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Focuses on the implementation of a decomposition-coordination approach to petroleum refinery production scheduling. Formulation of a single mathematical programming process; Man-hours required for making a final schedule.

The immunohistochemical distribution of RON receptor tyrosine kinase in digestive organs of both human fetus and adult, including the esophagus, stomach, duodenum, small intestine, colon, rectum, liver, gallbladder, pancreas, and spleen, was investigated semiquantitively using an affinity-purified rabbit polyclonal antibody. RON was observed to be widely distributed throughout various digestive organs and cell types in humans. The immunoreactivity for RON was observed in the epithelium of the esophagus, small intestine, colon, hepatocytes, Kupffer cells, and splenic macrophages both in the adult and the fetus, suggesting that the MSP/RON signaling pathway possesses the proper biological properties to possibly be involved in morphogenesis or differentiation of cells in these organs and cell types. Several organs differed in immunoreactivity between adult and fetus. No immunoreactive cells were found in the pancreas of adults; however, immunoreactivity was observed in acinar cells and in some of the duct or ductular cells and endocrine cells of the islet of the fetus. Similarly, immunoreactivity was not observed in gastric mucosa except in the intestinal metaplastic cells in adults; however, immunoreactivity was found in the foveolar epithelium of the stomach of the fetus. Although the biological significance of RON in malignancy is unclear, the presence of RON immunoreactivity in the fetus and it lack in the adult may indicate that RON is a oncofetal substance in human pancreas and stomach. [ABSTRACT FROM AUTHOR]

Aims Dilated cardiomyopathy is partly caused by a mutation of some cytoskeletal or nuclear envelope proteins. It has been confirmed recently that a missense mutation of the gene encoding desmin, a cytoskeletal protein, can cause dilated cardiomyopathy. This study was aimed at elucidating the frequency and clinical characteristics of dilated cardiomyopathy caused by desmin mutation.Methods and Results We examined 265 Japanese patients with dilated cardiomyopathy (217 sporadic cases and 48 probands of familial dilated cardiomyopathy). The exon 8 of the desmin gene, the critical region for the pathogenesis of dilated cardiomyopathy, was analysed by polymerase chain reaction, single-strand conformation polymorphism and sequencing. The same missense mutation (Ile451Met) as reported previously was detected in three patients (1·1%). All these patients were male and sporadic, and more likely to be accompanied by characteristics such as younger age at diagnosis, lower fractional shortening and ejection fraction than each mean value of sporadic cases. The chronological changes in cardiac function were inconsistent in the three patients.Conclusion The missense mutation (Ile451Met) of the desmin gene can be the genetic cause of dilated cardiomyopathy, although with very low frequency. The ages at diagnosis were younger and the cardiac function had deteriorated further than general cases of sporadic dilated cardiomyopathy. [ABSTRACT FROM PUBLISHER]

To test the hypothesis that coronary spasm could be a coronary manifestation of systemic endothelial dysfunction and that the activity of coronary spasm could influence systemic endothelial function, we examined brachial flow-mediated, endothelium-dependent vasodilation and nitroglycerin-induced endothelium-independent vasodilation with high-resolution ultrasound in 11 men with variant angina pectoris (6 active and 5 inactive) without established coronary atherosclerosis. Endothelium-dependent vasodilation in peripheral circulation was preserved in men with active and inactive variant angina pectoris, suggesting that systemic endothelial dysfunction is not involved in either the pathogenesis or the activity of coronary spasm. [ABSTRACT FROM AUTHOR]

