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Colorectal adenoma is linked to metabolic dysfunction. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a precise definition and three subtypes, including non-obese MAFLD. We aimed to investigate the impact of MAFLD on the prevalence of colorectal adenoma by comparing it to non-alcoholic fatty liver disease (NAFLD) in health check-up examinees. This is a multicenter retrospective study. We enrolled 124 consecutive health check-up examinees who underwent colonoscopy. NAFLD and MAFLD were present in 58 and 63 examinees, respectively. Colorectal adenoma was diagnosed by biopsy. The impact of the MAFLD definition on the prevalence of colorectal adenoma was investigated by logistic regression, decision-tree, and random forest analyses. In logistic regression analysis, MAFLD was identified as the only independent factor associated with the presence of colorectal adenoma (OR 3.191, 95% CI 1.494–7.070, p = 0.003). MAFLD was also identified as the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (29 variable importance value). Among the three subtypes of MAFLD, non-obese MAFLD was the sole independent factor associated with the presence of colorectal adenoma (OR 3.351, 95% CI 1.589–7.262, p ≤ 0.001). Non-obese MAFLD was also the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (31 variable importance value). MAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.

Inducing oligodendrocyte progenitor cell (OPC) differentiation is a novel therapeutic strategy for the treatment of demyelinating diseases such as multiple sclerosis (MS). In the preceding article, we detailed the discovery of compound 1, a potent inducer of OPC differentiation possessing a characteristic spiroindoline structure. Also, we found that N-methylation and des-carbonyl compound 1 (4) led to a loss in potency. Herein, we describe our investigations of a conformation-based hypothesis for OPC differentiation activity based on the preferred conformation of the spiro core, and further structure-activity relationship (SAR) exploration led to the identification of 6-CF3 derivative 8, which was more potent compared to compound 1.

A novel series of spiroindoline derivatives was discovered for use as inducers of oligodendrocyte progenitor cell (OPC) differentiation, resulting from optimization of screening hit 1. Exploration of structure-activity relationships led to compound 18, which showed improved potency (rOPC EC50 = 0.0032 μM). Furthermore, oral administration of compound 18 significantly decreased clinical severity in an experimental autoimmune encephalomyelitis (EAE) model.

Previous data shows that colorectal serrated lesions are precursor of carcinogenesis. It has been advancing even molecular biological analysis, SSA/P become microsatellite instability (MSI) positive colon cancers and TSA become microsatellite stable (MSS) positive colon cancers. It is observed that redness and double elevation in conventional endoscopy, CP type II (Sano classification) in the NBI endoscopy, type III pit pattern in magnifying endoscopy, if SSA/P have cytological dysplastic change. Especially, if SSA/P have cancerous change, CP type III and type V pit pattern are observed.

AIM To determine the usefulness of assigning narrow-band imaging (NBI) scores for predicting tumor grade and invasion depth in colorectal tumors. METHODS A total of 161 colorectal lesions were analyzed from 138 patients who underwent endoscopic or surgical resection after conventional colonoscopy and magnifying endoscopy with NBI. The relationships between the surface and vascular patterns of the lesions, as visualized with NBI, and the tumor grade and depth of submucosa (SM) invasion were determined histopathologically. Scores were assigned to distinct features of the surface microstructures of tubular and papillary-type lesions. Using a multivariate analysis, a model was developed for predicting the tumor grade and depth of invasion based on NBI-finding scores. RESULTS NBI findings that correlated with a high tumor grade were associated with the “regular/irregular” (P < 0.0001) surface patterns and the “avascular area” pattern (P = 0.0600). The vascular patterns of “disrupted vessels” (P = 0.0714) and “thick vessels” (P = 0.0133) but none of the surface patterns were associated with a depth of invasion of ≥ 1000 μm. In our model, a total NBI-finding score ≥ 1 was indicative of a high tumor grade (sensitivity: 0.97; specificity: 0.24), and a total NBI-finding score ≥ 9 (sensitivity: 0.56; specificity: 1.0) was predictive of a SM invasion depth ≥ 1000 μm. Scores less than these cutoff values signified adenomas and a SM invasion depth < 1000 μm, respectively. Associations were also noted between selected NBI findings and tumor tissue architecture and histopathology. CONCLUSION Our multivariate statistical model for predicting tumor grades and invasion depths from NBI-finding scores may help standardize the diagnosis of colorectal lesions and inform therapeutic strategies.

In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV1.5 channels, and was identified as an orally bioavailable compound.

