Recent Progresses in <em>Ab Initio</em> Electronic Structure Calculation toward Understandings of Functional Mechanisms of Biological Macromolecular Systems

In this chapter, we present recent advances of theoretical analyses toward understandings of functional mechanisms of biological macromolecular systems, employing ab initio electronic structure calculations. Two distinct types of triggers to invoke dramatic rearrangements of electronic structures in the reaction centers are revealed by full ab initio quantum mechanics (QM) calculations (first example) and hybrid ab initio QM/molecular mechanics (MM) molecular dynamics (MD) calculations (second example). First, we demonstrate dramatic rearrangements of molecular orbitals (MOs) induced by binding of a hydroxyl ion (OH−) to the [4Fe-3S] cluster found in hydrogenases, which catalyzes both dissociation and production of dihydrogen (H2). This induces the significant delocalization of the LUMO, resulting in formation of electron transfer pathways required for the catalysis. Thus, in organisms, just a tiny species (e.g. OH− ligand) can play a key role for the biological functions. Second, we indicate dynamical rearrangements of MOs occurring in the enzymatic reactions of RNA-protein complexes. As the catalysis proceeds, the reactive MOs, which do not belong to the frontier orbitals in the initial stages of the reaction, are dramatically reconstituted in the hybrid ab initio QM/MM MD simulations, resulting in the frontier orbitals, which is a feature characteristic to biological macromolecular systems

Biological Applications of Hybrid Quantum Mechanics/Molecular Mechanics Calculation

Since in most cases biological macromolecular systems including solvent water molecules are remarkably large, the computational costs of performing ab initio calculations for the entire structures are prohibitive. Accordingly, QM calculations that are jointed with MM calculations are crucial to evaluate the long-range electrostatic interactions, which significantly affect the electronic structures of biological macromolecules. A UNIX-shell-based interface program connecting the quantum mechanics (QMs) and molecular mechanics (MMs) calculation engines, GAMESS and AMBER, was developed in our lab. The system was applied to a metalloenzyme, azurin, and PU.1-DNA complex; thereby, the significance of the environmental effects on the electronic structures of the site of interest was elucidated. Subsequently, hybrid QM/MM molecular dynamics (MD) simulation using the calculation system was employed for investigation of mechanisms of hydrolysis (editing reaction) in leucyl-tRNA synthetase complexed with the misaminoacylated tRNALeu, and a novel mechanism of the enzymatic reaction was revealed. Thus, our interface program can play a critical role as a powerful tool for state-of-the-art sophisticated hybrid ab initio QM/MM MD simulations of large systems, such as biological macromolecules

Topoisomerase II beta targets DNA crossovers formed between distant homologous sites to induce chromatin opening

Type II DNA topoisomerases (topo II) flip the spatial positions of two DNA duplexes, called G- and T- segments, by a cleavage-passage-resealing mechanism. In living cells, these DNA segments can be derived from distant sites on the same chromosome. Due to lack of proper methodology, however, no direct evidence has been described so far. The beta isoform of topo II (topo II beta) is essential for transcriptional regulation of genes expressed in the final stage of neuronal differentiation. Here we devise a genome-wide mapping technique (eTIP-seq) for topo II beta target sites that can measure the genomic distance between G- and T-segments. It revealed that the enzyme operates in two distinctive modes, termed proximal strand passage (PSP) and distal strand passage (DSP). PSP sites are concentrated around transcription start sites, whereas DSP sites are heavily clustered in small number of hotspots. While PSP represent the conventional topo II targets that remove local torsional stresses, DSP sites have not been described previously. Most remarkably, DSP is driven by the pairing between homologous sequences or repeats located in a large distance. A model-building approach suggested that topo II beta acts on crossovers to unknot the intertwined DSP sites, leading to chromatin decondensation

Attitude of young psychiatrists toward coercive measures in psychiatry: a case vignette study in Japan

<p>Abstract</p> <p>Background</p> <p>Every psychiatrist must pay careful attention to avoid violating human rights when initiating coercive treatments such as seclusion and restraint. However, these interventions are indispensable in clinical psychiatry, and they are often used as strategies to treat agitated patients. In this study, we investigated young psychiatrists' attitudes toward psychiatric coercive measures.</p> <p>Methods</p> <p>A total of 183 young psychiatrists participated as subjects in our study. A questionnaire with a case vignette describing a patient with acute psychosis was sent to the study subjects via the Internet or by mail. This questionnaire included scoring the necessity for hospitalization, and the likelihood of prescribing seclusion and/or restraint, on a 9-point Likert scale (with 9 indicating strong agreement).</p> <p>Results</p> <p>There was general agreement among the study subjects that the case should be admitted to a hospital (8.91 ± 0.3) and secluded (8.43 ± 1.0). The estimated length of hospitalization was 13.53 ± 6.4 weeks. Regarding the likelihood of prescribing restraint, results showed great diversity (5.14 ± 2.5 on 9-point scale); psychiatrists working at general hospitals scored significantly higher (6.25 ± 2.5) than those working at university hospitals (5.02 ± 2.3) or psychiatric hospitals (4.15 ± 2.6). A two-group comparison of the length of inpatient care revealed a significant difference between those psychiatrists who scored 1-3 (n = 55, 14.22 ± 7.4 wks) and those who scored 7-9 (n = 62, 12.22 ± 4.0) regarding the need to use restraint.</p> <p>Conclusion</p> <p>Our results may reflect the current dilemma in Japanese psychiatry wherein psychiatrists must initiate coercive measures to shorten hospitalization stays. This study prompted its subject psychiatrists to consider coercive psychiatric treatments.</p

Pervasive Developmental Disorders and Autism Spectrum Disorders: Are These Disorders One and the Same?

