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B Blumberg

Publications and source records attributed to B Blumberg.

At least 37 records · Page 2Linked to original sources
PubMed1997

An essential role for retinoid signaling in anteroposterior neural specification and neuronal differentiation.

Vitamin A and its derivatives, the retinoids, have been implicated as important signaling molecules in vertebrate development, primarily due to numerous gain-of-function experiments involving treatment of embryos with exogenous retinoic acid. Collectively, the results from these experiments suggested that retinoids were sufficient to mimic the action of endogenous factors which posteriorize the embryonic axis, however the question of their necessity has remained unclear. Recent loss-of-function experiments from several laboratories have shown that retinoids are indispensable for regionalizing the anteroposterior axis and promoting neuronal differentiation. These results firmly establish retinoids as endogenous signaling molecules that are required for embryonic patterning.

Journal Article↗
PubMed1997

Transcription regulation and alternative splicing of an early zygotic gene encoding two structurally distinct zinc finger proteins in Xenopus laevis.

We describe the structural organization of a gene, termed XFDL 141/156, that is transiently activated during early Xenopus development. XFDL 141/156 is first transcribed at the midblastula transition (MBT) and during early gastrulation events. A roughly 200 nucleotide fragment immediately 5' to the transcription start site is sufficient for transient, early zygotic activation of gene expression. The primary transcript is subject to alternative splicing. Corresponding cDNAs encode two structurally related but completely distinct C2H2-type zinc finger proteins of unknown biological function.

Alternative Splicing↗
PubMed1997

An essential role for retinoid signaling in anteroposterior neural patterning.

The vertebrate central nervous system (CNS) is induced by signals emanating from the dorsal mesoderm, or organizer, that divert the ectoderm away from an epidermal and towards a neural fate. Additional signals from the organizer pattern the neural ectoderm along the anteroposterior axis. We devised highly specific methods utilizing constitutively active or dominant negative receptors to evaluate the role of retinoids in neural patterning. Microinjection of these reagents either augments or reduces retinoid signaling in specific regions of the embryo. We show that increased receptor activity suppresses anterior neural structures while dominant negative receptors lead to anterior enhancement. Similarly, microinjection of the dominant negative receptor leads to the loss of posterior marker genes. We demonstrate that retinoid receptors comprise a critical component in neural posteriorization and are required for proper neuronal differentiation. These results support a quantitative role for retinoid signaling in regionalization of the CNS.

Animals↗
PubMed1996

Novel retinoic acid receptor ligands in Xenopus embryos.

Retinoids are a large family of natural and synthetic compounds related to vitamin A that have pleiotropic effects on body physiology, reproduction, immunity, and embryonic development. The diverse activities of retinoids are primarily mediated by two families of nuclear retinoic acid receptors, the RARs and RXRs. Retinoic acids are thought to be the only natural ligands for these receptors and are widely assumed to be the active principle of vitamin A. However, during an unbiased, bioactivity-guided fractionation of Xenopus embryos, we were unable to detect significant levels of all-trans or 9-cis retinoic acids. Instead, we found that the major bioactive retinoid in the Xenopus egg and early embryo is 4-oxoretinaldehyde, which is capable of binding to and transactivating RARs. In addition to its inherent activity, 4-oxoretinaldehyde appears to be a metabolic precursor of two other RAR ligands, 4-oxoretinoic acid and 4-oxoretinol. The remarkable increase in activity of retinaldehyde and retinol as a consequence of 4-oxo derivatization suggests that this metabolic step could serve a critical regulatory function during embryogenesis.

Animals↗
PubMed1996

4-Oxoretinol, a new natural ligand and transactivator of the retinoic acid receptors.

All-trans-retinoic acid (at-RA) induces cell differentiation in a wide variety of cell types, including F9 embryonic teratocarcinoma cells, and can influence axial pattern formation during embryonic development. We now identify a novel retinoid synthetic pathway in differentiating F9 cells that results in the intracellular production of 4-oxoretinol (4-oxo-ROL) from retinol (vitamin A). Approximately 10-15% of the total retinol in the culture is metabolized to 4-hydroxyretinol and 4-oxo-ROL by the at-RA-treated, differentiating F9 cells over an 18-hr period, but no detectable metabolism of all-trans-retinol to at-RA or 9-cis-retinoic acid is observed in these cells. Remarkably, we show that 4-oxo-ROL can bind and activate transcription of the retinoic acid receptors whereas all-trans-retinol shows neither activity. Low doses of 4-oxo-ROL (e.g., 10(-9) or 10(-10 M) can activate the retinoic acid receptors even though, unlike at-RA, 4-oxo-ROL does not contain an acid moiety at the carbon 15 position. 4-oxo-ROL does not bind or transcriptionally activate the retinoid X receptors. Treatment of F9 cells with 4-oxo-ROL induces differentiation without conversion to the acid and 4-oxo-ROL is active in causing axial truncation when administered to Xenopus embryos at the blastula stage. Thus, 4-oxo-ROL is a natural, biologically active retinoid that is present in differentiated F9 cells. Our data suggest that 4-oxo-ROL may be a novel signaling molecule and regulator of cell differentiation.

