Functional modulation of a peroxygenase cytochrome P450: novel insight into the mechanisms of peroxygenase and peroxidase enzymes

AbstractCytochrome P450BSβ is a peroxygenase that catalyzes the α- or β-hydroxylation of myristic acid by utilizing H2O2. The wild-type enzyme not only hydroxylated myristic acid, but oxidized 3,5,3′,5′-tetramethylbenzidine (TMB), a peroxidase substrate, in a myristic acid-dependent reaction. Study of inhibition of hydroxylation of myristic acid by TMB indicates these two substrates compete for the same highly reactive intermediate during the course of their respective reactions. When deuterated myristic acid was used as a substrate to decrease hydroxylation activity, the rate of TMB oxidation increased. This increased rate of TMB oxidation was greatly enhanced when the R242K mutant enzyme bound with deuterated myristic acid was used. These results suggest that there are critical structural elements at the distal active site which determine whether this enzyme acts as a peroxygenase or a peroxidase

Emotional Similarity Word Embedding Model for Sentiment Analysis

We propose a method for constructing a dictionary of emotional expressions, which is an indispensable language resource for sentiment analysis in the Japanese. Furthermore, we propose a method for constructing a language model that reproduces emotional similarity between words, which to date has yet not been considered in conventional dictionaries and language models. In the proposed method, we pre-trained sentiment labels for the distributed representations of words. An intermediate feature vector was obtained from the pre-trained model. By learning an additional semantic label on this feature vector, we can construct an emotional semantic language model that embeds both emotion and semantics. To confirm the effectiveness of the proposed method, we conducted a simple experiment to retrieve similar emotional words using the constructed model. The results of this experiment showed that the proposed method can retrieve similar emotional words with higher accuracy than the conventional word-embedding model

Longevity-associated NADH Dehydrogenase Subunit-2 237 Leu/Met Polymorphism Modulates the Effects of Daily Alcohol Drinking on Yearly Changes in Serum Total and LDL Cholesterol in Japanese Men

Reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism, is reportedly associated with longevity in the Japanese population. The ND2-237Met genotype may exert resistance to atherogenic diseases, such as myocardial infarction or cerebrovascular disorders. To investigate whether ND2-237 Leu/Met polymorphism is associated with yearly changes in serum lipid levels, we conducted a longitudinal study of 107 healthy Japanese male subjects. Analysis of covariance revealed that the interaction between the ND2-237 Leu/Met genotypes and habitual drinking was significantly associated with yearly changes in serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels (p0.036 and p0.006, respectively). In multiple regression analysis, daily drinking was significantly and positively associated with yearly changes in serum LDLC levels in men with ND2-237Met (p0.026). After adjusting for covariates, yearly changes in serum LDLC levels were significantly lower in non-daily drinkers with ND2-237Met than in those with ND2-237Leu (p0.047). These results suggest that ND2-237Met has a beneficial impact on yearly changes in serum LDLC in non-daily drinkers but not in daily drinkers.</p

Crystal Structure of the Complex between Calyculin A and the Catalytic Subunit of Protein Phosphatase 1

AbstractThe crystal structure of the catalytic subunit of the protein phosphatase 1 (PP1), PP1γ, in complex with a marine toxin, calyculin A, was determined at 2.0 Å resolution. The metal binding site contains the phosphate group of calyculin A and forms a tight network via the hydrophilic interactions between PP1 and calyculin A. Calyculin A is located in two of the three grooves, namely, in the hydrophobic groove and the acidic groove on the molecular surface. This is the first observation to note that the inhibitor adopts not a pseudocyclic conformation but an extended conformation in order to form a complex with the protein. The amino acid terminus of calyculin A contributes, in a limited manner, to the binding to PP1γ, which is consistent with findings from the studies of dose-inhibition analysis

Optimal Collection of Peripheral Blood Stem Cells By Assessing CD34+ cells in Cancer Patients Administered with G-CSF after Chemotherapy

The mobilization of stem cells from bone marrow to peripheral blood in can-cer patients administered with recombinant human granulocyte colony-stimulat-ing factor (G-CSF) were examined. Eight patients were injected with G-CSF subcutaneously at a dosage of 250 μg/body daily from WBC nadir by chemother-apy. The quantity of peripheral blood stem cells (PBSC) was assessed by the colony assay of CFU-GM, which peaked on the third to fifth day after the com-mencement of daily G-CSF administration. G-CSF significantly amplified the amount of PBSC in five of eight patients. These results suggest that a sufficient amount of stem cells for transplantation (1.7 × 105-5.4 × 105 CFU-GM/Kg) can be obtained in such cases if 5 L of blood was processed by leukapheresis. A flow cytometry analysis revealed that CD34+ cells measured by mononuclear cell gat-ing coincidentaly increased with the peak of CFU-GM and therefore their assess-ment may serve an useful index for rapid monitoring of PBSC. And, days 3-5 after the commencement of G-CSF injection may be the optimal timing for PBSC collection

