1,3,5-トリアジン及びその構造異性体を基盤とする酸触媒アルキル化剤の開発

13301甲第4372号博士(薬学)金沢大学博士論文要旨Abstract 要約Outlin

Characterization of pullulanase (PUL)-deficient mutants of rice (Oryza sativa L.) and the function of PUL on starch biosynthesis in the developing rice endosperm

Rice (Oryza sativa) allelic sugary1 (sug1) mutants defective in isoamylase 1 (ISA1) accumulate varying levels of starch and phytoglycogen in their endosperm, and the activity of a pullulanase-type of a debranching enzyme (PUL) was found to correlate closely with the severity of the sug1 phenotype. Thus, three PUL-deficient mutants were generated to investigate the function of PUL in starch biosynthesis. The reduction of PUL activity had no pleiotropic effects on the other enzymes involved in starch biosynthesis. The short chains (DP ≤13) of amylopectin in PUL mutants were increased compared with that of the wild type, but the extent of the changes was much smaller than that of sug1 mutants. The α-glucan composition [amylose, amylopectin, water-soluble polysaccharide (WSP)] and the structure of the starch components (amylose and amylopectin) of the PUL mutants were essentially the same, although the average chain length of the B2-3 chains of amylopectin in the PUL mutant was ∼3 residues longer than that of the wild type. The double mutants between the PUL-null and mild sug1 mutants still retained starch in the outer layer of endosperm tissue, while the amounts of WSP and short chains (DP ≤7) of amylopectin were higher than those of the sug1 mutant; this indicates that the PUL function partially overlaps with that of ISA1 and its deficiency has a much smaller effect on the synthesis of amylopectin than ISA1 deficiency and the variation of the sug1 phenotype is not significantly dependent on the PUL activities

Decontamination of metal-contaminated waste foundry sands using an EDTA-NaOH-NH3 washing solution

Waste foundry sand (WFS), which is a hazardous byproduct from the foundry industry, is often contaminated with potentially toxic elements (PTEs), such as Cu, Pb and Zn, and widely re-utilized as a construction material. Therefore, the depollution of WFS has been suggested due to its environment friendly reprocessing to avoid potential long-term hazardous impacts. In the current study, a unique chemically induced technique has been proposed for the removal of PTEs from WFS. EDTA, NaOH and NH3 were used as extractants in combination or in succession. The optimum removal of PTEs was accomplished using a solid (WFS) to solution (50 mmol L-1 EDTA) ratio of 10 under strongly basic pH conditions, which was achieved with NaOH addition. The washing efficiency was further enhanced with the addition of NH3 to the solution. The complete process cycle duration was adjusted to 9 h with a washing sequence that was repeated three times for 3 h each. The ultimate efficiencies (%) for the removal of PTEs were as follows: Cu, 98; Pb, 81; Sn, 83; and Zn, 50. The leaching of residual PTEs (%) from the decontaminated WFS was also in compliance with the regulatory levels that are defined by the monitoring authorities. © 2016 Elsevier B.V.Embargo Period 24 month

Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.ArticleeNeuro.4(2):e0250(2017)journal articl

EGUIDE project and treatment guidelines

Aim: Although treatment guidelines for pharmacological therapy for schizophrenia and major depressive disorder have been issued by the Japanese Societies of Neuropsychopharmacology and Mood Disorders, these guidelines have not been well applied by psychiatrists throughout the nation. To address this issue, we developed the ‘Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)’ integrated education programs for psychiatrists to disseminate the clinical guidelines. Additionally, we conducted a systematic efficacy evaluation of the programs. Methods: Four hundred thirteen out of 461 psychiatrists attended two 1‐day educational programs based on the treatment guidelines for schizophrenia and major depressive disorder from October 2016 to March 2018. We measured the participants’ clinical knowledge of the treatment guidelines using self‐completed questionnaires administered before and after the program to assess the effectiveness of the programs for improving knowledge. We also examined the relation between the participants’ demographics and their clinical knowledge scores. Results: The clinical knowledge scores for both guidelines were significantly improved after the program. There was no correlation between clinical knowledge and participant demographics for the program on schizophrenia; however, a weak positive correlation was found between clinical knowledge and the years of professional experience for the program on major depressive disorder. Conclusion: Our results provide evidence that educational programs on the clinical practices recommended in guidelines for schizophrenia and major depressive disorder might effectively improve participants’ clinical knowledge of the guidelines. These data are encouraging to facilitate the standardization of clinical practices for psychiatric disorders

Breakfast Staple Types Affect Brain Gray Matter Volume and Cognitive Function in Healthy Children

Childhood diet is important for brain development. Furthermore, the quality of breakfast is thought to affect the cognitive functioning of well-nourished children. To analyze the relationship among breakfast staple type, gray matter volume, and intelligence quotient (IQ) in 290 healthy children, we used magnetic resonance images and applied voxel-based morphometry. We divided subjects into rice, bread, and both groups according to their breakfast staple. We showed that the rice group had a significantly larger gray matter ratio (gray matter volume percentage divided by intracranial volume) and significantly larger regional gray matter volumes of several regions, including the left superior temporal gyrus. The bread group had significantly larger regional gray and white matter volumes of several regions, including the right frontoparietal region. The perceptual organization index (POI; IQ subcomponent) of the rice group was significantly higher than that of the bread group. All analyses were adjusted for age, gender, intracranial volume, socioeconomic status, average weekly frequency of having breakfast, and number of side dishes eaten for breakfast. Although several factors may have affected the results, one possible mechanism underlying the difference between the bread and the rice groups may be the difference in the glycemic index (GI) of these two substances; foods with a low GI are associated with less blood-glucose fluctuation than are those with a high GI. Our study suggests that breakfast staple type affects brain gray and white matter volumes and cognitive function in healthy children; therefore, a diet of optimal nutrition is important for brain maturation during childhood and adolescence

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

ジアルキルアミノ基を凌駕する新規な中性π電子供与基の開発と機能性分子への応用

金沢大学先端科学・社会共創推進機構電子供与基の導入による共鳴効果を介したπ系電子密度増加は、有機化学の基礎的概念の1つである。ジアルキルアミノ基に代表される中性π電子供与基は、共役系のπ電子密度を向上させる目的で様々な機能性分子に導入され、広く役立てられている。そこで本研究では、ジアルキルアミノ基より強力なπ電子供与性を発揮する新しい置換基を開発することを目的として、その合成法、基本的な性質、そして機能性分子への応用性について検討を行った。Electron-donating groups increase pi-electron density by resonance effect. Neutral pi-electron-donating groups, such as dialkylamino groups, have been widely used in various functional molecules to improve the pi-electron density of conjugated systems. In this study, novel substituents that exhibit stronger pi-electron-donating properties than dialkylamino groups were developed. Their synthesis, basic properties, and applicability to functional molecules were investigated.研究課題/領域番号:19K23798, 研究期間(年度):2019-08-30 – 2021-03-31出典：「ジアルキルアミノ基を凌駕する新規な中性π電子供与基の開発と機能性分子への応用」研究成果報告書　課題番号19K23798（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-19K23798/19K23798seika/）を加工して作