This paper proposes a new method of ice production using a simple insulation lid and a self-contained ice production. Results of experiments in a freezer showed that ice could be produced with three proposed containers. It was possible to produce ice using a flat-plate-type simple insulation lid with the 1-ton and 0.5-ton containers. It was also proven that self-contained ice production was possible using a cap-type simple insulation lid with the 135-kg container. Outdoor experiments were also conducted. It was confirmed that ice could be produced outdoors and shown that the production method for ice intended for space cooling with a mixture of snow and water was effective. Furthermore, a method of production for high-value-added clear ice was proposed based on the outcomes of indoor and outdoor experiments. It was confirmed that all the items of the relevant standards were satisfied as a result of water quality examination of edible ice and ice intended for space cooling.

This paper proposes a snow storage system in a renovated space for efficient energy use and reduction of the costs related to snow utilization, and aims to clarify the system’s effectiveness. First, it gives an outline of the system together with a description of the facility used for demonstration testing. Second, it highlights the results of long-term measurements relating to snow storage characteristics, which showed that 59% of the latent energy in the initially stored snow had been used for cooling by the end of the relevant period. The authors discuss how heat balance analysis revealed a relatively high level of heat loss from the floor due to the storage facility’s location in an underground space, and confirm that the system has the potential to secure a high level of energy conservation. Finally, the paper outlines the results of analysis conducted throughout the construction and operation phases of the cooling system, which revealed that the initial cost was 96% that of a conventional cooling system.

We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimization of S1 and S4 ligands. Incorporating the interaction with S1-β pocket enhanced in vitro factor Xa inhibitory activity to less than 1 nM. Many zwitter ionic compounds showed long duration of action and potent inhibitory activity and high AUC values in oral administration tests to monkeys.

In this study, a system for the simple cooling of temporary spaces using ice was evaluated with the two cooling methods of natural and forced circulation. First, the predicted cooling capacity was calculated. The results indicated the suitability of the forced circulation type for buildings with high cooling loads and the natural circulation type for those with low cooling loads. The outcomes of preliminary experiments for verification of applicability to actual space cooling were also examined, and roughly confirmed the accuracy of the calculated cooling capacity. This system was actually introduced for space cooling at a real exhibition, and its performance was monitored. The results of the measurements taken indicated that it is capable of providing sufficient cooling capacity for temporary prefabricated buildings.

We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 μM) and in vivo antithrombotic efficacy.

Rohan Koda (1867-1947) was born toward the very end of the shogun’s reign of Japan and kept writing for six decades, until his death after the end of World War II. Unlike many other intellectuals of his generation, he did not study abroad or receive Westernized higher education. His works are based on East Asian aesthetics and Buddhist philosophy rather than the European literary trends that dominated Japanese literature in his time. In addition to novels and short stories, his works include large number of historical biographies, essays on classic literature or natural history, and annotation of Basho Matsuo’s haiku corpus.

A series of cis-1,2-diaminocyclohexane derivatives possessing a 6-6 fused ring for the S1 moiety were synthesized as novel factor Xa (fXa) inhibitors. The synthesis, structure-activity relationship (SAR), and physicochemical properties are reported herein, together with the discovery of compound 45c, which has potent anti-fXa activity, good physicochemical properties and pharmacokinetic (PK) profiles, including a reduced negative food effect.

Compound 7 was identified as the active metabolite of 6 by HPLC and mass spectral analysis. Modification of lead compound 7 by transformation of its N -oxide 6–6 biaryl ring system and fused aromatics produced a series of non-basic fXa inhibitors with excellent potency in anti-fXa and anticoagulant assays. The optimized compounds 73b and 75b showed sub to one digit micromolar anticoagulant activity (PTCT2). Particularly, anti-fXa activity was detected in plasma of rats orally administered with 1 mg/kg of compound 75b .

The desired 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole (VII) is readily prepared via a Mitsunobu reaction of diol (IV) with sulfonamide (V).

Acid treatment of α-hydroxy acetals induced 1,2-alkyl, aryl, or alkenyl migration. An alkenyl migration product was utilized as a starting material of methyl l -mycaroside synthesis.

The position of a production management system in a computer-integrated manufacturing (CIM) system is to serve as the nucleus of the plant CIM system that connects the plant production to other departments such as marketing, research and development, and distribution departments. A production management system that integrates the flow of goods with information in a plant, and thus manages production in it, was developed as the first step toward application of CIM to a powder plant. The method of building a distributed system is one way to build a CIM system. This method creates a system in the required function units, which are connected by a network to expand the system function. It offers advantages in extensibility, flexibility, and rapid implementation.

We have been researching orally active factor Xa inhibitor for a long time. We explored the new diamine linker using effective ligands to obtain a new attractive original scaffold 2-aminomethylphenylamine derivative. Compound 1D showed very strong in vitro and in vivo factor Xa inhibitory activity, as well as favorable PK profiles in po administration to monkeys.

Acid treatment of α-hydroxy acetals induced 1,2-alkyl, aryl, or alkenyl migration. An alkenyl migration product was utilized as a starting material of methyl l -mycaroside synthesis.

