bluuebunny/crossref_metadata_2025_split huggingface dataset:
The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects
Authors: Kavvadias Dominique , Sand Philipp , Youdim Kuresh A , Qaiser M Zeeshan , Rice‐Evans Catherine , Baur Roland , Sigel Erwin , Rausch Wolf‐Dieter , Riederer Peter , Schreier Peter 
Published: July 2004

The functional characterization of hispidulin (4′,5,7‐trihydroxy‐6‐methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity.
After chemical synthesis, hispidulin was investigated at recombinant GABAA/BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nM and higher stimulated the GABA‐induced chloride currents at tested receptor subtypes (α1−3,5,6β2γ2S) indicating positive allosteric properties. Maximal stimulation at α1β2γ2S was observed with 10 μM hispidulin. In contrast to diazepam, hispidulin modulated the α6β2γ2S‐GABAA receptor subtype.
When fed to seizure‐prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg−1 body weight (BW) per day) and diazepam (2 mg kg−1 BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group).
Permeability across the blood–brain barrier for the chemically synthesized, 14C‐labelled hispidulin was confirmed by a rat in situ perfusion model. With an uptake rate (Kin) of 1.14 ml min−1 g−1, measurements approached the values obtained with highly penetrating compounds such as diazepam.
Experiments with Caco‐2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 μM, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.

British Journal of Pharmacology (2004) 142, 811–820. doi:10.1038/sj.bjp.0705828
A quantitative and comparative study of the effects of a synthetic ciguatoxin CTX3C on the kinetic properties of voltage‐dependent sodium channels
Authors: Yamaoka Kaoru , Inoue Masayuki , Miyahara Hidemichi , Miyazaki Keisuke , Hirama Masahiro 
Published: July 2004

Ciguatoxins (CTXs) are known to bind to receptor site 5 of the voltage‐dependent Na channel, but the toxin's physiological effects are poorly understood. In this study, we investigated the effects of a ciguatoxin congener (CTX3C) on three different Na‐channel isoforms, rNav1.2, rNav1.4, and rNav1.5, which were transiently expressed in HEK293 cells.
The toxin (1.0 μmol l−1) shifted the activation potential (V1/2 of activation curve) in the negative direction by 4–9 mV and increased the slope factor (k) from 8 mV to between 9 and 12 mV (indicative of decreased steepness of the activation curve), thereby resulting in a hyperpolarizing shift of the threshold potential by 30 mV for all Na channel isoforms.
The toxin (1.0 μmol l−1) significantly accelerated the time‐to‐peak current from 0.62 to 0.52 ms in isoform rNav1.2. Higher doses of the toxin (3–10 μmol l−1) additionally decreased time‐to‐peak current in rNav1.4 and rNav1.5.
A toxin effect on decay of INa at −20 mV was either absent or marginal even at relatively high doses of CTX3C.
The toxin (1 μmol l−1) shifted the inactivation potential (V1/2 of inactivation curve) in the negative direction by 15–18 mV in all isoforms.
INa maxima of the I–V curve (at −20 mV) were suppressed by application of 1.0 μmol l−1 CTX3C to a similar extent (80–85% of the control) in all the three isoforms. Higher doses of CTX3C up to 10 μmol l−1 further suppressed INa to 61–72% of the control.
Recovery from slow inactivation induced by a depolarizing prepulse of intermediate duration (500 ms) was dramatically delayed in the presence of 1.0 μmol l−1 CTX3C, as time constants describing the monoexponential recovery were increased from 38±8 to 588±151 ms (n=5), 53±6 to 338±85 ms (n=4), and 23±3 to 232±117 ms (n=3) in rNav1.2, rNav1.4, and rNav1.5, respectively.
CTX3C exerted multimodal effects on sodium channels, with simultaneous stimulatory and inhibitory aspects, probably due to the large molecular size (3 nm in length) and lipophilicity of this membrane‐spanning toxin.

