Small Molecules as Chemical Tools for Regulation of Metal-Amyloid-?? Aggregation

Department of ChemistryAlzheimer???s disease (AD) is most common form of dementia. Symptomatically, memory loss and cognitive decline is observed. In 2016, more than 33 million people worldwide are suffered from AD. The complexity of AD, however, stems from the inter-relation of multiple pathological factors upon initiation and progression of the disease. For example, the amyloid-?? (A??) peptides aggregate toward bigger species and form the senile plaque in AD brain. The high concentration of metal ions [e.g., Cu(I/II), Zn(II), and Fe(II/III)] are observed in this senile plaques. Metal ions also could bind to A?? and show different properties with metal-free A??. Additionally, from these redox active metal ions [e.g., Cu(I/II) and Fe(II/III)], could overproduce the reactive oxygen species (ROS) through Fenton-like reactions. To identify the involvement of metal-bound amyloid-?? (metal???A??) aggregation in AD pathology, small molecules as chemical tools capable of controlling metal???A?? aggregation have been developed. Herein, we describe the design of small molecules as chemical tools to target metal???A??. Introduction of hypotheses of the AD and previous reported chemical tools for metal???A?? in Chapter 1, and 2,2???-bipyridine (bpy) derivatives (1???4) rationally designed to be chemical modulators towards metal???A??? aggregation over metal-free A?? analog will be described in Chapter 2. Additionally, design molecule to inhibit the transcription factor, ??FosB are proposed in Appendix A. Overall, our studies of the bpy derivatives demonstrate that the alteration of metal binding properties as well as the installation of an A?? interacting capability onto a metal chelating framework, devised via the rational structure-based design, were able to achieve evident modulating reactivity against metal???A?? aggregation. Obviating the need for complicated structures, our design approach could be appropriately utilized for inventing small molecules as chemical tools for studying desired metal-related targets in biological systems.ope

Drivers of the perceived social impact of the Super Bowl: mediation and moderation analyses

Purpose: Building on the social leverage model (SLM), this study aims to examine the influence of event-related attributes on residents' perceived social impact of a major sport event, as mediated by event involvement. It also investigates the moderating effect of event rights holders' credibility on the relationship between event involvement and perceived social impact. Design/methodology/approach: Using a two-wave, time-lagged survey, data were collected from 220 residents of a Super Bowl host city. Hypotheses were tested using structural equation modeling (SEM). Findings: High celebratory atmosphere, social camaraderie and social responsibility as perceived before the event were associated with residents' perceptions of the social impact of the Super Bowl. Moreover, the association between social camaraderie and perceived social impact was mediated by event involvement. When appraising the rights holder as credible, involved residents reported an increased level of perceived social impact. Originality/value: This study contributes to research on the SLM by demonstrating its application among indirect participants of major sport events. Additionally, it suggests the imperative role of rights holders' credibility in promoting the perceived social impact among involved residents

Ring finger protein 126 (RNF126) suppresses ionizing radiation-induced p53-binding protein 1 (53BP1) focus formation

Cells have evolved sophisticated mechanisms to maintain genomic integrity in response to DNA damage. Ionizing radiation (IR)-induced DNA damage results in the formation of IR-induced foci (iRIF) in the nucleus. The iRIF formation is part of the DNA damage response (DDR), which is an essential signaling cascade that must be strictly regulated because either the loss of or an augmented DDR leads to loss of genome integrity. Accordingly, negative regulation of the DDR is as critical as its activation. In this study, we have identified ring finger protein 126 (RNF126) as a negative regulator of the DDR from a screen of iRIF containing 53BP1. RNF126 overexpression abolishes not only the formation of 53BP1 iRIF but also of RNF168, FK2, RAP80, and BRCA1. However, the iRIF formation of H2AX, MDC1, and RNF8 is maintained, indicating that RNF126 acts between RNF8 and RNF168 during the DDR. In addition, RNF126 overexpression consistently results in the loss of RNF168-mediated H2A monoubiquitination at lysine 13/15 and inhibition of the non-homologous end joining capability. Taken together, our findings reveal that RNF126 is a novel factor involved in the negative regulation of DDR, which is important for sustaining genomic integrity

Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer???s disease

The absence of effective therapeutics against Alzheimer???s disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-?? (A??), metal-A??, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets??? reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.ope

Biologically Inspired Control for Robotic Arm Using Neural Oscillator Network

It is known that biologically inspired neural systems could exhibit natural dynamics efficiently and robustly for motion control, especially for rhythmic motion tasks. Inaddition, humans or animals exhibit natural adaptive motionswithout considering their kinematic configurations againstunexpected disturbances or environment changes. In this paper, we focus on rhythmic arm motions that can be achieved by using a controller based on neural oscillators and virtual force. In comparison with conventional researches, this work treats neither trajectories planning nor inverse kinematics. Instead of those, a few desired points in task-space and a control method with Jacobian transpose and joint velocity damping are merely adopted. In addition, if the joints of robotic arms are coupled toneural oscillators, they may be capable of achieving biologically inspired motions corresponding to environmental changes. To verify the proposed control scheme, we perform some simulations to trace a desired motion and show the potential features related with self-adaptation that enables a three-link planar arm to make adaptive changes from the given motion to a compliant motion. Specifically, we investigate that human-likemovements and motion repeatability are satisfied underkinematic redundancy of joints

