bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of macroeconomic variables on suicide
Authors: BERK MICHAEL , DODD SEETAL , HENRY MARGARET 
Published: December 2005

Background. There are a large number of factors mediating suicide. Many studies have searched for a direct causal relationship between economic hardship and suicide, however, findings have been varied.Method. Suicide data was obtained from the Australian Bureau of Statistics for the period between January 1968 and August 2002. These were correlated with a suite of macroeconomic data including housing loan interest rates, unemployment rates, days lost to industrial disputes, Consumer Price Index, gross domestic product, and the Consumer Sentiment Index.Results. A total of 51845 males and 16327 females committed suicide between these dates. There were significant associations between suicide rates and eleven macroeconomic indicators for both genders in at least one age range. Data was divided into male and female and five age ranges and pooled ages. Analyses were conducted on these 132 datasets resulting in 80 significant findings. The data was generally stronger for indices measuring economic performance than indices measuring consumers' perceptions of the state of the economy. A striking difference between male and female trends was seen. Generally, male suicide rates increased with markers of economic adversity, while the opposite pattern was seen in females. There were significantly different patterns in age-stratified data, with for example higher housing loan interest rates having a positive association with suicide in younger people and a negative association in older age groups.Conclusion. Macroeconomic trends are significantly associated with suicide. The patterns in males and females are very different, and there are further substantial age-related differences.
Detecting single atoms of calcium and iron in biological structures by electron energy‐loss spectrum‐imaging
Authors: Leapman R. D. 
Published: December 2005

SummaryAs techniques for electron energy‐loss spectroscopy (EELS) reach a higher degree of optimization, experimental detection limits for analysing biological structures are approaching values predicted by the physics of the electron scattering. Theory indicates that it should be possible to detect a single atom of certain elements like calcium and iron contained in a macromolecular assembly using a finely focused probe in the scanning transmission electron microscope (STEM). To test this prediction, EELS elemental maps have been recorded with the spectrum‐imaging technique in a VG Microscopes HB501 STEM coupled to a Gatan Enfina spectrometer, which is equipped with an efficient charge‐coupled device (CCD) array detector. By recording spectrum‐images of haemoglobin adsorbed onto a thin carbon film, it is shown that the four heme groups in a single molecule can be detected with a signal‐to‐noise ratio of ∼10 : 1. Other measurements demonstrate that calcium adsorbed onto a thin carbon film can be imaged at single atom sensitivity with a signal‐to‐noise ratio of ∼5 : 1. Despite radiation damage due to the necessarily high electron dose, it is anticipated that mapping single atoms of metals and other bound elements will find useful applications in characterizing large protein assemblies.
Successful application of spatial difference technique to electron energy‐loss spectroscopy studies of Mo/SrTiO3 interfaces
Authors: Gao M. , Scheu C. , Tchernychova E. , Rühle M. 
Published: December 2005

SummaryThe electron energy‐loss near‐edge structure (ELNES) of Mo/SrTiO3 interfaces has been studied using high spatial resolution electron energy‐loss spectroscopy (EELS) in a dedicated scanning transmission electron microscope. Thin films of Mo with a thickness of 50 nm were grown on (001)‐orientated SrTiO3 surfaces by molecular beam epitaxy at 600 °C. High‐resolution transmission electron microscopy revealed that the interfaces were atomically abrupt with the (110)Mo plane parallel to the substrate surface. Ti‐L2,3 (∼460 eV), O‐K (∼530 eV), Sr‐L2,3 (∼1950 eV) and Mo‐L2,3 (∼2500 eV) absorption edges were acquired by using the Gatan Enfina parallel EELS system with a CCD detector. The interface‐specific components of the ELNES were extracted by employing the spatial difference method. The interfacial Ti‐L2,3 edge shifted to lower energy values and the splitting due to crystal field became less pronounced compared to bulk SrTiO3, which indicated that the Ti atoms at the interface were in a reduced oxidation state and that the symmetry of the TiO6 octahedra was disturbed. No interfacial Sr‐L2,3 edge was observed, which may demonstrate that Sr atoms do not participate in the interfacial bonding. An evident interface‐specific O‐K edge was found, which differs from that of the bulk in both position (0.8 ± 0.2 eV positive shift) and shape. In addition, a positive shift (0.9 ± 0.3 eV) occurred for the interfacial Mo‐L2,3, revealing an oxidized state of Mo at the interface. Our results indicated that at the interface SrTiO3 was terminated with TiO2. The validity of the spatial difference technique is discussed and examined by introducing subchannel drift intentionally.
Advances in EELS spectroscopy by using new detector and new specimen preparation technologies
Authors: Scheu C. , Gao M. , Van Benthem K. , Tsukimoto S. , Schmidt S. , Sigle W. , Richter G. , Thomas J. 
Published: December 2005

