Skin capillary extraction technique based on independent component analysis and Frangi filter using videomicroscopy.

BACKGROUND: Videomicroscopy can be used to observe skin capillaries easily and non-invasively. In this study, we develop an algorithm that can handle skin regions by combining color component separation methods as pre-processing based on blood vessel extraction filtering. MATERIALS AND METHODS: Images of skin on the inner upper arm were acquired using videomicroscopy. An algorithm using independent component analysis (ICA) and the Frangi filter was constructed, and capillary regions were extracted. The capillary blood vessel extraction images were compared with ground truth to verify accuracy. An evaluation of the physiological responses of skin exposed to carbon dioxide (CO2 ) water, local heating, and methyl nicotinate was performed to test blood vessels with different mechanisms of action and layer depth. RESULTS: Based on a comparison with ground truth images, a Dice coefficient of 0.82 was calculated. In examining physiological responses to stimuli on the skin, it was found that exposure to CO2 for 2 minutes significantly increased the capillary area compared with the steady state. CONCLUSION: An algorithm to extract capillaries from skin images using ICA and the Frangi filter method was proposed. Results suggest that this algorithm can quantitatively analyze physiological changes in capillaries on the skin surface.

Proposal and Evaluation of Visual Haptics for Manipulation of Remote Machine System.

Remote machine systems have drawn a lot of attention owing to accelerations of virtual reality (VR), augmented reality (AR), and the fifth generation (5G) networks. Despite recent trends of developing autonomous systems, the realization of sophisticated dexterous hand that can fully replace human hands is considered to be decades away. It is also extremely difficult to reproduce the sensilla of complex human hands. On the other hand, it is known that humans can perceive haptic information from visual information even without any physical feedback as cross modal sensation between visual and haptics sensations or pseudo haptics. In this paper, we propose a visual haptic technology, where haptic information is visualized in more perceptual images overlaid at the contact points of a remote machine hand. The usability of the proposed visual haptics was evaluated by subject's brain waves aiming to find out a new approach for quantifying "sense of oneness." In our proof-of-concept experiments using VR, subjects are asked to operate a virtual arm and hand presented in the VR space, and the performance of the operation with and without visual haptics information as measured with brain wave sensing. Consequently, three results were verified. Firstly, the information flow in the brain were significantly reduced with the proposed visual haptics for the whole α, ß, and θ-waves by 45% across nine subjects. This result suggests that superimposing visual effects may be able to reduce the cognitive burden on the operator during the manipulation for the remote machine system. Secondly, high correlation (Pearson correlation factor of 0.795 at a p-value of 0.011) was verified between the subjective usability points and the brainwave measurement results. Finally, the number of the task successes across sessions were improved in the presence of overlaid visual stimulus. It implies that the visual haptics image could also facilitate operators' pre-training to get skillful at manipulating the remote machine interface more quickly.

Discovery of novel 5-oxa-2,6-diazaspiro[3.4]oct-6-ene derivatives as potent, selective, and orally available somatostatin receptor subtype 5 (SSTR5) antagonists for treatment of type 2 diabetes mellitus.

Somatostatin receptor subtype 5 (SSTR5) has emerged as a novel attractive drug target for type 2 diabetes mellitus. Starting from N-benzyl azetidine derivatives 1 and 2 as in-house hit compounds, we explored the introduction of a carboxyl group into the terminal benzene of 1 to enhance SSTR5 antagonistic activity by the combination of the substituents at the 3-position of the isoxazoline. Incorporation of a carboxyl group at the 4-position of the benzene ring resulted in a significant enhancement in potency, however, the 4-benzoic acid derivative 10c exhibited moderate human ether-a-go-go related gene (hERG) inhibitory activity. A subsequent optimization study revealed that replacement of the 4-benzoic acid with an isonipecotic acid dramatically reduced hERG inhibition (5.6% inhibition at 30µM) by eliminating π-related interaction with hERG K+ channel, which resulted in the identification of 1-(2-((2,6-diethoxy-4'-fluorobiphenyl-4-yl)methyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)piperidin-4-carboxylic acid 25a (hSSTR5/mSSTR5 IC50=9.6/57nM). Oral administration of 25a in high-fat diet fed C57BL/6J mice augmented insulin secretion in a glucose-dependent manner and lowered blood glucose concentration.

A motivation model for interaction between parent and child based on the need for relatedness.

