Water supply and sewage disposal at Mohenjo-Daro.
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Archaeology↗
Biomedical subjects
M Jansen
Publications and source records attributed to M Jansen.
The human somatomedin/insulin-like growth factor genes: organization and development-specific expression.
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Chromosomes, Human, Pair 11↗
Total deficiency of growth hormone and prolactin, and partial deficiency of thyroid stimulating hormone in two Dutch families: a new variant of hereditary pituitary deficiency.
Four out of 10 children in two unrelated families presented with a total pituitary growth hormone (GH) and prolactin deficiency and a partial thyrotropin (TSH) deficiency. The GH gene was intact in family I. The pituitaries, visualized by magnetic resonance imaging, were normal. All children responded well to GH and L-thyroxine therapy. Baseline plasma somatostatin and its peak response to arginine infusion were elevated in family I and they had a milder TSH deficiency than family II. Plasma insulin showed a poor response to arginine infusion. This hereditary combination of pituitary deficiencies suggests a deficiency of a common positive transcription factor.
Adult↗
Differential expression of the human insulin-like growth factor II gene. Characterization of the IGF-II mRNAs and an mRNA encoding a putative IGF-II-associated protein.
Insulin-like growth factor II (IGF-II) is a polypeptide of 67 amino acids which is thought to play an important role in fetal growth and development. The human IGF-II gene is situated on chromosome 11, very close to the insulin gene. It extends over 30 kb of chromosomal DNA and consists of five noncoding exons (exons 1-4 and 4B) followed by three protein encoding exons (exons 5-7), one of which (exon 7) contains a long 3'-untranslated region. Here we show that differential initiation of transcription can occur at three distinct promoter sites, resulting in the appearance of mRNA species of different lengths. These promoters show a tissue-specific and a development-specific regulation of expression. Furthermore, we have determined the entire nucleotide sequence of the 3'-terminal exon, exon 7, which is about 4 kb long and contains 3.8 kb of 3'-untranslated sequences. This completes the elucidation of the human IGF-II gene structure. Surprisingly, Northern blot analysis of fetal and adult RNA with a probe derived from the 3'-nontranslated region of exon 7 detects a novel 1.8 kb mRNA which appears to be coordinately expressed with the IGF-II mRNAs. In vitro translation of this 1.8 kb mRNA results in the formation of a translation product of 8.3 kDa, which compares well with the size of a predicted translation product from a 252-nucleotides-long open reading frame.
Amino Acid Sequence↗
Bst NI (Eco RII) RFLP in the lipoprotein lipase gene (LPL).
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Chromosomes, Human, Pair 8↗
Isolation of an insulin-like growth factor II cDNA with a unique 5' untranslated region from human placenta.
Human insulin-like growth factor II (IGF-II) cDNA from a placental library was isolated and sequenced. The 5' untranslated region (5'-UTR) sequence of this cDNA differs completely from that of adult human liver and has considerable base sequence identity to the same region of an IGF-II cDNA of a rat liver cell line, BRL-3A. Human placental poly(A)+ RNA was probed with either the 5'-UTR of the isolated human placental IGF-II cDNA or the 5'-UTR of the IGF-II cDNA obtained from adult human liver. No transcripts were detected by using the 5'-UTR of the adult liver IGF-II as the probe. In contrast, three transcripts of 6.0, 3.2, and 2.2 kilobases were detected by using the 5'-UTR of the placental IGF-II cDNA as the probe or the probe from the coding sequence. A fourth IGF-II transcript of 4.9 kilobases presumably containing a 5'-UTR consisting of a base sequence dissimilar to that of either IGF-II 5'-UTR was apparent. Therefore, IGF-II transcripts detected may be products of alternative splicing as their 5'-UTR sequence is contained within the human IGF-II gene or they may be a consequence of alternative promoter utilization in placenta.
Amino Acid Sequence↗
Heterozygotes for 17 alpha-hydroxylase deficiency can be detected with a short ACTH test.
A short ACTH test was performed in the six parents, and four siblings, of three cases with 17 alpha-hydroxylase deficiency. Baseline steroid levels were all normal in female heterozygotes but in males 17 alpha-hydroxyprogesterone levels were elevated. After ACTH-stimulation, plasma levels of corticosterone were elevated in five obligate heterozygotes and 18-hydroxydeoxycorticosterone levels were increased in four of them. Two of the four siblings had biochemical signs of heterozygosity. The short ACTH test appears to be an efficient method for detecting heterozygosity, but the abnormalities found are more heterogeneous than previously suggested.