SummaryFirst results obtained with a Gatan UHV Enfina system, which was attached to a VG HB 501 UX dedicated STEM, are reported. The Enfina system is based on a CCD detector and offers, compared to the previously used photodiode array, a narrower point‐spread function, higher sensitivity, and faster read‐out capabilities. These improvements are demonstrated with electron energy‐loss measurements on various oxides, such as Al2O3, TiO2 and SrTiO3. It is shown that a better energy resolution is achieved and that acquisition of high‐energy absorption edges with a reasonable signal‐to‐noise ratio becomes possible. Furthermore, we report on the influence of the TEM specimen quality on the energy‐loss spectra. Thin amorphous layers at the specimen surfaces, which are induced by ion‐milling processes, can modify specific electron energy‐loss near‐edge structure features. We found that for the investigated ceramics the use of low‐energy ion‐milling systems is highly recommended, since the loss of energy‐loss near‐edge structure details by the presence of the amorphous layers is considerably reduced. This is especially true for very thin specimens.
Acid sphingomyelinase and inhibition by phosphate ion: role of inhibition by phosphatidyl‐myo‐inositol 3,4,5‐triphosphate in oligodendrocyte cell signaling
Authors: Testai F. D. , Landek M. A. , Goswami R. , Ahmed M. , Dawson G. 
Published: December 2005

AbstractThere is ample evidence that both acid (ASMase) and neutral (NSMase) sphingomyelinases play a role in cell death so inhibitors of either enzyme could have significant value as protectors against neurodegeneration. We used a fluorogenic sphingomyelinase substrate, 6‐hexadecanoylamino‐4‐methylumbelliferyl‐phosphorylcholine, and a [14C]choline‐labeled sphingomyelin substrate to screen large numbers of phosphocompounds for inhibition of ASMase in extracts of human oligodendroglioma cells (HOG) and neonatal rat oligodendrocytes. Non‐competitive inhibition was observed with inorganic phosphate and AMP, which was a more potent inhibitor of ASMase than cyclic AMP, ADP or ATP. However, other nucleotide phosphates, sugar phosphates, nucleotide sugars and glycerol phosphate did not inhibit ASMase. Our key finding was that phosphatidyl‐myo‐inositol 3,4,5‐triphosphate [PtdIns (3,4,5)P3] was a much more potent inhibitor of ASMase than lysophosphatidic acid or phosphatidyl‐myo‐inositol 4,5‐diphosphate [PtdIns(4,5)P2]. When PtdIns(3,4,5)P3 was added to cultured cells we observed 50% inhibition of ASMase but no inhibition of other lysosomal hydrolases. After transfection of HOG cells with the tumor supressor phosphatase and tensin homolog protein (PTEN), which hydrolyses PtdIns(3,4,5)P3 to PtdIns(4,5)P2, we observed a two‐fold increase in ASMase activity. Furthermore, the phosphatidylinositol‐3‐kinase inhibitor wortmannin (which reduces PtdIns(3,4,5)P3 levels) also resulted in activation of ASMase. We propose that the small amount of ASMase activity associated with detergent‐resistant cell membranes (Rafts) is regulated by PtdIns(3,4,5)P3 and is most likely involved in receptor clustering and capping.
Group I metabotropic glutamate receptors mediate the inhibition of phosphatidylserine synthesis in rat cerebellar slices: a possible role in physiology and pathology
Authors: Buratta Sandra , Mambrini Raffaela , Miniaci Maria Concetta , Tempia Filippo , Mozzi Rita 
Published: December 2005

