Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment

The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty-five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related homology modeling templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less-characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe. © 2011 Elsevier Ltd. All rights reserved

Parathyroid hormone 1 (1-34) acts on the scales and involves calcium metabolism in goldfish

金沢大学環日本海域環境研究センターThe effect of fugu parathyroid hormone 1 (fugu PTH1) on osteoblasts and osteoclasts in teleosts was examined with an assay system using teleost scale and the following markers: alkaline phosphatase (ALP) for osteoblasts and tartrate-resistant acid phosphatase (TRAP) for osteoclasts. Synthetic fugu PTH1 (1-34) (100 pg/ml-10 ng/ml) significantly increased ALP activity at 6 h of incubation. High-dose (10 ng/ml) fugu PTH1 significantly increased ALP activity even after 18 h of incubation. In the case of TRAP activity, fugu PTH1 did not change at 6 h of incubation, but fugu PTH1 (100 pg/ml-10 ng/ml) significantly increased TRAP activity at 18 h. Similar results were obtained for human PTH (1-34), but there was an even greater response with fugu PTH1 than with human PTH. In vitro, we demonstrated that both the receptor activator of the NF-κB ligand in osteoblasts and the receptor activator NF-κB mRNA expression in osteoclasts increased significantly by fugu PTH1 treatment. In an in vivo experiment, fugu PTH1 induced hypercalcemia resulted from the increase of both osteoblastic and osteoclastic activities in the scale as well as the decrease of scale calcium contents after fugu PTH1 injection. In addition, an in vitro experiment with intramuscular autotransplanted scale indicated that the ratio of multinucleated osteoclasts/mononucleated osteoclasts in PTH-treated scales was significantly higher than that in the control scales. Thus, we concluded that PTH acts on osteoblasts and osteoclasts in the scales and regulates calcium metabolism in goldfish. © 2011 Elsevier Inc. All rights reserved

発症早期ALS患者に対する超高用量メチルコバラミンの有効性・安全性について : ランダム化比較試験

Importance: Post hoc analysis in a phase 2/3 trial indicated ultra-high dose methylcobalamin slowed decline of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score at week 16 as well as at week 182, without increase of adverse events, in patients with amyotrophic lateral sclerosis (ALS) who were enrolled within 1 year from onset. Objective: To validate the efficacy and safety of ultra-high dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design: A multicenter, placebo-controlled, double-blind, randomized phase 3 trial with 12-week observation and 16-week randomized period, conducted from October 2017 to September 2019. Setting: Twenty-five neurology centers in Japan. Participants: Patients with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in ALSFRS-R total score, a percent forced vital capacity over 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulant. The target number was 64 in both methylcobalamin and placebo groups. Of 203 patients enrolled in the observation, 130 patients (age, 61.0 ± 11.7 years; female, 56) met the criteria and were randomly assigned through an electronic web-response system to methylcobalamin or placebo (65 for each). Of these, 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Interventions: Intramuscular injection of methylcobalamin 50 mg or placebo twice weekly for 16 weeks. Main outcomes and measures: The primary endpoint was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: The least-squares mean difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (−2.66 versus −4.63; 95% CI, 0.44–3.50; P = 0.012). The incidence of adverse events was similar between the two groups. Conclusions and relevance: Ultra-high dose methylcobalamin was efficacious in slowing functional decline and safe in the 16-week treatment period in ALS patients in the early stage and with moderate progression rate. Trial registration: UMIN-CTR Identifier: UMIN000029588 (umin.ac.jp/ctr); ClinicalTrials.gov Identifier: NCT03548311 (clinicaltrials.gov

Dr. PIAS: an integrative system for assessing the druggability of protein-protein interactions

<p>Abstract</p> <p>Background</p> <p>The amount of data on protein-protein interactions (PPIs) available in public databases and in the literature has rapidly expanded in recent years. PPI data can provide useful information for researchers in pharmacology and medicine as well as those in interactome studies. There is urgent need for a novel methodology or software allowing the efficient utilization of PPI data in pharmacology and medicine.</p> <p>Results</p> <p>To address this need, we have developed the 'Druggable Protein-protein Interaction Assessment System' (Dr. PIAS). Dr. PIAS has a meta-database that stores various types of information (tertiary structures, drugs/chemicals, and biological functions associated with PPIs) retrieved from public sources. By integrating this information, Dr. PIAS assesses whether a PPI is druggable as a target for small chemical ligands by using a supervised machine-learning method, support vector machine (SVM). Dr. PIAS holds not only known druggable PPIs but also all PPIs of human, mouse, rat, and human immunodeficiency virus (HIV) proteins identified to date.</p> <p>Conclusions</p> <p>The design concept of Dr. PIAS is distinct from other published PPI databases in that it focuses on selecting the PPIs most likely to make good drug targets, rather than merely collecting PPI data.</p

