bluuebunny/crossref_metadata_2025_split huggingface dataset:
The molecular architecture of glucose‐1‐phosphate uridylyltransferase
Authors: Thoden James B. , Holden Hazel M. 
Published: February 2007

AbstractGlucose‐1‐phosphate uridylyltransferase, also referred to as UDP‐glucose pyrophosphorylase or UGPase, catalyzes the formation of UDP‐glucose from glucose‐1‐phosphate and UTP. Not surprisingly, given the central role of UDP‐glucose in glycogen synthesis and in the production of glycolipids, glycoproteins, and proteoglycans, the enzyme is ubiquitous in nature. Interestingly, however, the prokaryotic and eukaryotic forms of the enzyme are unrelated in amino acid sequence and structure. Here we describe the cloning and structural analysis to 1.9 Å resolution of the UGPase from Escherichia coli. The protein is a tetramer with 222 point group symmetry. Each subunit of the tetramer is dominated by an eight‐stranded mixed β‐sheet. There are two additional layers of β‐sheet (two and three strands) and 10 α‐helices. The overall fold of the molecule is remarkably similar to that observed for glucose‐1‐phosphate thymidylyltransferase in complex with its product, dTDP‐glucose. On the basis of this similarity, a UDP‐glucose moiety has been positioned into the active site of UGPase. This protein/product model predicts that the side chains of Gln 109 and Asp 137, respectively, serve to anchor the uracil ring and the ribose of UDP‐glucose to the protein. The β‐phosphoryl group of the product is predicted to lie within hydrogen bonding distance to the ε‐nitrogen of Lys 202 whereas the carboxylate group of Glu 201 is predicted to bridge the 2′‐ and 3′‐hydroxyl groups of the glucosyl moiety. Details concerning the overall structure of UGPase and a comparison with glucose‐1‐phosphate thymidylyltransferase are presented.
Solution structure of the coxsackievirus and adenovirus receptor domain 2
Authors: Jiang Shaokai , Caffrey Michael 
Published: February 2007

AbstractThe coxsackievirus and adenovirus receptor (CAR) mediates entry of coxsackievirus and adenovirus. CAR possesses an extracellular region that is comprised of 2 immunoglobulin domains termed CAR–D1 and CAR–D2. In the present work, the solution structure of CAR–D2, consisting of residues 142–235 of human CAR, has been determined by NMR spectroscopy. CAR–D2 is shown to be a β‐sandwich motif comprised of two β‐sheets, which are stabilized by two disulfide bonds. The first β‐sheet is comprised of β‐strands A, B, and E, and the second β‐sheet is comprised of β‐strands C, F, and G. A relatively hydrophobic helix is found between β‐strands C and E, which replaces β‐strand D of the classical c‐type immunoglobulin fold.
Important roles of hydroxylic amino acid residues in the function of Bacillus subtilis adenylosuccinate lyase
Authors: Segall Mark L. , Cashman Meghan A. , Colman Roberta F. 
Published: February 2007

AbstractThr93, Ser94, Thr140, and Ser306 are conserved in all adenylosuccinate lyases (ASL) and are close to other amino acids previously identified by mutagenesis as being in the active site. To test their involvement in the enzyme's function, each of these amino acids was replaced by alanine. All the mutants exhibit circular dichroism spectra which are similar to that of wild‐type enzyme, indicating there is no appreciable change in secondary structure. T93A exhibits 0.5% of the Vmax of wild‐type ASL with a 10‐fold increase in Km for adenylosuccinate. S94A has 65% of the Vmax of wild‐type ASL with little change in Km. T140A exhibits 0.03% of the activity of wild‐type enzyme with an 11‐fold increase in Km. S306A has 0.4% of the Vmax of wild‐type ASL with a sevenfold increase in Km. Measurements of the pH‐Vmax profile reveal a pK2 value for S94A of 7.83 and S306A of 7.65, in contrast to 8.24 for the wild‐type enzyme and 8.42 for T93A. Thr93 may orient adenylosuccinate optimally for catalysis, while Ser94 stabilizes protonated His89, a determinant of pK2. Thr140 may, through hydrogen bonding, interact with Asn270, an amino acid essential for catalysis. Ser306 may be involved in a hydrogen bond network that ultimately stabilizes protonated His68, which is probably the general acid in the reaction of enzyme with substrate. The results of this paper demonstrate the importance in the catalytic function of ASL of hydrogen bonds and hydrogen bonding networks involving serine and threonine.
A unified mechanism for protein folding: Predetermined pathways with optional errors
Authors: Krishna Mallela M.G. , Englander S. Walter 
Published: February 2007