Adolescent↗
Glial swelling during extracellular acidosis in vitro.
Intracellular and extracellular acidosis may determine the ultimate outcome for brain tissue in cerebral ischemia. An extracellular acidosis that occurs in the penumbra zone was investigated in vitro as to its role in the formation of cytotoxic cell swelling. For that purpose, C6 glioma cells or primary cultured astrocytes were suspended in normal isotonic medium in normoxia during acidification to a final pH of 6.2. The cell volume response was determined by flow cytometry using hydrodynamic focusing, which allows one to recognize changes in cell size of less than 1%. A threshold pH of 6.8 was found that had to be crossed to induce cell swelling by acidosis. Once pH fell below this threshold, the increase in cell size appeared to be an all-or-nothing phenomenon. The cells rapidly assumed a final cell size of 115% of normal in the case of C6 glioma or of 118% in the case of primary cultured astrocytes independent of the actual level of acidosis or the duration of exposure. Acidosis-induced glial swelling could be significantly attenuated by 1) addition of amiloride, 2) administration of acetazolamide, or 3) replacement of bicarbonate buffer against N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). Replacement of extracellular Na+ by choline chloride led to complete prevention of the acidosis-induced cell swelling. Taken together, the findings strongly indicate a central involvement of Na+/H+ and Cl-/HCO3- exchange mechanisms in the development of cell swelling under these conditions. Activation of the Na+/H+ antiporter can be considered an attempt to maintain a normal intracellular pH at the expense of an abnormal cell volume.(ABSTRACT TRUNCATED AT 250 WORDS)
Acidosis↗
Expression of insulin-like growth factor-I and -II genes in rat medullary thyroid carcinoma.
Several types of cancer cells produce polypeptide growth factors and often the same cells have functional receptors for the released growth factor (autocrine secretion). We have studied expression of genes encoding somatomedin-C/insulin-like growth factor-I (Sm-C/IGF-I) and IGF-II, in rat medullary thyroid carcinomas (MTCs) in different stages of tumour differentiation. RNAs hybridizing specifically to an IGF-I cDNA probe were detected in 6 out of 7 differentiated MTCs and IGF-II related RNAs were demonstrated in 5 out of these 7 differentiated MTCs. In 5 anaplastic MTCs no IGF RNAs were detected, except for a small amount of IGF-II related RNA in one tumour.
Carcinoma↗
The human insulin-like growth factor II gene contains two development-specific promoters.
The insulin-like growth factors (IGF) play an important role in fetal and postnatal development. Recently, the nucleotide sequences of the cDNAs encoding IGF-I and IGF-II and part of the human IGF genes were reported. In this communication we describe two distinct IGF-II cDNAs isolated from a human adult liver and a human hepatoma cDNA library, respectively. Using these two cDNAs, we have established that the human IGF-II gene contains at least 7 exons. Two different IGF-II promoters have been identified, 19 kilobases (kb) apart, which are active in a development-specific manner. The promoter, active in the adult stage, is located only 1.4 kb downstream from the insulin gene.
Base Sequence↗
Growth hormone dependence of somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II messenger ribonucleic acids.
The GH dependence of somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) and insulin like growth factor II (IGF-II) mRNAs was investigated by Northern blot hybridizations of polyadenylated RNAs from liver, pancreas, and brain of normal rats, untreated hypophysectomized rats, and hypophysectomized rats 4 h or 8 h after an ip injection of human GH (hGH). Using a 32P-labeled human Sm-C/IGF-I cDNA as probe, four Sm-C/IGF-I mRNAs of 7.5, 4.7, 1.7, and 1.2 kilobases (kb) were detected in rat liver and pancreas but were not detectable in brain. In both liver and pancreas, the abundance of these Sm-C/IGF-I mRNAs was 8- to 10-fold lower in hypophysectomized rats than in normal rats. Within 4 h after injection of hGH into hypophysectomized animals, the abundance of liver and pancreatic Sm-C/IGF-I mRNAs was restored to normal. A human IGF-II cDNA was used as a probe for rat IGF-II mRNAs which were found to be very low in abundance in rat liver and showed no evidence of regulation by GH status. In pancreas, IGF-II mRNA abundance was below the detection limit of the hybridization procedures. The brain contained two IGF-II mRNAs of 4.7 and 3.9 kb that were 5-fold lower in abundance in hypophysectomized rats than in normal rats. These brain IGF-II mRNAs were not, however, restored to normal abundance at 4 or 8 h after ip hGH injection into hypophysectomized animals. To investigate further, the effect of GH status on abundance of Sm-C/IGF-I and IGF-II mRNAs in rat brain, a second experiment was performed that differed from the first in that hypophysectomized rats were given an injection of hGH into the lateral ventricle (intracerebroventricular injection) and a rat Sm-C/IGF-I genomic probe was used to analyze Sm-C/IGF-I mRNAs. In this experiment, a 7.5 kb Sm-C/IGF-I mRNA was detected in brain polyadenylated RNAs. The abundance of the 7.5 kb mRNA was 4-fold lower in hypophysectomized rats than in normal rats and was increased to 80% of normal within 4 h after icv administration of hGH to hypophysectomized animals. As in the first experiment, the abundance of the 4.7 and 3.9 kb brain IGF-II mRNAs was lower than normal in hypophysectomized rats. Brain IGF-II mRNAs were increased to 50% of normal in hypophysectomized rats given an icv injection of hGH but within 8 h after the injection rather than at 4 h as with Sm-C/IGF-I mRNAs.