Elite athletes frequently invest in the use of supplements to optimize their dietary regimens and enhance their athletic performance. However, unregulated and unplanned use of supplements can lead to adverse consequences, including anti-doping rule violations or health issues. Thus, athletes should verify their diets, consider scientific evidence, and take necessary precautions regarding supplements before use. To date, no study has explored whether athletes check these factors before using supplements. This study aimed to investigate supplement use using a questionnaire administered to 1,392 athletes (including candidate athletes) who participated in the Tokyo 2020 Olympic/Paralympic and Beijing 2022 Winter Olympic/Paralympic Games. Participants were categorized as follows: 1,040 participants in the Tokyo 2020 Olympic Games, 83 in the Tokyo 2020 Paralympic Games, 239 in the Beijing 2022 Winter Olympic Games, and 30 in the Beijing 2022 Winter Paralympic Games. We collected data on supplement use and gained further knowledge through interviews with the athletes. Approximately 70% of Tokyo 2020 Olympic/Paralympic and Beijing 2022 Winter Olympic athletes and approximately 50% of Beijing 2022 Winter Paralympians used supplements. Over 50% of athletes had not received a doctor's diagnosis or a dietitian's evaluation before supplement use. Moreover, only 50% of the athletes who used dietary supplements reviewed the scientific evidence for the dietary supplements before using them and justified their choice based on their own investigation, while those who did not use dietary supplements cited either a lack of need or fear of an anti-doping rule violation. Considering the holistic health and performance of athletes, as well as the risk associated with unregulated use, such as overdose and anti-doping rule violations, there is a need for nutritional education on supplement use for athletes and their entourages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Myoenzono, Yasuda, Takai, Shinagawa, Kaneko, Yoshizaki, Namma-Motonaga, Yoshino, Kondo, Nakajima, Hangai, Kamahara, Kamihigashi, Kusano and Kamei.)

The "meal first" strategy is traditionally recommended for athletes' conditioning. However, the importance of the "meal first" principle has not been detailly well documented in athletes' lives. Supplement use has recently become a common part of athletes' diets, but unmonitored supplement use can cause negative consequences, such as anti-doping violations and health issues. Therefore, this review summarizes how the "meal first" strategy and planned supplement use are important for enhancing athletes' health and performance. We believe that the "meal first" strategy is beneficial in terms of the following aspects: (1) consumption of multi-nutrients and other functional components simultaneously; (2) positive effects on psychological well-being; (3) contribution to athletes' health by way of mastication; and (4) less risk for anti-doping violations. Before supplement use, we recommend that athletes first verify their basic factors (e.g., diet, training, and sleep), given that the benefits of supplements are examined and demonstrated with the control of those factors. Otherwise, athletes cannot obtain maximal benefits from the supplements. In contrast, there are situations in which supplements in athletes' lives can be advantageous, such as (1) nutrient deficiency due to ongoing dietary characteristics; (2) interruption of meals due to disease; (3) inaccessibility of quality food during athletic travel; (4) difficulty preparing food due to societal restrictions associated with disasters or infection outbreaks; (5) having a meal before, during, or after exercise is difficult; and (6) achieving targeted intake of performance-enhancing ingredients is not practical. In summary, we emphasize that the "meal first" strategy is recommended for athletes' conditioning, but there are several contexts when supplement use can be more useful in athletes' lives., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Yasuda, Myoenzono, Takai, Toguchi, Tsunezumi, Kondo, Kaizaki, Ode, Ohno, Namma-Motonaga and Kamei.)

