bluuebunny/crossref_metadata_2025_split huggingface dataset:
Annual changes in the proportions of wild and hatchery Atlantic salmon (Salmo salar) caught in the Baltic Sea
Authors: Koljonen Marja-Liisa 
Published: July 2006

Abstract
DNA-level information from an eight-loci microsatellite baseline database of 32 Atlantic salmon (Salmo salar) stocks was used with a Bayesian estimation method to assess the stock and stock group proportions of Finnish salmon catches in the Baltic Sea area. The proportions of seven stock groups, important to fisheries management, were assessed in catch samples taken between 2000 and 2005. In the Gulf of Bothnia area, the proportion of wild fish in catches showed an increasing trend in all areas until 2003, mainly because of the decrease in total catches caused by the relatively greater mortality of hatchery-reared fish compared with wild fish. In 2004, the total number of wild fish caught had also increased, indicating an increase in the abundance of wild stocks. In catches from the Åland Sea, the proportion of wild fish increased from 44% in 2000 to 70% in 2004, while the catch during the same period increased from 4628 to 7329 fish. In the Gulf of Finland, the local Neva salmon stock, which is released by Estonia, Finland, and Russia, made the largest contribution. In the western part of the Gulf of Finland, fish originating in the Baltic Main Basin also made a substantial contribution to catches. The threatened eastern Estonian and Russian wild stocks were recorded only in the western part of the Gulf of Finland, where the proportion of wild fish increased from 9% in 2003 to 19% in 2004.
Vitamin A active metabolite, all‐trans retinoic acid, induces spinal cord sensitization. II. Effects after intrathecal administration
Authors: Alique M , Lucio F J , Herrero J F 
Published: July 2006

Background and purpose:In our previous study (see accompanying paper) we observed that all‐trans retinoic acid (ATRA) p.o. induces changes in spinal cord neuronal responses similar to those observed in inflammation‐induced sensitization. In the present study we assessed the it. effects of ATRA, and its mechanisms of action.Experimental approach:The effects of all drugs were studied after it. administration in nociceptive withdrawal reflexes using behavioural tests in awake male Wistar rats.Key results:The administration of ATRA in normal rats induced a dose‐dependent enhancement of nociceptive responses to noxious mechanical and thermal stimulation, as well as responses to innocuous stimulation. The intensity of the responses was similar to that observed in non‐treated animals after carrageenan‐induced inflammation. The effect induced by ATRA was fully prevented by the previous administration of the retinoic acid receptor (RAR) pan‐antagonist LE540 but not by the retinoid X receptor (RXR) pan‐antagonist HX531, suggesting a selective action on spinal cord RARs. The COX inhibitor dexketoprofen and the interleukin‐1 receptor antagonist IL‐1ra inhibited ATRA effect. The results indicate that COX and interleukin‐1 are involved in the effects of ATRA in the spinal cord, similar to that seen in inflammation.Conclusions and implications:In conclusion, ATRA induces changes in the spinal cord similar to those observed in inflammation. The sensitization‐like effect induced by ATRA was mediated by RARs and associated with a modulation of COX‐2 and interleukin‐1 activities. ATRA might be involved in the mechanisms underlying the initiation and/or maintenance of sensitization in the spinal cord.British Journal of Pharmacology (2006) 149, 65–72. doi:10.1038/sj.bjp.0706826
Preclinical pharmacokinetics, pharmacodynamics, and activity of a humanized anti‐CD40 antibody (SGN‐40) in rodents and non‐human primates
Authors: Kelley Sean K , Gelzleichter Thomas , Xie Dong , Lee Wyne P , Darbonne Walter C , Qureshi Ferhan , Kissler Kim , Oflazoglu Ezogelin , Grewal Iqbal S 
Published: July 2006

