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PubMedDate not supplied

Neurobehavioral and neurochemical abnormalities of pre- and postnatally lead-exposed rats: zinc, copper and calcium status.

Although diverging opinions have been expressed, there is a body of evidence of a cause-effect relationship between chronic exposure to lead and altered behavior in children. There are several problems in the interpretation of the behavioral and biochemical anomalies described in experimental models of lead intoxication due mainly to the different experimental conditions used. One of the major criticisms is linked with the claim that in several studies too high levels of exposure were used, hence inducing the suspicion that the effects specifically attributed to lead intoxication could be related to unspecific actions. Here we report that, using an experimental model of pre- and postnatal intoxication of rats exposed to a very low amount of lead (1 mg/kg/day), in parallel with behavioral anomalies, there are slight changes in cerebral dopaminergic and GABAergic receptors. A new finding was the discovery that in this condition there is a markedly increased number of opiate receptors in the hypothalamus (and other brain areas) in parallel with a decrease of beta-endorphin and an increase of Met-enkephalin. Therefore, low levels of lead intoxication which could be pertinent to the human situation, seem to induce neurotoxic effects which may be responsible for the behavioral anomalies in rats and, maybe, in children.

Animals↗
PubMed1994

Divergent patterns of ELAM-1, ICAM-1, and VCAM-1 expression on cytomegalovirus-infected endothelial cells.

Endothelial cells, one of several in vivo host cells for cytomegalovirus (CMV), participate in solid organ allograft rejection in part through the expression of leukocyte adhesion molecules. The hypothesis that CMV infection alters the constitutive and induced expression of ELAM-1, ICAM-1, and VCAM-1 on infected human umbilical vein endothelial cells (HUVECs) was examined. HUVECs were infected with an endothelial cell-propagated strain of CMV (VHL/E) for various periods, treated with tumor necrosis factor-alpha (TNF alpha), and examined by flow cytometry or immunohistochemically dual-labeled with monoclonal antibodies to CMV immediate early nuclear protein and ELAM-1, ICAM-1, or VCAM-1. Neither ELAM-1 nor VCAM-1 was induced on CMV-infected HUVECs, and treatment with TNF alpha treatment did not result in their induction. In contrast, ICAM-1 was induced on infected HUVECs by 24 hr postinfection. Endothelial ICAM-1 induction may represent a mechanism by which CMV infection exacerbates the recipient cellular immune response to allografts.

Antibodies, Viral↗
PubMed1994

Differential responses of fetal, neonatal, and adult myelopoietic progenitors to interferon and tumor necrosis factor.

Human fetal liver (FL) and neonatal cord blood (CB) granulocyte-monocyte colony-forming progenitor cells (GM-CFC) are unique in their physiological environment and in certain proliferative and differentiative capacities. Tumor necrosis factor (TNF) and interferon (IFN) may inhibit or stimulate the growth of human bone marrow GM-CFC in vitro. The effects of recombinant human (rh) TNF-alpha, rhIFN-alpha, and rhIFN-tau on recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF)-stimulated clonogenic cultures of day 7 GM-CFC from FL and umbilical CB were compared with rhGM-CSF-stimulated GM-CFC from normal human bone marrow (BM). We demonstrate that, in comparison to BM progenitor cells, GM-CFC from both FL and CB were highly resistant to growth inhibition by all three cytokines. Furthermore, clonogenic growth of progenitors from FL and CB was markedly potentiated by IFN-tau in GM-CSF-stimulated cultures and was stimulated by IFN-tau in the absence of GM-CSF. Depletion of potential accessory cells resulted in a marked stimulatory response of CB cells to TNF-alpha, in the presence of GM-CSF, while it did not alter the responses to IFN. The stimulatory effects of IFN-tau and TNF-alpha may be indirectly mediated, at least in part, through induction of increased GM-CSF production and increased GM-CSF receptor expression by fetal cells. Divergent responses of myelopoietic cells, derived from various hematopoietic compartments, to regulatory actions of cytokines may provide a basis for further understanding the role of the environment in maturation and differentiation of granulocytes and monocytes.