British Journal of Pharmacology (2004) 142, 879–889. doi:10.1038/sj.bjp.0705852
Nicotine blocks apomorphine‐induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic α7 receptors
Authors: Suemaru Katsuya , Yasuda Kayo , Umeda Kenta , Araki Hiroaki , Shibata Kazuhiko , Choshi Tominari , Hibino Satoshi , Gomita Yutaka 
Published: July 2004

Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats.
Over the dose range tested, nicotine (0.05–1 mg kg−1, s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5–5 mg kg−1, s.c.), an α7 nicotinic receptor antagonist, nor dihydro‐β‐erythroidine (0.5–2 mg kg−1, s.c.), an α4β2 nicotinic receptor antagonist, had any effect on PPI.
Nicotine (0.01–0.2 mg kg−1, s.c.) dose‐dependently reversed the disruption of PPI induced by apomorphine (1 mg kg−1, s.c.), but had no effect on the disruption of PPI induced by phencyclidine (2 mg kg−1, s.c.).
The reversal of apomorphine‐induced PPI disruption by nicotine (0.2 mg kg−1) was eliminated by mecamylamine (1 mg kg−1, i.p.), but not by hexamethonium (10 mg kg−1, i.p.), indicating the involvement of central nicotinic receptors.
The antagonistic action of nicotine on apomorphine‐induced PPI disruption was dose‐dependently blocked by methyllycaconitine (1 and 2 mg kg−1, s.c.). However, dihydro‐β‐erythroidine (1 and 2 mg kg−1, s.c.) had no effect.
These results suggest that nicotine reverses the disruption of apomorphine‐induced PPI through central α7 nicotinic receptors.

British Journal of Pharmacology (2004) 142, 843–850. doi:10.1038/sj.bjp.0705855
Pharmacological characterization of human S1P4 using a novel radioligand, [4,5‐3H]‐dihydrosphingosine‐1‐phosphate
Authors: Fossetta James , Deno Gregory , Gonsiorek Waldemar , Fan Xuedong , Lavey Brian , Das Pradip , Lunn Charles , Zavodny Paul J , Lundell Daniel , Hipkin R William 
Published: July 2004

Sphingosine‐1‐phosphate (S1P) is a bioactive lipid that affects a variety of cellular processes through both its actions as a second messenger and via activation of a family of G protein‐coupled receptors (S1P1–5).
The study of S1P receptor pharmacology, particularly S1P4, has been hindered by the lack of high‐affinity radioligands with good specific activity. The studies presented herein characterize [3H]DH‐S1P as a stable, high‐affinity radioligand for S1P4 pharmacology.
Using a transfected Ba/F3 cell line selected for high hS1P4 surface expression, we compared the consequences of different cellular backgrounds and commercial sources of sphingophospholipids on S1P4 characterization. The development and subsequent use of the assay described has enabled us to extensively and definitively characterize the pharmacology of the human S1P4 receptor.

British Journal of Pharmacology (2004) 142, 851–860. doi:10.1038/sj.bjp.0705856
Regional and time-resolved mutation patterns of the human genome
Authors: Arndt Peter F. , Hwa Terence 
Published: July 2004

Abstract
Motivation: Substantial regional variations of substitutional processes have recently been reported from human/mouse comparisons. However, several features including the C + G dependence and the CpG-based transition effect remain obscure.
Results: Utilizing the vast amount of transposable elements in the human genome, we performed detailed analysis of the substitutional and insertion/deletion patterns along the human lineage in a regional and time-resolved fashion. We observed a drastic increase in the CpG-based transition frequency at about the time of the mammalian radiation. We also observed clear regional biases of substitution patterns, most notably a bias to enrich the C+G content toward the telomeres.
Availability: The programs used are available upon request from the authors.
Using convex hulls to extract interaction interfaces from known structures
Authors: Dafas Panos , Bolser Dan , Gomoluch Jacek , Park Jong , Schroeder Michael 
Published: July 2004