Cell‐surface expression of CD40 in B‐cell malignancies and multiple solid tumors has raised interest in its potential use as a target for antibody‐based cancer therapy. SGN‐40, a humanized monoclonal anti‐CD40 antibody, mediates antibody‐dependent cytotoxicity and inhibits B‐cell tumor growth in vitro, properties of interest for the treatment of cancers, and is currently in Phase I clinical trials for B‐cell malignancies. In this study, we determined in vivo activity and pharmacokinetics properties of SGN‐40.
Effect of SGN‐40 in xenograft model of CD40‐expressing B‐cell lymphoma in severe‐combined immune deficiency mice and its in vivo pharmacokinetics properties in normal mice, rats and cynomolgus monkeys were studied.
Treatment with SGN‐40 significantly increased the survival of mice xenografted with human B‐cell lymphoma cell line. SGN‐40 exhibited nearly 100% bioavailability in mice and it cleared faster when given at a low dose. In monkeys, clearance of SGN‐40 was also much faster at low dose, suggesting nonlinear pharmacokinetics in these species. In rats, however, SGN‐40 clearance at all tested doses was similar, suggesting that pharmacokinetics were linear in this dose range in rats. Administration of SGN‐40 to monkeys also produced marked, dose‐dependent, and persistent depletion of peripheral CD20+ B lymphocytes.
Data presented in this report suggest that SGN‐40 is active in in vivo, and based upon interspecies scaling, SGN‐40 clearance in humans is predicted to be similar to observed SGN‐40 clearance in monkeys. These data suggest that SGN‐40 has appropriate pharmacokinetic properties that support its clinical use.

British Journal of Pharmacology (2006) 148, 1116–1123. doi:10.1038/sj.bjp.0706828
Neuronal and smooth muscle receptors involved in the PACAP‐ and VIP‐induced relaxations of the pig urinary bladder neck
Authors: Hernández M , Barahona M V , Recio P , Benedito S , Martínez A C , Rivera L , García‐Sacristán A , Prieto D , Orensanz L M 
Published: July 2006

Background and purpose:As pituitary adenylate cyclase‐activating polypeptide 38 (PACAP 38)‐ and vasoactive intestinal peptide (VIP) are widely distributed in the urinary tract, the current study investigated the receptors and mechanisms involved in relaxations induced by these peptides in the pig bladder neck.Experimental approach:Urothelium‐denuded strips were suspended in organ baths for isometric force recordings and the relaxations to VIP and PACAP analogues were investigated.Key results:VIP, PACAP 38, PACAP 27 and [Ala11,22,28]‐VIP produced similar relaxations. Inhibition of neuronal voltage‐gated Ca2+channels reduced relaxations to PACAP 38 and increased those induced by VIP. Blockade of capsaicin‐sensitive primary afferents (CSPA), nitric oxide (NO)‐synthase or guanylate cyclase reduced the PACAP 38 relaxations but failed to modify the VIP responses. Inhibition of VIP/PACAP receptors and of voltage‐gated K+channels reduced PACAP 38 and VIP relaxations, which were not modified by the K+channel blockers iberiotoxin, charybdotoxin, apamin or glibenclamide. The phosphodiesterase 4 inhibitor rolipram and the adenylate cyclase activator forskolin produced potent relaxations. Blockade of protein kinase A (PKA) reduced PACAP 38‐ and VIP‐induced relaxations.Conclusions and implications:PACAP 38 and VIP relax the pig urinary bladder neck through muscle VPAC2receptors linked to the cAMP‐PKA pathway and involve activation of voltage‐gated K+channels. Facilitatory PAC1receptors located at CSPA and coupled to NO release, and inhibitory VPAC receptors at motor endings are also involved in the relaxations to PACAP 38 and VIP, respectively. VIP/PACAP receptor antagonists could be useful in the therapy of urinary incontinence produced by intrinsic sphincter deficiency.British Journal of Pharmacology(2006)149, 100–109. doi:10.1038/sj.bjp.0706832
Leptin, the obesity‐associated hormone, exhibits direct cardioprotective effects
Authors: Smith C C T , Mocanu M M , Davidson S M , Wynne A M , Simpkin J C , Yellon D M 
Published: July 2006

