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At least 1,063 records · Page 59Linked to original sources
PubMed1993

Restriction fragment length polymorphisms and single germline coding region sequence in VH18/2, a duplicated gene encoding autoantibody.

In this study, we analyze the restriction fragment length polymorphisms of VH18/2, a gene encoding the heavy chain of an anti-DNA antibody, and correlate that with the germline sequence of the gene's coding region. Oligonucleotides probes complementary to the CDR1 and to both the 5' and 3' halves of the CDR2 gene segments were hybridized under stringent conditions to genomic DNA digested with XbaI, and yielded polymorphic bands of 26, 24 and 18 kb with all three probes. Individuals had either one, two, or three bands in common in their genomic DNA, indicating duplication of VH18/2 genes at two sites within the IgH locus. While it is difficult to say which of the three polymorphic gene segments constitute an allelic pair, the 26 and 24 kb fragments were the most commonly seen (97% of individuals had one or both). VH18/2 is known to be over-represented in the expressed repertoire with very little nucleotide divergence from the germline sequence. In order to determine whether the observed RFLPs are due to sequence polymorphism of the VH18/2 coding region, and whether differences in the expressed genes arise from somatic mutation, size-selected genomic DNA containing the gene was cloned and sequenced. A single coding region sequence was found in the germline. The results of this study suggest that overexpression of VH18/2 may in part be due to its duplication. Like other genes encoding autoantibody, which are well conserved, nonpolymorphic and expressed early in programmed immunologic development, VH18/2 may be instrumental in the establishment or regulation of the immune repertoire.

Antibodies, Antinuclear↗
PubMed1988

Lithium respecifies cyclic AMP-induced cell-type specific gene expression in Dictyostelium.

We investigated the effect of LiCl on pattern formation and cAMP-regulated gene expression in Dictyostelium discoideum. In intact slugs, 5 mM LiCl induces an almost complete redifferentiation of prespore into prestalk cells. We found that LiCl acts by interfering with the transduction of extracellular cAMP to cell-type-specific gene expression; LiCl inhibits the induction of prespore-specific gene expression by cAMP, while it promotes the induction of prestalk-associated gene expression by cAMP. Our results indicate that two divergent pathways transduce the extracellular cAMP signal to, respectively, prestalk and prespore gene expression.

Chlorides↗
PubMed2003

Differential regulation of renin and Cox-2 expression in the renal cortex of C57Bl/6 mice.

Based on the controversy about the relevance of cyclooxygenase-2 (Cox-2)-derived prostanoids from the macula densa for the control of the renin system, this study aimed to determine the interrelation between Cox-2 and renin expression in the mouse kidney. In control mice renin mRNA was readily detectable whilst renocortical Cox-2 mRNA abundance was at the detection limit of the RNase protection assay and no specific signals for Cox-2 were obtained by in situ hybridization or Western blot analysis. Experimental maneuvers such as low-salt diet, treatment with loop diuretics or angiotensin I converting enzyme inhibitors clearly increased renin mRNA abundance up to sevenfold, but under none of these conditions renocortical Cox-2 mRNA levels were significantly changed. Moreover, the strong stimulation of renin expression by angiotensin I-converting enzyme inhibition was not changed by the cyclooxygenase inhibitor ibuprofen, which in turn clearly lowered tissue prostanoid content. Our data suggest a marked divergence of renin and Cox-2 expression in the kidney cortex of C57Bl/6 mice with no clear evidence for a role of Cox-2-derived prostanoids from the macula densa in the regulation of renin expression.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

High expression of the mammalian X chromosome in brain.

Divergence between the sex chromosomes has led to loss and differentiation of Y-linked genes and haplo-insufficiency for X-linked genes in males. A mechanism of dosage compensation, for which we recently found evidence in mammals, evolved to restore a balanced expression of the genome by doubling the transcriptional output from the X chromosome. X inactivation would then serve to avoid hyper-transcription of X-linked genes in females by silencing one X chromosome. We also found that, compared to the rest of the genome, the X chromosome contains an excess of genes highly expressed in brain tissues. The exceptionally important role of the X chromosome in brain function, evident from the prevalence of X-linked forms of mental retardation, is discussed in view of sex chromosome regulation and evolution and sexual reproduction.

Animals↗
PubMed2003

Expression and function of a starfish Otx ortholog, AmOtx: a conserved role for Otx proteins in endoderm development that predates divergence of the eleutherozoa.