AbstractThere is a fundamental conflict between two different views of how proteins fold. Kinetic experiments and theoretical calculations are often interpreted in terms of different population fractions folding through different intermediates in independent unrelated pathways (IUP model). However, detailed structural information indicates that all of the protein population folds through a sequence of intermediates predetermined by the foldon substructure of the target protein and a sequential stabilization principle. These contrary views can be resolved by a predetermined pathway—optional error (PPOE) hypothesis. The hypothesis is that any pathway intermediate can incorporate a chance misfolding error that blocks folding and must be reversed for productive folding to continue. Different fractions of the protein population will then block at different steps, populate different intermediates, and fold at different rates, giving the appearance of multiple unrelated pathways. A test of the hypothesis matches the two models against extensive kinetic folding results for hen lysozyme which have been widely cited in support of independent parallel pathways. The PPOE model succeeds with fewer fitting constants. The fitted PPOE reaction scheme leads to known folding behavior, whereas the IUP properties are contradicted by experiment. The appearance of a conflict with multipath theoretical models seems to be due to their different focus, namely on multitrack microscopic behavior versus cooperative macroscopic behavior. The integration of three well‐documented principles in the PPOE model (cooperative foldons, sequential stabilization, optional errors) provides a unifying explanation for how proteins fold and why they fold in that way.
Crystal structure of AGR_C_4470p from Agrobacterium tumefaciens
Authors: Vorobiev Sergey M. , Neely Helen , Seetharaman Jayaraman , Ma Li‐Chung , Xiao Rong , Acton Thomas B. , Montelione Gaetano T. , Tong Liang 
Published: February 2007

AbstractWe report here the crystal structure at 2.0 Å resolution of the AGR_C_4470p protein from the Gram‐negative bacterium Agrobacterium tumefaciens. The protein is a tightly associated dimer, each subunit of which bears strong structural homology with the two domains of the heme utilization protein ChuS from Escherichia coli and HemS from Yersinia enterocolitica. Remarkably, the organization of the AGR_C_4470p dimer is the same as that of the two domains in ChuS and HemS, providing structural evidence that these two proteins evolved by gene duplication. However, the binding site for heme, while conserved in HemS and ChuS, is not conserved in AGR_C_4470p, suggesting that it probably has a different function. This is supported by the presence of two homologs of AGR_C_4470p in E. coli, in addition to the ChuS protein.
The X‐ray crystal structure of PA1607 from Pseudomonas aureginosa at 1.9 Å resolution—a putative transcription factor
Authors: Sieminska Edyta A.L. , Xu Xiaohui , Savchenko Alexei , Sanders David A.R. 
Published: February 2007

AbstractThe structure of the PA1607 protein from Pseudomonas aureginosa was determined at 1.85 Å resolution using the Se‐Met multiwavelength anomalous diffraction (MAD) technique. PA1607 forms a dimer and adopts a winged‐helix motif similar to the MarR family of transcription regulators, though it has an unusual dimerization profile. The DNA‐binding regions and a putative metal‐binding site are not conserved in PA1607.
A system for storage of references. A method of storage and retrieval of references on a personal microcomputer
Authors: Alagesan K. , McLeod G. F. 
Published: February 2007

SummaryA computer program, written in BBC BASIC, for storage and retrieval of literature references on a personal microcomputer Jilted with floppy disc drives is described. The storage capacity is 425 references per 100K disc. A versatile search function allows ready access to references by matching any number of combinations of the following 10 items; authors, name, year and volume of journal, pages, reference number, und up to four key words. The resulting bibliographic list can be formatted to any desired house style. There is a facility for sorting the list into alphabetical order of the authors und the use of a wordprocessor for special print styles on any BBC compatible printer. These two features make retyping the list unnecessary. A search can be done manually while browsing through the references. Advantages of this system over the existing packages are discussed. The program is totally run by on‐screen menus, and it is easy to use, even by a novice.
Propofol for intravenous sedation
Authors: MACKENZIE N. , GRANT I. S. 
Published: February 2007