Background and purpose: Protection against ischaemia‐reperfusion (I/R) injury involves PI3K‐Akt and p44/42 MAPK activation. Leptin which regulates appetite and energy balance also promotes myocyte proliferation via PI3K‐Akt and p44/42 MAPK activation. We, therefore, hypothesized that leptin may also exhibit cardioprotective activity.Experimental approach: The influence of leptin on I/R injury was examined in perfused hearts from C57Bl/6 J mice that underwent 35 min global ischaemia and 35 min reperfusion, infarct size being assessed by triphenyltetrazolium chloride staining. The concomitant activation of cell‐signalling pathways was investigated by Western blotting. The effect of leptin on mitochondrial permeability transition pore (MPTP) opening was studied in rat cardiomyocytes.Key results: Leptin (10 nM) administered during reperfusion reduced infarct size significantly. Protection was blocked by either LY294002 or UO126, inhibitors of Akt and p44/42 MAPK, respectively. Western blotting confirmed that leptin stimulated p44/42 MAPK phosphorylation significantly. Akt phosphorylation was also enhanced but did not achieve statistical significance. Additionally, leptin treatment was associated with a significant increase in p38 phosphorylation. By contrast, leptin caused downregulation of phosphorylated and non‐phosphorylated STAT3, and of total AMP‐activated kinase. Cardiomyocytes responded to leptin with delayed opening of the MPTP and delayed time until contracture.Conclusions and implications: Our data indicate for the first time that the adipocytokine, leptin, has direct cardioprotective properties which may involve the PI3‐Akt and p44/42 MAPK pathways.British Journal of Pharmacology (2006) 149, 5–13. doi:10.1038/sj.bjp.0706834
NF-Y and Sp1/Sp3 are involved in the transcriptional regulation of the peptidylarginine deiminase type III gene (PADI3) in human keratinocytes
Authors: Dong Sijun , Kanno Takuya , Yamaki Ayako , Kojima Toshio , Shiraiwa Masakazu , Kawada Akira , Méchin Marie-Claire , Chavanas Stéphane , Serre Guy , Simon Michel , Takahara Hidenari 
Published: July 2006

Human peptidylarginine deiminase type III gene (PADI3) encodes a crucial post-translational modification enzyme that converts protein-bound arginine residues into citrulline residues. Its expression is restricted to a few cell types, including keratinocytes in the granular layer of the epidermis and in the inner root sheath of hair follicles. In these cells, the enzyme is involved in terminal processing of intermediate filament-binding proteins such as filaggrin and trichohyalin. To study the molecular mechanisms that control the expression of PADI3 in human keratinocytes at the transcriptional level, we characterized its promoter region using human keratinocytes transfected with variously deleted fragments of the 5′-upstream region of PADI3 coupled to the luciferase gene. We found that as few as 129 bp upstream from the transcription initiation site were sufficient to direct transcription of the reporter gene. Electrophoretic mobility-shift and chromatin immunoprecipitation assays revealed that NF-Y (nuclear factor Y) and Sp1/Sp3 (specificity protein 1/3) bind to this region in vitro and in vivo. Moreover, mutation of the Sp1- or NF-Y-binding motif markedly reduced PADI3 promoter activity. Furthermore, Sp1 or NF-YA (NF-Y subunit) small interfering RNAs effectively diminished PADI3 expression in keratinocytes cultured in both low- and high-calcium medium. These data indicate that PADI3 expression is driven by Sp1/Sp3 and NF-Y binding to the promoter region.
Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient
Authors: Venkataraman Krishnan , Thangada Shobha , Michaud Jason , Oo Myat Lin , Ai Youxi , Lee Yong-Moon , Wu Mingtao , Parikh Nehal S. , Khan Faraz , Proia Richard L. , Hla Timothy 
Published: July 2006

Sphingosine 1-phosphate (S1P), produced by Sphks (sphingosine kinases), is a multifunctional lipid mediator that regulates immune cell trafficking and vascular development. Mammals maintain a large concentration gradient of S1P between vascular and extravascular compartments. Mechanisms by which S1P is released from cells and concentrated in the plasma are poorly understood. We recently demonstrated [Ancellin, Colmont, Su, Li, Mittereder, Chae, Stefansson, Liau and Hla (2002) J. Biol. Chem. 277, 6667–6675] that Sphk1 activity is constitutively secreted by vascular endothelial cells. In the present study, we show that among the five Sphk isoforms expressed in endothelial cells, the Sphk-1a isoform is selectively secreted in HEK-293 cells (human embryonic kidney cells) and human umbilical-vein endothelial cells. In sharp contrast, Sphk2 is not secreted. The exported Sphk-1a isoform is enzymatically active and produced sufficient S1P to induce S1P receptor internalization. Wild-type mouse plasma contains significant Sphk activity (179 pmol·min−1·g−1). In contrast, Sphk1−/− mouse plasma has undetectable Sphk activity and approx. 65% reduction in S1P levels. Moreover, human plasma contains enzymatically active Sphk1 (46 pmol·min−1·g−1). These results suggest that export of Sphk-1a occurs under physiological conditions and may contribute to the establishment of the vascular S1P gradient.
Integrin β3-mediated Src activation regulates apoptosis in IEC-6 cells via Akt and STAT3
Authors: Bhattacharya Sujoy , Ray Ramesh M. , Johnson Leonard R. 
Published: July 2006