Adult↗
PubMed1995

Polymorphic protein expression (profile) in numigall.

Ten protein and enzyme polymorphic systems, viz. haemoglobin, albumin, transferrin, adenosine deaminase, adenylate kinase phosphoglucomutase, esterase-D, glyoxalase, alkaline phosphatase and amylase were studied in numigall (guinea fowl x chicken hybrids) to assess structural gene expression and regulatory gene divergence between the parental species. The investigation revealed presence of both the maternal and paternal electrophoretic components in case of adenosine deaminase, alkaline phosphatase, amylase, albumin and transferrin although no clear differences could be identified for haemoglobin and glyoxalase. Esterase-D and adenylate kinase phenotypes showed a dominance of the chicken type.

Animals↗
PubMed2003

Myeloid differentiation factor 88-dependent post-transcriptional regulation of cyclooxygenase-2 expression by CpG DNA: tumor necrosis factor-alpha receptor-associated factor 6, a diverging point in the Toll-like receptor 9-signaling.

The immune stimulatory unmethylated CpG motifs present in bacterial DNA (CpG DNA) induce expression of cyclooxygenase-2 (cox-2). The present study demonstrates that CpG DNA can up-regulate cox-2 expression by post-transcriptional mechanisms in RAW264.7 cells. To determine the CpG DNA-mediated signaling pathway that post-transcriptionally regulates cox-2 expression, a cox-2 translational reporter (COX2-3'-UTR-luciferase) was generated by inserting sequences within the 3'-untranslated region (UTR) of cox-2 to the 3' end of the luciferase gene under control of the SV40 promoter. CpG DNA-induced COX2-3'-UTR-luciferase activity was completely inhibited by an endosomal acidification inhibitor chloroquine, a Toll-like receptor 9 antagonist inhibitory CpG DNA, or overexpression of a dominant negative (DN) form of MyD88. However, overexpression of DN-IRAK-1 or DN-TRAF6 resulted in substantial, but not complete, inhibition of the CpG DNA-induced COX2-3'-UTR-luciferase activity. Activation of all three MAPKs (ERK, p38, and JNK) was required for optimal COX2-3'-UTR-luciferase activity induced by CpG DNA. Overexpression of DN-TRAF6 suppressed CpG DNA-mediated activation of p38 and JNK, but not ERK, explaining the partial inhibitory effects of DN-TRAF6 on CpG DNA-induced COX2-3'-UTR-luciferase activity. Co-expression of DN-TRAF6 and N17Ras completely inhibited CpG DNA-induced COX2-3'-UTR-luciferase activity, indicating the involvement of Ras in CpG DNA-mediated ERK and COX2-3'-UTR regulation. Collectively, our results suggest that MyD88 and MAPKs play a key regulatory role in CpG DNA-mediated cox-2 expression at the post-transcriptional level and that TRAF6 is a diverging point in the Toll-like receptor 9-signaling pathway for CpG DNA-mediated MAPK activation.

3' Untranslated Regions↗
PubMed2005

SOX7 is an immediate-early target of VegT and regulates Nodal-related gene expression in Xenopus.

In zebrafish, the divergent F-type SOX casanova acts downstream of Nodal signaling to specify endoderm. While no casanova orthologs have been identified in tetrapods, the F-type SOX, SOX7, is supplied maternally in Xenopus (Fawcett and Klymkowsky, 2004. GER 4, 29). Subsequent RT-PCR and section-based in situ hybridization analyses indicate that SOX7 mRNA is localized to the vegetal region of the blastula-stage embryo. Overexpression and maternal depletion studies reveal that the T-box transcription factor VegT, which initiates mesoendodermal differentiation, directly regulates SOX7 expression. SOX7, but not SOX17 (another F-type SOX), binds to sites within the Xnr5 promoter and SOX7, but not SOX17, induces expression of the Nodal-related genes Xnr1, Xnr2, Xnr4, Xnr5, and Xnr6, the homeodomain transcription factor Mixer, and the endodermal marker SOX17beta; both SOX7 and SOX17 induce expression of the pan-endodermal marker endodermin. SOX7's induction of Xnr expression in animal caps is independent of Mixer and Nodal signaling. In animal caps, VegT's ability to induce Mixer and Edd appears to depend upon SOX7 activity. Whole embryo experiments suggests that vegetal factors partially compensate for the absence of SOX7. Based on the antagonistic effects of SOX7 and SOX3 (Zhang et al., 2004. Dev. Biol. 273, 23) and their common binding sites in the Xnr5 promoter, we propose a model in which competitive interactions between these two proteins are involved in refining the domain of endodermal differentiation.

