Publications
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Blackhart BD, Ludwig EM, Pierotti VR, et al., 1986, Structure of the human apolipoprotein B gene., J Biol Chem, Vol: 261, Pages: 15364-15367, ISSN: 0021-9258
Human apolipoprotein B100 cDNA is 14 kilobases in length and encodes a 4563-amino acid precursor protein. The corresponding human gene has been isolated as a series of overlapping lambda clones and extends over 43 kilobases. The gene comprises 29 exons and 28 introns. The distribution of introns is extremely asymmetrical, most of them appearing in the 5'-terminal one-third of the gene. Although most of the exons fall within the normal size limits for mammalian genes, two are unusually long: 1906 and 7572 base pairs. The latter exon is by far the longest reported for a vertebrate gene.
Knott TJ, Wallis SC, Pease RJ, et al., 1986, A hypervariable region 3' to the human apolipoprotein B gene., Nucleic Acids Res, Vol: 14, Pages: 9215-9216, ISSN: 0305-1048
Knott TJ, Pease RJ, Powell LM, et al., 1986, Complete protein sequence and identification of structural domains of human apolipoprotein B., Nature, Vol: 323, Pages: 734-738, ISSN: 0028-0836
Epidemiological, pathological and genetic studies show a strong positive correlation between elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol and the risk of premature coronary heart disease. Apolipoprotein (apo) B-100 is the sole protein component of LDL and is the ligand responsible for the receptor-mediated uptake and clearance of LDL from the circulation. Apo B-100 is made by the liver and is essential for the assembly of triglyceride-rich very low-density lipoproteins (VLDL) in the cisternae of the endoplasmic reticulum and for their secretion into the plasma. VLDL transports triglyceride to peripheral muscle and adipose tissue, where the triglyceride is hydrolysed by lipoprotein lipase. The resultant particle, relatively enriched in cholesteryl ester, constitutes LDL. LDL delivers cholesterol to peripheral tissues where it is used for membrane and steroid hormone biosynthesis and to the liver, the only organ which can catabolize and excrete cholesterol. Plasma LDL levels are therefore determined by the balance between their rate of production from VLDL and clearance by the hepatic LDL (apo B/E) receptor pathway. Here we report the complete 4,563-amino-acid sequence of apo B-100 precursor (relative molecular mass (Mr) 514,000 (514K] determined from complementary DNA clones. Numerous lipid-binding structures are distributed throughout the extraordinary length of apo B-100 and must underlie its special functions as a nucleus for lipoprotein assembly and maintenance of plasma lipoprotein integrity. A domain enriched in basic amino-acid residues has been identified as important for the cellular uptake of cholesterol by the LDL receptor pathway.
Forgez P, Gregory H, Young JA, et al., 1986, Identification of surface-exposed segments of apolipoprotein B-100 in the LDL particle., Biochem Biophys Res Commun, Vol: 140, Pages: 250-257, ISSN: 0006-291X
The isolation and amino acid sequence of eleven peptides liberated by tryptic treatment from surface-exposed regions of apolipoprotein B-100 in the native low-density lipoprotein particle are described. These peptides represent eight segments in the sequence of the B-100 protein, one of which was localised to the amino-terminal thrombolytic fragment T4 (1297 amino acids), four to the T3 fragment (2052 residues) and three to the carboxylterminal fragment T2 (1287 residues). An exposed segment was identified on each side of the T2/T3 cleavage site, in close proximity to two segments enriched in basic amino acids (residues 3147-3157 and 3359-3367 respectively). The surface exposure of this region is consistent with its contribution to the putative apo-B,E receptor binding domain. Four of the eight tryptic segments contribute to regions of proline-rich clusters. Homology between the sequence of the tryptic peptides and those predicted by cDNA cloning was complete.
