Development of an impulsive motion generator inspired by cocking slip joint of snapping shrimp.

We propose an impulsive motion generator inspired by snapping shrimp. The proposed device mimics the geometrical arrangement of a unique claw joint calledcocking slip jointand integrates it with an artificial rack-pinion actuator mechanism rather than adopting the musculoskeletal system as it is. The design approach allows the proposed device to reproduce the impulsive slip motion through the torque reversal and unlatching mechanism of the underlying unique joint by using a single servo motor. Static and dynamic analyses revealed that the actuator force required to store and release elastic energy was remarkably small compared with the resulting acceleration force and rotation/tip speed. Through simulations and experiments, we validated the mechanical analyses and confirmed that the resulting ultrafast slip motion was comparable with the claw closure of snapping shrimp based on the cocking slip joint. Moreover, from an engineering perspective, the motion profiles are modifiable through design parameters, and the repeatability of the impulsive slip motion is satisfactory.

Detailed Analysis of the Binding Mode of Vanilloids to Transient Receptor Potential Vanilloid Type I (TRPV1) by a Mutational and Computational Study.

Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel and a multimodal sensor protein. Since the precise structure of TRPV1 was obtained by electron cryo-microscopy, the binding mode of representative agonists such as capsaicin and resiniferatoxin (RTX) has been extensively characterized; however, detailed information on the binding mode of other vanilloids remains lacking. In this study, mutational analysis of human TRPV1 was performed, and four agonists (capsaicin, RTX, [6]-shogaol and [6]-gingerol) were used to identify amino acid residues involved in ligand binding and/or modulation of proton sensitivity. The detailed binding mode of each ligand was then simulated by computational analysis. As a result, three amino acids (L518, F591 and L670) were newly identified as being involved in ligand binding and/or modulation of proton sensitivity. In addition, in silico docking simulation and a subsequent mutational study suggested that [6]-gingerol might bind to and activate TRPV1 in a unique manner. These results provide novel insights into the binding mode of various vanilloids to the channel and will be helpful in developing a TRPV1 modulator.

Energy evaluation of a bio-inspired gait modulation method for quadrupedal locomotion.

We have proposed a bio-inspired gait modulation method, by means of which a simulated quadruped model can successfully perform smooth, autonomous gait transitions from a walk to a trot to a gallop, as observed in animals. The model is equipped with a rhythm generator called a central pattern generator (CPG) for each leg. The lateral neighbouring CPGs are mutually and inhibitorily coupled, and the CPG network is hardwired to produce a trot. Adding only the simple feedback of body tilt to each CPG, which was based on input from the postural reflex, led to the emergence of un-programmed walking and galloping at low and high speeds, respectively. Although this autonomous gait transition was a consequence of postural adaptation, it coincidentally also resulted in the minimization of energy consumption, as observed in real animals. In simulations at a variety of constant speeds the energy cost was lower for walking at low speeds and for galloping at high speeds than it was for trotting. Moreover, each gait transition occurred at the optimal speed, such that the model minimised its energy consumption. Thus, gait transitions in simulations that included the bio-inspired gait modulation method were similar to those observed in animals, even from the perspective of energy consumption. This method should therefore be a preferred choice for motion generation and control in biomimetic quadrupedal locomotion.

Clustering analysis of keishibukuryogan formulas by use of self-organizing maps.

Kampo medicines, traditional herbal medicines in Japan, are comprised of multiple botanical raw materials that contain a number of pharmacologically active substances. Conventionally, the quality control of kampo medicines has been performed by analyzing the contents of two or three representative components. However, it is not sufficient to check quality only with a limited number of specific components. We performed HPLC of 287 lots of keishibukuryogan formulas, calculated the areas of 11 components on chromatograms as feature values and made a cluster analysis using self-organizing maps (SOMs). We verified the precision (repeatability and intermediate precision) of clustering results when using the same samples and successfully established an clustering method using SOMs that is capable of precisely clustering differences in HPLC-fingerprints among pharmaceutical manufacturers, differences in HPLC-fingerprints due to the combination ratios of botanical raw materials, and differences in HPLC-fingerprints due to changes in component contents caused by time-course deterioration. Consequently, we could confirm that this method is useful for controlling the quality of multiple component drugs and analyzing quality differences.

Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors, derived from molecular modeling.

