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Dietary ω3 fatty acids have important health benefits and exert their potent bioactivity through conversion to lipid mediators. Here, we demonstrate that microbiota play an essential role in the body's use of dietary lipids for the control of inflammatory diseases. We found that amounts of 10-hydroxy-cis-12-cis-15-octadecadienoic acid (αHYA) and 10-oxo-cis-12-cis-15-octadecadienoic acid (αKetoA) increased in the feces and serum of specific-pathogen-free, but not germ-free, mice when they were maintained on a linseed oil diet, which is high in α-linolenic acid. Intake of αKetoA, but not αHYA, exerted anti-inflammatory properties through a peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway and ameliorated hapten-induced contact hypersensitivity by inhibiting the development of inducible skin-associated lymphoid tissue through suppression of chemokine secretion from macrophages and inhibition of NF-κB activation in mice and cynomolgus macaques. Administering αKetoA also improved diabetic glucose intolerance by inhibiting adipose tissue inflammation and fibrosis through decreased macrophage infiltration in adipose tissues and altering macrophage M1/M2 polarization in mice fed a high-fat diet. These results collectively indicate that αKetoA is a novel postbiotic derived from α-linolenic acid, which controls macrophage-associated inflammatory diseases and may have potential for developing therapeutic drugs as well as probiotic food products.

Dietary ω3 fatty acids have important health benefits and exert their potent bioactivity through conversion to lipid mediators. Here, we demonstrate that microbiota play an essential role in the body’s use of dietary lipids for the control of inflammatory diseases. We found that amounts of 10-hydroxy-cis-12-cis-15-octadecadienoic acid (αHYA) and 10-oxo-cis-12-cis-15-octadecadienoic acid (αKetoA) increased in the feces and serum of specific-pathogen-free, but not germ-free, mice when they were maintained on a linseed oil diet, which is high in α-linolenic acid. Intake of αKetoA, but not αHYA, exerted anti-inflammatory properties through a peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway and ameliorated hapten-induced contact hypersensitivity by inhibiting the development of inducible skin-associated lymphoid tissue through suppression of chemokine secretion from macrophages and inhibition of NF-κB activation in mice and cynomolgus macaques. Administering αKetoA also improved diabetic glucose intolerance by inhibiting adipose tissue inflammation and fibrosis through decreased macrophage infiltration in adipose tissues and altering macrophage M1/M2 polarization in mice fed a high-fat diet. These results collectively indicate that αKetoA is a novel postbiotic derived from α-linolenic acid, which controls macrophage-associated inflammatory diseases and may have potential for developing therapeutic drugs as well as probiotic food products.

IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM.ResultsWe describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3variant, including the patients that initially allowed reporting TFE3as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko’s lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants.ConclusionThis series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.

There are only a few effective molecular targeted agents for advanced unresectable or recurrent advanced gastric cancer (AGC), which has a poor prognosis with a median survival time of less than 14 months. Focusing on phosphorylation signaling in cancer cells, we have been developing deep phosphoproteome analysis from minute endoscopic biopsy specimens frozen within 20 seconds of collection. Phosphoproteomic analysis of 127 fresh-frozen endoscopic biopsy samples from untreated AGC patients revealed three subtypes reflecting different cellular signaling status. Subsequent serial biopsy analysis has revealed the dynamic mesenchymal transitions within cancer cells, along with the concomitant rewiring of the kinome network, ultimately resulting in the conversion to the epithelial-mesenchymal transition (EMT) subtype throughout treatment. We present our investigation of intracellular signaling related to EMT in gastric cancer and propose therapeutic approaches targeting AXL. This study also provides a wealth of resources for the future development of treatments and biomarkers for AGC.

Phosphorylation is a major post-translational modification that regulates protein function, with phosphotyrosine (pY) modifications being implicated in oncogenesis. However, global profiling of pY statuses without treatment with a tyrosine phosphatase inhibitor such as pervanadate is still challenging due to the low occupancy of pY sites. In this study, we greatly improved the identification of pY sites by liquid chromatography–tandem mass spectrometry (LC–MS/MS) by optimization of both the pY-immunoprecipitation (pY-IP) protocol and the LC–MS/MS parameters. Our highly sensitive method reproducibly identified more than 1000 pY sites from 8 mg of protein lysate without the need for tyrosine phosphatase inhibitor treatment. Furthermore, >30% of the identified pY sites were not assigned in the PhosphositePlus database. We further applied our method to the comparison of pY status between PC3 cells with and without treatment using the epidermal growth factor receptor (EGFR) inhibitor Erlotinib. Under Erlotinib treatment, we observed not only a decrease in well-known modes of EGFR downstream signaling but also modulations of kinases that are not relevant to the EGFR cascade, such as PTK6 and MAPK13. Our newly developed method for pY proteomics has the potential to reveal unknown pY signaling modes and to identify novel kinase anticancer targets.