Berg K, Powell LM, Wallis SC, et al., 1986, Genetic linkage between the antigenic group (Ag) variation and the apolipoprotein B gene: assignment of the Ag locus., Proc Natl Acad Sci U S A, Vol: 83, Pages: 7367-7370, ISSN: 0027-8424
The antigenic group (Ag) system of homospecific human serum antigens of low density lipoprotein is detected by antiserum from multiply transfused patients. A complex series of common Ag alleles has been described, but the biochemical nature of this polymorphism is uncertain. Here we report that DNA polymorphisms at the human apolipoprotein B (apoB) locus are very closely linked to alleles of the Ag system. We also show a strong association between Ag(x) and a polymorphism detected with the restriction endonuclease Xba I. We conclude that the immunologically determined Ag system represents protein polymorphism of apoB rather than primary genetic differences in posttranslational processing or lipid binding. These studies therefore demonstrate that the Ag locus is located on the short arm of human chromosome 2 in the region p23-p24 to which the apoB gene has been assigned. Since the Ag(x) antigen is associated with altered plasma lipid levels, this determinant may indicate a functionally important domain of apoB.
Knott TJ, Wallis SC, Powell LM, et al., 1986, Complete cDNA and derived protein sequence of human apolipoprotein B-100., Nucleic Acids Res, Vol: 14, Pages: 7501-7503, ISSN: 0305-1048
Law A, Wallis SC, Powell LM, et al., 1986, Common DNA polymorphism within coding sequence of apolipoprotein B gene associated with altered lipid levels., Lancet, Vol: 1, Pages: 1301-1303, ISSN: 0140-6736
60 of 83 middle-aged white men had an XbaI restriction site polymorphism within the coding sequence of the apolipoprotein B gene. Subjects homozygous and heterozygous for the presence of an XbaI restriction site had mean serum triglyceride levels 36% higher (p = 0.02) than those in homozygotes without the restriction site; there was a less substantial difference (p = 0.03) in serum cholesterol. The findings supported a dominant pattern of inheritance. The presence of this restriction site may increase the risk of atherosclerotic disease.
Lusis AJ, Heinzmann C, Sparkes RS, et al., 1986, Regional mapping of human chromosome 19: organization of genes for plasma lipid transport (APOC1, -C2, and -E and LDLR) and the genes C3, PEPD, and GPI., Proc Natl Acad Sci U S A, Vol: 83, Pages: 3929-3933, ISSN: 0027-8424
We report the regional mapping of human chromosome 19 genes for three apolipoproteins and a lipoprotein receptor as well as genes for three other markers. The regional mapping was made possible by the use of a reciprocal whole-arm translocation between the long arm of chromosome 19 and the short arm of chromosome 1. Examination of three separate somatic cell hybrids containing the long arm but not the short arm of chromosome 19 indicated that the genes for apolipoproteins CI, CII, and E (APOC1, APOC2, and APOE, respectively) and glucose-6-phosphate isomerase (GPI) reside on the long arm, whereas genes for the low density lipoprotein receptor (LDLR), complement component 3 (C3), and peptidase D (PEPD) reside on the short arm. When taken together with previous studies, our results suggest the following physical gene map: pter-LDLR-C3-p13.2-PEPD-centromere-(APOE, APOC1, APOC2, GPI)-qter. In addition, we have isolated a single lambda phage carrying both APOC1 and part of APOE. These genes are tandemly oriented and are separated by about 6 kilobases of genomic DNA. Since previous family studies indicate tight linkage of APOE and APOC2, the apolipoprotein genes APOC1, APOC2, and APOE form a tight complex on the long arm of chromosome 19, suggesting the possibility of coordinate regulation.
Betsholtz C, Johnsson A, Heldin CH, et al., 1986, cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines., Nature, Vol: 320, Pages: 695-699, ISSN: 0028-0836
The amino-acid sequence of the precursor of the human tumour cell line-derived platelet-derived growth factor (PDGF) A-chain has been deduced from complementary DNA clones and the gene localized to chromosome 7. The protein shows extensive homology to the PDGF B-chain precursor. Expression of the PDGF A-chain gene is independent of that of the PDGF B-chain in a number of human tumour cell lines, and secretion of a PDGF-like growth factor of relative molecular mass 31,000 correlates with expression of A- but not B-chain messenger RNA.
