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PubMed1990

Nucleotide sequence of the gene for the b subunit of human factor XIII.

Factor XIII (Mr 320,000) is a blood coagulation factor that stabilizes and strengthens the fibrin clot. It circulates in blood as a tetramer composed of two a subunits (Mr 75,000 each) and two b subunits (Mr 80,000 each). The b subunit consists of 641 amino acids and includes 10 tandem repeats of 60 amino acids known as GP-I structures, short consensus repeats (SCR), or sushi domains. In the present study, the human gene for the b subunit has been isolated from three different genomic libraries prepared in lambda phage. Fifteen independent phage with inserts coding for the entire gene were isolated and characterized by restriction mapping, Southern blotting, and DNA sequencing. The gene was found to be 28 kilobases in length and consisted of 12 exons (I-XII) separated by 11 intervening sequences. The leader sequence was encoded by exon I, while the carbonyl-terminal region of the protein was encoded by exon XII. Exons II-XI each coded for a single sushi domain, suggesting that the gene evolved through exon shuffling and duplication. The 12 exons in the gene ranged in size from 64 to 222 base pairs, while the introns ranged in size from 87 to 9970 nucleotides and made up 92% of the gene. The introns contained four Alu repetitive sequences, one each in introns A, E, I, and J. A fifth Alu repeat was present in the flanking 3' end of the gene. Two partial KpnI repeats were also found in the introns, including one in intron I and one in intron J. The KpnI repeat in intron J was 89% homologous to a sequence of approximately 2200 nucleotides flanking the gene coding for human beta globin and approximately 3800 nucleotides from the L1 insertion present in the gene for human factor VIII. Intron H also contained an "O" family repeat, while two potential regions for Z-DNA were identified within introns G and J. One nucleotide change was found in the coding region of the gene when its sequence was compared to that of the cDNA. This difference, however, did not result in a change in the amino acid sequence of the protein.

Amino Acid Sequence↗
PubMed2006

Ethnicity recording in general practice computer systems.

BACKGROUND: Ethnicity data in general practice (GP) computerized medical records can be utilized to audit equity in health care. METHODS: We evaluated a patient profiling project targeted to improve ethnicity recording. RESULTS: Data extracted from 16 practices showed an increase in ethnicity recording from <1% before the intervention to 48% after. Recorded codes could be mapped onto the basic national statistics six-category ethnicity classification headings, and their proportions were similar to the 2001 census values. CONCLUSION: Recording of data using multiple coding hierarchies has reduced the utility of data as clinically important ethnic subgroups cannot be identified. Practitioners should be encouraged to use the single recommended ethnicity coding hierarchy.

Adult↗
PubMed1996

Antigenicity of truncated forms of the human immunodeficiency virus type 1 envelope glycoprotein.

Chinese hamster ovary (CHO) cell lines secreting a series of truncated forms of human immunodeficiency virus type 1 (HIV-1) IIIB (clone BH10) gp12O were assembled. Using purified glycoproteins, we demonstrated the functional and structural integrity of these truncates by their reactivity with both sCD4 and anti-gp 120 monoclonal antibodies (MAbs). Deletion of the Vl, V2 and V3 regions had minimal effects on CD4 binding, but deletion of the NH2 terminus affected the folding of the truncated molecule. Deletion of either V1/V2 or V1/V2/V3 regions led to enhanced recognition by some, but not all, MAbs mapping to the CD4 binding site. In contrast, deletion of the V1/V2 regions had no effect on the ability of V3-specific MAbs to bind to the truncate. These results support the use of truncated forms of gp12O as components of potential HIV vaccines.

Animals↗
PubMed2002

Characterization of an antagonist interleukin-6 dimer by stable isotope labeling, cross-linking, and mass spectrometry.