Comparison of Mortality between Japanese Peritoneal Dialysis and Hemodialysis Patients: A 5-Year Multicenter Follow-Up Study

To examine the relationship between dialysis modality and prognosis in Japanese patients, we conducted a prospective multicenter observational study. We recruited 83 background-matched peritoneal dialysis (PD) and 83 hemodialysis (HD) patients (average age, 64.9 years; men, 53.6%; diabetic patients, 22.9%; median duration of dialysis, 48 months in all patients) and followed them for 5 years. During the follow-up period, 27 PD patients (16 cardiovascular and 11 non-cardiovascular deaths) and 27 HD patients died (14 cardiovascular and 13 non-cardiovascular deaths). There were 8 PD patients switched to HD, and 6 PD patients received renal transplantation. Kaplan-Meier analysis revealed that the crude survival rate was not significantly different at the end of 5 years (PD 67.5% versus 67.5%, log-rank P = 0.719). The difference in cardiovascular and non-cardiovascular mortalities between PD and HD was not statistically significant. Multivariate Cox analysis showed that the independent predictors for death were age and serum albumin levels, but not the dialysis modality. This study showed that the overall mortality was not significantly different between PD and HD patients, which suggests that dialysis modality might not be an independent factor for survival in Japanese patients

A Clinico-pathological Study of Gastric Polyps Treated with Endoscopic Polypestomy

181 gastric polyps obtained by endoscopic polypectomy were studied clinico-pathologically. The polyps occurred most frequently in the lower portion, and the incidence of the polyps tended to increase with age. 91% (164/181) of the polyps were occupied by hyperplastic polyps, and 3 polyps and one polyp respectively with dysplastic and carcinomatous foci were detected in 164 hyperplastic polyps. Although hyperplastic polyps rarely transform into dysplasia or carcinoma, careful follow-up is recommended

SLITRK1-mediated noradrenergic projection suppression in the neonatal prefrontal cortex

SLITRK1 is an obsessive-compulsive disorder spectrum-disorders-ssociated gene that encodes a neuronal transmembrane protein. Here we show that SLITRK1 suppresses noradrenergic projections in the neonatal prefrontal cortex, and SLITRK1 functions are impaired by SLITRK1 mutations in patients with schizophrenia (S330A, a revertant of Homo sapiensspecific residue) and bipolar disorder (A444S). Slitrk1-KO newborns exhibit abnormal vocalizations, and their prefrontal cortices show excessive noradrenergic neurites and reduced Semaphorin3A expression, which suppresses noradrenergic neurite outgrowth in vitro. Slitrk1 can bind Dynamin1 and L1 family proteins (Neurofascin and L1CAM), as well as suppress Semaphorin3A-induced endocytosis. Neurofascin-binding kinetics is altered in S330A and A444S mutations. Consistent with the increased obsessive-compulsive disorder prevalence in males in childhood, the prefrontal cortex of male Slitrk1-KO newborns show increased noradrenaline levels, and serotonergic varicosity size. This study further elucidates the role of noradrenaline in controlling the development of the obsessive-compulsive disorder-related neural circuit

Spatial distributions of oxygenated organic compounds (dicarboxylic acids, fatty acids, and levoglucosan) in marine aerosols over the western Pacific and off the coast of East Asia: Continental outflow of organic aerosols during the ACE-Asia campaign

Aerosol sampling for major oxygenated organic compounds (dicarboxylic acids, fatty acids, and levoglucosan) was conducted from 15 March to 19 April 2001 on board the National Oceanic and Atmospheric Administration R/V Ronald H. Brown over the western North Pacific, the East China Sea, and the Sea of Japan, as part of the Asian Pacific Regional Aerosol Characterization Experiment (ACE-Asia) campaign. During the cruise, aerosol particles were collected on quartz fiber filters using a high-volume air sampler. Diacids were also collected using an annular denuder sampling system to assess their gas-particle partitioning. Concentrations of total diacids, total fatty acids, and levoglucosan were found to be higher off the coasts of East Asia than in the remote Pacific. Contributions of these organic compounds to total organic carbon and total organic matter (OM) were calculated to be 9.8 ± 2.3% and 19.0 ± 4.8%, respectively, assuming OM to be organic carbon x 1.6. Diacid concentrations were highly correlated with nss-SO2-/4 and NO-3, which originate from anthropogenic sources over East Asia. The temporal variations and chain-length distributions of fatty acids suggest that atmospheric transport of terrestrial organic materials is important off the coast of the continent. C2 – C5 diacids were present predominantly in the particulate phase. The relative abundances of C2 – C5 diacids stayed almost unchanged throughout the cruise, suggesting that deposition is more important than chemical decomposition as a sink of diacids and that they are relatively stable end products in the atmosphere