Scott J, Knott TJ, 1986, The role of molecular biology in the assessment of the risk of atherosclerosis, Pharmacological control of hyperlipidaemia, Editors: Fears, Barcelona, Publisher: JR Prous Science, Pages: 491-508, ISBN: 9788439868156
Knott TJ, Rall SC, Innerarity TL, et al., 1985, Human apolipoprotein B: structure of carboxyl-terminal domains, sites of gene expression, and chromosomal localization., Science, Vol: 230, Pages: 37-43, ISSN: 0036-8075
Apolipoprotein (apo-) B is the ligand responsible for the receptor-mediated catabolism of low density lipoproteins, the principal cholesterol-transporting lipoproteins in plasma. The primary structure of the carboxyl-terminal 30 percent (1455 amino acids) of human apo-B (apo-B100) has been deduced from the nucleotide sequence of complementary DNA. Portions of the protein structure that may relate to its receptor binding function and lipid binding properties have been identified. The apo-B100 messenger RNA is about 19 kilobases in length. The apo-B100 gene is expressed primarily in liver and, to a lesser extent, in small intestine, but in no other tissues. The gene for apo-B100 is located in the p24 region (near the tip of the short arm) of chromosome 2.
Priestley L, Knott T, Wallis S, et al., 1985, RFLP for the human apolipoprotein B gene: V;XbaI., Nucleic Acids Res, Vol: 13, ISSN: 0305-1048
Priestley L, Knott T, Wallis S, et al., 1985, RFLP for the human apolipoprotein B gene: I;BamHI., Nucleic Acids Res, Vol: 13, ISSN: 0305-1048
Priestley L, Knott T, Wallis S, et al., 1985, RFLP for the human apolipoprotein B gene: II;EcoRI., Nucleic Acids Res, Vol: 13, ISSN: 0305-1048
Priestley L, Knott T, Wallis S, et al., 1985, RFLP for the human apolipoprotein B gene: III;EcoRV., Nucleic Acids Res, Vol: 13, ISSN: 0305-1048
Priestley L, Knott T, Wallis S, et al., 1985, RFLP for the human apolipoprotein B gene: IV;MspI., Nucleic Acids Res, Vol: 13, ISSN: 0305-1048
Scott J, Cowell J, Robertson ME, et al., 1985, Insulin-like growth factor-II gene expression in Wilms' tumour and embryonic tissues., Nature, Vol: 317, Pages: 260-262, ISSN: 0028-0836
Wilms' tumour (nephroblastoma) is an embryonal neoplasm occurring in hereditary and spontaneous forms. Both types show rearrangements of the short arm of chromosome 11. The germ line of children with the rare inherited triad of aniridia, genito-urinary abnormality and mental retardation carry a chromosome 11 that has a deletion in its short arm (band 11p13) and these children are at increased risk of developing Wilms' tumour. Neonates with the Beckwith-Wiedemann syndrome, in which there may be duplication of the 11p13-11p15 region, are similarly predisposed. In the spontaneous form of the tumour a deletion of the 11p14 band in tumour cells, but not in normal cells, has been reported, and the development of homozygosity for recessive mutations in the 11p region is implicated in the aetiology of Wilms' tumour. In view of these chromosomal rearrangements and because Wilms' tumour is histologically indistinguishable from the early stages of kidney development, we have now examined the expression of genes localized to 11p in Wilms' tumour and human embryonic tissue. In 12 sporadic tumours examined, the expression of the gene coding for insulin-like growth factor-II (IGF-II), localized to the 11p15 region, was markedly increased relative to adult tissues, but was comparable to the level of expression in several fetal tissues including kidney, liver, adrenals and striated muscle. This may reflect the stage of tumour differentiation, but could also contribute to the malignant process, as IGF-II is an embryonal mitogen.
Knott TJ, Wallis SC, Robertson ME, et al., 1985, The human apolipoprotein AII gene: structural organization and sites of expression., Nucleic Acids Res, Vol: 13, Pages: 6387-6398, ISSN: 0305-1048
The complete nucleotide sequence of the human apolipoprotein All gene together with 911 bases of 5' flanking sequence and 687 bases of 3' flanking sequence have been determined. The mRNA coding region is interrupted by three introns of 169, 293 and 395bp. The Intro-exon structure of the apo All gene is similar to that of the apo AI, apo CIII and apo E genes: three introns separate 4 coding sequences specifying the 5' untranslated region, pre-peptide, a short N-terminal domain and a C-terminal domain composed of a variable number of lipid-binding amphipathic helices. Intron II carries a 33bp dG-dT repetitive element adjacent to the 3' splice junction which has the potential to adopt the Z-DNA conformation. The 5' and 3' terminuses of the mRNA have been identified by primer extension and S1 nuclease mapping. A number of short direct repeats are found in the 5' flanking region and an inverted repeat occurs between the CAAT and TATA boxes. Downstream of the the gene is an Alu family repeat containing a polymorphic MspI site, the deletion of which is associated with increased circulating levels of apoAII. ApoAII gene expression was demonstrated in adult human liver and HepG2 cells but not in human small intestine. Of ten Rhesus monkey tissues examined apo All mRNA was detected only in liver.