Neuroendocrine carcinoma (NEC) is a highly aggressive subtype of the neuroendocrine tumor with an extremely poor prognosis. We have previously conducted a comprehensive genomic analysis of over 100 cases of NEC of the gastrointestinal system (GIS-NEC) and unraveled its unique and organ-specific genomic drivers. However, the epigenomic features of GIS-NEC remain unexplored. In this study, we have described the epigenomic landscape of GIS-NEC and small cell lung carcinoma (SCLC) by integrating motif enrichment analysis from the assay of transposase-accessible chromatin sequencing (ATAC-seq) and enhancer profiling from a novel cleavage under targets and tagmentation (CUT&Tag) assay for H3K27ac and identified ELF3 as one of the super-enhancer-related transcriptional factors in NEC. By combining CUT&Tag and knockdown RNA sequencing for ELF3, we uncovered the transcriptional network regulated by ELF3 and defined its distinctive gene signature, including AURKA, CDC25B, CLDN4, ITGB6, and YWAHB. Furthermore, a loss-of-function assay revealed that ELF3 depletion led to poor cell viability. Finally, using gene expression of clinical samples, we successfully divided GIS-NEC patients into two subgroups according to the ELF3 signature and demonstrated that tumor-promoting pathways were activated in the ELF3 signature-high group. Our findings highlight the transcriptional regulation of ELF3 as an oncogenic transcription factor and its tumor-promoting properties in NEC., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Neuronal intranuclear inclusion disease (NIID) is a clinically complex neurological disorder that appears sporadically or autosomally. Expansions of intronic GGC trinucleotide repeats in the NOTCH2 N-terminal-like C (NOTCH2NLC) gene cause NIID. In this study, to clarify the clinical characteristics useful for the differential diagnosis of NIID, clinical data of neurological examination, neuroimaging, and nerve conduction studies of six NIID patients diagnosed by pathological or genetic investigations were analyzed. Clinically useful characteristics for diagnosing NIID include general hyporeflexia, episodic disturbance of consciousness, sensory disturbance, miosis, and dementia. Furthermore, neuroimaging findings, such as leukoencephalopathy in T2-weighted magnetic resonance imaging and a linear high intensity of subcortical U-fibers in diffusion-weighted imaging (DWI), as well as decreased motor nerve conduction velocity, are especially important biomarkers for NIID. However, it is necessary to remember that these features may not always be present, as shown in one of the cases who did not have a DWI abnormality in this study. This study also investigated whether expanded GGC repeats were translated into polyglycine. Immunohistochemical analysis using a custom antibody raised against putative C-terminal polypeptides followed by polyglycine of uN2CpolyG revealed that polyglycines were localized in the intranuclear inclusions in skin biopsy specimens from all six patients, suggesting its involvement in the pathogenesis of NIID., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Muscle glycogen storage before a race is necessary for endurance athletes to achieve the best performance. Generally, the recommended carbohydrate intake for preparation over 90 min of the race is 10-12 g·kg--1·day--1. However, it remains unclear whether an elite athlete with an already high-carbohydrate diet can further increase muscle glycogen through a very-high-carbohydrate intake. Therefore, we compared the effects of three types of glycogen loading in a 28-year-old male athlete who belongs to the top 50 racewalkers in the world, consuming a daily energy intake of 4507 kcal and a carbohydrate intake of 12.7 g·kg--1·day--1., Methods: The racewalker consumed very-high-carbohydrate diets three times for 2 days each, 13.7 g·kg--1·day--1 for trial 1, 13.9 g·kg--1·day--1 for trial 2, and 15.9 g·kg--1·day-1 for trial 3. Muscle glycogen concentrations in the anterior (vastus lateralis and vastus intermedius) and posterior thighs (semimembranosus, semitendinosus, and biceps femoris) were measured using carbon-13 magnetic resonance spectroscopy., Results: Muscle glycogen concentrations in both the anterior and posterior thighs increased in all trials, particularly in trial 3. Body mass also increased by 1.5 kg in trials 1 and 2 and by 1.8 kg in trial 3 before and after the trials. The participant felt satiated throughout the day and experienced stomach discomfort during trial 3., Conclusion: We found that a 2-day very-high-carbohydrate diet and tapering of training could further increase the muscle glycogen concentration in athletes. However, we speculated that 15.9 g·kg--1·day--1 carbohy.

A highly sensitive and highly multiplexed quantification technique for nucleic acids is necessary to predict and evaluate cancer treatment by liquid biopsy. Digital PCR (dPCR) is a highly sensitive quantification technique, but conventional dPCR discriminates multiple targets by the color of the fluorescent dye of the probe, which limits multiplexing beyond the number of colors of fluorescent dyes. We previously developed a highly multiplexed dPCR technique combined with melting curve analysis. Herein, we improved the detection efficiency and accuracy of multiplexed dPCR with melting curve analysis to detect KRAS mutations in circulating tumor DNA (ctDNA) prepared from clinical samples. The mutation detection efficiency was increased from 25.9% of the input DNA to 45.2% by shortening the amplicon size. The limit of detection of mutation was improved from 0.41 to 0.06% by changing the mutation type determination algorithm for G12A, resulting in a limit of detection of less than 0.2% for all the target mutations. Then, ctDNA in plasma from pancreatic cancer patients was measured and genotyped. The measured mutation frequencies correlated well with those measured by conventional dPCR, which can measure only the total frequency of KRAS mutants. KRAS mutations were detected in 82.3% of patients with liver or lung metastasis, which was consistent with other reports. Accordingly, this study demonstrated the clinical utility of multiplex dPCR with melting curve analysis to detect and genotype ctDNA from plasma with sufficient sensitivity., (© 2023. The Author(s).)

