinic are designed to target the HTT gene to decrease the expression of the protein, overlooking the mHTT load outside of the cell boundaries and/or which has accumulated in the system prior to the application of gene silencing/editing. Hence, a combinational therapy addressing both the intracellular and extracellular expression of mHTT could serve as a more global treatment of HD

Hybrid Passive Control Strategies for Reducing the Displacements at the Base of Seismic Isolated Structures

In this paper, the use of hybrid passive control strategies to mitigate the seismic response of a base-isolated structure is examined. The control performance of three different types of devices used for reducing base displacements of isolated buildings is investigated. Specifically, the Tuned Mass Damper (TMD), the New Tuned Mass Damper (New TMD) and the Tuned Liquid Column Damper (TLCD), each one associated to a Base Isolated structure (BI), have been considered. The seismic induced vibration control of base-isolated structures equipped with the TMD, New TMD or the TLCD is examined and compared with that of the base-isolated system without devices, using real recorded seismic signals as external input. Data show that the New TMD is the most effective in controlling the response of base-isolated structures so that it can be considered as a practical and appealing means to mitigate the dynamic response of base-isolated structures

A novel identification procedure from ambient vibration data for buildings of the cultural heritage

Ambient modal identification, also known as Operational Modal Analysis (OMA), aims to identify the modal properties of a structure based on vibration data collected when the structure is under its operating conditions, i.e., no initial excitation or known artificial excitation. This procedure for testing and/or monitoring historic buildings, is particularly attractive for civil engineers concerned with the safety of complex historic structures. However, since the external force is not recorded, the identification methods have to be more sophisticated and based on stochastic mechanics. In this context, this contribution will introduce an innovative ambient identification method based on applying the Hilbert Transform, to obtain the analytical representation of the system response in terms of the correlation function. In particular, it is worth stressing that the analytical signal is a complex representation of a time domain signal: the real part is the time domain signal itself, while the imaginary part is its Hilbert transform. A 3DOF numerical example will be presented to show the accuracy of the proposed procedure, and comparisons with data from other methods assess the reliability of the approach

Efficient estimation of tuned liquid column damper inerter (TLCDI) parameters for seismic control of base-isolated structures

This paper presents an enhanced base-isolation (BI) system equipped with a novel passive control device composed of a tuned liquid damper and an inerter (TLCDI). With the aim of reducing the seismic response of BI systems, this contribution focuses on the design of the TLCDI providing analytical solutions for the optimal TLCDI parameters, easily implementable in the design phase. The effectiveness of the proposed approach in terms of seismic response reduction and computational gain is validated by comparison with classical numerical optimization techniques. The control performance of two different base-isolated TLCDI-controlled structures is assessed by employing real-ground motion records, and relevant comparisons with both uncontrolled base-isolated structures and equipped with a conventional TLCD are presented

Sliding TLCD for vibration control of base-isolation systems: Experimental comparison with traditional TLCD and TMD

In the context of hybrid passive vibration control, the effectiveness of the Tuned Liquid Column Damper (TLCD) for seismic protection of base-isolated (BI) systems has been demonstrated both numerically and experimentally. In contrast to the previous studies on TLCDs, the present study explores the possibility of equipping a BI system with a sliding model of TLCD (STLCD), until now introduced only for the suppression of wind-induced vibrations of fixed-base structures. Specifically, the proposed STLCD consists of a U-shaped tank partially filled with water, mounted on a roller support and connected to the BI system via a spring dashpot system. The validity of the introduced mathematical model is assessed by means of an extensive shaking table testing campaign at the Laboratory of Experimental Dynamics at the University of Palermo, Italy. For the experimental tests, a small-scale model of a single-degree of-freedom (SDOF) BI structure with the STLCD is constructed, and the effectiveness of the proposed combined control strategy is experimentally evaluated. Finally, comparisons with traditional TLCDs and TMDs are made and the control efficiency is discussed with emphasis on the reduction of the accelerations of the BI system

Assessment of the tuned mass damper inerter for seismic response control of base-isolated structures