Wion D, Barrand P, Dicou E, et al., 1985, Serum and thyroid hormones T3 and T4 regulate nerve growth factor mRNA levels in mouse L cells., FEBS Lett, Vol: 189, Pages: 37-41, ISSN: 0014-5793
Mouse L cells synthesize and secrete a neurotrophic factor related to the beta subunit of the submaxillary gland nerve growth factor (NGF) of male mice. Use of a cDNA probe which encodes the beta-NGF mRNA demonstrated that L cells produce a transcript identical in size to that of the submaxillary gland. Moreover, target sites of restriction enzymes EcoRI, PstI and BamHI were not significantly rearranged in the beta-NGF gene locus of these cells. The abundance of the beta-NGF transcript was found to depend on culture conditions. Removal of serum depressed the cellular content of polyadenylated RNA by a factor of 1.7, and decreased specifically the pool of beta-NGF transcript by an additional factor of 4. The presence of 10(-7) M testosterone in the serum-free medium did not modify the level of beta-NGF mRNA, while addition of 10(-7) M T3 (or T4) increased this level by a factor of 1.5. These data provide the first evidence that the beta-NGF mRNA of L cells is subjected to regulation, but in a way apparently different from that described for the submaxillary gland.
, 1985, Polypeptide growth factors: a clinical perspective., Lancet, Vol: 2, Pages: 251-253, ISSN: 0140-6736
Korsching S, Auburger G, Heumann R, et al., 1985, Levels of nerve growth factor and its mRNA in the central nervous system of the rat correlate with cholinergic innervation., EMBO J, Vol: 4, Pages: 1389-1393, ISSN: 0261-4189
The levels of nerve growth factor (NGF) and its mRNA in the rat central nervous system were determined by two-site enzyme immunoassay and quantitative Northern blots, respectively. Relatively high NGF levels (0.4-1.4 ng NGF/g wet weight) were found both in the regions innervated by the magnocellular cholinergic neurons of the basal forebrain (hippocampus, olfactory bulb, neocortex) and in the regions containing the cell bodies of these neurons (septum, nucleus of the diagonal band of Broca, nucleus basalis of Meynert). Comparatively low, but significant NGF levels (0.07-0.21 ng NGF/g wet weight) were found in various other brain regions. mRNANGF was found in the hippocampus and cortex but not in the septum. This suggests that magnocellular cholinergic neurons of the basal forebrain are supplied with NGF via retrograde axonal transport from their fields of innervation. These results, taken together with those of previous studies showing that these neurons are responsive to NGF, support the concept that NGF acts as trophic factor for magnocellular cholinergic neurons.
Bell GI, Rall LB, Sanchez-Pescador R, et al., 1985, Human alpha 2-macroglobulin gene is located on chromosome 12., Somat Cell Mol Genet, Vol: 11, Pages: 285-289, ISSN: 0740-7750
A cDNA clone encoding amino acids 809-1451 of the protease inhibitor alpha 2-macroglobulin has been isolated from an adult human liver cDNA library. This cDNA was used to examine DNA samples prepared from a panel of human-mouse somatic cell hybrids with different numbers and combinations of human chromosomes for the presence of the human alpha 2-macroglobulin gene. The cosegregation of this gene and chromosome 12 in the cell hybrid panel indicated that the alpha 2-macroglobulin structural gene (designated A2M) is on human chromosome 12.