Animals↗
PubMed1996

A program for eradication of hepatitis B from Taiwan by a 10-year, four-dose vaccination program.

Approximately 15 percent of the Taiwanese population are chronic carriers of hepatitis B virus (HBV), among the highest rates in Asia. In July 1984, the Taiwanese government initiated a nationwide HBV-vaccination program. The program began with educational efforts and voluntary prenatal screening for HBsAg. Infants of HBsAg-carrier mothers received a four-dose regimen of hepatitis B vaccine. Those born to highly infectious mothers also received a dose of hepatitis-B immune globulin within 24 hours after birth. Seroepidemiologic studies were conducted using a random sample of infants. Serum samples were collected at 18, 24, 36, and 48 months and analyzed via radioimmunoassay for HBsAg, anti-HBs, and anti-HBc. Infants of highly infectious mothers had HBsAg positivity rates of 14.2 percent (vaccine plus HBIG) and 19.7 percent (vaccine only) when on schedule, and 17.0 percent when off schedule. Infants of moderately infectious mothers had an HBsAg positivity rate of 3.0 percent when on schedule and 6.4 percent when off schedule. These low positivity rates persisted throughout the 48-month follow-up period. This represents a dramatic improvement upon the 40 to 96 percent vertical transmission rate seen before the program implementation. This program demonstrates that mass immunoprophylaxis for HBV is feasible, and provides practical strategies for other Asian countries.

Adolescent↗
PubMed1996

Nerve dependency of regeneration: the role of Distal-less and FGF signaling in amphibian limb regeneration.

Dlx-3, a homolog of Drosophila Dll, has been isolated from an axolotl blastema cDNA library, and its expression in developing and regenerating limbs characterized. The normal expression pattern, and the changes that occur during experimental treatments, indicate a correlation between Dlx-3 expression and the establishment of the outgrowth-permitting epidermis. Dlx-3 is expressed at high levels in a distal-to-proximal gradient in the epidermis of developing limb buds, and is upregulated in the apical ectodermal cap (AEC) during limb regeneration. Expression is maximal at the late bud stage of regeneration, coincident with the transition from the early phase of nerve dependency to the later phase of nerve independence. Dlx-3 expression in the epidermis is rapidly downregulated by denervation during the nerve-dependent phase and is unaffected by denervation during the nerve-independent phase. We investigated this relationship between nerves and Dlx-3 expression by implanting FGF-2 beads into regenerates that had been denervated at a nerve-dependent stage. Dlx-3 expression was maintained by FGF-2 after denervation, and regeneration progressed to completion. In addition, we detected FGF-2 protein in the AEC and in nerves, and observed that the level of expression in both tissues decreases dramatically in response to denervation. We conclude that both limb development and regeneration require a permissive epidermis, characterized by Dlx-3 and FGF expression, both of which are maintained by FGF through an autocrine loop. The transformation of the limb epidermis into a functional AEC that produces and responds to FGF autocatalytically, is presumed to be induced by FGF. Since nerves appear to be a source of this priming FGF, it is possible that a member of the FGF family of growth factors is the elusive neurotrophic factor of limb regeneration.

Ambystoma↗
PubMed1996

Cystic fibrosis heterozygote screening in 5,161 pregnant women.