In this paper, the hybrid control of structures subjected to seismic excitation by means of tuned mass damper inerter (TMDI) and base-isolation subsystems is studied with the aim of improving the dynamic performance of base-isolated structures by reducing the displacement demand of the isolation subsystem. The seismic performance of TMDI hybrid controlled structures is investigated in a comparative study, considering simple isolated systems and systems equipped with other absorber devices such as the tuned mass damper (TMD) and the tuned liquid column damper (TLCD). The TMDI has been optimized by performing a simplified approach based on minimizing the base-isolation subsystem displacement variance, which provides simple analytical formulae for a quick definition of the TMDI parameters. The reliability of this approach is demonstrated by a comparison with a more accurate and computationally complex numerical optimization procedure. The control performance of three types of hybrid controlled structures exposed to a set of 44 recorded ground motions is investigated. Numerical results show that the TMDI can more efficiently control the structural response of low-damped isolated structures, even compared to the TMD and the TLCD

A novel identification procedure from ambient vibration data

Ambient vibration modal identification, also known as Operational Modal Analysis, aims to identify the modal properties of a structure based on vibration data collected when the structure is under its operating conditions, i.e., no initial excitation or known artificial excitation. This procedure for testing and/or monitoring historic buildings, is particularly attractive for civil engineers concerned with the safety of complex historic structures.However, since the external force is not recorded, the identification methods have to be more sophisticated and based on stochastic mechanics. In this context, this contribution will introduce an innovative ambient identification method based on applying the Hilbert Transform, to obtain the analytical representation of the system response in terms of the correlation function. In particular, it is worth stressing that the analytical signal is a complex representation of a time domain signal: the real part is the time domain signal itself, while the imaginary part is its Hilbert transform. A 3DOF numerical example will be presented to show the accuracy of the proposed procedure, and comparisons with data from other methods assess the reliability of the approach. Finally, the identification method will be extended to the real case study of the Chiaramonte Palace, a historic building located in Palermo and known as “Steri”

Markers for the detection of Lewy body disease versus Alzheimer's disease in mild cognitive impairment: a systematic review and meta-analysis

Background Mild cognitive impairment (MCI) may evolve into dementia. Early recognition of possible evolution to Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB) is of importance, but actual diagnostic criteria have some limitations. In this systematic review and meta-analysis, we aimed to find the most accurate markers that can discriminate patients with DLB versus AD, in MCI stage. Methods We searched several databases up to 17 August 2023 including studies comparing markers that may distinguish DLB-MCI from AD-MCI. We reported data regarding sensitivity, specificity, and the area under the curves (AUCs) with their 95% confidence intervals (CIs). Results Among 2219 articles initially screened, eight case-control studies and one cohort study were included for a total of 832 outpatients with MCI. The accuracy of cerebrospinal fluid (CSF) markers was the highest among the markers considered (AUC > 0.90 for the CSF markers), with the AUC of CSF A beta 42/A beta 40 of 0.94. The accuracy for clinical symptom scales was very good (AUC = 0.93), as evaluated in three studies. Although limited to one study, the accuracy of FDG-PET (cingulate island sign ratio) was very good (AUC = 0.95) in discriminating DLB from AD in MCI, while the accuracy of SPECT markers and EEG frequencies was variable. Conclusions Few studies have assessed the accuracy of biomarkers and clinical tools to distinguish DLB from AD at the MCI stage. While results are promising for CSF markers, FDG-PET and clinical symptoms scales, more studies, particularly with a prospective design, are needed to evaluate their accuracy and clinical usefulness

War and dissociation : the case of futurist aesthetics

Thanks to their deliberate engagement in state propaganda Italian Futurists deserved a prominent spot in the history of military aesthetics in the 20th century. However, under what looked like an unequivocal expression of support for war, lied a deep philosophical disagreement concerning its existential and epistemological value. The bone of contention concerned the effects of warfare on perception and, consequently, the means of its depiction. The author analyses this intellectual disagreement within the group and focuses, in particular, on its philosophical implications