Amino Acid Sequence↗
PubMed2001

Sequence and expression of the hunchback gene in Lucilia sericata: a comparison with other Dipterans.

We have found that the hunchback (hb)gene from Lucilia sericata is conserved in its functional domains in comparison with related flies, although there is divergence in the protein outside these regions. The expression patterns of Lucilia hb in early embryos are broadly similar to other higher Dipterans. However, in the posterior region we report blastoderm and post-gastrulation expression patterns, which are diverged from Musca and Drosophila. These patterns are reminiscent of hb expression in more primitive insects and could be indicative of changes in the regulation of hb in Lucilia by the terminal system.

Amino Acid Sequence↗
PubMed2001

Distinct expression patterns of two zebrafish homologues of the human APP gene during embryonic development.

The human amyloid protein precursor (APP) gene correlates with early onset of Alzheimer's disease in humans. We have identified two APP homologues in zebrafish, which we call appa and appb. They show a high degree of identity to human APP particularly in the beta APP42 and the transmembrane domain. Widespread expression of both appa and appb was detected from mid-gastrulation until the bud stage. During segmentation, the two genes diverged in their pattern of expression: at 14 h post-fertilisation (hpf) and 18 hpf both genes were expressed rostrally in the prospective CNS, but only appa was found caudally in the paraxial segmental plate and presomitic mesoderm, excluding the midline. In contrast, appb was found caudally in the neural rod at 14 hpf and the developing spinal cord at 18 hpf. Later, at 24 hpf both genes shared common expression domains, namely the telencephalon, the ventral diencephalon, the trigeminal ganglia, and the posterior lateral line ganglia. Unique expression domains for appa were the lens, the otic vesicles and the somites, while appb was expressed in a serially repeated set of nuclei within the hindbrain, the ventral mesencephalon and the motoneurones of the developing spinal cord.

Amyloid beta-Protein Precursor↗
PubMed2001

The effects of DNA supercoiling on the expression of operons of the ilv regulon of Escherichia coli suggest a physiological rationale for divergently transcribed operons.

Transcriptional activities of closely spaced divergent promoters are affected by the accumulation of local negative superhelicity in the region between transcribing RNA polymerase molecules (transcriptional coupling). The effect of this transcription-induced DNA supercoiling on these promoters depends on their intrinsic properties. As the global superhelical density of the chromosome is controlled by the energy charge of the cell, which is affected by environmental stresses and transitions from one growth state to another, the transcriptional coupling that occurs between divergently transcribed promoters is likely to serve a physiological purpose. Here, we suggest that transcriptional coupling between the divergent promoters of the ilvYC operon of Escherichia coli serves to co-ordinate the expression of this operon with other operons of the ilv regulon during metabolic adjustments associated with growth state transitions. As DNA supercoiling-dependent transcriptional coupling between the promoters of other divergently transcribed operons is investigated, additional global gene regulatory mechanisms and physiological roles are sure to emerge.

Bacterial Proteins↗
PubMed2004

Testosterone modulates mitochondrial aconitase in the full-length human androgen receptor-transfected PC-3 prostatic carcinoma cells.