Scott J, Knott TJ, Priestley LM, et al., 1985, High-density lipoprotein composition is altered by a common DNA polymorphism adjacent to apoprotein AII gene in man., Lancet, Vol: 1, Pages: 771-773, ISSN: 0140-6736
25 of a group of 87 White men had Msp 1 restriction site polymorphism within an Alu sequence 3' to the human apo AII gene. Homozygosity for the polymorphism in 8 men was associated with a significant increase in serum apo AII levels (35.4 +/- 1.70 mg/dl, mean +/- SEM) and altered HDL composition, compared with heterozygotes (31.7 +/- 1.29; n = 17) and normal subjects (29.4 +/- 0.64; n = 62). This is the first account of a common variant of an HDL apoprotein gene that affects HDL composition. In view of its association with a high apo AII concentration homozygosity may protect against atherosclerosis.
Rall LB, Scott J, Bell GI, et al., 1985, Mouse prepro-epidermal growth factor synthesis by the kidney and other tissues., Nature, Vol: 313, Pages: 228-231, ISSN: 0028-0836
Epidermal growth factor (EGF), a protein comprising 53 amino acids, is derived from a precursor of 1,217 amino acids that includes at least seven EGF-like sequences. EGF has diverse biological activities: it is a potent mitogen for many tissue culture cells, inhibits gastric acid secretion from the intestinal mucosa and promotes healing of the corneal epithelium. EGF given to fetal animals accelerates several developmental processes including palate formation, incisor eruption, eyelid opening and lung maturation. However, the physiological roles of EGF in vivo are unknown. The presence of high-affinity receptors in many fetal and adult tissues suggests that EGF is involved in normal cellular functions. Immunocytochemical studies have revealed the presence of EGF in mouse and human submaxillary glands, rat brain and human intestine. The low levels of EGF in extracts from many tissues may reflect sequestration rather than synthesis of the polypeptide. We show here that several mouse tissues contain preproEGF mRNA and that it is synthesized mainly in the distal tubules of the kidney. PreproEGF does not seem to be processed to EGF or other peptides in this tissue.
Zabel BU, Eddy RL, Lalley PA, et al., 1985, Chromosomal locations of the human and mouse genes for precursors of epidermal growth factor and the beta subunit of nerve growth factor., Proc Natl Acad Sci U S A, Vol: 82, Pages: 469-473, ISSN: 0027-8424
DNA probes for pre-pro-epidermal growth factor (EGF) and the precursor of the beta subunit of nerve growth factor (NGF) were used to chromosomally map human and mouse EGF and NGF genes in panels of human-mouse and mouse-Chinese hamster somatic cell hybrids. The EGF and NGF genes were mapped to human chromosomes 4 and 1, respectively, by using human-mouse cell hybrids. A combination of regional mapping using a chromosome 1 translocation and comparative gene mapping suggests that the human NGF gene is in the p21-p22.1 region of chromosome 1. In mouse-Chinese hamster cell hybrids, both genes were assigned to mouse chromosome 3. A knowledge of the chromosomal assignment of these genes should help in our understanding of their regulation and role in development and disease.
Scott J, Knott TJ, Shaw DJ, et al., 1985, Localization of genes encoding apolipoproteins CI, CII, and E to the p13----cen region of human chromosome 19., Hum Genet, Vol: 71, Pages: 144-146, ISSN: 0340-6717
The genes encoding apolipoproteins CI, CII, and E have been previously localized to chromosome 19. By use of rodent-human hybrid cell lines containing translocations of chromosome 19 we have now mapped these three genes to the region 19p13-19q13 and most probably 19p13-19cen. The clustering of APOC1, APOC2, and APOE must reflect their common evolutionary background and suggests that they may be coordinately regulated. Polymorphisms detected for any one gene will be useful for inheritance studies of all three.
Scott J, Patterson S, Rall L, et al., 1985, The structure and biosynthesis of epidermal growth factor precursor., J Cell Sci Suppl, Vol: 3, Pages: 19-28, ISSN: 0269-3518
The structure of mouse submaxillary gland epidermal growth factor (EGF) precursor has been deduced from complementary DNAs. The mRNA is approximately 4800 bases and predicts prepro EGF to be a protein of 1217 amino acid residues (133 X 10 Mr). EGF (53 amino acid residues) is flanked by polypeptides of 188 and 976 residues at its carboxy and amino termini, respectively. The amino terminus of the precursor contains seven cysteine-rich peptides that resemble EGF. Towards the carboxy terminus is a 20-residue hydrophobic membrane spanning domain. The mild portion of the EGF precursor shares a 33% homology with the low density lipoprotein receptor, which extends over 400 amino acid residues. These features suggest that EGF precursor could function as a membrane-bound receptor. RNA dot-blot analysis and in situ hybridization show EGF mRNA to be abundant in the submaxillary gland, kidney and incisor tooth buds. Lower EGF mRNA levels were found in the lactating breast, pancreas, small intestine, ovary, spleen, lung, pituitary and liver. In the kidney EGF mRNA was most abundant in the distal convoluted tubules. Analysis of EGF precursor biosynthesis in organ culture of the submaxillary gland and kidney showed differential processing of the precursor in the two tissues. In the submaxillary gland immunoreactive low molecular weight EGF was produced, but in the kidney the high molecular weight precursor was not processed. In the distal convoluted tubule of the kidney EGF precursor may act as a receptor that is involved in ion transport.