SummaryThis study investigated the properties of propofol when given by subanaesthetic infusion to provide sedation as an adjunct to spinal anaesthesia for lower limb surgery in 40 patients. Sedation, defined as sleep with preservation of eyelash reflex and purposeful reaction to verbal or mild physical stimulation, was satisfactorily achieved and maintained with minimal complications. The mean duration of infusion was 98 minutes and a mean infusion rate of 3.0 mg/kg/hour was required in patients over 65. This was significantly less (p < 0.005) than the 4.1 mg/kg/hour required in younger patients. Recovery was impressively rapid; patients regained full consciousness approximately 4 minutes after the end of infusion, and were free from minor postoperative sequelae. Conversion to general anaesthesia was achieved in three patients where surgery encroached outside the analgesic field of the regional block, simply by increasing the infusion rate to approximately 10 mg/kg/hour.
Pharmacokinetics of a novel agent, R667, in patients with emphysema
Authors: Chiu Yu‐Yuan , Roth Michael D , Kolis Stanley , Rogovitz David , Davies Brian 
Published: February 2007

AimsTo evaluate the pharmacokinetics of R667, a novel emphysema agent, in patients with moderate to severe emphysema.MethodsMultiple‐dose pharmacokinetics of R667 and its metabolites in emphysematous patients were studied in a multicentre, randomized, single‐blind, and placebo‐controlled trial. Four groups of 10 patients per group received placebo, 0.2, 0.5, or 1 mg R667 once a day for 14–16 days. On day 14 (±1), blood samples were taken at predose and 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after dosing.ResultsPharmacokinetic analysis of the data indicated that the mean steady‐state Cmax and AUC(0,τ) of R667 appeared to be dose proportional over the dose range of 0.2–1 mg when administered to emphysematous patients. Mean metabolite to R667 ratios for Cmax or AUC(0,τ) were, in general, similar across the dose range of 0.2–1 mg.ConclusionsThe pharmacokinetics of R667 and its metabolites appeared to be similar for patients with emphysema and healthy volunteers. Multiple‐dose administration of 0.2–1 mg of R667 for up to 16 days was well tolerated in patients with emphysema.
Piloerection induced by replacing fluvoxamine with milnacipran
Authors: Hori Satoko , Matsuo Nobuko , Yamamoto Akiko , Hazui Tomomi , Yagi Hiromi , Nakano Marumi , Suzuki Yuka , Miki Akiko , Ohtani Hisakazu , Sawada Yasufumi 
Published: February 2007

AimsTo present a case of piloerection after replacing fluvoxamine maleate with milnacipran hydrochloride, and to analyse this effect based on receptor occupancy theory.MethodsA 40‐year‐old female with a 3‐year history of panic disorder was prescribed fluvoxamine 50 mg day−1 in addition to clorazepate dipotassium and sulpiride. Depression was not improved and she complained of fatigue, lack of energy and drowsiness. These symptoms worsened within a few days of an increase in the dose of fluvoxamine to 50 mg twice daily. Since an interaction between fluvoxamine and tizanidine, prescribed by another clinic, was suspected, fluvoxamine was replaced with milnacipran 50 mg day−1. Although her drowsiness improved, she complained of piloerection throughout her body. This symptom gradually abated within a week and when the dosage of milnacipran was increased to 100 mg day−1 at 2 months, no further piloerection occurred. We calculated the changes in α1‐adrenoceptor occupancy by endogenous norepinephrine during treatment with the usual doses of milnacipran, fluvoxamine and imipramine by using pharmacokinetic and pharmacodynamic parameters obtained from the literature.ResultsThe ratios of α1‐adrenoceptor occupancy by endogenous norepinephrine during the treatment with milnacipran, fluvoxamine and imipramine to that without drug were estimated to be 7.13, 1.00 and 4.12, respectively. The α1‐adrenoceptor occupancy by endogenous norepinephrine was increased in a dose‐dependent manner by milnacipran, whereas fluvoxamine had essentially no effect.ConclusionsThe piloerection observed after the replacement of fluvoxamine with milnacipran in this patient appears to have been due to an increase in the α1‐adrenoceptor occupancy by endogenous norepinephrine induced by milnacipran.
Population pharmacokinetic and pharmacodynamic models of remifentanil in healthy volunteers using artificial neural network analysis
Authors: Kang S. H. , Poynton M. R. , Kim K. M. , Lee H. , Kim D. H. , Lee S. H. , Bae K. S. , Linares O. , Kern S. E. , Noh G. J. 
Published: February 2007