PHYSIOLOGICAL REACTION OF MEN UNDER EXERCISE TO RADIANT HEAT

To investigate the effect of the radiant heat on the human body in a hot environment, the subjects exposed their nude back to a radiant heat of 1.3 and 2.6 cal/ cm2. min, using the exsiccating infrared illuminators under a hot ambient condition of a temperature 31℃, with a relative humidity of 55% and a 0.5 m/sec air flow. The 8 subjects were healthy male college students aged 20 to 25. The following results were obtained by estimating the physiological reactions to different degrees of radiant heat at rest for 60 minutes and during exercise for 30 minutes on a bicycle e1gomete1·by 272 kg. m / min (or 600 kp. m/ min). 1) The mean skin temperature, heart rate, respiration rate and body weight loss r ate increased at rest in parallel with the degree of the radiant heat, and during exercise the mean skin temperature, heart rate, respiration rate, body weight loss rate and respiratory volume increased, but the Na+ loss rate decreased. The regression equation was obtained to show the quantitative relationship between the degree of the radiant heat and the physiological body reactions. 2) By computing the Heat Tolerance Index by Inoue et al., it was clarified that the higher the degree of the radiant heat was, the smaller was the index. And as there was a close correlation between the indices both at rest and during exercise, it was suggested that for the evaluation of heat tolerance, the radiant heat by the infra1ed illuminators is applicable as additional heat loading besides hot water bathing or staying in a hot chamber

Lattice and Grain-boundary Diffusion of Uranium in UO_2

The lattice and the grain-boundary diffusion of uranium ion in sintered UO_2 were measured within the temperature range 1900°～2150℃ with uranium-237 as a tracer by the sectioning method. The data obtained were analysed in the light of the theory of the grain-boundary diffusion based on an instantaneous source model. The lattice diffusion coefficient D can be obtained by the following equation : D=5.82×10^ exp(-72, 700/RT)cm^2/sec. On the other hand, the product D\u27・2α peculiar to the grain-boundary diffusion follows the equation : D\u27・2α= 5.19×10^ exp(-47, 200/RT)cm^3/sec, where D\u27 and 2α are the grain-boundary diffusion coefficient and the grain-boundary width, respectively

Performance of Air Curtain located at the top of entrance opening - Difference among indoor/outdoor/double-sided installation

Large openings of buildings are often used open, which results in heat loss due to intrusion of outdoor airflow and leakage of indoor air through the opening. To reduce air-conditioning load and to improve thermal environment in such a building, installing an air curtain at the opening can be a beneficial technique. The airflow blowing out of the device suppresses the heat exchange by buoyancy-induced convection through the opening. The impact of temperature difference, blowing speed, and installation position of the air curtain on temperature distribution and invasion flow rate of outdoor air was investigated by full-scale experiment under heating operation. Thermocouples were installed to measure vertical temperature distribution. Outdoor air infiltration was measured using tracer-gas method. The amount of outdoor air infiltration was evaluated based on both temperature difference and CO2 concentration. Comparing the results, it was found that the indoor air curtain was able to suppress the airflow through the opening. The indoor-outdoor temperature difference and CO2 concentration were highest when the air velocity was 4 m/s, suggesting that there is an optimal air velocity at which the air curtain can effectively suppress the airflow through the opening

A case of bloodstream co-infection of Saccharomyces cerevisiae and Candida glabrata while using micafungin

Abstract Background Saccharomyces cerevisiae is ubiquitous in the gastrointestinal tract and known as brewer's or baker's yeast. We experienced a case of S. cerevisiae and Candida glabrata co-infectious bloodstream infection. It is rare to detect both S. cerevisiae and Candida species in blood cultures together. Case We treated a 73-year-old man who developed a pancreaticoduodenal fistula infection after pancreaticoduodenectomy. The patient had a fever on postoperative day 59. We took blood cultures and detected C. glabrata. Thus, we started micafungin. On postoperative day 62, we retested blood cultures, and detected S cerevisiae and C. glabrata. We changed micafungin to liposomal amphotericin B. Blood cultures became negative on postoperative day 68. We changed liposomal amphotericin B to fosfluconazole and micafungin because of hypokalemia. He got well, and we terminated antifungal drugs 18 days after the blood cultures became negative. Conclusion Co-infection with S. cerevisiae and Candida species is rare. In addition, in this case, S. cerevisiae developed from blood cultures during micafungin administration. Thus, micafungin may not be effective enough to treat S. cerevisiae fungemia, although echinocandin is considered one of the alternative therapy for Saccharomyces infections