AbstractIn cerebellar slices, the lowering of oxygen availability, obtained by bubbling N2 in the medium, reduced the incorporation of radioactive serine into phosphatidylserine (PtdSer). CPCCOEt, an antagonist of metabotropic glutamate receptors type 1 (mGluR1) counteracted the effect, whereas antagonists of NMDA or AMPA receptors were ineffective. In oxygenated slices, agonists of Group I mGluRs, which include mGluR1, inhibited PtdSer synthesis. This effect was also counteracted by CPCCOEt. These findings indicate that glutamate inhibits PtdSer synthesis by acting on mGluR1. This could be important in relation to the known release of glutamate in hypoxia–ischaemia conditions. In cerebellar Purkinje cells, mGluR1 are involved in the generation of mGluR‐EPSP evoked by parallel fibre stimulation. The administration of l‐serine to cerebellar slices reduced in a dose‐dependent manner the mGluR‐EPSP evoked by parallel fibre stimulation. The effect was mostly due to the increased synthesis of PtdSer. Thus inhibition of PtdSer synthesis, mediated by mGluR1, may participate in the generation of mGluR‐EPSP.
Structure of MurF from Streptococcus pneumoniae co‐crystallized with a small molecule inhibitor exhibits interdomain closure
Authors: Longenecker Kenton L. , Stamper Geoffrey F. , Hajduk Philip J. , Fry Elizabeth H. , Jakob Clarissa G. , Harlan John E. , Edalji Rohinton , Bartley Diane M. , Walter Karl A. , Solomon Larry R. , Holzman Thomas F. , Gu Yu Gui , Lerner Claude G. , Beutel Bruce A. , Stoll Vincent S. 
Published: December 2005

AbstractIn a broad genomics analysis to find novel protein targets for antibiotic discovery, MurF was identified as an essential gene product for Streptococcus pneumonia that catalyzes a critical reaction in the biosynthesis of the peptidoglycan in the formation of the cell wall. Lacking close relatives in mammalian biology, MurF presents attractive characteristics as a potential drug target. Initial screening of the Abbott small‐molecule compound collection identified several compounds for further validation as pharmaceutical leads. Here we report the integrated efforts of NMR and X‐ray crystallography, which reveal the multidomain structure of a MurF–inhibitor complex in a compact conformation that differs dramatically from related structures. The lead molecule is bound in the substrate‐binding region and induces domain closure, suggestive of the domain arrangement for the as yet unobserved transition state conformation for MurF enzymes. The results form a basis for directed optimization of the compound lead by structure‐based design to explore the suitability of MurF as a pharmaceutical target.
A statistical approach to the interpretation of molecular dynamics simulations of calmodulin equilibrium dynamics
Authors: Likić Vladimir A. , Gooley Paul R. , Speed Terence P. , Strehler Emanuel E. 
Published: December 2005

AbstractA sample of 35 independent molecular dynamics (MD) simulations of calmodulin (CaM) equilibrium dynamics was prepared from different but equally plausible initial conditions (20 simulations of the wild‐type protein and 15 simulations of the D129N mutant). CaM's radius of gyration and backbone mean‐square fluctuations were analyzed for the effect of the D129N mutation, and simulations were compared with experiments. Statistical tests were employed for quantitative comparisons at the desired error level. The computational model predicted statistically significant compaction of CaM relative to the crystal structure, consistent with the results of small‐angle X‐ray scattering (SAXS) experiments. This effect was not observed in several previously reported studies of (Ca2+)4‐CaM, which relied on a single MD run. In contrast to radius of gyration, backbone mean‐square fluctuations showed a distinctly non‐normal and positively skewed distribution for nearly all residues. Furthermore, the D129N mutation affected the backbone dynamics in a complex manner and reduced the mobility of Glu123, Met124, Ile125, Arg126, and Glu127 located in the adjacent α‐helix G. The implications of these observations for the comparisons of MD simulations with experiments are discussed. The proposed approach may be useful in studies of protein equilibrium dynamics where MD simulations fall short of properly sampling the conformational space, and when the comparison with experiments is affected by the reproducibility of the computational model.
The kinetic behavior of insulin fibrillation is determined by heterogeneous nucleation pathways
Authors: Librizzi Fabio , Rischel Christian 
Published: December 2005

AbstractWhen subjected to acidic conditions and high temperature, insulin is known to produce fibrils that display the common properties of disease amyloids. Thus, clarifying the mechanisms of insulin fibrillation can help the general understanding of amyloidal aggregation. Insulin fibrillation exhibits a very sharp time dependence, with a pronounced lag phase and subsequent explosive growth of amyloidal aggregates. Here we show that the initial stages of this process can be well described by exponential growth of the fibrillated proteins. This indicates that the process is mainly controlled by a secondary nucleation pathway.
Gateway vectors for the production of combinatorially‐tagged His6‐MBP fusion proteins in the cytoplasm and periplasm of Escherichia coli
Authors: Nallamsetty Sreedevi , Austin Brian P. , Penrose Kerri J. , Waugh David S. 
Published: December 2005