AimsAn ordinary sigmoidEmaxmodel could not predict overshoot of electroencephalographic approximate entropy (ApEn) during recovery from remifentanil effect in our previous study. The aim of this study was to evaluate the ability of an artificial neural network (ANN) to predict ApEn overshoot and to evaluate the predictive performance of the pharmacokinetic model, and pharmacodynamic models of ANN with respect to data used.MethodsUsing a reduced number of ApEn instances (n = 1581) to make NONMEM modelling feasible and complete ApEn data (n = 24 509), the presence of overshoot was assessed. A total of 1077 measured remifentanil concentrations and ApEn data, and a total of 24 509 predicted concentrations and ApEn data were used in the pharmacodynamic model A and B of ANN, respectively. The testing subset of model B (n = 7352) was used to evaluate the ability of ANN to predict overshoot of ApEn. Mean squared error (MSE) was calculated to evaluate the predictive performance of the ANN models.ResultsWith complete ApEn data, ApEn overshoot was observed in 66.7% of subjects, but only in 37% with a reduced number of ApEn instances. The ANN model B predicted 77.8% of ApEn overshoot. MSE (95% confidence interval) was 57.1 (3.22, 71.03) for the pharmacokinetic model, 0.148 (0.004, 0.007) for model A and 0.0018 (0.0017, 0.0019) for model B.ConclusionsThe reduced ApEn instances interfered with the approximation of true electroencephalographic response. ANN predicted 77.8% of ApEn overshoot. The predictive performance of model B was significantly better than that of model A.
Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease
Authors: Lehr Thorsten , Staab Alexander , Tillmann Christiane , Trommeshauser Dirk , Raschig Andreas , Schaefer Hans Guenter , Kloft Charlotte 
Published: February 2007

What is already known about this subject • Several studies in predominantly healthy subjects have investigated the pharmacokinetics of NS2330 and its major metabolite M1.• However, its pharmacokinetics have not been characterized in Alzheimer's disease patients, the target population for NS2330.• In addition, no covariates have previously been found to influence the plasma concentration‐time profiles of NS2330 and/or M1. What this study adds • A descriptive and predictive population pharmacokinetic model for NS2330 and its metabolite was successfully developed in a population of patients with Alzheimer's disease.• A covariate analysis elucidated sex and creatinine clearance as having an influence on the plasma concentration‐time profiles of NS2330 after long‐term treatment.AimsTo develop a population pharmacokinetic model for NS2330 and its major metabolite M1 based on data from a 14 week proof of concept study in patients with Alzheimer's disease, and to identify covariates that might influence the pharmacokinetic characteristics of the drug and/or its metabolite.MethodsPlasma data from 320 subjects undergoing multiple oral dosing, and consisting of 1969 NS2330 and 1714 metabolite concentrations were fitted simultaneously using NONMEM.ResultsPlasma concentration‐time profiles of NS2330 and M1 were best described by one‐compartment models with first‐order elimination for both compounds. Absorption of NS2330 was best modelled by a first‐order process. Low apparent clearances together with large apparent volumes of distribution resulted in long half‐lives of 234 h (NS2330) and 374 h (M1). The covariate analysis identified weight, sex, CLCR, BMI and age as influencing the pharmacokinetics of NS2330 and/or M1. However, simulations performed revealed that only CLCR and sex had a significant effect on the steady‐state plasma concentration‐time profiles. Females with a creatinine clearance of 35.6 ml min−1 showed a 62% increased exposure compared with males without renal impairment. The robustness and accuracy of the model were demonstrated by the successful predictivity of an external dataset.ConclusionsA descriptive, robust and predictive model for NS2330 and its M1 metabolite was developed. Important covariates influencing pharmacokinetics were identified, which might guide the further development of NS2330 and optimize its long‐term use in the treatment of Alzheimer's disease.
A population pharmacokinetic approach to ceftazidime use in burn patients: influence of glomerular filtration, gender and mechanical ventilation
Authors: Conil Jean Marie , Georges Bernard , Lavit Michel , Laguerre Jacky , Samii Kamram , Houin Georges , Saivin Sylvie 
Published: February 2007

