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Evaluation of torsional natural frequencies for non-tubular bonded joints
Pugno, Nicola,Ruotolo, Romualdo Techno-Press 2002 Structural Engineering and Mechanics, An Int'l Jou Vol.13 No.1
During the last several years, research activity on non-tubular bonded joints has concentrated on the effects of normal stress, bending moments and shear. Nevertheless, in certain situations, the structure may be subjected to twisting moments, so that the evaluation of its dynamic behaviour to torsional vibrations becomes of great importance even though evaluations of such loading conditions is entirely lacking in the literature. The aim of this article is to show that torsional natural frequencies of the non-tubular joint can be evaluated by determining the roots of a determinantal equation, derived by taking advantage of some analytical results obtained in a previous paper dealing with the analysis of the state of stress in the adhesive. Numerical results related to clamped-free and clamped-clamped joints complete the article.
Derrick, Jeffrey S.,Kerr, Richard A.,Korshavn, Kyle J.,McLane, Michael J.,Kang, Juhye,Nam, Eunju,Ramamoorthy, Ayyalusamy,Ruotolo, Brandon T.,Lim, Mi Hee American Chemical Society 2016 Inorganic Chemistry Vol.55 No.10
<P>The complex and multifaceted pathology of Alzheimer's disease (AD) continues to present a formidable challenge to the establishment of long-term treatment strategies. Multifunctional compounds able to modulate the reactivities of various pathological features, such as amyloid-beta (A beta) aggregation, metal ion dyshomeostasis, and oxidative stress, have emerged as useful tactic. Recently, an incorporation approach to the rational design of multipurpose small molecules has been validated through the production of a multifunctional ligand (ML) as a potential chemical tool for AD. In order to further the development of more diverse and improved multifunctional reagents, essential pharmacophores must be identified. Herein, we report a series of aminoquinoline derivatives (AQ1-4, AQP1-4, and AQDA1-3) based on ML's framework, prepared to gain a structure reactivity understanding of ML's multifunctionality in addition to tuning its metal binding affinity. Our structure reactivity investigations have implicated the dimethylamino group as a key component for supplying the antiamyloidogenic characteristics of ML in both the absence and presence of metal ions. Two-dimensional NMR studies indicate that structural variations of ML could tune its interaction sites along the A beta sequence. In addition, mass spectrometric analyses suggest that the ability of our aminoquinoline derivatives to regulate metal-induced A beta aggregation may be influenced by their metal binding properties. Moreover, structural modifications to ML were also observed to noticeably change its metal binding affinities and metal-to-ligand stoichiometries that were shown to be linked to their antiamyloidogenic and antioxidant activities. Overall, our studies provide new insights into rational design strategies for multifunctional ligands directed at regulating metal ions, A beta, and oxidative stress in AD and could advance the development of improved next-generation multifunctional reagents.</P>
Beck, Michael W.,Oh, Shin Bi,Kerr, Richard A.,Lee, Hyuck Jin,Kim, So Hee,Kim, Sujeong,Jang, Milim,Ruotolo, Brandon T.,Lee, Joo-Yong,Lim, Mi Hee Royal Society of Chemistry 2015 Chemical Science Vol.6 No.3
<▼1><P>An <I>in vivo</I> chemical tool designed to target metal–Aβ complexes and modulate their activity was applied to the 5XFAD mouse model of Alzheimer’s disease (AD) demonstrating the involvement of metal–Aβ in AD pathology.</P></▼1><▼2><P>Multiple factors, including amyloid-β (Aβ), metals, and reactive oxygen species (ROS), are involved in the development of Alzheimer's disease (AD). Metal ions can interact with Aβ species generating toxic oligomers and ROS <I>in vitro</I>; however, the involvement of metal–Aβ complexes in AD pathology <I>in vivo</I> remains unclear. To solve this uncertainty, we have developed a chemical tool (<B>L2-b</B>) that specifically targets metal–Aβ complexes and modulates their reactivity (<I>i.e.</I>, metal–Aβ aggregation, toxic oligomer formation, and ROS production). Through the studies presented herein, we demonstrate that <B>L2-b</B> is able to specifically interact with metal–Aβ complexes over metal-free Aβ analogues, redirect metal–Aβ aggregation into off-pathway, nontoxic less structured Aβ aggregates, and diminish metal–Aβ-induced ROS production, overall mitigating metal–Aβ-triggered toxicity, confirmed by multidisciplinary approaches. <B>L2-b</B> is also verified to enter the brain <I>in vivo</I> with relative metabolic stability. Most importantly, upon treatment of 5XFAD AD mice with <B>L2-b</B>, (i) metal–Aβ complexes are targeted and modulated in the brain; (ii) amyloid pathology is reduced; and (iii) cognition deficits are significantly improved. To the best of our knowledge, by employing an <I>in vivo</I> chemical tool specifically prepared for investigating metal–Aβ complexes, we report for the first time experimental evidence that metal–Aβ complexes are related directly to AD pathogenesis.</P></▼2>