bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late Quaternary Diatom Assemblages from Prydz Bay, Eastern Antarctica
Authors: Taylor Fiona , McMinn Andrew 
Published: September 2002

AbstractThe paleo-depositional environment of inner Prydz Bay, East Antarctica, has been reconstructed for the past 21,320 14C yr B.P., using diatom assemblages and sediment facies from a short, 352-cm-long gravity core. Between 21,320 and 11,650 14C yr B.P., compact tillite and diamicton are present in the core, and diatom frustules are rare to absent. These data suggest that an ice sheet grounded over the site during the last glacial maximum. Following glacial retreat, siliceous muddy ooze was deposited, from 11,650 to 2600 14C yr B.P., in an open marine setting. During this stage, diatom frustules are abundant and well preserved, and Thalassiosira antarctica resting spores and Fragilariopsis curta dominate the assemblage. This assemblage suggests open marine deposition in an environment where the spatial and temporal distribution of sea ice is less than today. Since 2600 14C yr B.P., sea-ice and ice-edge diatom species have become more abundant, and neoglacial cooling is inferred. The assemblage is similar to that forming currently in Prydz Bay, where sea ice is absent (<10% cover) for 2–3 months of the year and permanent ice edge and/or multiyear sea ice remains in close proximity to the site.
Two Tephra Layers Bracketing Late Holocene Paleoecological Changes in Northern Germany
Authors: van den Bogaard Christel , Dörfler Walter , Glos Rainer , Nadeau Marie-Josée , Grootes Pieter M. , Erlenkeuser Helmut 
Published: September 2002

AbstractPaleoecological records from two Holocene peat bogs in northern Germany are linked by two microscopic volcanic ash layers, correlated by petrology and geochemistry to explosive volcanism on Iceland. The younger “Microlite tephra” cannot be correlated to any known eruption, while the older tephra layer is identified as a deposit of the Hekla 3 eruption. The tephra layers are dated by an age–depth regression of accelerator mass spectrometry 14C ages that have been calibrated and combined in probability distributions. This procedure gives an age of 730–664 cal yr B.C. for the “Microlite tephra” event and 1087–1006 cal yr B.C. for the Hekla 3 event. Accordingly, the tephra layers were deposited during the late Bronze Age. At this time, human settlement slowly increased pressure on the environment, as indicated by changes in woodland pollen composition at the two bogs. The tephra-marker horizons further show that the palynologically defined transition from the Subboreal to the Subatlantic Period is synchronous in the investigated area. However, the macroscopic visible marker in peat, the change from fibrous to sapric peat, the “Schwarztorf-Weißtorf-Kontakt,” is asynchronous. Bog vegetation did not immediately react in unison to a climatic change at this pollen zone boundary; instead, the timing of vegetation change depended on the location within the bog.
Studies of GABAB receptors labelled with [3H]‐CGP62349 in hippocampus resected from patients with temporal lobe epilepsy
Authors: Princivalle A P , Duncan J S , Thom M , Bowery N G 
Published: September 2002

The aim of this study was to investigate the binding of a novel GABAB receptor radioligand, [3H]‐CGP62349, to human post‐mortem control and epileptic hippocampal sections using quantitative receptor autoradiography. Utilizing human control hippocampal sections it was shown that [3H]‐CGP62349 bound with high affinity (KD 0.5 nM) to this tissue.
Hippocampal slices from surgical specimens obtained from patients with hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) were compared with neurologically normal post‐mortem control subjects for neuropathology and GABAB receptor density and affinity. Neuronal loss was observed in most of the hippocampal subregions, but in the subiculum no significant difference was detected.
The localization of GABAB receptors with the antagonist [3H]‐CGP62349 in human control hippocampal sections supported and extended earlier studies using the agonist ligand [3H]‐GABA.
The kinetics of binding to the GABAB receptor in human hippocampus using this novel compound was comparable to previous data obtained in rat hippocampal membranes.
GABAB receptor density (Bmax) was significantly reduced in CA3, hilus, and dentate gyrus (DG); the affinity was increased exclusively in DG. The trend is identical in all the hippocampal subregions with the agonist and the antagonist, although significant differences with the antagonist where recorded in CA3 and hilus, whereas with the agonist a significant reduction was reported in all of the hippocampal subfields.
GABAB receptor expression per remaining neuron appeared significantly increased in CA3 and hilus. These results suggest altered GABAB receptor function may occur in human TLE, possibly as a result of synaptic reorganization, and may contribute to epileptogenesis.