Animals↗
Common site of mutation in the erbB gene of avian erythroblastosis virus mutants that are temperature sensitive for transformation.
The genome of the avian erythroblastosis virus temperature sensitive mutant ts34 was cloned from a cell line that was shown to contain a single integrated copy of the virus. The mutation was localized to the v-erbB gene by making chimeric viruses between the mutant genome and that of wildtype. Sequencing of the mutant v-erbB gene revealed a single amino acid change of a histidine to an aspartate residue at a position equivalent to amino-acid 826 of the human epidermal growth factor receptor. Interestingly this is the identical mutation to that recently reported for another temperature sensitive mutant ts167, indicating that this may be a hot spot for mutations in the v-erbB gene that give rise to ts transformation mutants. In addition, the different biological phenotypes of ts34 and ts167 are suggested to be due to an additional mutation in v-erbA in ts167.
Alpharetrovirus↗
Somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II mRNAs in rat fetal and adult tissues.
Somatomedin-C or insulin-like growth factor I (Sm-C/IGF-I) and insulin-like growth factor II (IGF-II) have been implicated in the regulation of fetal growth and development. In the present study 32P-labeled complementary DNA probes encoding human and mouse Sm-C/IGF-I and human IGF-II were used in Northern blot hybridizations to analyse rat Sm-C/IGF-I and IGF-II mRNAs in poly(A+) RNAs from intestine, liver, lung, and brain of adult rats and fetal rats between day 14 and 17 of gestation. In fetal rats, all four tissues contained a major mRNA of 1.7 kilobases (kb) that hybridized with the human Sm-C/IGF-I cDNA and mRNAs of 7.5, 4.7, 1.7, and 1.2 kb that hybridized with the mouse Sm-C/IGF-I cDNA. Adult rat intestine, liver, and lung also contained these mRNAs but Sm-C/IGF-I mRNAs were not detected in adult rat brain. These findings provide direct support for prior observations that multiple tissues in the fetus synthesize immunoreactive Sm-C/IGF-I and imply a role for Sm-C/IGF-I in fetal development as well as postnatally. The abundance of a 7.5-kb Sm-C/IGF-I mRNA in poly(A+) RNAs from adult rat liver was 10-50-fold higher than in other adult rat tissues which provides further evidence that in the adult rat the liver is a major site of Sm-C/IGF-I synthesis and source of circulating Sm-C/IGF-I. Multiple IGF-II mRNAs of estimated sizes 4.7, 3.9, 2.2, 1.75, and 1.2 kb were observed in fetal rat intestine, liver, lung, and brain. The 4.7- and 3.9-kb mRNAs were the major hybridizing IGF-II mRNAs in all fetal tissues. Higher abundance of IGF-II mRNAs in rat fetal tissues compared with adult tissues supports prior hypotheses, based on serum IGF-II concentrations, that IGF-II is predominantly a fetal somatomedin. IGF-II mRNAs are present, however, in some poly(A+) RNAs from adult rat tissues. The brain was the only tissue in the adult rat where the 4.7- and 3.9-kb IGF-II mRNAs were consistently detected. Some samples of adult rat intestine contained the 4.7- and 3.9-kb IGF-II mRNAs and some samples of adult liver and lung contained the 4.7-kb mRNA. These findings suggest that a role for IGF-II in the adult rat, particularly in the central nervous system, cannot be excluded.
Animals↗
Microsomal and cytosolic epoxide hydrolase in Drosophila melanogaster.