The homodimeric form of a recombinant cytokine interleukin-6 (IL-6(D)) is known to antagonize IL-6 signaling. In this study, spatially proximal residues between IL-6 chains in IL-6(D) were identified using a method for specific recognition of intermolecular cross-linked peptides. Our strategy involved mixing 1:1 (15)N-labeled and unlabeled ((14)N) protein to form a mixture of isotopically labeled and unlabeled homodimers, which was chemically cross-linked. This cross-linked IL-6(D) was subjected to proteolysis by trypsin and the generated peptides were analyzed by electrospray ionization time-of-flight mass spectrometry (MS). Molecular ions from cross-linked peptides of intermolecular origin are labeled with [(15)N/(15)N] + [(15)N/(14)N] + [(14)N/(15)N] + [(14)N/(14)N] yielding readily identified triplet/quadruplet MS peaks. All other peptide species are labeled with [(15)N] + [(14)N] yielding doublet peaks. Intermolecular cross-linked peptides were identified by MS, and cross-linked residues were identified. This intermolecular cross-link detection method, which we have designated "mixed isotope cross-linking" MIX may have more general application to protein-protein interaction studies. The pattern of proximal residues found was consistent with IL-6(D) having a domain-swapped fold similar to IL-10 and interferon-gamma. This fold implies that IL-6(D)-mediated antagonism of IL-6 signaling is caused by obstruction of cooperative gp130 binding on IL-6(D), rather than direct blocking of gp-130-binding sites on IL-6(D).

Dimerization↗
PubMed2002

GP letter writing in colorectal cancer: a qualitative study.

BACKGROUND: The usual mode of communication with the specialist in the UK is a referral letter. Letters now primarily document the GPs' concerns for the patient and are no longer required to persuade the specialist to offer an appointment. The content of referral letters from GPs has failed to satisfy specialists responding to a series of surveys. Evidence suggests that GPs who improve their letters to specialists also refer more cases with significant pathology. AIMS: The aims of this research are to explore the factors that may influence GPs in writing the referral letter when consulting patients presenting with lower bowel symptoms. METHODS: A convenience sample of twelve GPs was interviewed in Nottinghamshire and inner city Sheffield practices. A framework approach was utilised in the analysis of data. Data from the interviews followed the prescribed steps, including: familiarisation, identifying a thematic framework, indexing, charting and mapping, and interpretation. RESULTS: The thematic framework reflected four major themes. These were: (1) the nature and content of referral letters, (2) knowledge about colorectal cancer, (3) issues relating to the quality of referral letters in colorectal cases and (4) factors that effect the use of guidelines for referral. CONCLUSIONS: GPs only have very short consultations in which to address many and complex issues. Pre-referral assessment in colorectal cases includes intimate examination of the patient. Therefore the writing of the letter of referral is often postponed until long after the patient has left the GP's office. Some GPs do not believe the consultant reads the letter of referral. However, GPs are keen to provide best care and welcome feedback about the quality of their letters. They acknowledge the responsibility to communicate with colleagues effectively and have differing ideas about what constitutes an adequate referral letter.

Adult↗
PubMed1993

Where does damage lead to enhanced food aversion: the ventral pallidum/substantia innominata or lateral hypothalamus?

It is well known that lesions of the lateral hypothalamus (LH) produce aphagia. Several previous studies have reported that lateral hypothalamus damage produces food aversion in addition to aphagia. However, damage to other regions near the LH also produce aphagia and enhanced aversion. The purpose of this study was to resolve where the site or sites for aversion-inducing lesions is/are located. Small, bilateral excitotoxin lesions (QUIN, 10 micrograms in 1 microliter or IBO, 15 micrograms in 1 microliter) or bilateral sham injections of vehicle were made into the globus pallidus (GP), the ventral pallidum/substantia innominata (VP/SI) or the lateral hypothalamus (LH). Affective reactions to taste were elicited by infusing sucrose solutions (1 M) into the mouth via chronic oral cannulae. The number of aversive responses (gapes, chin-rubbing, head-shaking and forelimb flails) emitted was tallied. Individual lesions were mapped and a single 'necessary and sufficient' site for damage-induced aversion was identified (the area of overlapping damage common to all rats that showed enhanced aversive reactions). To identify the lesions, two lesion-mapping techniques were used: (1) a conventional neuron-counting procedure in which an attempt is made to count all neurons within a brain region, and (2) a new modified 'fractionator' procedure consisting of exhaustive 400 x magnification counts at point locations within a brain region. Results indicated that aversive reactions to food are enhanced only following bilateral neuron loss (> 70%) from the caudal ventromedial VP/SI alone. This shared site has a lateral diameter of 1.0 mm, a dorsoventral diameter of 0.5 mm and a rostrocaudal diameter of 1.0 mm. Damage restricted to the LH never produced enhanced aversion even when it produced aphagia. The crucial region for aversion is located ventral and medial to the globus pallidus and dorsal and lateral to the lateral hypothalamus.

