bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of CB1 receptors increases noradrenaline release in vas deferens without affecting atrial noradrenaline release or cortical acetylcholine release
Authors: Schlicker Eberhard , Redmer Agnes , Werner André , Kathmann Markus 
Published: September 2003

We studied whether cannabinoid CB1 receptor gene disruption (to yield CB1−/− mice) affects the electrically evoked tritium overflow from vas deferens and atrial pieces preincubated with [3H]‐noradrenaline (NA) (‘noradrenaline release’) and from cerebral cortex slices preincubated with [3H]‐choline (‘acetylcholine release’).
NA release was higher by 37% in vas deferens from CB1−/− mice than in vas deferens from CB1+/+ mice. The cannabinoid receptor agonist WIN 55,212‐2 inhibited, and the CB1 receptor inverse agonist/antagonist SR 141716, increased NA release in vas deferens from CB1+/+ mice without affecting it in vas deferens from CB1−/− mice.
Atrial NA release did not differ between CB1+/+ and CB1−/− mice nor did WIN 55,212‐2 affect NA release in either strain.
Cortical acetylcholine (Ach) release did not differ between CB1+/+ and CB1−/− mice. WIN 55,212‐2 inhibited, but SR 141716 did not affect, Ach release in the cortex from CB1+/+ mice. Both drugs did not alter Ach release in the cortex from CB1−/− mice.
Tritium content did not differ between CB1+/+ and CB1−/− mice in any preparation.
In conclusion, the increase in NA release associated with CB1 receptor deficiency in the vas deferens, which cannot be ascribed to an alteration of tritium content of the preparations, suggests an endogenous tone at the CB1 receptors of CB1+/+ mice in this tissue. Furthermore, the effect of WIN 55,212‐2 on NA release in the vas deferens and on cortical Ach release involves CB1 receptors, whereas the involvement of non‐CB1–non‐CB2 receptors can be excluded.

British Journal of Pharmacology (2003) 140, 323–328. doi:10.1038/sj.bjp.0705449
MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity
Authors: Yang Wu , Guastella John , Huang Jin‐Cheng , Wang Yan , Zhang Li , Xue Dong , Tran Minhtam , Woodward Richard , Kasibhatla Shailaja , Tseng Ben , Drewe John , Cai Sui Xiong 
Published: September 2003

Caspases play a critical role in apoptosis, and are considered to be key targets for the design of cytoprotective drugs. As part of our antiapoptotic drug‐discovery effort, we have synthesized and characterized Z‐VD‐fmk, MX1013, as a potent, irreversible dipeptide caspase inhibitor.
MX1013 inhibits caspases 1, 3, 6, 7, 8, and 9, with IC50 values ranging from 5 to 20 nM. MX1013 is selective for caspases, and is a poor inhibitor of noncaspase proteases, such as cathepsin B, calpain I, or Factor Xa (IC50 values >10 μM).
In several cell culture models of apoptosis, including caspase 3 processing, PARP cleavage, and DNA fragmentation, MX1013 is more active than tetrapeptide‐ and tripeptide‐based caspase inhibitors, and blocked apoptosis at concentrations as low as 0.5 μM.
MX1013 is more aqueous soluble than tripeptide‐based caspase inhibitors such as Z‐VAD‐fmk.
At a dose of 1 mg kg−1 i.v., MX1013 prevented liver damage and the lethality caused by Fas death receptor activation in the anti‐Fas mouse‐liver apoptosis model, a widely used model of liver failure.
At a dose of 20 mg kg−1 (i.v. bolus) followed by i.v. infusion for 6 or 12 h, MX1013 reduced cortical damage by approximately 50% in a model of brain ischemia/reperfusion injury.
At a dose of 20 mg kg−1 (i.v. bolus) followed by i.v. infusion for 12 h, MX1013 reduced heart damage by approximately 50% in a model of acute myocardial infarction.
Based on these studies, we conclude that MX1013, a dipeptide pan‐caspase inhibitor, has a good combination of in vitro and in vivo properties. It has the ability to protect cells from a variety of apoptotic insults, and is systemically active in three animal models of apoptosis, including brain ischemia.