In vitro studies indicated that dihydrotestosterone (DHT) stimulates the enzymatic activity of the mitochondrial aconitase (mACON) in androgen-sensitive prostatic carcinoma cells, LNCaP. Cell proliferation assay determined that DHT doubles the optimal proliferation response of LNCaP cells. The androgen-insensitive human prostatic carcinoma cells, PC-3, were overexpressed in the human androgen receptor to assess the involvement of the native androgen receptor in the regulation by DHT of mACON gene expression. A stable-transfected clone that expresses the full-length androgen receptor was selected and termed PCAR9. The results revealed that DHT-treated PCAR9 cells paradoxically not only reduced the enzymatic activity of mACON but also blocked the biosynthesis of intracellular ATP attenuating cell proliferation. Transient gene expression assay indicated that DHT divergently regulates the promoter activity of the mACON gene in LNCaP and PCAR9 cells. This study suggested that DHT regulates mACON gene expression and the proliferation of cells in a receptor-dependent model through modulation by unidentified non-receptor factors.

Aconitate Hydratase↗
PubMed1991

Developmental expression of CD45 alternate exons in murine T cells. Evidence of additional alternate exon use.

The CD45 glycoprotein family exhibits cell line-age-associated structural heterogeneity arising in part from alternate 5' exon shuffling. Previous studies of exons involved in the final glycoprotein structure have provided evidence of alternate exon use for only three exons (Ex-4, 5 and 6). However, our prior data using reverse transcription-polymerase chain reaction (RT-PCR) suggested the presence of at least one additional CD45 alternate exon. By using RT-PCR, Southern blotting with exon-specific or exon splice junction-specific oligonucleotide probes and direct DNA sequencing of RT-PCR products, we demonstrated additional alternate use involving Ex-7. PCR analysis of stage I thymocytes (CD4-CD8-) revealed only faintly detectable bands for two isoforms: one lacking Ex-4, 5, 6 and 7 (a "minus-one" [Ex(-1)] isoform), and a smaller isoform preliminarily characterized as also lacking Ex-8. Stage II thymocytes (CD4+CD8+) prominently expressed both Ex(-1) and zero alternate exon (Ex(0] isoforms, with one exon (Ex(1] and two exon (Ex(2] isoforms also present. Among stage III thymocytes, both CD4+CD8- and CD4-CD8+ cells expressed only Ex(-1) and Ex(0) isoforms. CD45 alternate exon use in resting CD4+ and CD8+ lymph node T cells was divergent, with CD8+ cells additionally expressing an Ex(2) isoform. Among alloreactive T cell clones, band intensity for the Ex(1) isoform in CD4+ BC-3 cells was much less than for resting CD4+ T cells, while the CD8+ CTL clone 8.2.2 exhibited production of the higher alternate exon isoforms, Ex(2) and Ex(3). We conclude that at least four and possibly five alternate exons exist in the CD45 glycoprotein family, with a previously unrecognized isoform lacking Ex-4, 5, 6 and 7 prominently expressed in T cells. Shuffling of CD45 alternate exons appears to occur in an organized and predictable sequence during cellular maturation and activation.

Animals↗
PubMed1993

Phase variation of H. influenzae fimbriae: transcriptional control of two divergent genes through a variable combined promoter region.

The expression of H. influenzae fimbriae is subject to reversible phase variation between three expression levels. This phenomenon is controlled at the transcriptional level of two divergently orientated genes, hifA and hifB, encoding the major fimbrial subunit and the fimbrial chaperone, respectively. The hifA and hifB promoter regions were found to be clustered through an almost complete divergent overlap with a variable DNA backbone of repetitive TA units. Variation in the number of units changes the normally strictly constrained spacing between the -35 and -10 sequences and controls the bidirectional transcription initiation, thus forming a novel mechanism directing multiple gene transcription.

Attachment Sites, Microbiological↗
PubMed1991

Cytotoxic activity and phenotypic characteristics of lymphocyte subsets after therapy of cancer patients with interleukin-2.