Abstract
Motivation: Protein interactions provide an important context for the understanding of function. Experimental approaches have been complemented with computational ones, such as PSIMAP, which computes domain–domain interactions for all multi-domain and multi-chain proteins in the Protein Data Bank (PDB). PSIMAP has been used to determine that superfamilies occurring in many species have many interaction partners, to show examples of convergent evolution through shared interaction partners and to uncover complexes in the interaction map.
To determine an interaction, the original PSIMAP algorithm checks all residue pairs of any domain pair defined by classification systems such as SCOP. The computation takes several days for the PDB. The computation of PSIMAP has two shortcomings: first, the original PSIMAP algorithm considers only interactions of residue pairs rather than atom pairs losing information for detailed analysis of contact patterns. At the atomic level the original algorithm would take months. Second, with the superlinear growth of PDB, PSIMAP is not sustainable.
Results: We address these two shortcomings by developing a family of new algorithms for the computation of domain–domain interactions based on the idea of bounding shapes, which are used to prune the search space. The best of the algorithms improves on the old PSIMAP algorithm by a factor of 60 on the PDB. Additionally, the algorithms allow a distributed computation, which we carry out on a farm of 80 Linux PCs. Overall, the new algorithms reduce the computation at atomic level from months to 20 min. The combination of pruning and distribution makes the new algorithm scalable and sustainable even with the superlinear growth in PDB.
Threshold extraction in metabolite concentration data
Authors: Flöter A. , Nicolas J. , Schaub T. , Selbig J. 
Published: July 2004

Abstract
Motivation: Continued development of analytical techniques based on gas chromatography and mass spectrometry now facilitates the generation of larger sets of metabolite concentration data. An important step towards the understanding of metabolite dynamics is the recognition of stable states where metabolite concentrations exhibit a simple behaviour. Such states can be characterized through the identification of significant thresholds in the concentrations. But general techniques for finding discretization thresholds in continuous data prove to be practically insufficient for detecting states due to the weak conditional dependences in concentration data.
Results: We introduce a method of recognizing states in the framework of decision tree induction. It is based upon a global analysis of decision forests where stability and quality are evaluated. It leads to the detection of thresholds that are both comprehensible and robust. Applied to metabolite concentration data, this method has led to the discovery of hidden states in the corresponding variables. Some of these reflect known properties of the biological experiments, and others point to putative new states.
Availability: An implementation of this approach can be obtained from the authors upon request.
Conserved RNA secondary structures in viral genomes: a survey
Authors: Hofacker I.L. , Stadler P.F. , Stocsits R.R. 
Published: July 2004

Abstract
Summary: The genomes of RNA viruses often carry conserved RNA structures that perform vital functions during the life cycle of the virus. Such structures can be detected using a combination of structure prediction and co-variation analysis. Here we present results from pilot studies on a variety of viral families performed during bioinformatics computer lab courses in past years.
Gene expression analysis on biochemical networks using the Potts spin model
Authors: König Rainer , Eils Roland 
Published: July 2004

Abstract
Motivation: Microarray technology allows us to profile the expression of a large subset or all genes of a cell. Biochemical research over the last three decades has elucidated an increasingly complete image of the metabolic architecture. For less complex organisms, such as Escherichia coli, the biochemical network has been described in much detail. Here, we investigate the clustering of such networks by applying gene expression data that define edge lengths in the network.
Results: The Potts spin model is used as a nearest neighbour based clustering algorithm to discover fragmentation of the network in mutants or in biological samples when treated with drugs. As an example, we tested our method with gene expression data from E.coli treated with tryptophan excess, starvation and trpyptophan repressor mutants. We observed fragmentation of the tryptophan biosynthesis pathway, which corresponds well to the commonly known regulatory response of the cells.
Bifurcation analysis of the regulatory modules of the mammalian G1/S transition
Authors: Swat Maciej , Kel Alexander , Herzel Hanspeter 
Published: July 2004