AbstractMany proteins that accumulate in the form of insoluble aggregates when they are overproduced in Escherichia coli can be rendered soluble by fusing them to E. coli maltose binding protein (MBP), and this will often enable them to fold in to their biologically active conformations. Yet, although it is an excellent solubility enhancer, MBP is not a particularly good affinity tag for protein purification. To compensate for this shortcoming, we have engineered and successfully tested Gateway destination vectors for the production of dual His6MBP‐tagged fusion proteins in the cytoplasm and periplasm of E. coli. The MBP moiety improves the yield and solubility of its fusion partners while the hexahistidine tag (His‐tag) serves to facilitate their purification. The availability of a vector that targets His6MBP fusion proteins to the periplasm expands the utility of this dual tagging approach to include proteins that contain disulfide bonds or are toxic in the bacterial cytoplasm.
A common dimerization interface in bacterial response regulators KdpE and TorR
Authors: Toro‐Roman Alejandro , Wu Ti , Stock Ann M. 
Published: December 2005

AbstractBacterial response regulators are key regulatory proteins that function as the final elements of so‐called two‐component signaling systems. The activities of response regulators in vivo are modulated by phosphorylation that results from interactions between the response regulator and its cognate histidine protein kinase. The level of response regulator phosphorylation, which is regulated by intra‐or extracellular signals sensed by the histidine protein kinase, ultimately determines the output response that is initiated or carried out by the response regulator. We have recently hypothesized that in the OmpR/PhoB subfamily of response regulator transcription factors, this activation involves a common mechanism of dimerization using a set of highly conserved residues in the α4–β5–α5 face. Here we report the X‐ray crystal structures of the regulatory domains of response regulators TorR (1.8 Å), Ca2+‐bound KdpE (2.0 Å), and Mg2+/BeF3−‐bound KdpE (2.2 Å), both members of the OmpR/ PhoB subfamily from Escherichia coli. Both regulatory domains form symmetric dimers in the asymmetric unit that involve the α4–β5–α5 face. As observed previously in other OmpR/PhoB response regulators, the dimer interfaces are mediated by highly conserved residues within this subfamily. These results provide further evidence that most all response regulators of the OmpR/ PhoB subfamily share a common mechanism of activation by dimerization.
Polypharmacy and falls in the middle age and elderly population
Authors: Ziere G. , Dieleman J. P. , Hofman A. , Pols H A. P. , Van Der Cammen T. J. M. , Stricker B. H. CH. 
Published: December 2005

AimFalls in the elderly are common and often serious. We studied the association between multiple drug use (polypharmacy) and falls in the elderly.MethodsThis was a population‐based cross‐sectional study, part of the Rotterdam Study. The participants were 6928 individuals aged ≥ 55 years. The prevalence of falls in the previous year was assessed. Medication use was determined with an interviewer‐administered questionnaire with verification of use. Polypharmacy was defined as the use of four or more drugs per day.ResultsThe prevalence of falls strongly increased with age. Falls were more common in women than in men. Fall risk increased with increasing disability, presence of joint complaints, use of a walking aid and fracture history. The risk of falling increased significantly with the number of drugs used per day (P for trend < 0.0001). After adjustment for a large number of comorbid conditions and disability, polypharmacy remained a significant risk factor for falling. Stratification for polypharmacy with or without at least one drug which is known to increase fall risk (notably CNS drugs and diuretics) disclosed that only polypharmacy with at least one risk drug was associated with an increased risk of falling.ConclusionsFall risk is associated with the use of polypharmacy, but only when at least one established fall risk‐increasing drug was part of the daily regimen.
Pharmacokinetic–pharmacodynamic modelling of QT interval prolongation following citalopram overdoses
Authors: Friberg Lena E. , Isbister Geoffrey K. , Duffull Stephen B. 
Published: December 2005