British Journal of Pharmacology (2003) 140, 402–412. doi:10.1038/sj.bjp.0705450
Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin‐induced carotid haemodynamic changes in anaesthetised pigs
Authors: Kapoor Kapil , Arulmani Udayasankar , Heiligers Jan P C , Garrelds Ingrid M , Willems Edwin W , Doods Henri , Villalón Carlos M , Saxena Pramod R 
Published: September 2003

Calcitonin gene‐related peptide (CGRP), a potent vasodilator released from capsaicin‐sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 μg kg−1, i.v.), a potent and selective CGRP receptor antagonist, on capsaicin‐induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone.
Infusions of capsaicin (0.3, 1, 3 and 10 μg kg−1 min−1, i.c.) did not alter the heart rate, but dose‐dependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS.
Capsaicin infusion (10 μg kg−1 min−1, i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose‐dependently blocked by BIBN4096BS.
Capsaicin infusion (10 μg kg−1 min−1, i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS.
The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin‐induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine.

British Journal of Pharmacology (2003) 140, 329–338. doi:10.1038/sj.bjp.0705451
The ability of neuropeptide Y to mediate responses in the murine cutaneous microvasculature: an analysis of the contribution of Y1 and Y2 receptors
Authors: Chu Duc Quyen , Cox Helen M , Costa Soraia K P , Herzog Herbert , Brain Susan D 
Published: September 2003

The ability of neuropeptide Y (NPY) to modulate skin blood flow, oedema formation and neutrophil accumulation was investigated. Experiments were designed to examine the possible contribution of the Y2 receptor, in addition to the Y1 receptor, through use of Y2 receptor knockout mice (Y2−/−) and selective receptor antagonists.
The development of a 99mTc clearance technique for the measurement of microvascular blood flow changes in mouse dorsal skin revealed a dose‐dependent ability of picomole amounts of NPY, and also of the Y1‐preferred agonist Pro34NPY and the Y2‐preferred agonist PYY(3–36) to decrease blood flow.
The Y1 receptor antagonist BIBO3304 blocked responses to the Y1 agonist at the lower doses, but only partially inhibited at the higher doses tested in Y2+/+. In Y2−/− receptor mice, the responses to the Y2 agonist were abolished at the lower doses and partially reduced at the highest dose tested, while those to the Y1 agonist were similar in both Y2+/+ and Y2−/−receptor mice.
In Y2+/+ receptor mice, the simultaneous injection of the Y2 antagonist BIIE0246 with BIBO3304 abolished Y2 agonist‐induced decreases in blood flow over the dose range used (10–100 pmol). When the Y2 receptor antagonist BIIE0246 was given alone, it was not able to significantly affect the PYY(3–36)‐induced response, whereas the Y1 receptor antagonist BIBO3304 partially (P<0.001) inhibited the decrease in blood flow evoked by PYY(3–36) at the highest dose.
NPY did not mediate either oedema formation, even when investigated in the presence of the vasodilator calcitonin gene‐related peptide (CGRP), or neutrophil accumulation in murine skin.
We conclude that the major vasoactive activity of NPY in the cutaneous microvasculature is to act in a potent manner to decrease blood flow via Y1 receptors, with evidence for the additional involvement of postjunctional Y2 receptors. Our results do not provide evidence for a potent proinflammatory activity of NPY in the cutaneous microvasculature.

British Journal of Pharmacology (2003) 140, 422–430. doi:10.1038/sj.bjp.0705452
A model for receptor–peptide binding at the glucagon‐like peptide‐1 (GLP‐1) receptor through the analysis of truncated ligands and receptors
Authors: Al‐Sabah Suleiman , Donnelly Dan 
Published: September 2003