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.

There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.

The sequential two-point method is a new method of straightness measurement with a simple algorithm which does not need a specific base line. Advantages of the method such as measurement of both the accuracy of tool movement and cut surface by the single path of data acquisition, good accuracy for the repeated measurement, and stable measurement even for dynamic conditions have been pointed out. In this paper, in addition to these, it is proposed that the accuracy can be improved by making use of the data which are interpolated by feeding the sensor device with shorter steps than the distance of the two sensors. The effectiveness of the method is proved by measuring the profile of aluminum thin film pasted on an aluminum disc cut by a diamond tool. It is also made obvious that the measured straightness can be corrected by adopting a series of the interpolated data whose distance is just equal to that of the sensors.

The nitroso form of the entitled tautomer increases with water content in the medium.The rates of nitroso-oxime tautomerization of the tautomer of p-nitrosophenol and p-benzoquinoneoxime in the absence of catalyst in binary media of 40, 50, 60 and 80 vol% water and methanol at 1525°C were measured by means of UV spectrophotometry, using a calibration curve for the reaction prepared by wave analysis.The reaction followed reversible first-order kinetics : Rate=k1 (a-c-x) -k-1 (c+x).Here, k1 and k-1 are first-order rate constants for the nitrosozation and the oximization;a, c and x are the concentration of the whole tautomer, nitroso form at the initial time, and consumed oxime or formed nitroso form at time t, respectively.The entropy term is more predominant than the enthalpy term both for the forward and reverse reactions.The slopes of log k1 and log k-1 against log aH2O were 3 and 2 for the forward and reverse reactions, respectively.From these findings, a mechanism is presented, involving the intermediate hydrogen bonding perfect annular complex by three molecules of water between hydroxylamino hydrogen and ketonyl oxygen for nitrosozation and the imperfect annular complex by two water molecules with phenolic hydrogen and/or nitroso oxygen for oximization.

In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.

There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.

This paper describes the synthesis of orally available potent fXa inhibitors 2 and 3 by modification of the piperazine part of lead compound 1. Carbonyl derivative 3 showed potent fXa activity but not sulfonyl derivative 2. Among the compounds synthesized, cyclohexane derivatives 3g and 3h and cycloheptane derivative 3j had potent anticoagulant activity as well as anti-fXa activity. Synthetic study of the optical isomers of 3g demonstrated that (-)-3g had more potent activity.

Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.

Based on the both of results for X-ray studies of tetrahydrothiazolopyridine derivative 1c and FXV673 , we synthesized a series of thiazol-5-ylpyridine derivatives containing pyridine N -oxide and 2-carbamoylthiazole units to optimize the S4 binding element. N -Oxidation of thiazol-5-ylpyridine increased the anti-fXa activity more than 10-fold independent on the position of N -oxide. The 4-pyridine N -oxide derivatives 3a and 3d excelled over the tetrahydrothiazolopyridine 1b in potency. 2-Methylpyridine N -oxide 3d exhibited 49-fold selectivity over thrombin. Our modeling study proposed a binding mode that the pyridine N -oxide ring of 3a stuck into the ‘cation hole’, and the oxide anion of 3a occupied in the almost same space to that of FXV673 . From observations of the SAR and modeling studies, we suggested the possibilities that the formation of hydrogen bond with the oxide anion in the ‘cation hole’ and the affinity of cationic pyridine ring to S4 subsite were responsible for increase in anti-fXa activity.

The improved routes to prepare tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylic acid lithium salts (2 and 3) were developed. Route A is consisted of the improved preparation of thiazolopyridine intermediates, and Route B is applicable for a large scale synthesis of tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid derivatives. The methods we developed may serve as facile means for preparing thiazolopyridine and tetrahydrothiazolopyridine derivatives.

Releases of sodium benzoate from calcium alginate (CaAlg) gel beads were studied during deformation processes resulting from the changes of osmotic pressures. The releases were found to be suppressed concomitant with the deformation in the region of high concentrations of adding substances. The suppression was discussed from an advancing boundary.

A non-contact communication system was developed for a ventilator-assisted patient with Werdnig-Hoffmann disease who had lost all voluntary movements except for those of the eye. The system detects the extraocular movements and converts them to either a 'yes' signal (produced by one lateral eyeball movement) or a 'no' signal (produced by two successive lateral eyeball movements) using a video camera placed outside the patient's visual field. The patient is thus able to concentrate on performing a task without any intrusion from the detection system. Once the setting conditions of the device have been selected, there is no need for any resetting, as the patient is unable to move his body. In addition to playing television games, the child can use the device to select television channels, compose music, and learn written Japanese and Chinese characters. This seems to broaden the patient's daily world and promote mental development.