Animals↗
PubMed1991

A single gene encodes membrane-bound and free forms of GP-2, the major glycoprotein in pancreatic secretory (zymogen) granule membranes.

GP-2, a 75-kDa glycoprotein, was isolated from dog pancreatic zymogen granule membranes (ZGMs). In a carbohydrate-shift strategy, N-terminal and internal peptide sequences were obtained on glycosylated and deglycosylated forms of GP-2, respectively, by gas-phase sequencing. Sets of mixed oligonucleotides and the polymerase chain reaction were used to obtain a double-stranded cDNA probe, which was used to isolate overlapping cDNA clones from a dog pancreatic cDNA library. The sequence of these clones revealed an open reading frame that encodes a protein of 509 amino acids, eight N-linked oligosaccharide attachment sites, and an N-terminal signal sequence absent from the mature form of GP-2 associated with ZGMs. The C terminus shows a 20-residue hydrophobic transmembrane domain preceded by a decapeptide containing potential phosphatidylinositol-glycan attachment sites. GP-2 completely released from ZGMs by exogenous phospholipase C showed similar immunochemical properties and electrophoretic mobilities compared to the form associated with ZGMs. A similar form of GP-2 was released from zymogen granules permeabilized with saponin and incubated in the absence of added phospholipase C. Kinetic analysis of GP-2 release at 0 degrees C and 37 degrees C suggested the presence of a granule enzyme responsible for endogenous release of GP-2 to granule contents and into the apical medium. The data indicate that GP-2 is a phosphatidylinositol-glycan-linked membrane protein released from the membrane of mature zymogen granules by an enzymatic mechanism. The cDNA structure presented here thus encodes both membrane-bound and free forms of GP-2.

Amino Acid Sequence↗
PubMed2006

The ERK mitogen-activated protein kinase pathway contributes to Ebola virus glycoprotein-induced cytotoxicity.

Ebola virus is a highly lethal pathogen that causes hemorrhagic fever in humans and nonhuman primates. Among the seven known viral gene products, the envelope glycoprotein (GP) alone induces cell rounding and detachment that ultimately leads to cell death. Cellular cytoxicity is not seen with comparable levels of expression of a mutant form of GP lacking a mucin-like domain (GPDeltamuc). GP-induced cell death is nonapoptotic and is preceded by downmodulation of cell surface molecules involved in signaling pathways, including certain integrins and epidermal growth factor receptor. To investigate the mechanism of GP-induced cellular toxicity, we analyzed the activation of several signal transduction pathways involved in cell growth and survival. The active form of extracellular signal-regulated kinases types 1 and 2 (ERK1/2), phospho-ERK1/2, was reduced in cells expressing GP compared to those expressing GPDeltamuc as determined by flow cytometry, in contrast to the case for several other signaling proteins. Subsequent analysis of the activation states and kinase activities of related kinases revealed a more pronounced effect on the ERK2 kinase isoform. Disruption of ERK2 activity by a dominant negative ERK or by small interfering RNA-mediated ERK2 knockdown potentiated the decrease in alphaV integrin expression associated with toxicity. Conversely, activation of the pathway through the expression of a constitutively active form of ERK2 significantly protected against this effect. These results indicate that the ERK signaling cascade mediates GP-mediated cytotoxicity and plays a role in pathogenicity induced by this gene product.

Cell Proliferation↗
PubMed1978

[Responses of cat cerebellar cortex neurons to stimulation of the caudate nucleus, globus pallidus and substantia nigra].

