83 research outputs found

    Fast Sensing and Adaptive Actuation for Robust Legged Locomotion

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    Robust legged locomotion in complex terrain demands fast perturbation detection and reaction. In animals, due to the neural transmission delays, the high-level control loop involving the brain is absent from mitigating the initial disturbance. Instead, the low-level compliant behavior embedded in mechanics and the mid-level controllers in the spinal cord are believed to provide quick response during fast locomotion. Still, it remains unclear how these low- and mid-level components facilitate robust locomotion. This thesis aims to identify and characterize the underlining elements responsible for fast sensing and actuation. To test individual elements and their interplay, several robotic systems were implemented. The implementations include active and passive mechanisms as a combination of elasticities and dampers in multi-segment robot legs, central pattern generators inspired by intraspinal controllers, and a synthetic robotic version of an intraspinal sensor. The first contribution establishes the notion of effective damping. Effective damping is defined as the total energy dissipation during one step, which allows quantifying how much ground perturbation is mitigated. Using this framework, the optimal damper is identified as viscous and tunable. This study paves the way for integrating effective dampers to legged designs for robust locomotion. The second contribution introduces a novel series elastic actuation system. The proposed system tackles the issue of power transmission over multiple joints, while featuring intrinsic series elasticity. The design is tested on a hopper with two more elastic elements, demonstrating energy recuperation and enhanced dynamic performance. The third contribution proposes a novel tunable damper and reveals its influence on legged hopping. A bio-inspired slack tendon mechanism is implemented in parallel with a spring. The tunable damping is rigorously quantified on a central-pattern-generator-driven hopping robot, which reveals the trade-off between locomotion robustness and efficiency. The last contribution explores the intraspinal sensing hypothesis of birds. We speculate that the observed intraspinal structure functions as an accelerometer. This accelerometer could provide fast state feedback directly to the adjacent central pattern generator circuits, contributing to birds’ running robustness. A biophysical simulation framework is established, which provides new perspectives on the sensing mechanics of the system, including the influence of morphologies and material properties. Giving an overview of the hierarchical control architecture, this thesis investigates the fast sensing and actuation mechanisms in several control layers, including the low-level mechanical response and the mid-level intraspinal controllers. The contributions of this work provide new insight into animal loco-motion robustness and lays the foundation for future legged robot design

    (b2023 to 2014) The UNBELIEVABLE similarities between the ideas of some people (2006-2016) and my ideas (2002-2008) in physics (quantum mechanics, cosmology), cognitive neuroscience, philosophy of mind, and philosophy (this manuscript would require a REVOLUTION in international academy environment!)

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    (b2023 to 2014) The UNBELIEVABLE similarities between the ideas of some people (2006-2016) and my ideas (2002-2008) in physics (quantum mechanics, cosmology), cognitive neuroscience, philosophy of mind, and philosophy (this manuscript would require a REVOLUTION in international academy environment!

    DEsignBench: Exploring and Benchmarking DALL-E 3 for Imagining Visual Design

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    We introduce DEsignBench, a text-to-image (T2I) generation benchmark tailored for visual design scenarios. Recent T2I models like DALL-E 3 and others, have demonstrated remarkable capabilities in generating photorealistic images that align closely with textual inputs. While the allure of creating visually captivating images is undeniable, our emphasis extends beyond mere aesthetic pleasure. We aim to investigate the potential of using these powerful models in authentic design contexts. In pursuit of this goal, we develop DEsignBench, which incorporates test samples designed to assess T2I models on both "design technical capability" and "design application scenario." Each of these two dimensions is supported by a diverse set of specific design categories. We explore DALL-E 3 together with other leading T2I models on DEsignBench, resulting in a comprehensive visual gallery for side-by-side comparisons. For DEsignBench benchmarking, we perform human evaluations on generated images in DEsignBench gallery, against the criteria of image-text alignment, visual aesthetic, and design creativity. Our evaluation also considers other specialized design capabilities, including text rendering, layout composition, color harmony, 3D design, and medium style. In addition to human evaluations, we introduce the first automatic image generation evaluator powered by GPT-4V. This evaluator provides ratings that align well with human judgments, while being easily replicable and cost-efficient. A high-resolution version is available at https://github.com/design-bench/design-bench.github.io/raw/main/designbench.pdf?download=Comment: Project page at https://design-bench.github.io