AimsTo develop a pharmacokinetic–pharmacodynamic model describing the time‐course of QT interval prolongation after citalopram overdose and to evaluate the effect of charcoal on the relative risk of developing abnormal QT and heart‐rate combinations.MethodsPlasma concentrations and electrocardiograph (ECG) data from 52 patients after 62 citalopram overdose events were analysed in WinBUGS using a Bayesian approach. The reported doses ranged from 20 to 1700 mg and on 17 of the events a single dose of activated charcoal was administered. The developed pharmacokinetic–pharmacodynamic model was used for predicting the probability of having abnormal combinations of QT‐RR, which was assumed to be related to an increased risk for torsade de pointes (TdP).ResultsThe absolute QT interval was related to the observed heart rate with an estimated individual heart‐rate correction factor [α = 0.36, between‐subject coefficient of variation (CV) = 29%]. The heart‐rate corrected QT interval was linearly dependent on the predicted citalopram concentration (slope = 40 ms l mg−1, between‐subject CV = 70%) in a hypothetical effect‐compartment (half‐life of effect‐delay = 1.4 h). The heart‐rate corrected QT was predicted to be higher in women than in men and to increase with age. Administration of activated charcoal resulted in a pronounced reduction of the QT prolongation and was shown to reduce the risk of having abnormal combinations of QT‐RR by approximately 60% for citalopram doses above 600 mg.ConclusionCitalopram caused a delayed lengthening of the QT interval. Administration of activated charcoal was shown to reduce the risk that the QT interval exceeds a previously defined threshold and therefore is expected to reduce the risk of TdP.
Warfarin use and the risk of motor vehicle crash in older drivers
Authors: Delaney J. A. ‘Chris’ , Opatrny Lucie , Suissa Samy 
Published: December 2005

AimOn the basis of a recent report, we assessed whether the use of warfarin by elderly drivers results in an increased risk of motor vehicle crash.MethodsWe used computerized records of Quebec insurance programmes, covering a population of 7 million people, to conduct a case–control study based on 5579 cases and 12 911 controls.ResultsThe rate of injurious motor vehicle crash associated with the use of warfarin in the past year was not elevated (rate ratio 0.74; 95% confidence interval 0.55, 1.05).ConclusionsWarfarin therapy does not appear to increase the risk of motor vehicle accidents in elderly drivers.
Different effects of fluvoxamine on rabeprazole pharmacokinetics in relation to CYP2C19 genotype status
Authors: Uno Tsukasa , Shimizu Mikiko , Yasui‐Furukori Norio , Sugawara Kazunobu , Tateishi Tomonori 
Published: December 2005

AimsRabeprazole is known to be a substrate of CYP2C19. Our objective was to evaluate the possible effect of an inhibitor of CYP2C19, fluvoxamine, and compare the inhibitory effect of fluvoxamine on the metabolism of rabeprazole between CYP2C19 genotypes.MethodsA two‐way randomized double‐blind, placebo‐controlled crossover study was performed. Twenty‐one volunteers, of whom seven were homozygous extensive metabolizers (EMs), eight were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, received two 6‐day courses of either fluvoxamine 50 mg or placebo daily in a randomized fashion with a single oral dose of rabeprazole 20 mg on day 6 in all cases. Plasma concentrations of rabeprazole and its metabolite rabeprazole thioether were monitored up to 24 h after dosing.ResultsDuring placebo administration, the mean AUCs(0,∞) of rabeprazole in homozygous EMs, heterozygous EMs and PMs were 882 (95% CI, 602, 1162) ng ml−1h , 1214 (975, 1453) ng ml−1 h and 2762 (2482, 3042) ng ml−1 h (P < 0.001), respectively. Fluvoxamine treatment increased AUC(0,∞) of rabeprazole and rabeprazole thioether by 2.8‐fold (P < 0.001) and 5.1‐fold (P < 0.01) in homozygous EMs, and by 1.7‐fold (P < 0.01) and 2.6‐fold (P < 0.01) in heterozygous EMs, and significantly prolonged the elimination half‐life of rabeprazole and rabeprazole thioether in homozygous EMs and in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in fluvoxamine‐mediated percentage increase in AUC(0,∞) of rabeprazole and rabeprazole thioether between CYP2C19 genotypes.ConclusionsThe present study indicates that there are significant drug interactions between rabeprazole and fluvoxamine in EMs of CYP2C19. It is predominantly involved in rabeprazole and rabeprazole thioether metabolism in EMs. Therefore, CYP2C19 is the key determinant of rabeprazole disposition in EMs.