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An IgG1 monoclonal antibody, FDC-6, was established, which defines a unique fibronectin (FN) domain, located between the ``Hep-2'' and the ``Fib-2'' domains, in the COOH-terminal region of FNs isolated from hepatoma, sarcoma, and fetal fibroblasts. A systematic study with this antibody indicates the presence of two classes of human FNs. (i) FN from fetal connective tissue, placenta, amniotic fluid, hepatoma, and colon carcinoma as well as cell lines from fetal tissues (WI-38), hepatomas (HuH-6 and HuH-7), and sarcoma (VA13) was characterized by the presence of the FDC-6-defined domain and by a high molecular weight (subunit Mr, 310,000-335,000). (ii) In contrast, FN from normal adult tissues and plasma was characterized by a lower molecular weight (subunit Mr, 285,000-295,000) and lack of reactivity with FDC-6 and is therefore devoid of the FDC-6-defined domain. The FDC-6-defined domain is therefore called the ``oncofetal'' domain, and FN containing this domain is hereby called ``oncofetal FN'' (onf FN). The onf FN is similar to the previously known ``cellular-form'' FN. FN from normal adult tissues and plasma, lacking the oncofetal domain, is hereby called ``normal FN'' (nor FN). The nor FN is similar to the previously known ``plasma-form'' FN. Development of FN from fetal to adult form is associated with loss of the oncofetal domain defined by the FDC-6 antibody, and oncogenic transformation is associated with activation in synthesis of the oncofetal domain defined by the FDC-6 antibody.

The genes for two of the proteins of the plasma lipid transport system, apolipoprotein AI (apoAI) and CIII (apoCIII) are closely linked in the human genome. An ≈ 30-kilobase (kb) DNA segment containing these genes and their flanking sequences has been cloned and extensively characterized. Hybridization studies revealed that a DNA fragment located 12 kb 3′to the apoAI gene contains sequences homologous to a 1.8-kb mRNA transcript in human fetal intestine and adult liver but not in fetal liver, kidney, heart, brain, or muscle. This DNA fragment was used as a probe to isolate a clone from an adult human liver cDNA library. The nucleotide sequence of this clone is 74.8% homologous to the cDNA sequence of rat apolipoprotein AIV (apoAIV), another protein of the lipid transport system, and codes for a protein that is 58.6% identical to rat apoAIV. These results indicate that apoAI, apoCIII, and apoAIV genes are closely linked in the human genome and suggest that all three of them are derived from a common ancestral precursor.

Expression of the apolipoprotein B (apoB) gene was examined in a variety of fetal, neonatal, and adult rat tissues by probing RNA blots with a cloned rat apoB cDNA. Among 10 adult male tissues surveyed, small intestine had the highest concentration of apoB mRNA. Its abundance in liver and adrenal gland was 40% and 0.5%, respectively, of that in small bowel, while none was detected in colon, kidney, testes, spleen, lung, heart, or brain. ApoB mRNA is as abundant in 18-day fetal liver as at any subsequent period of hepatic development. In contrast, the concentration of apoB mRNA remains low in fetal intestine until the last (21st) day of gestation, when it increases sharply to levels that are severalfold higher than in the liver. ApoB mRNA levels in fetal membranes harvested during this late gestational period were 10 times greater than in fetal liver. Since the major lipoprotein species in 19-day fetal plasma is low density lipoprotein, these observations suggest that fetal liver, and particularly its functional homologue, the yolk sac, are the principal sites of fetal lipoprotein synthesis at this stage of development. A 20-fold increase in placental apoB mRNA concentrations during the last 48 hr of pregnancy (to a level that is 50% of that encountered in fetal membrane RNA) suggests a specific role for this organ in maternal-fetal lipid transport immediately prior to parturition. Pulse-labeling experiments using 21-day fetal tissue slices showed that the liver synthesizes both apoB-100 (B-PI) and apoB-48 (B-PIII) albeit in somewhat different ratios than the adult organ. Fetal intestine produces almost exclusively the smaller apoB species, while fetal membranes and placenta synthesize only the larger peptide. The postnatal pattern of apoB mRNA accumulation is similar in liver and intestine. Profound decreases were observed during the late suckling and weaning periods, followed by an increase to adult levels. These final concentrations were similar to those encountered at birth. Analysis of these developmental changes offers an opportunity to generate testable hypotheses about the factors that modulate apoB synthesis.