Intestinal epithelial (IEC-6) cells are resistant to apoptosis following the inhibition of ODC (ornithine decarboxylase) and subsequent polyamine depletion. The depletion of polyamines rapidly activates NF-κB (nuclear factor κB) and STAT3 (signal transducer and activator of transcription 3), which is responsible for the observed decrease in apoptosis. Since both NF-κB and STAT3 signalling pathways can be activated by Src kinase, we examined its role in the antiapoptotic response. Inhibition of ODC by DFMO (α-difluoromethylornithine) increased the activity of Src and ERK1/2 (extracellular-signal-regulated kinase 1/2) within 30 min, which was prevented by exogenous polyamines added to the DFMO-containing medium. Conversely, epidermal growth factor-mediated Src and ERK1/2 activation was not prevented by the addition of polyamines. Inhibition of Src with PP2 {4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine} and a DN-Src (dominant-negative Src) construct prevented the activation of Akt, JAK (Janus kinase) and STAT3. Spontaneous apoptosis was increased in DN-Src-expressing cells and the protective effect of polyamine depletion was lost. Polyamine depletion by DFMO increased integrin β3 Tyr785 phosphorylation. Cells plated on fibronectin had significantly higher β3 phosphorylation and Src activation compared with plastic. Exogenous polyamines added to the fibronectin matrix prevented Src activation. Arg-Gly-Asp-Ser inhibited β3, Src and Akt phosphorylation and sensitized polyamine-depleted cells to tumour necrosis factor α/cycloheximide-mediated apoptosis. Fibronectin activated Src and subsequently protected cells from apoptosis. Together, these results suggest that the inhibition of ODC rapidly removes a small pool of available polyamines triggering the activation of β3 integrin, which in turn activates Src. The subsequent Akt and JAK activation is accompanied by translocation of NF-κB and STAT3 to the nucleus and the synthesis of antiapoptotic proteins.
Anomalous scattering analysis of Agrobacterium radiobacter phosphotriesterase: the prominent role of iron in the heterobinuclear active site
Authors: Jackson Colin J. , Carr Paul D. , Kim Hye-Kyung , Liu Jian-Wei , Herrald Paul , Mitić Nataša , Schenk Gerhard , Smith Clyde A. , Ollis David L. 
Published: July 2006

Bacterial phosphotriesterases are binuclear metalloproteins for which the catalytic mechanism has been studied with a variety of techniques, principally using active sites reconstituted in vitro from apoenzymes. Here, atomic absorption spectroscopy and anomalous X-ray scattering have been used to determine the identity of the metals incorporated into the active site in vivo. We have recombinantly expressed the phosphotriesterase from Agrobacterium radiobacter (OpdA) in Escherichia coli grown in medium supplemented with 1 mM CoCl2 and in unsupplemented medium. Anomalous scattering data, collected from a single crystal at the Fe–K, Co–K and Zn–K edges, indicate that iron and cobalt are the primary constituents of the two metal-binding sites in the catalytic centre (α and β) in the protein expressed in E. coli grown in supplemented medium. Comparison with OpdA expressed in unsupplemented medium demonstrates that the cobalt present in the supplemented medium replaced zinc at the β-position of the active site, which results in an increase in the catalytic efficiency of the enzyme. These results suggest an essential role for iron in the catalytic mechanism of bacterial phosphotriesterases, and that these phosphotriesterases are natively heterobinuclear iron–zinc enzymes.
Structural features of mouse telomerase RNA are responsible for the lower activity of mouse telomerase versus human telomerase
Authors: Garforth Scott J. , Wu Yan Yun , Prasad Vinayaka R. 
Published: July 2006