British Journal of Pharmacology (2002) 136, 1099–1106 doi:10.1038/sj.bjp.0704812
Role of the endocannabinoid system in MDMA intracerebral self‐administration in rats
Authors: Braida Daniela , Sala Mariaelvina 
Published: September 2002

I.c.v. self‐administration of MDMA (0.01–2 μg per infusion), alone and in combination with CP 55,940 (0.4 μg infusion−1), was studied on an operant responding procedure. On the basis of individual preference for one of two levers, developed during training, rats were allowed to self‐administer vehicle from the preferred lever and MDMA from the other. Pressings on the MDMA associated‐lever, except for the maximal unit dose, progressively increased. The combination of CP 55,940 with MDMA (1 μg infusion−1) reduced the number of drug‐associated lever pressings compared to the single drugs. Pre‐treatment with SR 141716A (0.5 mg kg−1 i.p.), 15 min before each daily session, significantly increased MDMA self‐administration. These findings suggest that MDMA self‐administration is under endogenous tonic control by the endocannabinoid system.British Journal of Pharmacology (2002) 136, 1089–1092. doi:10.1038/sj.bjp.0704825
Comparative pharmacology of rat and human α7 nAChR conducted with net charge analysis
Authors: Papke Roger L , Porter Papke Julia K 
Published: September 2002

Pharmacological studies of α7 nicotinic acetylcholine receptors are confounded by the fact that rapid desensitization to high agonist concentration causes α7 peak responses to occur well in advance of complete solution exchange. For this reason, peak currents are an invalid measure of response to applied agonist concentrations. We show that results comparable to those that have been corrected for instantaneous concentration are obtained if net charge is used as the measure of receptor response.
Dose response curves obtained with these methods indicate that α7 receptors are approximately 10 fold more sensitive to agonist than previously reported. The agonists, ACh, choline, cytisine, GTS‐21, 4OH‐GTS‐21 and 4‐MeO‐CA have the same rank order potency for both human and rat receptors: 4‐MeO‐CA > 4OH‐GTS‐21 > GTS‐21 > cytisine > ACh > choline. However, differences in efficacy exist between rat and human receptors. GTS‐21 is more efficacious for rat than human α7 receptors and cytisine more efficacious for human than rat α7 receptors.
Choline is the least potent agonist for both human and rat α7, with a potency approximately 10 fold lower than that of ACh. While the EC50 for the activation of α7 receptors by choline (400–500 μM) is outside the normal physiological range (10–100 μM), choline can nonetheless produce detectable levels of channel activation in the physiological concentration range. Since these concentrations are relatively non‐desensitizing, the contribution of choline‐activated α7 receptor current may play a significant role in the regulation of calcium homeostasis in α7‐expressing neurons.

British Journal of Pharmacology (2002) 137, 49–61. doi:10.1038/sj.bjp.0704833
Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene‐related peptide induced dilation of dural meningeal vessels
Authors: Akerman S , Williamson D J , Kaube H , Goadsby P J 
Published: September 2002

The detailed pathophysiology of migraine is beginning to be understood and is likely to involve activation of trigeminovascular afferents.
Clinically effective anti‐migraine compounds are believed to have actions that include peripheral inhibition of calcitonin gene‐related peptide (CGRP) release from trigeminal neurones, or preventing dural vessel dilation, or both. CGRP antagonists can block both neurogenic and CGRP‐induced dural vessel dilation.
Nitric oxide (NO) can induce headache in migraine patients and often triggers a delayed migraine. The initial headache is thought to be caused via a direct action of the NO–cGMP pathway that causes vasodilation by vascular smooth muscle relaxation, while the delayed headache is likely to be a result of triggering trigeminovascular activation. Nitric oxide synthase (NOS) inhibitors are effective in the treatment of acute migraine.
The present studies used intravital microscopy to examine the effects of specific NOS inhibitors on neurogenic dural vasodilation (NDV) and CGRP‐induced dilation.
The non‐specific and neuronal NOS (nNOS) inhibitors were able to partially inhibit NDV, while the non‐specific and endothelial NOS (eNOS) inhibitors were able to partially inhibit the CGRP induced dilation.
There was no effect of the inducible NOS (iNOS) inhibitor.
The data suggest that the delayed headache response triggered by NO donors in humans may be due, in part, to increased nNOS activity in the trigeminal system that causes CGRP release and dural vessel dilation.
Further, eNOS activity in the endothelium causes NO production and smooth muscle relaxation by direct activation of the NO–cGMP pathway, and may be involved in the initial headache response.