After a 5-day period of continuous intravenous infusion of recombinant interleukin 2 (rIL-2) in seven patients with malignant melanoma or gastric or pancreatic cancer, different lymphocyte subsets were separated from patients' blood and tested ex vivo for cytotoxic activity against various tumour cell lines. Lytic activity was mediated by CD3+CD56+, CD3-CD56+, CD3-CD2+ and CD8+CD56+ lymphocytes. No cytotoxic activity could be observed within the CD3+CD56-, CD3+CD2+ or CD4+ T cell subsets. To characterize CD56+ cytotoxic cells further, the expression of other antigens on this population was analysed before and after IL-2 therapy. CD3, CD4, CD16 and CD57 antigens were weakly expressed, and the IL-2 receptor (CD25) was not detectable on these cells either before and after treatment with IL-2. In contrast, increased expression of CD2. CD8 and HLA-DR antigens occurred following therapy. The divergence of CD3 and CD8 antigen expression after IL-2 therapy was caused by an increase in CD3-CD8+ cells, detectable as a low-density CD8+ subset. This study shows that cytotoxic activity of in vivo IL-2-activated killer cells is predominantly, but not exclusively, mediated by CD3-CD56+ lymphocytes, partially coexpressing the CD8 antigen and lacking the expression of CD16 antigens.

Antigens, CD↗
PubMed2006

Evolutionary constraints on codon and amino acid usage in two strains of human pathogenic actinobacteria Tropheryma whipplei.

The factors governing codon and amino acid usages in the predicted protein-coding sequences of Tropheryma whipplei TW08/27 and Twist genomes have been analyzed. Multivariate analysis identifies the replicational-transcriptional selection coupled with DNA strand-specific asymmetric mutational bias as a major driving force behind the significant interstrand variations in synonymous codon usage patterns in T. whipplei genes, while a residual intrastrand synonymous codon bias is imparted by a selection force operating at the level of translation. The strand-specific mutational pressure has little influence on the amino acid usage, for which the mean hydropathy level and aromaticity are the major sources of variation, both having nearly equal impact. In spite of the intracellular lifestyle, the amino acid usage in highly expressed gene products of T. whipplei follows the cost-minimization hypothesis. The products of the highly expressed genes of these relatively A + T-rich actinobacteria prefer to use the residues encoded by GC-rich codons, probably due to greater conservation of a GC-rich ancestral state in the highly expressed genes, as suggested by the lower values of the rate of nonsynonymous divergences between orthologous sequences of highly expressed genes from the two strains of T. whipplei. Both the genomes under study are characterized by the presence of two distinct groups of membrane-associated genes, products of which exhibit significant differences in primary and potential secondary structures as well as in the propensity of protein disorder.

Actinobacteria↗
PubMed1999

Activation of Hex and mEg5 by retroviral insertion may contribute to mouse B-cell leukemia.

AKXD recombinant inbred mice develop a variety of leukemias and lymphomas due to retrovirally mediated insertional activation of cellular proto-oncogenes. We describe a new retroviral insertion site that is the most frequent genetic alteration in AKXD B-cell leukemias. Multiple genes flank the site of viral insertion, but the expression of just two, Hex and mEg5, is significantly upregulated. Hex is a divergent homeobox gene that is transiently expressed in many hematopoietic lineages, suggesting an involvement in cellular differentiation. mEg5 is a member of the bim-C subfamily of kinesin related proteins that are necessary for spindle formation and stabilization during mitosis. Our data provide the first genetic evidence for the activation of these genes in leukemia, and suggest that unscheduled expression of Hex and mEg5 contributes to the development of B-cell leukemia. In addition, this work highlights the use of genomic approaches for the study of position effect mutations.

Animals↗
PubMed2004

Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes.