We previously reported a quinoxalin-2-one compound (Compound 1) that had inhibitory activity equivalent to existing platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors. Lead optimization of Compound 1 to increase its activity and selectivity, using structural information regarding PDGFbeta R-ligand interactions, is urgently needed. Here we present models of the PDGFbeta R kinase domain complexed with quinoxalin-2-one derivatives. The models were constructed using comparative modeling, molecular dynamics (MD) and ligand docking. In particular, conformations derived from MD, and ligand binding site information presented by alpha-spheres in the pre-docking processing, allowed us to identify optimal protein structures for docking of target ligands. By carrying out molecular modeling and MD of PDGFbeta R in its inactive state, we obtained two structural models having good Compound 1 binding potentials. In order to distinguish the optimal candidate, we evaluated the structural activity relationships (SAR) between the ligand-binding free energies and inhibitory activity values (IC50 values) for available quinoxalin-2-one derivatives. Consequently, a final model with a high SAR was identified. This model included a molecular interaction between the hydrophobic pocket behind the ATP binding site and the substitution region of the quinoxalin-2-one derivatives. These findings should prove useful in lead optimization of quinoxalin-2-one derivatives as PDGFb R inhibitors.

Potent platelet-derived growth factor-beta receptor (PDGF-betaR) inhibitors: Synthesis and structure-activity relationships of 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one derivatives.

We found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one (7d-6) has considerable potency as a PDGF inhibitor. This compound showed potent inhibitory activity in a PDGF-induced CPA (Cell Proliferation Assay) and APA (Auto-Phosphorylation Assay) (IC50 = 0.05 micromol/l in CPA, 0.03 micromol/l in APA). Therefore, we tried to develop a novel and effective PDGF-betaR inhibitor by optimizing a series of its derivatives. We found that trifluoroacetic acid (TFA)-catalyzed coupling of pyrrolo[2,3-b]pyridines with quinoxalin-2-ones proceeded efficiently under mild oxidation condition with manganese(IV) oxide (MnO2) in situ, so this method was applied to prepare a series of derivatives. Results of in vitro screening of newly synthesized derivatives identified compound 7d-9 as having potent (IC50 = 0.014 micromol/l in CPA, 0.007 micromol/l in APA) and selective [IC50 values against vascular endothelial growth factor receptor 2 (VEGFR2, kinase domain region, KDR), epidermal growth factor receptor (EGFR), c-Met (hepatocyte growth factor receptor) and insulin growth factor I receptor (IGF-IR)/IC50 against PDGFR were each >1000] inhibitory activity. Moreover, in this series of derivatives, 7b-2 showed potent inhibitory activity toward both PDGF- and VEGF-induced signaling (PDGFR: IC50 = 0.004 micromol/l in CPA, 0.0008 micromol/l in APA, KDR: IC50 = 0.008 micromol/l in APA). Herein we report a new and convenient synthetic method for this series of derivatives and its SAR study.

A practical synthesis of (+)-biotin from L-cysteine.

Alpha-amino aldehyde 4, which is readily derived from L-cysteine through cyclization and elaboration of the carboxy group, was subjected to the Strecker reaction, which, via sodium bisulfite adduct 16, afforded alpha-amino nitrile 5 with high diastereoselectivity (syn/anti=11:1) and in high yield. Amide 6, derived from 5, was converted to thiolactone 8, a key intermediate in the synthesis of (+)-biotin (1), by a novel S,N-carbonyl migration and cyclization reaction. The Fukuyama coupling reaction of 8 with the zinc reagent 21, which has an ester group, in the presence of a heterogeneous Pd/C catalyst allowed the efficient installation of the 4-carboxybutyl chain to provide 9. Compound 9 was hydrogenated and the protecting groups removed to furnish 1 in 10 steps and in 34 % overall yield from L-cysteine.

Pd(OH)2/C (Pearlman's catalyst): a highly active catalyst for Fukuyama, Sonogashira, and Suzuki coupling reactions.

Treatment of thiol esters 1 with zinc reagent 2 in the presence of a small amount (

A novel synthesis of (+)-biotin from L-cysteine.

(+)-Biotin (1) was synthesized in 25% overall yield over 11 steps from L-cysteine. The contiguous asymmetric centers at C-3a and C-6a were formed through a novel and highly stereoselective Lewis base-catalyzed cyanosilylation of alpha-amino aldehyde 3 to provide anti-O-TMS-cyanohydrin 4 with high stereoselectivity and in high yield (anti/syn = 92:8, 96%). Treatment of 4 with a di-Grignard reagent, 1,4-bis(bromomagnesio)butane, followed by carbon dioxide, efficiently installed the 4-carboxybutyl chain at C-4 to give keto acid 5. The final cyclization to bicyclic compound 7b, a precursor to 1, was realized by a palladium-catalyzed intramolecular allylic amination of cis-allylic carbonate 6b that was elaborated from 5.