In parent-child communication, emotions are evoked by various types of intrinsic and extrinsic motivation. Those emotions encourage actions that promote more interactions. We present a motivation model of infant-caregiver interactions, in which relatedness, one of the most important basic psychological needs, is a variable that increases with experiences of emotion sharing. Besides being an important factor of pleasure, relatedness is a meta-factor that affects other factors such as stress and emotional mirroring. The proposed model is implemented in an artificial agent equipped with a system to recognize gestures and facial expressions. The baby-like agent successfully interacts with an actual human and adversely reacts when the caregiver suddenly ceases facial expressions, similar to the "still-face paradigm" demonstrated by infants in psychological experiments. In the simulation experiment, two agents, each controlled by the proposed motivation model, show relatedness-dependent emotional communication that mimics actual human communication.

Discovery of a novel acyl-CoA: cholesterol acyltransferase inhibitor: the synthesis, biological evaluation, and reduced adrenal toxicity of (4-phenylcoumarin)acetanilide derivatives with a carboxylic acid moiety.

As a part of our research for novel potent and orally available acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors that can be used as anti-atherosclerotic agents, we recently reported the discovery of the (4-phenylcoumarine)acetanilide derivative 1. However, compound 1 showed adrenal toxicity in animal models. In order to search for safer ACAT inhibitors that do not have adrenal toxicity, we examined the inhibitory activity of ACAT in human macrophage and adrenal cells. The introduction of a carboxylic acid moiety on the pendant phenyl ring and the adjustment of the lipophilicity led to the discovery of (2E)-3-[7-chloro-3-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]acrylic acid (21e), which showed potent ACAT inhibitory activity in macrophages and a selectivity of around 30-fold over adrenal cells. In addition, compound 21e showed high adrenal safety in guinea pigs.

Discovery of a potent and orally available acyl-CoA: cholesterol acyltransferase inhibitor as an anti-atherosclerotic agent: (4-phenylcoumarin)acetanilide derivatives.

Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure-activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).

Novel acyl coenzyme A: diacylglycerol acyltransferase 1 inhibitors-synthesis and biological activities of N-(substituted heteroaryl)-4-(substituted phenyl)-4-oxobutanamides.

In a program to discover new small molecule diacylglycerol acyltransferase (DGAT)-1 inhibitors, screening of our in-house chemical library was carried out using recombinant human DGAT-1 enzyme. From this library, the lead compound 1a was identified as a new class of DGAT-1 inhibitor. A series of novel N-(substituted heteroaryl)-4-(substituted phenyl)-4-oxobutanamides 2 was designed from 1a, synthesized and evaluated for inhibitory activity against DGAT-1 enzyme. Among these compounds, N-(5-benzyl-4-phenyl-1,3-thiazol-2-yl)-4-(4,5-diethoxy-2-methylphenyl)-4-oxobutanamide 9 was found to exhibit potent inhibitory activity and good enzyme selectivities. Following administration in KKA(y) mice with 3 mg/kg high fat diet admixture for four weeks, 9 reduced body weight gain and white adipose tissue weight without affecting total food intake. These results suggested that the small molecule DGAT-1 inhibitor might have potential in the treatment of obesity and metabolic syndrome.

Coenzyme A: diacylglycerol acyltransferase 1 inhibitor ameliorates obesity, liver steatosis, and lipid metabolism abnormality in KKAy mice fed high-fat or high-carbohydrate diets.

Coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of the 2 known DGAT enzymes that catalyze the final and only committed step in triacylglycerol synthesis; this enzyme is considered to be a potential therapeutic target in metabolic disorders such as obesity and its related lipid abnormalities. Compound-Z, a novel specific small-molecule DGAT1 inhibitor, significantly reduced adipose tissue weight and tended to hepatic lipid accumulation in genetically obese KKAy mice. These actions were shown to almost the same extent in both a high-fat feeding condition in which triacylglycerols are synthesized mainly via exogenous fatty acid and a low-fat, high-carbohydrate feeding condition in which triacylglycerols are synthesized mainly via de novo fatty acid synthesis. This inhibitor also significantly reduced plasma and/or hepatic cholesterol levels in KKAy mice in a high-fat feeding condition. This cholesterol-lowering effect was suggested to be due to mainly decreases in cholesterol absorption from the small intestine. These results suggest that Compound-Z is a promising and attractive agent not only for the treatment of obesity but also hepatic steatosis and circulating lipid abnormalities that are the leading causes of atherosclerosis.