    A Pendulum-Driven Legless Rolling Jumping Robot

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    In this paper, we present a novel rolling, jumping robot. The robot consists of a driven pendulum mounted to a wheel in a compact, lightweight, 3D printed design. We show that by driving the pendulum to shift the robot's weight distribution, the robot is able to obtain significant rolling speed, achieve jumps of up to 2.5 body lengths vertically, and clear horizontal distances of over 6 body lengths. The robot's dynamic model is derived and simulation results indicate that it is consistent with the rolling motion and jumping observed on the robot. The ability to both roll and jump effectively using a minimalistic design makes this robot unique and could inspire the use of similar mechanisms on robots intended for applications in which agile locomotion on unstructured terrain is necessary, such as disaster response or planetary exploration.Comment: Final version of paper in IROS 2023. View the supplemental video at https://youtu.be/9hKQilCpea

    From template to anchors: transfer of virtual pendulum posture control balance template to adaptive neuromuscular gait model increases walking stability

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    Biomechanical models with different levels of complexity are of advantage to understand the underlying principles of legged locomotion. Following a minimalistic approach of gradually increasing model complexity based on Template & Anchor concept, in this paper, a spring-loaded inverted pendulumbased walking model is extended by a rigid trunk, hip muscles and reflex control, called nmF (neuromuscular force modulated compliant hip) model. Our control strategy includes leg force feedback to activate hip muscles (originated from the FMCH approach), and a discrete linear quadratic regulator for adapting muscle reflexes. The nmF model demonstrates human-like walking kinematic and dynamic features such as the virtual pendulum (VP) concept, inherited from the FMCH model. Moreover, the robustness against postural perturbations is two times higher in the nmF model compared to the FMCH model and even further increased in the adaptive nmF model. This is due to the intrinsic muscle dynamics and the tuning of the reflex gains. With this, we demonstrate, for the first time, the evolution of mechanical template models (e.g. VP concept) to a more physiological level (nmF model). This shows that the template model can be successfully used to design and control robust locomotor systems with more realistic system behaviours

    Collected Papers (on Physics, Artificial Intelligence, Health Issues, Decision Making, Economics, Statistics), Volume XI

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    This eleventh volume of Collected Papers includes 90 papers comprising 988 pages on Physics, Artificial Intelligence, Health Issues, Decision Making, Economics, Statistics, written between 2001-2022 by the author alone or in collaboration with the following 84 co-authors (alphabetically ordered) from 19 countries: Abhijit Saha, Abu Sufian, Jack Allen, Shahbaz Ali, Ali Safaa Sadiq, Aliya Fahmi, Atiqa Fakhar, Atiqa Firdous, Sukanto Bhattacharya, Robert N. Boyd, Victor Chang, Victor Christianto, V. Christy, Dao The Son, Debjit Dutta, Azeddine Elhassouny, Fazal Ghani, Fazli Amin, Anirudha Ghosha, Nasruddin Hassan, Hoang Viet Long, Jhulaneswar Baidya, Jin Kim, Jun Ye, Darjan Karabašević, Vasilios N. Katsikis, Ieva Meidutė-Kavaliauskienė, F. Kaymarm, Nour Eldeen M. Khalifa, Madad Khan, Qaisar Khan, M. Khoshnevisan, Kifayat Ullah,, Volodymyr Krasnoholovets, Mukesh Kumar, Le Hoang Son, Luong Thi Hong Lan, Tahir Mahmood, Mahmoud Ismail, Mohamed Abdel-Basset, Siti Nurul Fitriah Mohamad, Mohamed Loey, Mai Mohamed, K. Mohana, Kalyan Mondal, Muhammad Gulfam, Muhammad Khalid Mahmood, Muhammad Jamil, Muhammad Yaqub Khan, Muhammad Riaz, Nguyen Dinh Hoa, Cu Nguyen Giap, Nguyen Tho Thong, Peide Liu, Pham Huy Thong, Gabrijela Popović‬‬‬‬‬‬‬‬‬‬, Surapati Pramanik, Dmitri Rabounski, Roslan Hasni, Rumi Roy, Tapan Kumar Roy, Said Broumi, Saleem Abdullah, Muzafer Saračević, Ganeshsree Selvachandran, Shariful Alam, Shyamal Dalapati, Housila P. Singh, R. Singh, Rajesh Singh, Predrag S. Stanimirović, Kasan Susilo, Dragiša Stanujkić, Alexandra Şandru, Ovidiu Ilie Şandru, Zenonas Turskis, Yunita Umniyati, Alptekin Ulutaș, Maikel Yelandi Leyva Vázquez, Binyamin Yusoff, Edmundas Kazimieras Zavadskas, Zhao Loon Wang.‬‬‬