Subcellular fractions from Drosophila melanogaster and rat liver were investigated on their epoxide hydrolase activity. Both microsomes and the post-microsomal supernatant of Drosophila appeared to contain epoxide hydrolase activity using styrene-7,8-oxide as the substrate. Based on body weight, these activities were in the same order of magnitude. Rat liver cytosol was able to catalyze the hydrolysis of styrene oxide only if the glutathione S-transferase activity was blocked.
Animals↗
Organization of the human genes for insulin-like growth factors I and II.
Recently, we have reported the isolation of cDNAs encoding the precursors of insulin-like growth factors I and II (IGF-I and II) [(1983) Nature 306, 609-611; (1985) FEBS Lett. 179, 243-246. These cDNAs were employed as specific probes to detect and isolate the corresponding genes from human cosmid DNA libraries. Three cosmids were detected, together containing the entire cDNA sequence of IGF-I, and one cosmid containing the sequence of IGF-II cDNA. Southern blot hybridization, physical mapping and nucleotide sequence analysis of these cosmids revealed that the IGF-I and -II genes have a discontinous structure. The IGF-I gene contains at least four exons spanning a region of probably more that 45 kilobasepairs (kb), while the IGF-II gene consists of at least five exons, spanning a region of 16 kb.
Amino Acid Sequence↗
Expression of insulin-like growth factor II in human placentas from normal and diabetic pregnancies.
The growth and development of the placenta is critical to fetal growth and development; however, little is known regarding the mechanisms controlling placental growth and development. Human placental membranes are known to possess receptors for insulin-like growth factors I and II (IGF-I and IGF-II) from early gestation, and increasing evidence supports a major role for IGF-I and/or IGF-II in fetal growth and development. Therefore, the IGFs may also play a significant role in regulating placental growth and development. We report here that an adult human liver IGF-II cDNA hybridizes to poly(A)+ RNAs of human placentas from different gestational ages. There are four placental poly(A)+ RNA species that hybridize to IGF-II cDNA, the major one of which is about 6000 bases. The sizes of the hybridized transcripts are the same for placentas of different gestational ages. Furthermore, the IGF-II sequences expressed in the human placenta were quantitated by dot blot hybridization. The second trimester placenta expresses more IGF-II mRNA sequences than placenta of first trimester and term. Interestingly, the term placentas from diabetic pregnancies also express more of these sequences than those from normal pregnancies. These results suggest that there are developmental changes in the expression of the IGF-II gene in the placenta and that IGF-II may promote placental growth by way of an autocrine and/or paracrine mechanism. Moreover, fetuses developing in diabetic pregnancies receive a large influx of glucose, which in turn may stimulate the expression of IGF-II sequences in placenta, resulting in higher utilization of glucose and overgrowth of placenta. This may explain the macrosomia and high incidence of malformations and stillbirths known to result from pregnancies in diabetics.
Female↗
Possible role of calcium entry blockers in brain protection.
Cerebral protection in its proper meaning is understood as a method to suppress electrophysiological and metabolic activity of the CNS. More generally, methods which avert injury to the brain, particularly when anticipated, can be considered as cerebral protection. Prevention of secondary brain damage following a primary ischemic or traumatic lesion is a particularly important goal of cerebral protection. The concept of secondary brain damage implies that secondary changes in principle should be prevented by inhibition of the pathomechanisms involved. The introduction of Ca2+ antagonists into the treatment of traumatic or ischemic cerebral injury is an excellent example of a powerful therapeutical method, which is developed on the basis of an understanding of the underlying pathophysiological mechanisms. Ca2+ antagonists may interfere at various levels, e.g. blood flow, cellular destruction or other forms of secondary brain damage. Intracellular Ca2+ overload appears to be a common pathway to failure of pertinent cell functions, and eventually cell death. Thus, inhibition of this process might be central for cell and, hence, cerebral tissue protection. However, the use of Ca2+ antagonists requires careful considerations of the type of drug needed and of their potential side effects.
Animals↗
Molecular aspects of the human somatomedins.
The primary structure of the somatomedins (SM) IGF-I and IGF-II has been known for some years. Both from isolation of the SMs from plasma and from the study of cDNAs it has become evident that there are more SMs, needing further study. In plasma the SMs are present in larger molecules of two size-classes: 150 kD and 40 kD, behaving as specific SM-binding proteins. The possibility that such protein classes are heterogeneous and also contain precursor molecules undergoing proteolytic processing is considered. The somatomedin genes are discontinuous and span large regions of the human genome.
Base Sequence↗