The receptor for glucagon‐like peptide‐1 (GLP‐1) can be activated by both its physiological hormone and a peptide discovered in the venom of the Gila Monster, exendin‐4, which shows promise as an antidiabetic agent.
Exendin‐4 displays receptor‐binding properties not observed for GLP‐1. Firstly, exendin‐4 can be truncated by up to eight residues at its N‐terminus without a significant loss of affinity. Secondly, exendin‐4 maintains high affinity for the isolated N‐terminal domain of the receptor, suggesting that exendin‐4 makes additional contacts with this domain of the receptor, which nullify the requirement for ligand–receptor interactions involving the extracellular loops and/or transmembrane helices of the receptor's core domain.
In order to further understand the nature of the receptor–peptide interaction, a variety of full length and truncated peptide analogues were used to quantify the contribution of each distinct region of exendin‐4 and GLP‐1 to receptor affinity.
Our data show that, for both exendin‐4 and GLP‐1, the primary interaction is between the putative helical region of the peptide and the extracellular N‐terminal domain of the receptor.
However, we demonstrate that the contribution to receptor affinity provided by the N‐terminal segment of GLP‐1 is greater than that of exendin‐4, while the C‐terminal nine residue extension of exendin‐4, absent in GLP‐1, forms a compensatory interaction with the N‐terminal domain of the receptor.
We describe a peptide–receptor binding model to account for these data.

British Journal of Pharmacology (2003) 140, 339–346. doi:10.1038/sj.bjp.0705453
Mapping and SNP analysis of bovine candidate genes for meat and carcass quality
Authors: Haegeman A. , Williams J. L. , Law A. , Van Zeveren A. , Peelman L. J. 
Published: September 2003

SummaryThe chromosomal localization of 13 bovine genes was determined using radiation hybrid (RH) mapping. The RH mapping data were in agreement with published data using either linkage, somatic cell hybrids or in situ hybridization. Mutation analysis using single‐stranded conformational polymorphism, restriction fragment length polymorphism (RFLP) and sequencing revealed 13 SNPs in four different genes, namely carboxypeptidase E (CPE), uncoupling protein 2 (UCP2), single‐minded (Drosophila) homologue 1 (SIM1) and methallothionein IIa (MT2A). With the exception of one mutation in CPE, all other mutations are either silent or are situated in an intron. The polymerase chain reaction RFLP was used on unrelated animals from different cattle breeds for determing allelic distribution.
Mitochondrial DNA sequence variation and phylogenetic relationships among Iberian pigs and other domestic and wild pig populations
Authors: Alves E. , Óvilo C. , Rodríguez M. C. , Silió L. 
Published: September 2003

SummaryNucleotide sequences of mitochondrial DNA (mtDNA) cytochrome B gene (1140 bp) and control region (707 bp) were used to determine the phylogenetic relationships among 51 pig samples representing ancient and current varieties of Iberian pigs (26), Spanish wild boars (seven) and other domestic pigs (18) of cosmopolitan (Duroc, Large White, Landrace, Pietrain and Meishan) and local (Spotted Black Jabugo, Basque and Mangalitza) breeds. A neighbour‐joining tree constructed from pairwise distances provide evidence of the European origin of both Iberian pigs and Spanish wild boars. The introgression of Asian mtDNA haplotypes in the genetic pool of the Iberian breed seems unlikely. Four estimates of sequence divergence between European and Asian clades were calculated from the two main domains of the D‐loop region and the synonymous and nonsynonymous nucleotide substitutions in the cytochrome B gene. The time since the divergence of pig ancestors was estimated at about 600 000 years before present.
DGAT1, a new positional and functional candidate gene for intramuscular fat deposition in cattle
Authors: Thaller G. , Kühn C. , Winter A. , Ewald G. , Bellmann O. , Wegner J. , Zühlke H. , Fries R. 
Published: September 2003

SummaryIntramuscular fat content, also assessed as marbling of meat, represents an important beef quality trait. Recent work has mapped a quantitative trait locus (QTL) with an effect on marbling to the centromeric region of bovine chromosome 14, with the gene encoding thyroglobulin (TG) being proposed as a positional and functional candidate gene for this QTL. Recently, the gene encoding diacylglycerol O‐acyltransferase (DGAT1), which also has been mapped within the region of the marbling QTL, has been demonstrated to affect the fat content of milk. In the present study, the effects of a 5′‐polymorphism of TG and of a lysine/alanine polymorphism of DGAT1 on the fat content of musculus (m.) semitendinosus and m. longissimus dorsi in 55 bovine animals (28 German Holstein and 27 Charolais) has been investigated. Significant effects were found for both candidate genes in both the breeds. These effects seem to be independent of one another because the alleles of the two polymorphisms showed no statistically significant disequilibrium. The DGAT1 effect is mainly on the m. semitendinosus. The TG polymorphism only affects m. longissimus dorsi. However, both intramuscular fat enhancing effects seem to be recessive. The possibility of two linked loci, acting recessively on intramuscular fat content, will require special strategies when selecting for higher marbling scores.
No disease‐associated mutations found in the coding sequence of the canine polycystic kidney disease gene 1 in Bull Terriers with polycystic kidney disease
Authors: O'Leary C. A. , Atwell R. B. , Laing N. G. 
Published: September 2003