    Reward - based advertisement in online games: a win for advertisers, developers, and gamers

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    This study examines factors affecting gamers’ attitude towards reward-based advertisements (RBA) in online games. A conceptual model is developed based on the Ducoffe’s web advertising model and tested using a quantitative design through data collected from 532 online gamers in Fiji. Covariance-based structural equation modelling (CB-SEM) was employed to perform the analysis. Results reveal that informativeness, credibility, entertainment, and incentive positively influence advertisement value. Advertisement value was found to positively influences attitude towards RBA. The moderating factors of perceived competitiveness and gamer envy were found to strengthen the positive association between perceived advertisement value and attitude towards RBA. This study is novel is it is the first exploration of RBA in online gaming. In so doing, this study contributes to both marketing and gaming literature and provides valuable insight for marketers and game developers to influence customers to be more receptive to advertisements in online games

    Studies of the membrane influenza A/M2 protein with aminoadamantane drugs using experimental and computational biophysics

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    Chapter 1 refers to the description of the basic features for influenza A virus replication, with emphasis on the function of influenza A M2. In Chapter 2, is described the structure of influenza A matrix 2 (M2) wild type (WT) proton protein channel, which is an archetypal ion channel. It is the target of the antiviral drugs amantadine and rimantadine. A number of methods were used to understand structural and functional features of this channel included neutron diffraction, electrophysiology, solution NMR spectroscopy, solid state NMR (ssNMR) spectroscopy, X-ray crystallography etc during an adventure of three decades with a lot of controversies. The experimental structure of influenza A M2(22-46) transmembrane domain (M2TM), the pore of the M2 protein channel, was solved in 2000 and X-ray structures of its complexes with amantadine, rimantadine etc were published by 2018. Till now basic characteristics of the influenza A M2 conductance domain (CD) protein M2CD or M2AH including M2TM and the amphipathic helices (46-62) have been also solved using ssNMR.The basic features of the experimental biophysical methods used in this PhD thesis, i.e. Differential Scanning Calorimetry (DSC), X-ray scattering at small and wide angles (SAXS/WAXS) and ssNMR are discussed in Chapter 3. Aminoadamantane drugs, e.g. amantadine and rimantadine, are lipophilic amines that bind to membrane embedded influenza A WT M2 protein. In Chapter 4, are investigated the comparative perturbation effects exerted by the influenza M2 WT protein inhibitors amantadine and it’s spiro[pyrrolidine-2,2'-adamantane] variant AK13 to membrane bilayers using biophysical methods and molecular dynamics (MD) simulations. This is a work performed in close collaboration with Professor’s Thomas Mavromoustakos and Professor’s Costas Demetzos groups as well as Dr Barbara Sartori and Professor Heinz Amenitsch. The experimental biophysical methods used included, DSC, X-ray scattering and ssNMR. All three experimental methods pointed out that the two analogs perturbed drastically the DMPC bilayers with AK13 to be more effective at high concentrations. At high ligand concentrations AK13 was tolerated in lipid bilayers while Amt was crystallized. This is an important consideration in possible formulations of these drugs as it designates a limitation of aminoadamantane drug incorporation. MD simulations provided details about the strong interactions of the drugs in the interface region between glycerol backbone and lipophilic segments. The two drugs form hydrogen bonding with both water and sn-2 carbonyls or phosphate oxygens. Such localization of the drugs explains their strong perturbing effect evidenced by all biophysical methodologies applied.In Chapter 5, is described our work to investigate the interactions of M2TM WT with bilayers. This is a work performed in close collaboration with Professor Thomas Mavromoustakos, Professor Costas Demetzos, groups as well as Dr Barbara Sartori and Professor Heinz Amenitsch. The M2TM peptide was synthesized by Professor Thedoros Tselios group. We focused on (a) the characterization of changes in bilayer organization from changes in micromolar concentrations of M2TM WT without or with aminoadamantane (Aamt) ligands, and from changes in Aamt ligand structure included with M2TM, (b) exploring how common biophysical methods can be applied to identify the membrane perturbations effected by the protein without or with the ligand.A variety of biophysical methods, including DSC, SAXS/WAXS, MD simulations, and one-dimension (1D) ssNMR, were used to study two micromolar concentrations of M2TM without or with a small excess of amantadine or its spiro-pyrrolidine analogue, AK13, in DMPC bilayers.DSC and SAXS showed that at a low micromolar M2TM concentration, two lipid domains are observed, which likely correspond to M2TM boundary lipids and bulk lipids. At a higher M2TM concentration, only one domain is identified, indicating that all of the lipids behave as boundary lipids. 