The concept of pervasive developmental disorders (PDD) and autism spectrum disorders (ASD) closely resemble each other. Both ICD-10 and DSM-IV use the term PDD. The authors surveyed the perception of PDD/ASD and attitudes toward terminology. The subjects of this study were 205 medical/social-welfare professionals working in fields relating to developmental disorders. Questionnaires were mailed to site investigators at the collaborating institutes. With regard to what the scope of ASD and PDD encompasses, the answers were almost equally divided among three views: ASD and PDD are the same, PDD is wider in scope and ASD is wider. The terms PDD and autism were used in slightly different ways depended upon the situation. Our results demonstrate that the parameters of PDD and ASD are unclear and that the terms related to PDD/ASD are often used differently. Further studies are required to develop more clear and reliable diagnostic criteria for PDD

Suicidal ideation and burnout among psychiatric trainees in Japan

AIM: Burnout is a psychological condition that may occur in all workers after being exposed to excessive work-related stresses. We investigated suicidal ideation and burnout among Japanese psychiatric trainees as a part of the Burnout Syndrome Study (BoSS) International.  METHODS: In the Japanese branch, 91 trainees fully completed suicide ideation and behaviour questionnaire (SIBQ) and Maslach Burnout Inventory-General Survey (MBI-GS).  RESULTS: Passive suicidal ideation was reported by 38.5% of Japanese trainees and 22.0% of them had experienced active suicidal ideation. The burnout rate among Japanese subjects was 40.0%. These results were worse compared to the all 1980 trainees who fully completed the main outcome measure in BoSS International, 25.9%, 20.4% and 36.7%, respectively.  CONCLUSIONS: Our results suggest a higher risk of suicide among Japanese residents. Japan has a higher suicide rate than other countries. Early detection of, and appropriate intervention for, suicidal ideation is important in preventing suicide in psychiatry residents

Apolipoprotein E4 Frequencies in a Japanese Population with Alzheimer's Disease and Dementia with Lewy Bodies

BACKGROUND: The apolipoprotein E (APOE) ε4 allele has been reported to be a risk factor for Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Previous neuropathological studies have demonstrated similar frequencies of the APOE ε4 allele in AD and DLB. However, the few ante-mortem studies on APOE allele frequencies in DLB have shown lower frequencies than post-mortem studies. One reason for this may be inaccuracy of diagnosis. We examined APOE genotypes in subjects with AD, DLB, and a control group using the latest diagnostic criteria and MRI, SPECT, and MIBG myocardial scintigraphy. METHODS: The subjects of this study consisted of 145 patients with probable AD, 50 subjects with probable DLB, and a control group. AD subjects were divided into two groups based on age of onset: early onset AD (EOAD) and late onset AD (LOAD). All subjects had characteristic features on MRI, SPECT, and/or myocardial scintigraphy. RESULTS: The rate of APOE4 carrier status was 18.3% and the frequency of the ε4 allele was 9.7% in controls. The rate of APOE4 carrier status and the frequency of the ε4 allele were 47% and 27% for LOAD, 50% and 31% for EOAD, and 42% and 31% for DLB, respectively. CONCLUSION: The APOE4 genotypes in this study are consistent with previous neuropathological studies suggesting accurate diagnosis of AD and DLB. APOE4 genotypes were similar in AD and DLB, giving further evidence that the ε4 allele is a risk factor for both disorders

Pathway to psychiatric care in Japan: A multicenter observational study

<p>Abstract</p> <p>Background</p> <p>This study examines pathways to psychiatric care in Japan using the same method as the collaborative study carried out in 1991 under the auspices of the World Health Organization.</p> <p>Methods</p> <p>Thirteen psychiatric facilities in Japan were involved. Of the 228 patients who contacted psychiatric facilities with any psychiatric illness, eighty four visiting psychiatric facilities for the first time were enrolled. Pathways to psychiatric care, delays from the onset of illness to treatment prior to reaching psychiatrists were surveyed.</p> <p>Results</p> <p>Thirty three patients (39.4%) directly accessed mental health professionals, 32 patients (38.1%) reached them via general hospital, and 13 patients (15.5%) via private practitioners. The patients who consulted mental health professionals as their first carers took a longer time before consulting psychiatrists than the patients who consulted non-mental health professionals as their first carers. The patients who presented somatic symptoms as their main problem experienced longer delay from the onset of illness to psychiatric care than the patients who complained about depressive or anxiety symptoms. Prior to the visit to mental health professionals, patients were rarely informed about their diagnosis and did not receive appropriate treatments from their physicians. Private practitioners were more likely to prescribe psychotropics than physicians in general hospitals, but were less likely to inform their patients of their diagnosis.</p> <p>Conclusion</p> <p>This first pathway to psychiatric care study in Japan demonstrated that referral pathway in Japan heavily relies on medical resources. The study indicates possible fields and gives indications, underlining the importance of improving skills and knowledge that will facilitate the recognition of psychiatric disorders presenting with somatic and depressive symptoms in the general health care system and by private practitioners.</p