SummaryThe aim of this study was to identify possible disease‐associated mutations in the canine homologue of the polycystic kidney disease gene 1 (PKD1) in Bull Terriers with autosomal dominant polycystic kidney disease. Messenger RNA was obtained from the blood or renal tissue of five Bull Terriers with the disease and four close relatives without the disease. Reverse transcription, PCR and 3′ rapid amplification of cDNA ends were used to amplify the coding and 3′ untranslated regions of this transcript. Comparison of PKD1 sequence between the affected and unaffected Bull Terriers, revealed six polymorphisms, but no disease‐associated mutations.
Mapping of 1400 expressed sequence tags in the bovine genome using a somatic cell hybrid panel
Authors: Itoh T. , Takasuga A. , Watanabe T. , Sugimoto Y. 
Published: September 2003

SummaryA bovine/hamster hybrid cell panel consisting of 30 independent hybrids was developed to locate genes. Polymerase chain reaction analysis of 279 microsatellites on the cattle linkage map in this panel revealed the presence of all chromosomes in either entire or fragmented form. Among primer pairs prepared from bovine 3′‐expressed sequence tags (ESTs), 1400 ESTs were assigned to specific chromosomes, of which 1303 were newly assigned in this study, and mapped 854 (61%) to 1 of 192 chromosomal segments using this panel. The regional mapping of new genes to cattle chromosomes can be rapidly achieved using this panel.
Experimental population design for estimation of dominant molecular marker effect on egg‐production traits
Authors: Kaiser M. G. , Lakshmanan N. , Arthur J. A. , O'Sullivan N. P. , Lamont S. J. 
Published: September 2003

SummaryA potential limitation of the use of a dominant molecular marker system such as DNA fingerprinting (DFP) is the inability to distinguish homozygous from heterozygous allele state in an individual, and a resulting inaccuracy in estimating effects of the marker alleles. The objective of this study was to accurately estimate the effect of DFP markers on egg‐production traits. A BC1 population was produced from two distinct layer lines. Four DFP bands, each originating predominantly in one of the two parental lines, were evaluated for linkage with egg‐production quantitative trait loci in the BC1 population. The egg‐production traits consisted of eight early period and seven late period measurements. Eight marker‐trait linkages were identified out of 60 total statistical tests. By utilizing information on frequency of DFP bands in two parental lines, selecting F1 sires with DFP bands present, and backcrossing to the line lacking these bands, the population design allowed definitive identification of the DFP zygosity in the BC1 resource population hens. In this manner, accurate estimates of marker allele effects on egg‐production traits were obtained from the dominant marker system of DNA fingerprinting.
Association of twelve candidate gene polymorphisms and response to challenge with Salmonella enteritidis in poultry
Authors: Kramer J. , Malek M. , Lamont S. J. 
Published: September 2003