1H and 31P ssNMR showed that M2TM in either apo or drug-bound form spans the membrane, interacting strongly with lipid acyl chain-tails and the phosphate groups of the polar head surface. The 13C ssNMR experiments allowed the inspection of excess drug molecules and the assessment of their impact on the lipid head group region.According to SAXS, WAXS, and DSC, in the absence of M2TM both aminoadamantane drugs exert a similar perturbing effect on the bilayer at low concentrations, i.e., mole fractions (relative to lipid) of x=0.05-0.08. At the same concentrations of the drug when M2TM is present, the amantadine and, to a lesser extent, AK13 cause a significant disordering of chain-stacking. This different effect between the two drugs is likely due, according to the MD simulations, to the preference of the excess of the more lipophilic AK13 to locate closer to M2TM. In contrast, amantadine perturbs the lipids through the stronger ionic interactions of its ammonium group with phosphate groups (compared with the buried ammonium group in AK13) and influences the formation of two lipid domains. The preference of AK13 to concentrate inside the lipid may contribute to its six-fold higher binding affinity (compared to amantadine) if drug binding occurs from the lipid by way of a path between the transmembrane helices.The results showed that DSC and SAXS are useful methods to detect changes in membrane organization caused by small changes in M2TM or aminoadamantane drug concentration and structure and that WAXS and MD simulations can suggest details of ligand topology. Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a ligand-based only approach is often viewed as insufficient to achieve high affinity and specificity. In Chapter 6, are showed that small molecules, i.e. amantadine and rimantadine, can enable potent inhibition by targeting key waters using as example the M2 WT proton channel of influenza A which is the target of the antiviral drugs amantadine and rimantadine. This is a work performed in close collaboration with Professor William DeGrado and Associate Professor Jun Wang groups. Structural studies of drug binding to the channel using X-ray crystallography have been limited due to the challenging nature of the target, with the first crystal structure solved in 2008 limited to 3.5 Å resolution. We described crystal structures of amantadine bound to M2 in the Inwardclosed conformation (2.00 Å), rimantadine bound to M2 in both the Inwardclosed (2.00 Å) and Inwardopen (2.25 Å) conformations, and a spiro-adamantyl amine inhibitor bound to M2 in the Inwardclosed conformation (2.63 Å). These X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that ammonium groups bind to water-lined sites, formed by two layers of waters close to Ala30 and Gly34, respectively, observed in the X-ray structures, that are hypothesized to stabilize transient hydronium ions formed in the proton-conduction mechanism. Furthermore, the ammonium and adamantyl groups of the adamantyl-amine class of drugs are free to rotate in the channel, minimizing the entropic cost of binding. The MD simulation reproduced perfectly the X-ray structures of cautiously tuned. These drug-bound complexes provide the first high-resolution structures of drugs that interact with and disrupt networks of hydrogen-bonded waters that are widely utilized throughout nature to facilitate proton diffusion within proteins.The V27A mutation confers amantadine resistance to the influenza A M2 WT proton channel and is becoming more prevalent in circulating populations of influenza A virus. In Chapter 7, is described our collaborative work with DeGrado and Wang groups to solve M2TM V27A structure in complex with a spiro-adamantyl amine inhibitor bound to M2(22-46) V27A and also to M2(21-61) V27A in the Inwardclosed conformation using X-ray crystallography and MD simulations. The spiro-adamantyl amine binding site is nearly identical for the two crystal structures. Compared to the M2 WT with valine at position 27, we observed that the channel pore is wider at its N-terminus as a result of the V27A mutation and that this removes V27 side chain hydrophobic interactions that are important for binding of amantadine and rimantadine. The spiro-adamantyl amine inhibitor blocks proton conductance in both the WT and V27A