Heumann R, Korsching S, Scott J, et al., 1984, Relationship between levels of nerve growth factor (NGF) and its messenger RNA in sympathetic ganglia and peripheral target tissues., EMBO J, Vol: 3, Pages: 3183-3189, ISSN: 0261-4189
We have developed a sensitive assay for the quantification of nerve growth factor mRNA (mRNANGF) in various tissues of the mouse using in vitro transcribed RNANGF. Probes of both polarities were used to determine the specificity of the hybridization signals obtained. Comparison of NGF levels with its mRNA revealed that both were correlated with the density of sympathetic innervation. Thus, vas deferens contained high levels of both NGF and mRNANGF, whereas skeletal muscle levels were barely detectable, indicating that in peripheral tissues NGF levels are primarily regulated by the quantity of mRNANGF and not by the rate of processing of NGF precursor to NGF. However, although superior cervical ganglia contained the highest levels of NGF, its mRNA was barely detectable. Thus, the high levels of NGF in sympathetic ganglia result from retrograde axonal transport rather than local synthesis. The quantity of NGF found in the submandibular glands of female animals was three orders of magnitude higher than expected from their mRNA levels. This observation is discussed in the context of the difference between the mechanism of storage and exocytosis of exocrine glands versus the constitutive release from other tissues.
Knott TJ, Eddy RL, Robertson ME, et al., 1984, Chromosomal localization of the human apoprotein CI gene and of a polymorphic apoprotein AII gene., Biochem Biophys Res Commun, Vol: 125, Pages: 299-306, ISSN: 0006-291X
Human apoprotein(apo) CI and apo AII cDNA probes have been used to analyze the segregation of the human genes in panels of human-mouse hybrids. The apo CI (APOCI) gene segregates with chromosome 19 and the apo AII (APOA2) gene with chromosome 1. Somatic cell hybrids containing chromosome translocations were used to map the apo AII gene to the 1p21-1qter region. Human APOA2 is polymorphic for the restriction endonuclease Msp I. Comparison of human and mouse chromosome 1 reveals a conserved group including apo AII, renin and peptidase genes and suggests that APOA2 will be found distal to this group on human chromosome 1. The mouse apo AII gene is closely linked with genes that regulate HDL structure. Similar HDL regulatory genes will probably be found near human APOA2.
Bell GI, Merryweather JP, Sanchez-Pescador R, et al., 1984, Sequence of a cDNA clone encoding human preproinsulin-like growth factor II., Nature, Vol: 310, Pages: 775-777, ISSN: 0028-0836
The insulin-like growth factors (IGF) I and II are single-chain serum proteins of 70 and 67 amino acids, respectively, which are synthesized by the liver and possibly other tissues. They are probably required for normal fetal and postnatal growth and development. They also stimulate the growth of cultured cells, possibly by controlling the progression through the G1 phase of the cell cycle. In contrast to IGF-II whose concentration does not vary during postnatal development, the serum levels of IGF-I increase several-fold to adult levels during puberty. The serum concentration of IGF-I is a sensitive monitor of growth hormone levels and is decreased in individuals with growth hormone deficiency and elevated in those with growth hormone-secreting tumours. As a first step in studying the biosynthesis of these proteins and elucidating their role(s) in normal development and in tumorigenesis, we have isolated and sequenced cDNAs prepared from adult human liver mRNA which encode the precursors to IGF-I and -II. We report here the sequence of a cDNA encoding a 180-amino acid protein which is the precursor to IGF-II.
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