British Journal of Pharmacology (2002) 137, 62–68. doi:10.1038/sj.bjp.0704842
Characterization of the β‐adrenoceptor subtype involved in mediation of glucose transport in L6 cells
Authors: Nevzorova Julia , Bengtsson Tore , Evans Bronwyn A , Summers Roger J 
Published: September 2002

The receptor that mediates the increase in glucose transport (GT) in response to β‐adrenoceptor (β‐AR) agonists was characterized in the rat skeletal muscle cell line L6, using the 2‐deoxy‐[3H]‐D‐glucose assay.
The β3‐AR agonist BRL37344 (pEC50=6.89±0.21), the β‐AR agonist isoprenaline (pEC50=8.99±0.24) and the β2‐AR agonist zinterol (pEC50=9.74±0.15) increased GT as did insulin (pEC50=6.93±0.15). The highly selective β3‐AR agonist CL316243 only weakly stimulated GT.
The pKB values calculated from the shift of the pEC50 values of the agonists in the presence of the β1‐AR selective antagonist CGP 20712A or the β3‐AR selective antagonist SR 59230A were not indicative of activation of β1‐ or β3‐ARs. Only (−)‐propranolol and the β2‐AR selective antagonist ICI 118551 caused marked rightward shifts of CR curves to isoprenaline (pKB=10.2±0.2 and 9.6±0.3), zinterol (pKB=9.0±0.1 and 9.4±0.3) and BRL 37344 (pKB=9.4±0.3 and 8.4±.2), indicating participation of β2‐ARs.
The pharmacological analysis was supported by reverse transcription and polymerase chain reaction analysis of L6 mRNA, which showed high levels of expression of β2‐AR but not β1‐ or β3‐AR in these cells.
Forskolin and dibutyryl cyclic AMP produced negligible increases in GT while the phosphatidylinositol‐3 kinase inhibitor, wortmannin, significantly decreased both insulin‐ and zinterol‐stimulated GT, suggesting a possible interaction between the insulin and β2‐AR pathways.
This study demonstrates that β2‐ARs mediate the increase in GT in L6 cells to β‐AR agonists, including the β3‐AR selective agonist BRL 37344. This effect does not appear to be directly related to increases in cyclic AMP but requires P13K.

British Journal of Pharmacology (2002) 137, 9–18. doi:10.1038/sj.bjp.0704845
Advances in the understanding and future therapy of COPD
Authors: Fabbri L. , Rennard S. , Leff A. , O'Connor B. 
Published: September 2002

SummaryChronic obstructive pulmonary disease (COPD) is an enormous public health problem, which currently causes about 5% of all deaths worldwide. The main feature of COPD is a progressive loss of lung function as a result of structural changes in the airways and lung parenchyma. It is predominantly a disease of smokers, although only about 15% of smokers are thought to develop severe enough disease to be symptomatic. The reasons why some smokers are more susceptible to the disease than others are not clear, and are the subject of extensive research. Characteristically, inflammation is central to the pathophysiology of COPD, and it is clear that the inflammation of COPD differs from that seen in asthma. The most important treatment for COPD is smoking cessation, as other current treatments do not alter the course of the disease. Recent research into the cellular and molecular mechanisms underlying chronic obstructive pulmonary disease has provided potential new avenues for the development of rationally designed drugs, which may improve the outlook for patients with this debilitating condition. It is likely that different therapeutic approaches will be needed in different patients, because of the heterogeneity of the disease.
Allergic rhinitis: current and future treatments
Authors: Naclerio R. , Rosenwasser L. , Ohkubo K. 
Published: September 2002