mutant channels by shifting its binding site in the pore depending on which residue is present at position 27. Additionally, in the structure of the M2(21-61) V27A construct, the C-terminus of the channel is tightly packed relative to the M2(22-46) construct. We observed that residues Asp44, Arg45, and Phe48 face the center of the channel pore and would be well-positioned to interact with protons exiting the M2 channel after passing through the His37 gate. However, the orientation of AHs after residue 48 did not reproduce the almost vertical orientation as regards the M2TM, that found by Professor Tim Cross experimentally with ssNMR experiments. The MD simulations of the M2(22-46) V27A - spiro-adamantyl amine complex predicted with accuracy the position of the ligands and waters inside the pore in the X-ray crystal structure of the M2 V27A complex.The influenza A M2 wild type proton channel is the target of the anti-influenza drug rimantadine. Rimantadine has two enantiomers, though most investigations into drug binding and inhibition have used a racemic mixture. ssNMR experiments by Professor Tim Cross have shown significant spectral differences that were interpreted to indicate tighter binding for (R)- vs. (S)- rimantadine. However, it was unclear if this is due to the specific condition of the ssNMR experiments (i.e. close to 0 oC), correlates with a functional difference in drug binding and inhibition and we undertook to investigate this in collaboration with Professor DeGrado, Associate Professor Jun Wang and Professor Jon Essex. Thus, in Chapter 8, using X-ray crystallography, we have determined that both (R)- and (S)-rimantadine bind to the M2 pore with slight differences in the hydration of each enantiomer. However, this did not result in a difference in potency or binding kinetics, as we measured similar values for kon, koff, and Kd in electrophysiological assays and EC50 values in cellular assays. We concluded that the slight differences in hydration we observed in the X-ray structures for the (R)- and (S)-rimantadine enantiomers were not relevant to drug binding or channel inhibition. To further explore the effect of the hydration of the M2 pore on binding affinity, the water structure was evaluated by waters titration calculations Grand Canonical Monte Carlo simulations as a function of the chemical potential of the water. Initially, the two layers of ordered water molecules between the bound drug and the channel's gating His37 residues mask the drug’s chirality. As the chemical potential becomes more unfavorable and the waters from the two layers were removed from the M2 pore, the drug translocated down to the lower water layer, towards the His37 at the C-terminus of M2TM, and the interaction becomes more sensitive to chirality. These studies suggested the feasibility of displacing the upper water layer (toward the N-end close to Ala30) and specifically recognizing the lower water layers by novel chiral drugs.Chapter 1 refers to the description of the basic features for influenza A virus replication, with emphasis on the function of influenza A M2. In Chapter 2, is described the structure of influenza A matrix 2 (M2) wild type (WT) proton protein channel, which is an archetypal ion channel. It is the target of the antiviral drugs amantadine and rimantadine. A number of methods were used to understand structural and functional features of this channel included neutron diffraction, electrophysiology, solution NMR spectroscopy, solid state NMR (ssNMR) spectroscopy, X-ray crystallography etc during an adventure of three decades with a lot of controversies. The experimental structure of influenza A M2(22-46) transmembrane domain (M2TM), the pore of the M2 protein channel, was solved in 2000 and X-ray structures of its complexes with amantadine, rimantadine etc were published by 2018. Till now basic characteristics of the influenza A M2 conductance domain (CD) protein M2CD or M2AH including M2TM and the amphipathic helices (46-62) have been also solved using ssNMR.The basic features of the experimental biophysical methods used in this PhD thesis, i.e. Differential Scanning Calorimetry (DSC), X-ray scattering at small and wide angles (SAXS/WAXS) and ssNMR are discussed in Chapter 3. Aminoadamantane drugs, e.g. amantadine and rimantadine, are lipophilic amines that bind to membrane embedded influenza A WT M2 protein. In Chapter 4, are investigated the comparative perturbation effects exerted by the influenza M2 WT protein inhibitors amantadine and it’s spiro[pyrrolidine-2,2'-adamantane] variant AK13 to membrane bilayers using biophysical methods and molecular dynamics (MD) simulations. This is a work performed in close collaboration with Professor’s Thomas Mavromoustakos and Professor’s Costas Demetzos groups as well as Dr Barbara Sartori and Professor Heinz Amenitsch. The