Impulsive responses (IR) of the Purkinje cells (PC) and other units of the cerebellar cortex in the paramedian lobules, lobulus simplex and tuber vermis were evoked by stimulation of nucleus caudatus (NC) in cats under chloraloze-nembutal narcosis. The phasic IR as simple discharges (due to mossy fibre activation) were exhibited mainly with a latency of 5-12 and 14-20 ms; a latency of the compound responses ) due to climbing fibre PC activation) was equal to 5-6, 9-22 ms and more. There were differences in rhythmic reproduction of the responses depending on their latency. The recruitment responses were found during a 4-6/s NC stimulation. There was an inhibitory pause as an obligatory component of the tonic neuronal responses. Reactions of the same types (phasic and tonic) as in the case of the NC stimulation, but differing in unit's quantitative distribution according to the latency appeared in the globus pallidus (GP) stimulation. The minimal latency was 4 ms. Recruitment was observed as well. The substantia nigra (SN) stimulation evoked PC responses, activated by the climbing fibres with a stable latency (8.5 +/- 0.3 ms). SN, GP, n. inferior olive as well as thalamic nuclei are considered to play a definite role in realizing caudate-cerebellar connections, both oligosynaptic and polysynaptic.

Animals↗
PubMed2003

Mapping of brain function after MPTP-induced neurotoxicity in a primate Parkinson's disease model.

Neurophysiological studies of the brain in normal and Parkinson's disease (PD) patients have indicated intricate connections for basal ganglia-induced control of signaling into the motor cortex. To investigate if similar mechanisms are controlling function in the primate brain (Macaca fascicularis) after MPTP-induced neurotoxicity, we conducted PET studies of cerebral blood flow, oxygen and glucose metabolism, dopamine transporter, and D2 receptor function. Our observations after MPTP-induced dopamine terminal degeneration of the caudate and putamen revealed increased blood flow (15%) in the globus pallidus (GP), while blood flow was moderately decreased (15-25%) in the caudate, putamen, and thalamus and 40 % in the primary motor cortex (PMC). Oxygen extraction fraction was moderately increased (10-20%) in other brain areas but the thalamus, where no change was observable. Oxygen metabolism was increased in the GP and SMA (supplementary motor area including premotor cortex, Fig. 3) by a range of 20-40% and decreased in the putamen and caudate and in the PMC. Glucose metabolism was decreased in the caudate, putamen, thalamus, and PMC (range 35-50%) and enhanced in the GP by 15%. No change was observed in the SMA. In the parkinsonian primate, [(11)C]CFT (2beta-carbomethoxy-3beta-(4-fluorophenyltropane) dopamine transporter binding was significantly decreased in the putamen and caudate (range 60-65%). [(11)C]Raclopride binding of dopamine D(2) receptors did not show any significant changes. These experimental results obtained in primate studies of striato-thalamo-cortico circuitry show a similar trend as hypothetized in Parkinson's disease-type degeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Structural and functional similarities between the capsid proteins of bacteriophages T4 and HK97 point to a common ancestry.

Gene product (gp) 24 of bacteriophage T4 forms the pentameric vertices of the capsid. Using x-ray crystallography, we found the principal domain of gp24 to have a polypeptide fold similar to that of the HK97 phage capsid protein plus an additional insertion domain. Fitting gp24 monomers into a cryo-EM density map of the mature T4 capsid suggests that the insertion domain interacts with a neighboring subunit, effecting a stabilization analogous to the covalent crosslinking in the HK97 capsid. Sequence alignment and genetic data show that the folds of gp24 and the hexamer-forming capsid protein, gp23*, are similar. Accordingly, models of gp24* pentamers, gp23* hexamers, and the whole capsid were built, based on a cryo-EM image reconstruction of the capsid. Mutations in gene 23 that affect capsid shape map to the capsomer's periphery, whereas mutations that allow gp23 to substitute for gp24 at the vertices modify the interactions between monomers within capsomers. Structural data show that capsid proteins of most tailed phages, and some eukaryotic viruses, may have evolved from a common ancestor.