Self-adapting Robot Arm Movement Employing Neural Oscillators

This paper proposes a neural oscillator based control to attain rhythmically dynamic movements of a robot arm. In human or animal, it is known that neural oscillators could produce rhythmic commands efficiently and robustly under the changing task environment. In particular, entrainments of the neural oscillator play a key role to adapt the nervous system to the natural frequency of the interactedenvironments. Hence, we discuss how a robot arm controls forexhibiting natural adaptive motions as a controller employing the entrainment property. To demonstrate the excellence of entrainment, we implement the proposed control scheme to a real robot arm. Then this work shows the performance of the robot arm coupled to neural oscillators in various tasks that the arm traces a trajectory. Exploiting the neural oscillator and itsentrainment property, we experimentally verify an impressivecapability of self-adaptation of the neural oscillator that enables the robot arm to make adaptive changes corresponding to an exterior environment

CPG based Self-adapting Multi-DOF Robotic Arm Control

Recently, biologically inspired control approaches for robotic systems that involve the use of central patterngenerators (CPGs) have been attracting considerable attention owing to the fact that most humans or animals move and walk easily without explicitly controlling their movements. Furthermore, they exhibit natural adaptive motions against unexpected disturbances or environmental changes without considering their kinematic configurations. Inspired by such novel phenomena, this paper endeavors to achieve self-adapting robotic arm motion. For this, biologically inspired CPG based control is proposed. In particular, this approach deals with crucial problems such as motion generation and repeatability of the joints emerged remarkably in most of redundant DOF systems. These problems can be overcome by employing a control based on artificial neural oscillators, virtual force and virtual muscle damping instead of trajectories planning andinverse kinematics. Biologically inspired motions can beattained if the joints of a robotic arm are coupled to neural oscillators and virtual muscles. We experimentally demonstrate self-adaptation motions that that enables a 7-DOF robotic arm to make adaptive changes from the given motion to a compliant motion. In addition, it is verified with real a real robotic arm that human-like movements and motion repeatability are satisfied under kinematic redundancy of joints

ATM/CHK/p53 Pathway Dependent Chemopreventive and Therapeutic Activity on Lung Cancer by Pterostilbene

<div><p>Among the many stilbenoids found in a variety of berries, resveratrol and pterostilbene are of particular interest given their potential for use in cancer therapeutics and prevention. We purified four stilbenoids from <i>R</i>. <i>undulatum</i> and found that pterostilbene inhibits cancer cell proliferation more efficiently than rhapontigenin, piceatannol and resveratrol. To investigate the underlying mechanism of this superior action of pterostilbene on cancer cells, we utilized a reverse-phase protein array followed by bioinformatic analysis and found that the ATM/CHK pathway is modified by pterostilbene in a lung cancer cell line. Given that ATM/CHK signaling requires p53 for its biological effects, we hypothesized that p53 is required for the anticancer effect of pterostilbene. To test this hypothesis, we used two molecularly defined precancerous human bronchial epithelial cell lines, HBECR and HBECR/p53i, with normal p53 and suppressed p53 expression, respectively, to represent premalignant states of squamous lung carcinogenesis. Pterostilbene inhibited the cell cycle more efficiently in HBECR cells compared to HBECR/p53i cells, suggesting that the presence of p53 is required for the action of pterostilbene. Pterostilbene also activated ATM and CHK1/2, which are upstream of p53, in both cell lines, though pterostilbene-induced senescence was dependent on the presence of p53. Finally, pterostilbene more effectively inhibited p53-dependent cell proliferation compared to the other three stilbenoids. These results strongly support the potential chemopreventive effect of pterostilbene on p53-positive cells during early carcinogenesis.</p></div

Enhanced cytotoxic effects of pterostilbene in precancerous cell lines, HBECR and HBECR/p53i.

<p>(A) Western blotting analysis showing the presence and absence of p53 in HBECR and HBECR/p53i cell lines. (B) Cell viability of HBECR and HBECR/p53i cells (2×10³) treated with different concentrations of pterostilbene ranging from 0 to 100 μM. (C) Cell proliferation ELISA assay with BrdU incorporation. (D) HBECR and HBECR/p53i cell lines were synchronized by double thymidine block. The HBECR cells were only partly synchronized. Cells were released into S phase along with treatment of pterostilbene at the final concentration of 3 μM. At the indicated time point from the thymidine block, cells were harvested and fixed for cell cycle analysis.</p