A screening program for cystic fibrosis (CF) heterozygotes was conducted in a large HMO prenatal population, to evaluate the level of interest among eligible patients, the effectiveness of prescreening education, attitudes toward the screening process, psychological effects, and utilization of prenatal diagnosis and its outcomes. The heterozygote identification rate and frequency of specific CFTR mutations were also assessed. Identified carriers were offered genetic counseling and testing of male partners. Prenatal diagnosis was offered if both parents were identified as carriers. A total of 5,161 women underwent carrier testing; 947 others completed survey instruments only. The acceptance rate of screening was high (78%), and pretest education by videotape was generally effective. Adverse psychological effects were not reported. Participants generally found screening to be desirable and useful. Screening identified 142 female heterozygotes, 109 couples in which the male partner was not a carrier, and 7 high-risk couples. The incidence of R117H mutations was much higher than expected. The number of identified carriers was much lower in Hispanics than in Caucasians. We conclude that large-scale prenatal screening for CF heterozygotes in the absence of a family history of CF is an acceptable method for identifying couples at risk for affected fetuses. Sufficient pretest education can be accomplished efficiently, test insensitivity is well accepted, adverse psychological events are not observed, and general patient satisfaction is high.

Adult↗
PubMed1995

Regulation of HoxA expression in developing and regenerating axolotl limbs.

Homeobox genes are important in the regulation of outgrowth and pattern formation during limb development. It is likely that homeobox genes play an equally important role during limb regeneration. We have isolated and identified 17 different homeobox-containing genes expressed by cells of regenerating axolotl limbs. Of these, nearly half of the clones represent genes belonging to the HoxA complex, which are thought to be involved in pattern formation along the proximal-distal limb axis. In this paper we report on the expression patterns of two 5' members of this complex, HoxA13 and HoxA9. These genes are expressed in cells of developing limb buds and regenerating blastemas. The pattern of expression in developing axolotl limb buds is comparable to that in mouse and chick limb buds; the expression domain of HoxA13 is more distally restricted than that of HoxA9. As in developing mouse and chick limbs, HoxA13 likely functions in the specification of distal limb structures, and HoxA9 in the specification of more proximal structures. In contrast, during regeneration, HoxA13 and HoxA9 do not follow the rule of spatial colinearity observed in developing limbs. Instead, both genes are initially expressed in the same population of stump cells, giving them a distal Hox code regardless of the level of amputation. In addition, both are reexpressed within 24 hours after amputation, suggesting that reexpression may be synchronous rather than temporally colinear. Treatment with retinoic acid alters this Hox code to that of a more proximal region by the rapid and differential downregulation of HoxA13, at the same time that expression of HoxA9 is unaffected. HoxA reexpression occurs prior to blastema formation, 24-48 hours after amputation, and is an early molecular marker for dedifferentiation.

Ambystoma↗
PubMed1995

Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping.

The nuclear receptor superfamily of transcription factors, which includes the retinoic acid receptors and v-erb A, play important roles in the molecular control of hematopoiesis. To identify nuclear receptors expressed in hematopoietic cells, we screened a human bone marrow cDNA library using a degenerate oligonucleotide and isolated a 1.85-kb full-length cDNA encoding a new human member of this superfamily, the peroxisome proliferator activated receptor gamma (hPPAR gamma). Two different hPPAR gamma transcripts were expressed in hematopoietic cells: a 1.85-kb transcript, which corresponds to the full-length mRNA (PPAR gamma 1), and a 0.65-kb transcript (PPAR gamma 2), which cannot encode all of the nuclear receptor functional domains. Normal neutrophils and peripheral blood lymphocytes, as well as circulating leukemic cells from patients with AML, ALL, and CML, express only PPAR gamma 2 on Northern blot analysis. In contrast, only the PPAR gamma 1 transcript was detected in a variety of human leukemia cell lines and in cultured normal primary bone marrow stromal cells. Both transcripts were detected in various fetal and adult nonhematopoietic tissues. We mapped the location of the hPPAR gamma gene to human chromosome 3p25 by somatic cell hybridization and linkage analysis. PPARs have been shown to be activated by peroxisome proliferating agents, long-chain fatty acids and arachidonic acid. Human PPAR gamma, although homologous to the PPAR gamma s of other species, has unique sequence and amino acid differences. Identification of hPPAR gamma will allow further understanding of its role in human cellular leukotriene, prostaglandin, and peroxide degradative or synthetic pathways, as well as its role in lipid metabolism and regulation of adipocyte differentiation.

Adult↗
PubMed1994

Peroxidasin: a novel enzyme-matrix protein of Drosophila development.