We report a 4‐year‐old boy with generalized seizures with abrupt falling and unresponsive staring provoked by somatosensory stimuli of the face. Ictal manifestation comprised a sudden fall immediately after wiping the face, followed by unresponsive staring for around 10 seconds, during which time the video‐EEG recorded paroxysmal 3‐Hz diffuse spike‐wave complexes, which were followed by high‐voltage 3.5 to 4‐Hz delta wave discharges, predominantly appearing in the bilateral frontal areas. Seizures were not controlled by clonazepam, valproate or levetiracetam, but were successfully treated with lamotrigine added to valproate. This type of generalized reflex seizure has so far not been reported in the literature. [Published with video sequence] Content available: Video

Critical Dimension Scanning Electron Microscope (CD-SEM) recipe creation needs sample preparation necessary for matching pattern registration, and recipe creation on CD-SEM using the sample, which hinders the reduction in test production cost and time in semiconductor manufacturing factories. From the perspective of cost reduction and improvement of the test production efficiency, automated CD-SEM recipe creation without the sample preparation and the manual operation has been important in the production lines. For the automated CD-SEM recipe creation, we have introduced RecipeDirector (RD) that enables the recipe creation by using Computer-Aided Design (CAD) data and text data that includes measurement information. We have developed a system that automatically creates the CAD data and the text data necessary for the recipe creation on RD; and, for the elimination of the manual operation, we have enhanced RD so that all measurement information can be specified in the text data. As a result, we have established an automated CD-SEM recipe creation system without the sample preparation and the manual operation. For the introduction of the CD-SEM recipe creation system using RD to the production lines, the accuracy of the pattern matching was an issue. The shape of design templates for the matching created from the CAD data was different from that of SEM images in vision. Thus, a development of robust pattern matching algorithm that considers the shape difference was needed. The addition of image processing of the templates for the matching and shape processing of the CAD patterns in the lower layer has enabled the robust pattern matching. This paper describes the automated CD-SEM recipe creation technology for the production lines without the sample preparation and the manual operation using RD applied in Sony Semiconductor Kyusyu Corporation Kumamoto Technology Center (SCK Corporation Kumamoto TEC).

AbstractBlanket neutronics experiments were conducted for the development of the water-cooled pebble bed type ITER Test Blanket Module (TBM) using the Fusion Neutronics Source (FNS). Slab mockup assemblies based on the water-cooled pebble bed ITER TBM including water panels and/or a breeder pebble layer were irradiated by 14 MeV neutrons. After the irradiation, the amount of tritium produced in the diagnostic Li2CO3pellets or breeder pebbles is measured by liquid scintillation counting method. The C/E ratios for the tritium production rate in those experiments are within 1 ± 0.05. A plan of the neutronics test on ITER-TBM and the neutronic diagnostics in the module are discussed. Micro fission chambers and compact activation foil transfer systems to be embedded in TBM are proposed for the neutron flux and neutron spectrum measurements, respectively.

Neutronics experiments have been performed for the solid breeder blanket using a DT neutron source at the FNS facility in JAEA. We have applied the blanket mockup composed of two enriched Li2TiO3and three beryllium layers, and measured the detailed spatial distribution of the tritium production rate (TPR) using enriched Li2CO3pellets. TPRs in the pellets have been measured by a liquid scintillation counter. Experiments have been done under a condition with a neutron reflector surrounding the DT neutron source. Numerical simulations have been performed using the MCNP-4C with the FENDL-2.0 and JENDL-3.3. The ranges of ratios of calculation results to experimental ones (C/Es) are 0.97–1.17 concerning with local TPR, and 1.04–1.09 for the integrated tritium production. It is found that the total integrated tritium production, which corresponds to tritium breeding ratio, can be predicted within uncertainty of 10% using the Monte Carlo calculation code and latest nuclear data libraries.

Abstract: Hypothesis: Statins potently prevents cardiac myocytes from acute ischemia besides chronic inhibition of cholesterol synthesis. We investigated how pravastatin preserves the cardiac function after myocardial infarction (MI). Methods: Echocardiographically comparing rats with myocardial ischemia (MI group) with those treated with pravastatin (MI/statin group), we found that cardiac contractility was statistically preserved in the MI/statin whereas it was deteriorated in MI group. Results: Histochemical analysis suggested that ischemia-induced cardiac fibrosis was prevented by pravastatin. Because there was no significant myocyte apoptosis reflecting myocytes loss between two groups, ischemia-induced interstitial fibrosis might affect the contractility. Conclusion: We hypothesized that statin may directly affect vascular endothelial cells regulating blood supply to the myocardium rather than affecting myocytes. Pravastatin perturbed H2O2-induced endothelial NOS reduction and inhibited H2O2-increased caspase-3 activation in cultured vascular endothelial cells. These data suggested that pravastatin prevent cardiac dysfunction by acting on vascular endothelial cells. Furthermore, early administration of pravastatin to the patients during acute onset of myocardial infarction may be beneficial to prevent myocardial damage caused by fibrosis associated with ischemia.

