TD-DFT investigation on the electronic spectra of novel N-methylmaleimides linked with indolizine ring system

The major electronic absorption features in visible region were computationally investigated for a series of novel N-methylmaleimide derivatives. The newly synthesized compounds through the reaction of indolizines with N-methylmaleimides exhibited their maxima ranging 587?634 nm in solution at room temperature. Time dependent density functional theory (TD-DFT) calculations were performed in order to elucidate their structure?color relationship, as well as to assess its performance using a variety of exchange-correlation (XC) functionals and basis sets. 4-(Indolizin-3-yl)-1-methyl-2,5-dioxo-1H-pyrrole-3-carbonitrile (referred to 3a hereafter), a representative of the new compounds, was analyzed in detail on its intramolecular push?pull electronic structure. As a consequence of systematic evaluation of computational strategies for 3a, we found that the theoretical λmax obtained by PCM-TD-DFT/6-31+G(d, p)//DFT/6-311G(2d, 2p) level of theory, which was consistently employed throughout this study, has converged within 2 nm deviation from λmax of the most elaborated level considered. Among some of the molecules with near-planarity structure, unusual discrepancies between the theoretical and the experimental λmax were observed, which should be attributed to the well-known TD-DFT limitation to describe multi-configurational or charge transfer (CT) excitations

One-Pot Synthesis of 6-Substituted Amino-2,4-diaminopyrimidine Derivatives Using Ketene Dithioacetals with Amines and Guanidine Carbonate

6-Substituted amino-2,4-diaminopyrimidine derivatives were prepared by one-pot synthesis using ketene dithioacetals, amine compounds, and guanidine carbonate in pyridine. These pyrimidine products displayed blue fluorescence in the solid state

Social and cognitive functions in schizophrenia

Purpose: The purpose of the present study was to examine clinical factors related to social function in people with schizophrenia. Patients and methods: The participants were 55 stabilized outpatients with schizophrenia. Their mean age was 39.36 (SD =10.65) years. Social function was assessed using the Quality of Life Scale (QLS). Cognitive function was evaluated with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, and the Drug-Induced Extrapyramidal Symptoms Scale. Results: Neither the MCCB cognitive domain score nor composite score was correlated with the QLS scores. However, of the 10 MCCB subtests, the Trail Making Test Part A and the Brief Assessment of Cognition in Schizophrenia-Symbol Coding (BACS-SC) scores were positively correlated with the QLS scores. Among clinical variables, especially the PANSS negative syndrome scale score had a strong negative correlation with the QLS scores. Stepwise regression analyses showed that the PANSS negative syndrome scale score was an independent predictor of the QLS scores, and although the BACS-SC score predicted the QLS common objects and activities subscale score, the association was not so strong compared to the PANSS negative syndrome scale score. Conclusion: These results indicate that speed of processing evaluated by BACS-SC could predict some aspect of social function but negative symptoms have a much stronger impact on global social function in people with schizophrenia

Life skills in schizophrenia

Objective : The purpose of the present study is to examine clinical factors related to life skills in people with schizophrenia. Method : The participants were 51 stabilized outpatients with schizophrenia. Their mean age was 38.91 (SD = 10.73) years. Life skills were assessed using the Life skills profile (LSP). Cognitive function was evaluated with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Clinical symptoms were assessed using the Positive and Negative Syndrome scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS) and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Results : Cognitive function was not correlated with the LSP scores at all. Among clinical symptoms, scores of the PANSS positive and negative syndrome scales, the CDSS, and the DIEPSS had negative correlations with the LSP total score and the subscales. Stepwise regression analyses showed that the CDSS and PANSS negative syndrome scale scores were independent predictors of the LSP total score and two of the subscales. Conclusions : These results indicate that cognitive function is not associated with life skills but clinical symptoms such as depressive and negative symptoms have considerable impacts on life skills in people with schizophrenia

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Determination of Essential and Variable Residues in Pediocin PA-1 by NNK Scanning

Pediocin PA-1 is an antimicrobial peptide (called bacteriocin) that shows inhibitory activity against the food-borne pathogen Listeria monocytogenes. To elucidate which residue(s) is responsible for this function, the antimicrobial activities of pediocin PA-1 mutants were evaluated and compared. Each of the 44 native codons was replaced with the NNK triplet oligonucleotide in a technique termed NNK scanning, and 35 mutations at each position were examined for antimicrobial activities using a modified colony overlay screening method. As a consequence, the functional responsibility of each residue was estimated by counting the number of active mutants, allowing us to identify candidate essential/variable residues. Activity was abrogated by many of the mutations at residues Y2, G6, C9, C14, C24, W33, G37, and C44, indicating that these residues may be essential. In contrast, activity was retained by almost all versions harboring mutations at K1, T8, G10, S13, G19, N28, and N41, indicating that these are functionally redundant residues. Sequence analysis revealed that only the wild type was active and 14 and 11 substitutions were inactive at G6 and C14, respectively, while 12 and 11 substitutions were active and 2 and 0 substitutions were inactive at T8 and K1, respectively. These findings suggest that NNK scanning is effective for determining essential and variable residues in pediocin PA-1, leading to an elucidation of structure-function relationships and to improvements in the antimicrobial function efficiently by peptide engineering

<Preliminary>Changes in Levels of mRNAs for Cell Wall-related Enzymes in Growing Cotton Cells

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