Abstract
Motivation: Mathematical models of the cell cycle can contribute to an understanding of its basic mechanisms. Modern simulation tools make the analysis of key components and their interactions very effective. This paper focuses on the role of small modules and feedbacks in the gene–protein network governing the G1/S transition in mammalian cells. Mutations in this network may lead to uncontrolled cell proliferation. Bifurcation analysis helps to identify the key components of this extremely complex interaction network.
Results: We identify various positive and negative feedback loops in the network controlling the G1/S transition. It is shown that the positive feedback regulation of E2F1 and a double activator–inhibitor module can lead to bistability. Extensions of the core module preserve the essential features such as bistability. The complete model exhibits a transcritical bifurcation in addition to bistability. We relate these bifurcations to the cell cycle checkpoint and the G1/S phase transition point. Thus, core modules can explain major features of the complex G1/S network and have a robust decision taking function.
Thermodynamic and structural characterization of 2′-nitrogen-modified RNA duplexes
Authors: Pham John W. , Radhakrishnan Ishwar , Sontheimer Erik J. 
Published: July 2004

Abstract2′-aminonucleosides are commonly used as sites of post-synthetic chemical modification within nucleic acids. As part of a larger cross-linking strategy, we appended alkyl groups onto the N2′ position of 2′-amino-modified RNAs via 2′-ureido and 2′-amido linkages. We have characterized the thermodynamics of 2′-amino, 2′-alkylamido and 2′-alkylureido-modified RNA duplexes and show that 2′-ureido-modified RNAs are significantly more stable than analogous 2′-amido-modified RNAs. Using NMR spectroscopy and NMR-based molecular modeling of 2′-modified RNA duplexes, we examined the effects that 2′-nitrogen modifications have on RNA helices. Our data suggest that the 2′-ureido group forms a specific intra-nucleoside interaction that cannot occur within 2′-amido-modified helices. These results indicate that 2′-ureido modifications are superior to analogous 2′-amido ones for applications that require stable base pairing.
Causes and Treatment of Burns From Grease
Authors: Fiebiger Barbara , Whitmire Faye , Law Edward , Still Joseph M. 
Published: July 2004

Abstract
A large number of burns are sustained every year as the result of kitchen grease. A review of a 13-month period at the Joseph M. Still Burn Center in Augusta, Georgia, revealed 60 cases (9.4% of acute burn admissions). Forty-five (75%) of these patients were adults and 25% were children. There were 23 females and 37 males. Forty-two percent of the adults and 33% of the children had some percentage of third-degree injury. The average total body surface area burn in adults was 5.9% and in children 6.3%. There were no deaths in this series. Burns usually occurred as the result of scalds with grease while cooking. Spilling grease on children in the kitchen was a frequent problem. Burns due to ignition of grease was also a cause of injury. Most of the injuries were potentially preventable, and therefore the importance of burn appropriate safety programs is stressed.
Analysis of Burn Injuries in Frontal Automobile Crashes
Authors: Jernigan M. Virginia , Rath Amber L. , Duma Stefan M. 
Published: July 2004

Abstract
The purpose of this study was to investigate burn injuries resulting from frontal automobile crashes and to determine the effects of frontal airbags on the incidence of burn injuries. The study included 25,464 individual cases from the National Automotive Sampling System database files for the years 1993 to 2000. Occupants were at a significantly higher risk to sustain a burn injury when exposed to an airbag deployment (1.54%) compared with those who received a burn injury when not exposed to an airbag deployment (0.02%; P = 0.02). In contrast to previous publications, this study found that 1.53% of front seat occupants exposed to an airbag deployment sustained an airbag-induced burn injury. The vast majority of airbag-induced burn injuries were minor (98.7%); however, in cases with no airbag deployment, the burns were often much more serious, including fatal burns (29.6%). Occupant weight, height, sex, seatbelt use, and seat position were all found not to be significant in predicting the risk of airbag induced burn injury, whereas age and crash velocity were found to be significant.
Dynamic Patterns of Subcellular Protein Localization during Spore Coat Morphogenesis in
Bacillus subtilis
Authors: van Ooij Christiaan , Eichenberger Patrick , Losick Richard 
Published: July 2004