What is already known about this subject • There is only one published study of the population pharmacokinetics of ceftazidime in burn patients. Only one covariate (plasma creatinine concentration) was found to contribute to the interindividual variability in the disposition of the drug. What this study adds • Three other covariables (creatinine clearance, mechanical ventilation and gender) have been added to a two compartment pharmacokinetic model incorporating multiplicative error, and these are able to explain much of the interindividual variability in ceftazidime disposition in burn patients.AimsThe aim of this study was to evaluate the disposition of ceftazidime in burn patients using a population pharmacokinetic approach, and to identify the clinical and biological parameters influencing its pharmacokinetics.MethodsThe development of the pharmacokinetic model was based on 237 serum ceftazidime concentrations from 50 burn patients. The determination of the pharmacokinetic parameters and the selection of covariates were performed using a nonlinear mixed‐effect modelling method.ResultsA two‐compartment model with first order elimination incorporating a proportional error model best fitted the data. Ceftazidime clearance (CL, l h−1) was significantly correlated with creatinine clearance (CLCR), and the distribution volume of the peripheral compartment (V2, l) was correlated with gender, mechanical ventilation and the CLCR. The final model was defined by the following equations:
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Ceftazidime clearance was 6.1 and 5.7 l h−1 for mechanically ventilated males and females, respectively, and 7.2 and 6.6 l h−1 for nonventilated patients. The total volume of distribution was 31.6 and 49.4 l for mechanically ventilated males and females, respectively, and 22.8 and 28.1 l h −1for nonventilated patients.Conclusions We have shown that gender, mechanical ventilation and CLCR significantly influence the disposition of ceftazidime in burn patients. Interindividual variability in the pharmacokinetics of ceftazidime was significant and emphasizes the need for therapeutic monitoring.
No association between CYP2D6 polymorphisms and personality trait in Japanese
Authors: Iwashima Kumiko , Yasui‐Furukori Norio , Kaneda Ayako , Saito Manabu , Nakagami Taku , Sato Yasushi , Kaneko Sunao 
Published: February 2007

What is already known about this subject • CYP2D6 mediates, to some extent, the synthesis of the neurotransmitters, serotonin and dopamine in the brain. A positive relationship between CYP2D6 activity and personality has been suggested, while other studies have failed to find a relationship.• Therefore, because of these inconsistent findings, the association between CYP2D6 polymorphism and interindividual variability in personality has not yet been resolved. What this study adds • The detailed genotypes for CYP2D6 were identified using DNA tip in a large number of Japanese subjects. However there were no correlations between scores of personality and CYP2D6 genotypes.• This study demonstrated that there was no significant association between CYP2D6 activity and personality trait in the Japanese population.AimsThe polymorphic enzyme CYP2D6 is expressed not only in liver but also in brain at low concentrations. CYP2D6 mediates, to some extent, the synthesis of the neurotransmitters, serotonin and dopamine. We investigated a possible association between the genetic polymorphism of CYP2D6 and individual personality trait.MethodsMentally and physically healthy volunteers were recruited (n = 342). Temperament and Character Inventory (TCI) and CYP2D6 genotyping were performed in all subjects. We detected mutated alleles which were identified using the Amplichip CYP450 DNA chip.ResultsThe number of phenotypes, assumed by genotype for ultrarapid metabolizers (UM), extensive metabolizers (EM), intermediate metabolizers (IM) and poor metabolizers (PM) were 4 (1.1%), 262 (76.6%), 75 (21.9%) and 1 (0.3%), respectively. There were no differences in scores for novelty seeking, harm avoidance, reward dependence or persistence among the CYP2D6 phenotypes. The number of mutated alleles for CYP2D6 did not differ for scores of novelty seeking, harm avoidance, reward dependence or persistence. In subitem analyses, only RD3 (attachment) had a significant difference both in the CYP2D6 phenotype (P < 0.05) and genotype (P < 0.05).ConclusionsThis study did not demonstrate a significant association between CYP2D6 activity and personality trait because of the small interindividual variability in CYP2D6 activity within the Japanese population.