SummaryAllergic rhinitis is a highly prevalent respiratory disease, affecting up to 40% of the population in some countries, and has an important impact on quality of life. Although a number of different drug types are available for treating allergic rhinitis, antihistamines are currently considered first‐line therapy. Newer antihistamines, such as fexofenadine, are very effective in suppressing symptoms and are largely free of side‐effects. In addition, they have been shown to improve patient's quality of life. Some patients have residual symptoms despite the use of antihistamines and other available treatments. Moreover, most current treatments only relieve symptoms, and do not modify the course of the disease. Current research into the pathophysiology of the disease is opening many promising new avenues for improved treatments. Such possibilities include improving methods of immunotherapy, based on our greater understanding of the balance between Th1 and Th2 cells and of the cytokines that they produce; and targeting and blocking the effects of bradykinin, substance P, leukotrienes, IgE antibody, tryptase, platelet‐activating factor and prostaglandins. Refinements of immunotherapy are particularly promising, as they may provide a permanent cure for the disease in an increasing number of patients. Furthermore, recent evidence has shown that early intervention in children with allergic rhinitis, by antihistamine treatment or immunotherapy, can reduce the risk of developing asthma. Improved understanding of the links between allergic rhinitis and asthma is likely to advance the treatment of both diseases.
The origins of asymmetry in the folding transition states of protein L and protein G
Authors: Karanicolas John , Brooks Charles L. 
Published: September 2002

AbstractTopology has been shown to be an important determinant of many features of protein folding; however, the delineation of sequence effects on folding remains obscure. Furthermore, differentiation between the two influences proves difficult due to their intimate relationship. To investigate the effect of sequence in the absence of significant topological differences, we examined the folding mechanisms of segment B1 peptostreptococcal protein L and segment B1 of streptococcal protein G. These proteins share the same highly symmetrical topology. Despite this symmetry, neither protein folds through a symmetrical transition state. We analyzed the origins of this difference using theoretical models. We found that the strength of the interactions present in the N‐terminal hairpin of protein L causes this hairpin to form ahead of the C‐terminal hairpin. The difference in chain entropy associated with the formation of the hairpins of protein G proves sufficient to beget initiation of folding at the shorter C‐terminal hairpin. Our findings suggest that the mechanism of folding may be understood by examination of the free energy associated with the formation of partially folded microstates.
Structure and dynamics of copper‐free SOD: The protein before binding copper
Authors: Banci Lucia , Bertini Ivano , Cantini Francesca , D'Onofrio Mariapina , Viezzoli Maria Silvia 
Published: September 2002

AbstractThe solution structure of the copper‐free state of a monomeric form of superoxide dismutase (153 amino acids) was determined through 13C and 15N labeling. The protein contained two mutations at the native subunit–subunit interface (F50E and G51E) to obtain a soluble monomeric species and a mutation in the active site channel (E133Q). About 93% of carbon atoms, 95% of nitrogen atoms, and 96% of the protons were assigned. A total of 2467 meaningful NOEs and 170 dihedral angles provided a family of 35 conformers with RMSD values of 0.76 ± 0.09 Å for the backbone and 1.22 ± 0.13 Å for all heavy atoms. The secondary structure elements, connected by loops, produce the typical superoxide dismutase Greek key fold, formed by an eight‐stranded β‐barrel. The comparison with the copper‐bound monomeric and dimeric structures shows that the metal ligands have a conformation very close to that of the copper‐bound forms. This feature indicates that the copper‐binding site is preorganized and well ordered also in the absence of the copper ion. The active‐site channel shows a sizable increase in width, achieving a suitable conformation to receive the copper ion. The histidines ring NH resonances that bind the copper ion and the region around the active‐site channel experience, as found from 15N relaxation studies, conformational exchange processes. The increased width of the channel and the higher mobility of the histidine rings of the copper site in the copper‐free form with respect to the holoprotein is discussed in terms of the process of copper insertion.
Conformational transition states of a β‐hairpin peptide between the ordered and disordered conformations in explicit water
Authors: Kamiya Narutoshi , Higo Junichi , Nakamura Haruki 
Published: September 2002

AbstractThe conformational transition states of a β‐hairpin peptide in explicit water were identified from the free energy landscapes obtained from the multicanonical ensemble, using an enhanced conformational sampling calculation. The β‐hairpin conformations were significant at 300 K in the landscape, and the typical nuclear Overhauser effect signals were reproduced, consistent with the previously reported experiment. In contrast, the disordered conformations were predominant at higher temperatures. Among the stable conformations at 300 K, there were several free energy barriers, which were not visible in the landscapes formed with the conventional parameters. We identified the transition states around the saddle points along the putative folding and unfolding paths between the β‐hairpin and the disordered conformations in the landscape. The characteristic features of these transition states are the predominant hydrophobic contacts and the several hydrogen bonds among the side‐chains, as well as some of the backbone hydrogen bonds. The unfolding simulations at high temperatures, 400 K and 500 K, and their principal component analyses also provided estimates for the transition state conformations, which agreed well with those at 400 K and 500 K deduced from the current free energy landscapes at 400 K and 500 K, respectively. However, the transition states at high temperatures were much more widely distributed on the landscape than those at 300 K, and their conformations were different.
Changing the net charge from negative to positive makes ribonuclease Sa cytotoxic
Authors: Ilinskaya Olga N. , Dreyer Florian , Mitkevich Vladimir A. , Shaw Kevin L. , Pace C. Nick , Makarov Alexander A. 
Published: September 2002