Peroxidasin is a novel protein combining peroxidase and extracellular matrix motifs. Hemocytes differentiate early from head mesoderm, make peroxidasin and later phagocytose apoptotic cells. As hemocytes spread throughout the embryo, they synthesize extracellular matrix and peroxidasin, incorporating it into completed basement membranes. Cultured cells secrete peroxidasin; it occurs in larvae and adults. Each 1512 residue chain of the three-armed, disulfide-linked homotrimer combines a peroxidase domain with six leucine-rich regions, four Ig loops, a thrombospondin/procollagen homology and an amphipathic alpha-helix. The peroxidase domain is homologous with human myeloperoxidase and eosinophil peroxidase. This heme protein catalyzes H2O2-driven radioiodinations, oxidations and formation of dityrosine. We propose that peroxidasin functions uniquely in extracellular matrix consolidation, phagocytosis and defense.

Amino Acid Sequence↗
PubMed1994

Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.

To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in mammals, we have cloned and characterized two PPAR alpha-related cDNAs (designated PPAR gamma and -delta, respectively) from mouse. The three PPAR isoforms display widely divergent patterns of expression during embryogenesis and in the adult. Surprisingly, PPAR gamma and -delta are not activated by pirinixic acid (Wy 14,643), a potent peroxisome proliferator and activator of PPAR alpha. However, PPAR gamma and -delta are activated by the structurally distinct peroxisome proliferator LY-171883 and linoleic acid, respectively, indicating that each of the isoforms can act as a regulated activator of transcription. These data suggest that tissue-specific responsiveness to peroxisome proliferators, including certain fatty acids, is in part a consequence of differential expression of multiple, pharmacologically distinct PPAR isoforms.

Acetophenones↗
PubMed1994

Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors.

We have cloned Rev-erb beta, a novel isoform of the Rev-erb alpha orphan nuclear receptor. The DNA binding domains of Rev-erb alpha and beta are highly related to each other and to the retinoic acid related orphan receptor (ROR)/RZR subfamily of nuclear receptors. Indeed, we find that all three receptors bind as monomers to the sequence AATGT-AGGTCA. Whereas ROR alpha 1 constitutively activates transcription through this sequence, both isoforms of Rev-erb are inactive. When coexpressed, both Rev-erb isoforms suppress the transcriptional activity of ROR alpha 1. Our data define Rev-erb and ROR/RZR as a family of related receptors with opposing activities on overlapping regulatory networks.

Amino Acid Sequence↗
PubMed1993

Didanosine (ddI) and zidovudine (ZDV) susceptibilities of human immunodeficiency virus (HIV) isolates from long-term recipients of ddI.

Thirty HIV isolates, obtained from 15 patients before and after receiving single drug therapy with didanosine (ddI), were examined for sensitivity to ddI and zidovudine (ZDV) using a peripheral blood mononuclear leukocyte (PBML)-based assay. Fourteen of the patients had ARC, one had AIDS and 12 had received previous therapy with ZDV. After a median of 1 year of ddI therapy, isolates were significantly less sensitive to ddI than were isolates obtained prior to therapy (P = 0.03). A decrease in ddI sensitivity was observed in ten of the 15 isolate pairs. In contrast to ddI susceptibilities, sensitivity to ZDV increased over the same period of time (P = 0.03). Additional isolates were obtained from four patients who received ddI monotherapy for 2 years. Three of these isolates demonstrated no change in ddI sensitivity compared to baseline. No correlation could be made in this study between development of decreased ddI sensitivity and serum p24 levels, CD4 counts, or clinical outcome. Decreased ddI sensitivity occurs frequently among HIV isolates obtained from long-term recipients of ddI. This decreased sensitivity is modest in degree and is of unknown clinical significance.

AIDS-Related Complex↗
PubMed1993

Tail formation as a continuation of gastrulation: the multiple cell populations of the Xenopus tailbud derive from the late blastopore lip.

Three lines of evidence suggest that tail formation in Xenopus is a direct continuation of events initiated during gastrulation. First, the expression of two gene markers, Xbra and Xnot2, can be followed from the blastopore lip into distinct cell populations of the developing tailbud. Second, the tip of the tail retains Spemann's tail organizer activity until late stages of development. Third, lineage studies with the tracer DiI indicate that the cells of the late blastopore are fated to form specific tissues of the tailbud, and that intercalation of dorsal cells continues during tail elongation. In particular, the fate map shows that the tip of the tail is a direct descendant of the late dorsal blastopore lip. Thus, the tailbud is not an undifferentiated blastema as previously thought, but rather consists of distinct cell populations which arise during gastrulation.

Animals↗