Amino Acid Sequence↗
PubMed2004

Pharmacogenomics of MDR1/ABCB1 gene: the influence on risk and clinical outcome of haematological malignancies.

Pharmacogenomics is a rapidly developing field of biomedical research, which investigates phenotypic and pharmacodynamic consequences of the genetic variations among individuals. The multi-drug resistance-1, MDR1 (ABCB1) gene belongs to ATP-binding cassette (ABC) family and encodes for membrane transporter P-glycoprotein (P-gp). A wide array of P-gp substrates comprises toxic xenobiotics and numerous commonly used medications including anti-cancer drugs. Under physiological conditions P-gp protects cells against toxins, whereas in malignant cells P-gp confers multi-drug resistance phenotype. Moreover, characteristic tissue localisation enables P-gp to influence the uptake, tissue distribution and elimination of P-gp transported drugs. A number of recent studies identified variety of single nucleotide polymorphisms (SNPs) in the MDR1 gene and demonstrated significant ethnic differences in their allelic frequency distribution. Furthermore, it was shown that some of these SNPs, especially silent C3435T polymorphism in exon 26, may alter P-gp expression and transport activity. Consequently, it is likely that specific functional MDR1 haplotypes may result with altered exposure to toxins and drugs, thus influencing predisposition to certain diseases as well as efficacy or toxicity of pharmacotherapy. In this paper, we focus on the available data concerning the impact of MDR1 polymorphism on the risk and clinical outcome of haematological malignancies. The structure and function of P-gp as well as results of studies addressing the relevance of MDR1 polymorphism in non-haematological disorders are also briefly discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Crystal structure of the principal neutralization site of HIV-1.

The crystal structure of a complex between a 24-amino acid peptide from the third variable (V3) loop of human immunodeficiency virus-type 1 (HIV-1) gp 120 and the Fab fragment of a broadly neutralizing antibody (59.1) was determined to 3 angstrom resolution. The tip of the V3 loop containing the Gly-Pro-Gly-Arg-Ala-Phe sequence adopts a double-turn conformation, which may be the basis of its conservation in many HIV-1 isolates. A complete map of the HIV-1 principal neutralizing determinant was constructed by stitching together structures of V3 loop peptides bound to 59.1 and to an isolate-specific (MN) neutralizing antibody (50.1). Structural conservation of the overlapping epitopes suggests that this biologically relevant conformation could be of use in the design of synthetic vaccines and drugs to inhibit HIV-1 entry and virus-related cellular fusion.

Amino Acid Sequence↗
PubMed2000

Vital dye and radiolabelled colloids--complement or alternative?

Several different protocols for retrieval of the sentinel node (SN) have been described: gamma probe (GP) and/or dye guided biopsy, preceded by lymphoscintigraphy or not. Especially in American studies, predominantly executed by surgeons, dye or GP guidance only is used with good results. The disadvantages of applying dye only are: an extensive learning curve, lower retrieval rate of the SN and, especially in the learning phase, a higher rate of false negative biopsies. If only GP guidance is applied, the technique seems more simple to master. A recent multicentre study, however, revealed an unacceptably high false negative rate. It must be considered that most published studies were executed by highly experienced surgeons. In most European studies, scintigraphy is a standard part of the procedure. Lymphoscintigraphy provides the surgeon with a "road map", revealing the number and approximate location of the SNs in the lymphatic basin(s). Scintigraphy proves useful especially if an SN is situated close to the injection site (breast cancer), or if SNs are situated at unexpected locations (head-and-neck or trunk melanoma). A combination of all three available steps results in the highest number of successful procedures with the lowest false negative rate. This may prove to be especially important for general hospitals where the number of biopsy procedures is often smaller compared to specialized centres.

Axilla↗
PubMed1994

Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites.