AbstractRibonuclease Sa (pI = 3.5) from Streptomyces aureofaciens and its 3K (D1K, D17K, E41K) (pI = 6.4) and 5K (3K + D25K, E74K) (pI = 10.2) mutants were tested for cytotoxicity. The 5K mutant was cytotoxic to normal and v‐ras‐transformed NIH3T3 mouse fibroblasts, but RNase Sa and 3K were not. The structure, stability, and activity of the three proteins are comparable, but the net charge at pH 7 increases from −7 for RNase Sa to −1 for 3K and to +3 for 5K. These results suggest that a net positive charge is a key determinant of ribonuclease cytotoxicity. The cytotoxic 5K mutant preferentially attacks v‐ras‐NIH3T3 fibroblasts, suggesting that mammalian cells expressing the ras‐oncogene are potential targets for ribonuclease‐based drugs.
Replacement of the P1 Amino Acid of Human Immunodeficiency Virus Type 1 Gag Processing Sites Can Inhibit or Enhance the Rate of Cleavage by the Viral Protease
Authors: Pettit Steve C. , Henderson Gavin J. , Schiffer Celia A. , Swanstrom Ronald 
Published: September 2002

ABSTRACT

Processing of the human immunodeficiency virus type 1 (HIV-1) Gag precursor is highly regulated, with differential rates of cleavage at the five major processing sites to give characteristic processing intermediates. We examined the role of the P1 amino acid in determining the rate of cleavage at each of these five sites by using libraries of mutants generated by site-directed mutagenesis. Between 12 and 17 substitution mutants were tested at each P1 position in Gag, using recombinant HIV-1 protease (PR) in an in vitro processing reaction of radiolabeled Gag substrate. There were three sites in Gag (MA/CA, CA/p2, NC/p1) where one or more substitutions mediated enhanced rates of cleavage, with an enhancement greater than 60-fold in the case of NC/p1. For the other two sites (p2/NC, p1/p6), the wild-type amino acid conferred optimal cleavage. The order of the relative rates of cleavage with the P1 amino acids Tyr, Met, and Leu suggests that processing sites can be placed into two groups and that the two groups are defined by the size of the P1′ amino acid. These results point to a
trans
effect between the P1 and P1′ amino acids that is likely to be a major determinant of the rate of cleavage at the individual sites and therefore also a determinant of the ordered cleavage of the Gag precursor.
Mimovirus: a Novel Form of Vaccine That Induces Hepatitis B Virus-Specific Cytotoxic T-Lymphocyte Responses In Vivo
Authors: Wu Yu-Zhang , Zhao Jian-Ping , Wan Ying , Jia Zheng-Cai , Zhou Wei , Bian Jiang , Ni Bing , Zou Li-Yun , Tang Yan 
Published: September 2002

ABSTRACTCD8+cytotoxic T lymphocytes (CTLs) are now recognized as important mediators of immunity against intracellular pathogens, including human immunodeficiency virus and tumors. How to efficiently evoke antigen-specific CTL responses in vivo has become a crucial problem in the development of modern vaccines. Here, we developed a completely novel CTL vaccine—mimovirus, which is a kind of virus-size particulate antigen delivery system. It was formed by the self-assembly of a cationic peptide containing 18 lysines and a CTL-epitope peptide of HBsAg28-39, with a plasmid encoding mouse interleukin-12 (IL-12) through electrostatic interactions. We examined the formation of mimovirus by DNA retardation assay, DNase I protection assay, and transmission electron microscopy and demonstrated that mimovirus could efficiently transfer the plasmid encoding IL-12 into mammalian cells such as P815 cells in vitro. Furthermore, it was proved that mimovirus could induce an HBsAg28-39-specific CTL response in vivo. Considering its effectiveness, flexibility, and defined composition, mimovirus is potentially a novel system for vaccination against intracellular pathogens and tumors.