SummaryBreeding for disease resistance to Salmonella enteritidis (SE) could be an effective approach to control Salmonella in poultry. The candidate gene approach is a useful method to investigate genes that are involved in genetic resistance. In this study, 12 candidate genes that are involved in the pathogenesis of Salmonella infection were investigated using five different genetic groups of meat‐type chicken. The genes were natural resistance associated macrophage protein 1 (SLC11A1, previously known as NRAMP1), inhibitor of apoptosis protein 1 (IAP1), prosaposin (PSAP), Caspase‐1 (CASP1), inducible nitric oxide production (iNOS), interferon‐gamma (IFNG), interleukin‐2 (IL2), immunoglobulin light chain (IGL), ZOV3, and transforming growth factors B2, B3 and B4 (TGFB2, B3 and B4). In total, 117 birds of all groups were challenged with SE at the age of 3 weeks. In all birds at 7‐day post‐infection SE load in caecum content, spleen and liver were quantified. Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assays were used to genotype all animals for each gene. Overall we found the most significant associations with caecum content, nine of 12 genes showed a significant association (SLC11A1, IAP1, PSAP, CASP1, iNOS, IL2, IGL, TGFB2 and TGFB4). For liver, five genes (SLC11A1, CASP1, IL2, IGL, and TGFB4) and for spleen, only one gene (TGFB3) showed a significant association with SE load. By showing associations of 12 PCR‐RFLP assays with SE load after a pathogen challenge, this study confirmed the polygenic nature of disease resistance to SE.
A new mutation in the coding region of the bovine leptin gene associated with feed intake
Authors: Lagonigro R. , Wiener P. , Pilla F. , Woolliams J. A. , Williams J. L. 
Published: September 2003

SummaryAn experimental cattle population was screened for polymorphisms in the leptin gene and five SNPs were found in the regions containing the coding sequences. The association of these polymorphisms with feed intake and fat‐related traits was evaluated. The results suggest an association between a polymorphism in exon 2, described here for the first time, and feed intake. Individuals with genotype A/T at this position had 19% greater mean feed intake than individuals with genotype A/A. There was also evidence for a link between leptin haplotypes and some fat‐related traits.
Identification of a sex‐determining region in Nile tilapia (Oreochromis niloticus) using bulked segregant analysis
Authors: Lee B.‐Y. , Penman D. J. , Kocher T. D. 
Published: September 2003

SummarySex determination in the Nile tilapia (Oreochromis niloticus) is thought to be an XX‐XY (male heterogametic) system controlled by a major gene. We searched for DNA markers linked to this major locus using bulked segregant analysis. Ten microsatellite markers belonging to linkage group 8 were found to be linked to phenotypic sex. The putative Y‐chromosome alleles correctly predict the sex of 95% of male and female individuals in two families. Our results suggest a major sex‐determining locus within a few centimorgans of markers UNH995 and UNH104. A third family from the same population showed no evidence for linkage of this region with phenotypic sex, indicating that additional genetic and/or environmental factors regulate sex determination in some families. These markers have immediate utility for studying the strength of different Y chromosome alleles, and for identifying broodstock carrying one or more copies of the Y haplotype.
Progressive decline of vasopressin secretion in familial autosomal dominant neurohypophyseal diabetes insipidus presenting a novel mutation in the vasopressin‐neurophysin II gene
Authors: Elias Paula C. L. , Elias Lucila L. K. , Torres Natalia , Moreira Ayrton C. , Antunes‐Rodrigues Jose , Castro Margaret 
Published: September 2003

Summaryobjective  Familial autosomal dominant neurohypophyseal diabetes insipidus (FNDI) is a rare form of central diabetes insipidus (DI), which is caused by mutations in the vasopressin‐neurophysin II (AVP‐NPII) gene. The present study evaluated the AVP secretion over time and analysed the structure of the AVP‐NPII gene in a Brazilian family with FNDI.subjects and design  Four affected members and one nonaffected member from one Brazilian family with FNDI were studied. The diagnosis of central DI was established by fluid deprivation test and hypertonic saline infusion. Two affected members were assessed twice within a 6‐year interval. For molecular analysis, genomic DNA was extracted and the AVP‐NPII gene was amplified by polymerase chain reaction.results  The functional assessment of patients with FNDI over time confirmed a progressive loss in AVP secretion. Two patients were first diagnosed as partial central DI and, several years later, they developed severe central DI. Sequencing analysis revealed a heterozygous new point mutation in the nucleotide 1892 in the coding sequence for neurophysin‐II of the AVP‐NPII gene (1892G > C) predicting an amino acid substitution (A68P) in all affected members.conclusion  Our data demonstrate a gradual vasopressinergic deficiency due to a novel mutation in the AVP‐NPII gene in a Brazilian family with FNDI. The accumulation of A68P mutated precursor might have a cytotoxicity effect, leading to a gradual death of magnocellular neurones, and a progressive decline in AVP secretion.