Betaglycan, also known as the TGF-beta type III receptor, is a membrane-anchored proteoglycan that presents TGF-beta to the type II signaling receptor, a transmembrane serine/threonine kinase. The betaglycan extracellular region, which can be shed by cells into the medium, contains a NH2-terminal domain related to endoglin and a COOH-terminal domain related to uromodulin, sperm receptors Zp2 and 3, and pancreatic secretory granule GP-2 protein. We identified residues Ser535 and Ser546 in the uromodulin-related region as the glycosaminoglycan (GAG) attachment sites. Their mutation to alanine prevents GAG attachment but does not interfere with betaglycan stability or ability to bind and present TGF-beta to receptor II. Using a panel of deletion mutants, we found that TGF-beta binds to the NH2-terminal endoglin-related region of betaglycan. The remainder of the extracellular domain and the cytoplasmic domain are not required for presentation of TGF-beta to receptor II; however, membrane anchorage is required. Soluble betaglycan can bind TGF-beta but does not enhance binding to membrane receptors. In fact, recombinant soluble betaglycan acts as potent inhibitor of TGF-beta binding to membrane receptors and blocks TGF-beta action, this effect being particularly pronounced with the TGF-beta 2 isoform. The results suggest that release of betaglycan into the medium converts this enhancer of TGF-beta action into a TGF-beta antagonist.

Animals↗
PubMed1987

Identification and purification from bovine brain of a guanine-nucleotide-binding protein distinct from Gs, Gi and Go.

A guanine-nucleotide-binding protein (G-protein) was purified from cholate extracts of bovine brain membranes by sequential DEAE-Sephacel, Ultrogel AcA-34, heptylamine-Sepharose and Sephadex G-150 chromatography. Guanosine 5'-[gamma-[35S]thio]triphosphate (GTP[35S])-binding activity copurified with a 25,000 Da peptide and a 35,000-36,000 Da protein doublet. Neither pertussis toxin nor cholera toxin catalysed the ADP-ribosylation of a protein associated with the GTP[35S]-binding activity. Photoaffinity labelling of the purified protein with 8-azido[gamma-32P]GTP indicated that the GTP-binding site resides on the 25,000 Da protein. The 35,000-36,000 Da protein doublet was electrophoretically indistinguishable from the beta-subunits of other GTP-binding proteins, and the 36,000 Da protein was recognized by antiserum to oligomeric Gt. The purified protein specifically bound 17.2 nmol of GTP[35S]/mg of protein. The Kd of the binding site for radioligand was approx. 15 nM. The brain GTP-binding protein co-migrated during SDS/polyacrylamide-gel electrophoresis with a GTP-binding protein, named Gp, purified from human placenta [Evans, Brown, Fraser & Northup (1986) J. Biol. Chem. 261, 7052-7059], and cross-reacted with antiserum raised against the placental protein, but not with antiserum raised to brain Go. SDS/polyacrylamide-gel electrophoresis of the brain and placental GTP-binding proteins in the presence of Staphylococcus aureus V8 protease yielded identical peptide maps.

Animals↗
PubMed1994

Structural and functional characterization of estrogen sulfotransferase isoforms: distinct catalytic and high affinity binding activities.

Estrogen sulfotransferase (EST) purified from the guinea pig (gp) adrenal gland consists of multiple charge isoforms with isoelectric points (pls) ranging from 6.5 to 5.2. Four individual isoforms were isolated for use in antibody production, as well as for tryptic fragmentation analysis. The multiple charge isoforms manifested a high degree of relatedness as evidence by complete immunocross-reactivity. This relatedness was further demonstrated by peptide mapping analysis, which revealed essentially identical elution profiles for three of the isoforms, whereas the fourth most acidic isoform, although similar to the other three isoforms, demonstrated some differences. To further explore the nature of the charge isoforms, native gpEST and EST expressed by CHO-K1 cells transfected with the gpEST cDNA were subjected to additional biochemical characterization. An interesting finding was that, in addition to EST activity, gpEST bound estradiol with a high affinity [dissociation constant (Kd) 10 nM]; furthermore, the binding activity was absolutely dependent on the cofactor, adenosine-3',5'-diphosphate (3',5'-ADP). An unexpected and novel finding was that only the most basic pl 6.5 isoform was catalytically active, while estradiol-binding activity was associated with a more acidic isoform (pl 5.5-5.2); however, it has not as yet been possible to definitively assign the binding activity to a specific isoform.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