We investigated the contribution of the sympathetic nervous system SNS in maintaining blood pressure during administration of carvedilol in rats with dilated cardiomyopathy, and examined whether SNS hyperactivity induced by highdose carvedilol is related to severity of heart failure. The hypotensive effect of carvedilol in rats with heart failure Group F was not significantly different to that in rats without Group N. However, enhancement of the plasma norepinephrine concentration during carvedilol administration in Group F was higher than in Group N. The constitutive plasma NE concentration in Group F 562 ± 146 pgml was significantly higher than in Group N 203 ± 55 pgml and there was a significant positive correlation between the heart weight to body weight ratio and the plasma norepinephrine concentration. Values for the maximal effect of the norepinephrine hypertensive effect during norepinephrine intravenous infusion Emaxdecreased, and plasma norepinephrine concentrations at halfmaximal effect of the norepinephrine hypertensive effect EC50increased in Group F compared with Group N 20.8 ± 6.1 and 28.6 ± 2.2 mmHg, and 4.5 ± 1.9 and 1.5 ± 0.2 ngml, respectively. These results suggested that the number of receptors Emaxand sensitivity EC50to the norepinephrine hypertensive effect decreased in Group F. Changes in these parameters in Group F corresponded with the results of a adrenergic receptor binding assay using I125 iodocyanopindolol Bmax32 ± 4 in Group F and 53 ± 2 fmolmg protein in Group N. These results showed that the SNS presynaptic activity increased and the SNS receptor sensitivity in the blood pressure regulation system decreased in heart failure. Therefore, highdose carvedilol treatment should be used with caution to avoid worsening heart failure.

Angiotensinconverting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure. The angiotensin type1 blocking and cardioprotective properties of perindopril and enalapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Enalapril at 20 mgkg showed the same angiotensin type1 blocking action as perindopril at 2 mgkg in rats with heart failure. Twentyeight days after immunization, surviving Lewis rats 90120 75 were divided into six groups and administered perindopril at 0.02, 0.2 and 2 mgkg per day Groups P0.02, P0.2 and P2, enalapril at 2 and 20 mgkg per day Groups E2 and E20 or vehicle alone Group V, all groups n 15. After oral administration for 1 month, four of 15 27 rats in Group V, and two 13 in Groups P0.02 and E2 died. None of the animals in Groups P0.2, P2 and E20, or normal rats Group N died. Although both angiotensinconverting enzyme inhibitors improved ventricular function in a dosedependent manner, the left ventricular enddiastolic pressure and area of myocardial fibrosis were lower, and ± dPdtwas higher in Group P2 4.9 ± 0.6 mmHg, 7.5 ± 1.4 and 2651 ± 254 2622 ± 189 mmHgs, respectively than in Group V 16.7 ± 1.3, 36 ± 2.6 and 2659 ± 1762516 ± 205, respectively and Group E20 7.5 ± 2.5, 15.6 ± 2.0 and 2018 ± 1102097 ± 102, respectively. Although the expression levels of transforming growth factor1and collagenIII mRNA in Group V 36.3 ± 5.7 and 157.6 ± 12.7 were significantly higher than those in Group N 19.6 ± 3.0 and 65.2 ± 1.5, both p < 0.01, they were reduced in Group P2 21.4 ± 5.9 and 75.2 ± 9.3, both p < 0.01. These results suggest that although enalapril can block increases in blood pressure caused by circulating angiotensin type1, perindopril at 2 mgkg may confer greater protection than enalapril at 20 mgkg against injury from the reninangiotensin system in heart failure.

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ABSTRACTImaging plates were adopted as a convenient tool for measuring tritium distributions in tritium-containing components such as tritium targets, smeared sample pieces, etc. Procedure of the measurements was optimized and detailed distributions of tritium were obtained. As a result, the method was confirmed as useful in obtaining knowledge on the accelerator beam control and focusing, and the contamination check of peripheral components around tritium targets.

Irradiation of 8-azatricyclo[3.2.1.02,4]oct-6-enes in dry ether with a low pressure mercury lamp gave azabishomobenzenes through [2π+2σ]-type migration reactions between C–N bonds and olefin moieties.