Human and mouse telomerases show a high degree of similarity in both the protein and RNA components. Human telomerase is more active and more processive than the mouse telomerase. There are two key differences between hTR [human TR (telomerase RNA)] and mTR (mouse TR) structures. First, the mouse telomerase contains only 2 nt upstream of its template region, whereas the human telomerase contains 45 nt. Secondly, the template region of human telomerase contains a 5-nt alignment domain, whereas that of mouse has only 2 nt. We hypothesize that these differences are responsible for the differential telomerase activities. Mutations were made in both the hTR and mTR, changing the template length and the length of the RNA upstream of the template, and telomerase was reconstituted in vitro using mouse telomerase reverse transcriptase generated by in vitro translation. We show that the sequences upstream of the template region, with a potential to form a double-stranded helix (the P1 helix) as in hTR, increase telomerase activity. The longer alignment domain increases telomerase activity only in the context of the P1 helix. Thus the TR contributes to regulating the level of activity of mammalian telomerases.
Liver breath tests non-invasively predict higher stages of non-alcoholic steatohepatitis
Authors: Portincasa Piero , Grattagliano Ignazio , Lauterburg Bernhard H. , Palmieri Vincenzo O. , Palasciano Giuseppe , Stellaard Frans 
Published: July 2006

Effectively assessing subtle hepatic metabolic functions by novel non-invasive tests might be of clinical utility in scoring NAFLD (non-alcoholic fatty liver disease) and in identifying altered metabolic pathways. The present study was conducted on 39 (20 lean and 19 obese) hypertransaminasemic patients with histologically proven NAFLD {ranging from simple steatosis to severe steatohepatitis [NASH (non-alcoholic steatohepatitis)] and fibrosis} and 28 (20 lean and eight overweight) healthy controls, who underwent stable isotope breath testing ([13C]methacetin and [13C]ketoisocaproate) for microsomal and mitochondrial liver function in relation to histology, serum hyaluronate, as a marker of liver fibrosis, and body size. Compared with healthy subjects and patients with simple steatosis, NASH patients had enhanced methacetin demethylation (P=0.001), but decreased (P=0.001) and delayed (P=0.006) ketoisocaproate decarboxylation, which was inversely related (P=0.001) to the degree of histological fibrosis (r=−0.701), serum hyaluronate (r=−0.644) and body size (r=−0.485). Ketoisocaproate decarboxylation was impaired further in obese patients with NASH, but not in patients with simple steatosis and in overweight controls. NASH and insulin resistance were independently associated with an abnormal ketoisocaproate breath test (P=0.001). The cut-off value of 9.6% cumulative expired 13CO2 for ketoisocaproate at 60 min was associated with the highest prediction (positive predictive value, 0.90; negative predictive value, 0.73) for NASH, yielding an overall sensitivity of 68% and specificity of 94%. In conclusion, both microsomal and mitochondrial functions are disturbed in NASH. Therefore stable isotope breath tests may usefully contribute to a better and non-invasive characterization of patients with NAFLD.
Effect of fatty acids on endothelium-dependent relaxation in the rabbit aorta
Authors: Edirisinghe Indika , McCormick Hallam Kellie , Kappagoda C. Tissa 
Published: July 2006

The metabolic syndrome, Type II (non-insulin-dependent) diabetes and obesity are associated with endothelial dysfunction and increased plasma concentrations of NEFAs (non-esterified fatty acids; free fatty acids). The present study was undertaken to define the inhibitory effects of saturated NEFAs on EDR (endothelium-dependent relaxation). Experiments were performed in rings of rabbit aorta to establish (i) dose–response relationships, (ii) the effect of chain length, (iii) the effect of the presence of double bonds, (iv) reversibility and time course of inhibition, and (v) the effect on nitric oxide production. Aortic rings were incubated (1 h) with NEFA–albumin complexes derived from lauric (C12:0), myristic (C14:0), palmitic (C16:0), stearic (C18:0) and linolenic (C18:3) acids. EDR induced by acetylcholine (0.1–10 μmol/l) was measured after pre-contraction with noradrenaline. Inhibition of EDR was dose-dependent (0.5–2 mmol/l NEFA), and the greatest inhibition (51%) was observed with stearic acid (2 mmol/l). Lauric acid had the smallest inhibitory effect. The inhibitory effects were always reversible and were evident after 15 min of incubation. Linolenic acid caused a significantly lower inhibition of EDR than stearic acid. SOD (superoxide dismutase) restored the inhibitory effect caused by NEFAs, suggesting the involvement of ROS (reactive oxygen species) in removing nitric oxide. The nitric oxide concentration measured after exposure of the rings to acetylcholine was lower after incubation with NEFAs than with Krebs buffer alone. This finding is consistent with removal of nitric oxide by ROS. This claim was supported by the demonstration of increased concentrations of nitrated tyrosine in the rings incubated with NEFAs.