ABSTRACT

Endospores of
Bacillus subtilis
are encased in a thick, proteinaceous shell known as the coat, which is composed of a large number of different proteins. Here we report the identification of three previously uncharacterized coat-associated proteins, YabP, YheD, and YutH, and their patterns of subcellular localization during the process of sporulation, obtained by using fusions of the proteins to the green fluorescent protein (GFP). YabP-GFP was found to form both a shell and a ring around the center of the forespore across the short axis of the sporangium. YheD-GFP, in contrast, formed two rings around the forespore that were offset from its midpoint, before it eventually redistributed to form a shell around the developing spore. Finally, YutH-GFP initially localized to a focus at one end of the forespore, which then underwent transformation into a ring that was located adjacent to the forespore. Next, the ring became a cap at the mother cell pole of the forespore that eventually spread around the entire developing spore. Thus, each protein exhibited its own distinct pattern of subcellular localization during the course of coat morphogenesis. We concluded that spore coat assembly is a dynamic process involving diverse patterns of protein assembly and localization.
Phosphorus Limitation Enhances Biofilm Formation of the Plant Pathogen
Agrobacterium tumefaciens
through the PhoR-PhoB Regulatory System
Authors: Danhorn Thomas , Hentzer Morten , Givskov Michael , Parsek Matthew R. , Fuqua Clay 
Published: July 2004

ABSTRACT

The plant pathogen
Agrobacterium tumefaciens
forms architecturally complex biofilms on inert surfaces. Adherence of
A. tumefaciens
C58 was significantly enhanced under phosphate limitation compared to phosphate-replete conditions, despite slower overall growth under low-phosphate conditions. Replacement of P
i
with
sn
-glycerol-3-phosphate and 2-aminoethylphosphonate yielded similar results. The increase in surface interactions under phosphate limitation was observed in both static culture and continuous-culture flow cells. Statistical analysis of confocal micrographs obtained from the flow cell biofilms revealed that phosphate limitation increased both the overall attached biomass and the surface coverage, whereas the maximum thickness of the biofilm was not affected. Functions encoded on the two large plasmids of
A. tumefaciens
C58, pTiC58 and pAtC58, were not required for the observed phosphate effect. The phosphate concentration at which increased attachment was observed triggered the phosphate limitation response, controlled in many bacteria by the two-component regulatory system PhoR-PhoB. The
A. tumefaciens phoB
and
phoR
orthologues could only be disrupted in the presence of plasmid-borne copies of the genes, suggesting that this regulatory system might be essential. Expression of the
A. tumefaciens phoB
gene from a tightly regulated inducible promoter, however, correlated with the amount of biofilm under both phosphate-limiting and nonlimiting conditions, demonstrating that components of the Pho regulon influence
A. tumefaciens
surface interactions.
Helicobacter pyloriFlgR Is an Enhancer-Independent Activator of σ54-RNA Polymerase Holoenzyme
Authors: Brahmachary Priyanka , Dashti Mona G. , Olson Jonathan W. , Hoover Timothy R. 
Published: July 2004

ABSTRACTHelicobacter pyloriFlgR activates transcription with σ54-RNA polymerase holoenzyme (σ54-holoenzyme) from at least five flagellar operons. Activators of σ54-holoenzyme generally bind enhancer sequences located >70 bp upstream of the promoter and contact σ54-holoenzyme bound at the promoter through DNA looping to activate transcription.H. pyloriFlgR lacks the carboxy-terminal DNA-binding domain present in most σ54-dependent activators. As little as 42 bp of DNA upstream of theflaBpromoter and 26 bp of DNA sequence downstream of the transcriptional start site were sufficient for efficient FlgR-mediated expression from aflaB′-′xylEreporter gene inH. pylori, indicating that FlgR does not use an enhancer to activate transcription. Other examples of σ54-dependent activators that lack a DNA-binding domain includeChlamydia trachomatisCtcC and activators from the otherChlamydiaspp. whose genomes have been sequenced. FlgR fromHelicobacter hepaticusandCampylobacter jejuni, which are closely related toH. pylori, appear to have carboxy-terminal DNA-binding domains, suggesting that the loss of the DNA-binding domain fromH. pyloriFlgR occurred after the divergence of these bacterial species. Removal of the amino-terminal regulatory domain of FlgR resulted in a constitutively active form of the protein that activated transcription from σ54-dependent genes inEscherichia coli. The truncated FlgR protein also activated transcription withE. coliσ54-holoenzyme in an in vitro transcription assay.