experimental biophysical methods used included, DSC, X-ray scattering and ssNMR. All three experimental methods pointed out that the two analogs perturbed drastically the DMPC bilayers with AK13 to be more effective at high concentrations. At high ligand concentrations AK13 was tolerated in lipid bilayers while Amt was crystallized. This is an important consideration in possible formulations of these drugs as it designates a limitation of aminoadamantane drug incorporation. MD simulations provided details about the strong interactions of the drugs in the interface region between glycerol backbone and lipophilic segments. The two drugs form hydrogen bonding with both water and sn-2 carbonyls or phosphate oxygens. Such localization of the drugs explains their strong perturbing effect evidenced by all biophysical methodologies applied.In Chapter 5, is described our work to investigate the interactions of M2TM WT with bilayers. This is a work performed in close collaboration with Professor Thomas Mavromoustakos, Professor Costas Demetzos, groups as well as Dr Barbara Sartori and Professor Heinz Amenitsch. The M2TM peptide was synthesized by Professor Thedoros Tselios group. We focused on (a) the characterization of changes in bilayer organization from changes in micromolar concentrations of M2TM WT without or with aminoadamantane (Aamt) ligands, and from changes in Aamt ligand structure included with M2TM, (b) exploring how common biophysical methods can be applied to identify the membrane perturbations effected by the protein without or with the ligand.A variety of biophysical methods, including DSC, SAXS/WAXS, MD simulations, and one-dimension (1D) ssNMR, were used to study two micromolar concentrations of M2TM without or with a small excess of amantadine or its spiro-pyrrolidine analogue, AK13, in DMPC bilayers.DSC and SAXS showed that at a low micromolar M2TM concentration, two lipid domains are observed, which likely correspond to M2TM boundary lipids and bulk lipids. At a higher M2TM concentration, only one domain is identified, indicating that all of the lipids behave as boundary lipids. 1H and 31P ssNMR showed that M2TM in either apo or drug-bound form spans the membrane, interacting strongly with lipid acyl chain-tails and the phosphate groups of the polar head surface. The 13C ssNMR experiments allowed the inspection of excess drug molecules and the assessment of their impact on the lipid head group region.According to SAXS, WAXS, and DSC, in the absence of M2TM both aminoadamantane drugs exert a similar perturbing effect on the bilayer at low concentrations, i.e., mole fractions (relative to lipid) of x=0.05-0.08. At the same concentrations of the drug when M2TM is present, the amantadine and, to a lesser extent, AK13 cause a significant disordering of chain-stacking. This different effect between the two drugs is likely due, according to the MD simulations, to the preference of the excess of the more lipophilic AK13 to locate closer to M2TM. In contrast, amantadine perturbs the lipids through the stronger ionic interactions of its ammonium group with phosphate groups (compared with the buried ammonium group in AK13) and influences the formation of two lipid domains. The preference of AK13 to concentrate inside the lipid may contribute to its six-fold higher binding affinity (compared to amantadine) if drug binding occurs from the lipid by way of a path between the transmembrane helices.The results showed that DSC and SAXS are useful methods to detect changes in membrane organization caused by small changes in M2TM or aminoadamantane drug concentration and structure and that WAXS and MD simulations can suggest details of ligand topology. Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a ligand-based only approach is often viewed as insufficient to achieve high affinity and specificity. In Chapter 6, are showed that small molecules, i.e. amantadine and rimantadine, can enable potent inhibition by targeting key waters using as example the M2 WT proton channel of influenza A which is the target of the antiviral drugs amantadine and rimantadine. This is a work performed in close collaboration with Professor William DeGrado and Associate Professor Jun Wang groups. Structural studies of drug binding to the channel using X-ray crystallography have been limited due to the challenging nature of the target, with the first crystal structure solved in 2008 limited to 3.5 Å resolution. We described crystal structures of amantadine bound to M2 in the Inwardclosed conformation (2.00 Å), rimantadine bound to M2 in both the Inwardclosed (2.00 Å) and Inwardopen (2.25 Å) conformations, and a spiro-adamantyl amine inhibitor bound to M2 in the Inwardclosed conformation (2.63 Å). These X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that ammonium groups bind to water-lined sites, formed