Two human cDNA clones (HHO.c1.95 and HHO.c8.5111) containing a homeobox region have been characterized, and the respective genomic regions have been partially analyzed. Expression of the corresponding genes, termed c1 and c8, was evaluated in different organs and body parts during human embryonic/fetal development. HHO.c1.95 apparently encodes a 217-amino acid protein containing a class I homeodomain that shares 60 out of 61 amino acid residues with the Antennapedia homeodomain of Drosophila melanogaster. HHO.c8.5111 encodes a 153-amino acid protein containing a homeodomain identical to that of the frog AC1 gene. Clones HHO.c1 and HHO.c8 detect by blot-hybridization one and two specific polyadenylylated transcripts, respectively. These are differentially expressed in spinal cord, backbone rudiments, limb buds (or limbs), heart, and skin of human embros and early fetuses in the 5- to 9-week postfertilization period, thus suggesting that the c1 and c8 genes play a key role in a variety of developmental processes. Together, the results of the embryonic/fetal expression of c1 and c8 and those of two previously analyzed genes (c10 and c13) indicate a coherent pattern of expression of these genes in early human ontogeny.

Three overlapping genomic clones that contain the 5′-terminal portion of the human c-erbB-2 gene (ERBB2) were isolated. The promoter region was identified by nuclease S1 mapping with c-erbB-2 mRNA. Seven transcriptional start sites were identified. DNA sequence analysis showed that the promoter region contains a ``TATA box'' and a ``CAAT box'' about 30 and 80 base pairs (bp), respectively, upstream of the most downstream RNA initiation site. Two putative binding sites for transcription factor Sp1 were identified about 50 and 110 bp upstream of the CAAT box, and six GGA repeats were found between the CAAT box and the TATA box. This region had strong promoter activity when placed upstream of the bacterial chloramphenicol acetyltransferase gene and transfected into monkey CV-1 cells. These data indicate that the promoter of the human c-erbB-2 protooncogene is different from that of the protooncogene c-erbB-1 (epidermal growth factor receptor gene), which does not contain either a TATA box or a CAAT box. Comparison of the promoter sequences and activities of the two protooncogenes should be helpful in analysis of the regulatory mechanism of expression of their gene products, which are growth-factor receptors.

One of the earliest and most important abnormalities of fetal muscle in Duchenne muscular dystrophy is an increase in eosinophilic fibres (those that stain darkly with eosin). A study of normal and at-risk male fetuses after abortion was carried out, which showed that these eosinophilic fibres contain increased intracellular calcium, which suggests that this is an early biochemical change in the disorder. Since increased intracellular calcium would account for various biochemical and clinical features of the disease, it may be related to the primary defect. Thus an increase in muscle fibres containing increased intracellular calcium in at-risk fetuses may provide an additional means of assessing the validity of any future presumptive antenatal test for Duchenne muscular dystrophy.

Chorionic villi can be obtained by direct transcervical aspiration at 9 to 10 weeks' gestation and used for analysis of fetal DNA. However, for the method to be reliable, there must be no detectable contamination by maternal DNA. To investigate the question of contamination, we compared the DNA of chorionic villi from five fetuses with that obtained from maternal lymphocytes, using the restriction endonuclease Taq I and specific DNA probes for a pair of alleles on the X chromosome. The alleles yield fragments of different lengths when digested with Taq I (length polymorphism), which can be demonstrated by electrophoresis and hybridization with the radioactive DNA probes. If the pattern obtained with the chorionic DNA is different from that obtained with the maternal DNA, contamination is not present. In two cases the fetal DNA of the chorionic villi was shown to be uncontaminated by maternal tissue. In one of these cases the mother was heterozygous and the fetus was homozygous; in the other the mother was homozygous and the fetus was heterozygous. In three other cases no definitive conclusions could be drawn, because the genotypes of the fetus and mother were identical. We conclude that chorionic villi at 9 to 10 weeks' gestation are a source of fetal DNA that can be used for gene analysis, with no detectable contamination by maternal DNA. (N Engl J Med 1983; 308:1433–5.) In the first trimester of gestation, chorionic villi of the fetus are accessible by transcervical aspiration without anesthesia, as a source of trophoblasts for direct analysis of fetal DNA. 1 Although the method has been used for both the early diagnosis of hemoglobinopathies 2 and determination of fetal sex, 3 for its potential to be exploited, the chorionic tissue must be shown to be free of contaminating maternal tissue. Overgrowth by maternal cells is a documented risk. 4 In this article we show that chorionic villi obtained 9 to 10 weeks after the last menstrual period provide fetal DNA without detectable maternal contamination. The . . .

Autoradiography with $^{3}$H-labeled phorbol dibutyrate was used for the light microscopic detection of phorbol ester receptors in rat fetuses. In 15- and 18- day fetuses, as well as in adult rats, receptors were found to be concentrated in the central nervous system. The localization of receptors in the ventral marginal zone of the fetal neural tube, the lens of the eye, and other sites suggests a role for phorbol ester receptors in cellular process extension and cell-cell interaction.

Cytokeratins were studied by immunocytochemical techniques at light and electron microscopy on 12 normal pituitary glands, 30 pituitary adenomas and three craniopharyngiomas. The results are presented in relation to clinical and biochemical features and new information on the subcellular localisation of cytokeratins in pituitary cells is discussed.