Fms-like tyrosine kinase 3 (FLT3) mutations are associated with unfavorable outcomes in children with acute myeloid leukemia (AML). We used DNA microarrays to identify gene expression profiles related to FLT3 status and outcome in childhood AML. Among 81 diagnostic specimens, 36 had FLT3 mutations (FLT3-MUs), 24 with internal tandem duplications (ITDs) and 12 with activating loop mutations (ALMs). In addition, 8 of 19 specimens from patients with relapses had FLT3-MUs. Predictive analysis of microarrays (PAM) identified genes that differentiated FLT3-ITD from FLT3-ALM and FLT3 wild-type (FLT3-WT) cases. Among the 42 specimens with FLT3-MUs, PAM identified 128 genes that correlated with clinical outcome. Event-free survival (EFS) in FLT3-MU patients with a favorable signature was 45% versus 5% for those with an unfavorable signature (P = .018). Among FLT3-MU specimens, high expression of the RUNX3 gene and low expression of the ATRX gene were associated with inferior outcome. The ratio of RUNX3 to ATRX expression was used to classify FLT3-MU cases into 3 EFS groups: 70%, 37%, and 0% for low, intermediate, and high ratios, respectively (P < .0001). Thus, gene expression profiling identified AML patients with divergent prognoses within the FLT3-MU group, and the RUNX3 to ATRX expression ratio should be a useful prognostic indicator in these patients.

Acute Disease↗
PubMed1997

C-C chemokines differentially alter interleukin-4 production from lymphocytes.

The expression of cytokines can dictate the intensity, chronicity, and type of immune/inflammatory response that is produced. These events may be regulated by accumulation of particular cell populations at a site of immune response that can be regulated by the expression of specific chemokines. Recent data have indicated that chemokines also have direct effects on cellular activation. In particular, T lymphocyte responses have been divided into two distinct phenotypes, designated by TH1- and TH2-type cytokine expression. Although it is recognized that divergent T-lymphocyte-derived cytokine phenotypes exist, the mechanisms that dictate the expression of these cytokines and ultimately the division of these immune responses is not entirely clear. In the present study, we present data that the C-C chemokine family members may be a factor influencing the direction of T-cell-derived lymphokine production. To elucidate the role of C-C chemokines, MIP-1 alpha and MCP-1, we have used both antigen-specific (schistosomal egg antigen (SEA)) and nonspecific (conconavalin (Con) A) stimuli. Using TH2-type lymphocyte populations from SEA-sensitized mice, a significant increase in IL-4 mRNA expression and protein production was observed when MCP-1 was added to the culture. Conversely, MIP-1 alpha treatment appeared to decrease interleukin (IL)-4 production. Interestingly, the proliferative response in the TH2-type (SEA-specific) response was up-regulated by MIP-1 alpha whereas MCP-1 down-regulated the response, inversely correlating with IL-4 production. Primary stimulation of naive lymphocytes with Con A induces a predominant interferon (IFN)-gamma response, whereas the second stimulation of the same lymphocytes with Con A induces both IFN-gamma and IL-4. When the two C-C chemokines were individually co-incubated with Con-A-stimulated lymphocytes, both up-regulated IFN-gamma production and proliferation during the primary stimulation. Similarly, in the secondary response, both chemokines further upregulated IFN-gamma production; however, only MCP-1 co-stimulation increased IL-4 production, whereas MIP-1 alpha significantly decreased IL-4 production in these same cell populations. These results were also reflected in steady-state levels of mRNA expression. These results suggest that the production of C-C chemokines (MCP-1 or MIP-1 alpha) during an immune response may aid in determining the type of cytokines produced and the level of lymphocyte activation during a particular response.

Animals↗
PubMed2003

Expression of caveolin-1 in gastrointestinal and extraintestinal cancers.

Caveolae are uniform vesicular invaginations of the cell membrane. Caveolin-1 is responsible for the formation of caveolae and plays a key role in membrane traffic and signal transduction. The contribution of caveolin-1 to carcinogenesis has been widely investigated; however, the expression pattern of caveolin-1 is controversial both in gastrointestinal and extraintestinal cancers. Most of the results based on cancer cell line experiments suggest that caveolin-1 might act as a tumor-suppressor gene. On the contrary, several studies on the expression of caveolin-1 in tumor tissues indicate a possible tumor-promoting effect of caveolin-1. In this article we summarize the divergent results of caveolin-1 expression in gastrointestinal and extraintestinal cancer regarding possible future therapeutic implications.

Animals↗