Most of the odors that humans perceive daily are complex odors. It is believed that the modulation, enhancement, and suppression of overall complex odors are caused by interactions between odor molecules. In this study, to understand the interaction between odor molecules at the level of human olfactory receptor responses, the effects of 3-octen-2-one, which has been shown to modulate vanilla flavors, were analyzed using a human olfactory receptor sensor that uses all human olfactory receptors (388 types) as sensing molecules. As a result, the response intensity of 1 common receptor (OR1D2) was synergistically enhanced in vanilla flavor with 3-octen-2-one compared with vanilla flavor, and the response of 1 receptor (OR5K1) to vanilla flavor was completely suppressed. These results strongly suggested that the response of human olfactory receptors to complex odors is enhanced or suppressed by relatively few other odor molecules., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Caries sensitivity varies between the two strains of inbred mice, BALB/cA has high sensitivity and C3H/HeN has low sensitivity. One potential reason seems to be a difference in pellicle-forming saliva protein composition. Here, we performed a proteomic analysis in order to identify differences of hydroxyapatite (HAP) adsorbed saliva proteins between these two mouse strains. HAP column chromatography revealed twice the quantity of high-affinity saliva proteins in C3H/HeN compared to BALB/cA. One- and two-dimensional electrophoresis showed 2 bands/spots with deviating migration. They were identified as murine carbonic anhydrase VI (CAVI) by peptide mass fingerprinting and confirmed with western blotting using a specific polyclonal antibody. Total RNA from the salivary glands of both mouse strains, PCR amplification of cDNA with a CAVI specific primer, and sequence analysis revealed one different base in codon 96, resulting in one different amino acid. Glyco-chains of CAVI deviate in one N-glycan, confirmed by mass analysis. CAVI activity was estimated from distinct circular dichroism spectra of the molecules and found higher in C3H/HeN mice. In summary, the CAVI composition of BALB/cA and C3H/HeN differs in one amino acid and a glyco-chain modification. Further, saliva from caries resistant C3H/HeN mice displayed higher CAVI activity and also overall hydroxyapatite adsorption, suggesting a relationship with caries susceptibility., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

The use of dual-energy X-ray absorptiometry (DXA) may be invalid for assessing athletes with larger bodies, larger lean body mass, and thicker trunks. This study compared the athletes' visceral adipose tissue (VAT) assessed using DXA and magnetic resonance imaging (MRI). Eighty-two Japanese male collegiate athletes from 18 sports participated in this study. VAT was assessed using the dual-energy scan that coincided with the 4th lumbar vertebra. The sum of eight magnetic resonance slices corresponding to the region of the dual-energy scan was used for comparison. The VAT volume was higher with the dual-energy scan than with MRI (difference: 35 cm 3 , p<0.01). A significant correlation was noted between the volumes measured using both modalities (r=0.88, p<0.01). Magnetic resonance-derived volumes less than 600 cm 3 showed a stronger significant correlation with dual-energy-derived volumes. However, magnetic resonance-derived VAT volumes exceeding 600 cm 3 were not significantly correlated with dual-energy-derived volumes. In conclusion, VAT volumes derived from DXA were larger and significantly correlated with those derived from MRI across a wide range of values. Methods using DXA for assessing the visceral fat volume may require adjustment to estimate abdominal visceral fat volume in athletes, with care taken when using such methods for heavyweight athletes., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objective: The primary objective of this study was to identify novel genes that predispose people in the Japanese population to FPC., Summary of Background Data: Familial history of pancreatic cancer is an important risk factor but, to date, few genes predisposing individuals to increased risk of developing FPC have been identified., Methods: We performed whole-exome sequencing of germline DNA from 81 Japanese FPC patients. We also investigated somatic gene alterations in 21 matched tumor tissues through whole-exome sequencing and copy number analysis., Results: Our germline variants identified previously known FPC susceptibility genes such as ATM and BRCA2, and several novel tumor suppressor genes with potentially deleterious variants for FPC. Interestingly, somatic whole-exome analysis demonstrated that most tumor samples with suspicious loss of heterozygosity of candidate genes were KRAS wild-types, implying that these cases may not have required KRAS activation as a driver event for carcinogenesis., Conclusions: Our findings indicate that FPC patients harbor potentially deleterious causative germline variants in tumor suppressor genes, which are known to acquire somatic mutations in pancreatic cancer, and that somatic loss of heterozygosity of some FPC susceptibility genes may contribute to the development of FPC in the absence of somatic KRAS-activating mutation. Genetic testing for a wider variety of FPC-predisposition genes could provide better screening approach for high-risk groups of pancreatic cancer., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs could be classified into two subgroups (i.e., "ductal-type" and "acinar-type") based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, and most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer., Significance: GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., "ductal-type" and "acinar-type") based on genomic and epigenomic features. This article is highlighted in the In This Issue feature, p. 587., (©2021 The Authors; Published by the American Association for Cancer Research.)