by two layers of waters close to Ala30 and Gly34, respectively, observed in the X-ray structures, that are hypothesized to stabilize transient hydronium ions formed in the proton-conduction mechanism. Furthermore, the ammonium and adamantyl groups of the adamantyl-amine class of drugs are free to rotate in the channel, minimizing the entropic cost of binding. The MD simulation reproduced perfectly the X-ray structures of cautiously tuned. These drug-bound complexes provide the first high-resolution structures of drugs that interact with and disrupt networks of hydrogen-bonded waters that are widely utilized throughout nature to facilitate proton diffusion within proteins.The V27A mutation confers amantadine resistance to the influenza A M2 WT proton channel and is becoming more prevalent in circulating populations of influenza A virus. In Chapter 7, is described our collaborative work with DeGrado and Wang groups to solve M2TM V27A structure in complex with a spiro-adamantyl amine inhibitor bound to M2(22-46) V27A and also to M2(21-61) V27A in the Inwardclosed conformation using X-ray crystallography and MD simulations. The spiro-adamantyl amine binding site is nearly identical for the two crystal structures. Compared to the M2 WT with valine at position 27, we observed that the channel pore is wider at its N-terminus as a result of the V27A mutation and that this removes V27 side chain hydrophobic interactions that are important for binding of amantadine and rimantadine. The spiro-adamantyl amine inhibitor blocks proton conductance in both the WT and V27A mutant channels by shifting its binding site in the pore depending on which residue is present at position 27. Additionally, in the structure of the M2(21-61) V27A construct, the C-terminus of the channel is tightly packed relative to the M2(22-46) construct. We observed that residues Asp44, Arg45, and Phe48 face the center of the channel pore and would be well-positioned to interact with protons exiting the M2 channel after passing through the His37 gate. However, the orientation of AHs after residue 48 did not reproduce the almost vertical orientation as regards the M2TM, that found by Professor Tim Cross experimentally with ssNMR experiments. The MD simulations of the M2(22-46) V27A - spiro-adamantyl amine complex predicted with accuracy the position of the ligands and waters inside the pore in the X-ray crystal structure of the M2 V27A complex.The influenza A M2 wild type proton channel is the target of the anti-influenza drug rimantadine. Rimantadine has two enantiomers, though most investigations into drug binding and inhibition have used a racemic mixture. ssNMR experiments by Professor Tim Cross have shown significant spectral differences that were interpreted to indicate tighter binding for (R)- vs. (S)- rimantadine. However, it was unclear if this is due to the specific condition of the ssNMR experiments (i.e. close to 0 oC), correlates with a functional difference in drug binding and inhibition and we undertook to investigate this in collaboration with Professor DeGrado, Associate Professor Jun Wang and Professor Jon Essex. Thus, in Chapter 8, using X-ray crystallography, we have determined that both (R)- and (S)-rimantadine bind to the M2 pore with slight differences in the hydration of each enantiomer. However, this did not result in a difference in potency or binding kinetics, as we measured similar values for kon, koff, and Kd in electrophysiological assays and EC50 values in cellular assays. We concluded that the slight differences in hyd

    Gaming and luxury fashion: exploring factors driving gamers’ luxury virtual in - game fashion

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    This study investigates the factors driving gamers’ intention to purchase virtual luxury fashion in online games. The study’s conceptual framework is grounded in the social identity and social capital theory. A total of 468 responses were collected using an online survey from Fortnite players and analyzed using covariance-based structural equation modelling (CB-SEM). The results reveal that avatar identification was positively associated with perceived value, social presence, and intention to purchase virtual luxury fashion. Perceived value and social presence were positively associated with intending to purchase virtual luxury fashion. Brand love strengthened the positive association between the perceived value and social presence on the intention to purchase virtual luxury fashion. This study contributes to the marketing and information systems literature by offering the first insights into virtual luxury fashion in online games. The findings would assist game developers and marketers in better understanding gamer behaviour to capitalize on virtual luxury fashion
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