The sea urchin orthodenticle (Otx)-related transcription factor is an early activator of other endomesodermally expressed transcription factors. Its normal function is required for the development of the archenteron and to lock cells into endomesodermal fate. To determine if this is a basal Otx function in echinoderms we have studied the role of an Otx ortholog in a starfish, Asterina miniata. The patterns of AmOtx expression are found to be similar, in many details, to those reported for other indirectly developing echinoderms and hemichordates, suggestive of a conserved function both in endoderm development and ciliary band formation in these two phyla. When downstream targets of the AmOtx protein are suppressed using a dominant engrailed repressor strategy, embryos fail to develop the endodermal component of the archenteron, though initial phases of mesoderm development proceed normally. The function of Otx proteins in endodermal development at least predated the evolution of the free-living echinoderms (Eleutherozoa).

Alternative Splicing↗
PubMedDate not supplied

Exquisite specificity and peptide epitope recognition promiscuity, properties shared by antibodies from sharks to humans.

This review considers definitions of the specificity of antibodies including the development of recent concepts of recognition polyspecificity and epitope promiscuity. Using sets of homologous and unrelated peptides derived from the sequences of immunoglobulin and T cell receptor chains we offer operational definitions of cross-reactivity by investigating correlations of either identities in amino acid sequence, or in hydrophobicity/hydrophilicity profiles with degree of binding in enzyme-linked immunosorbent assays. Polyreactivity, or polyspecificity, are terms used to denote binding of a monoclonal antibody or purified antibody preparation to large complex molecules that are structurally unrelated, such as thyroglobulin and DNA. As a first approximation, there is a linear correlation between degree of sequence identity or hydrophobicity/hydrophilicity and antigenic cross-binding. However, catastrophic interchanges of amino acids can occur where changing of one amino acid out of 16 in a synthetic peptide essentially eliminates binding to certain antibodies. An operational definition of epitope promiscuity for peptides is the case where two peptides show little or no identity in amino acid sequence but bind strongly to the same antibody as shown by either direct binding or competitive inhibition. Analysis of antibodies of humans and sharks, the two most divergent species in evolution to express antibodies and the combinatorial immune response, indicates that the capacity for both exquisite specificity and epitope recognition promiscuity are essential conserved features of individual vertebrate antibodies.

Amino Acid Sequence↗
PubMed1995

Molecular properties of the lys1+ gene and the regulation of alpha-aminoadipate reductase in Schizosaccharomyces pombe.

The alpha-aminoadipate pathway for the biosynthesis of lysine is unique to fungi. Molecular properties of the cloned lys1+ gene and the regulation of the encoded alpha-aminoadipate reductase (AAR) were investigated in the fission yeast Schizosaccharomyces pombe. A 5.2-kb HindIII-EcoRI fragment of S. pombe DNA, containing a functional lys1+ gene and a promoter, was subcloned to make the 10.7-kb plasmid pLYS1H. A nested 1.778-kb HindIII-EcoRI DNA fragment that complemented the lys1-131 mutant phenotype was sequenced from the plasmid pLYS1D, and shown to contain an open reading frame (ORF) of 470 amino acids, preceded by putative POLII promoter elements (TATA and CCAAT box elements, and two potential yeast GCN4-binding motifs) within 368 bp upstream of the start codon. This ORF shared with the corresponding region of the isofunctional AAR of Saccharomyces cerevisiae 49% amino-acid identity (62% similarity) overall, within which were smaller regions of marked sequence conservation. One such region coincided (95% identity) with a putative AMP-binding domain motif identified in the AAR of S. cerevisiae. In wild-type S. pombe, AAR activity from cells grown in lysine-supplemented minimal or YEPD media was less than the activity of cells grown in minimal medium. The AAR of S. pombe was more sensitive to feedback inhibition by lysine in vitro than the AAR of S. cerevisiae. These results show the effects of extensive evolutionary divergence on the structure and expression of a pivotal enzyme in the alpha-aminoadipate pathway. Presumably, delineated regions of strong sequence conservation correspond to discrete domains essential to AAR function.

Aldehyde Oxidoreductases↗
PubMed1993

Pigmented pheochromocytomas of the adrenal medulla.

Three primary pigmented pheochromocytomas of the adrenal gland are presented. The pigment in all cases proved to be melanin. Two of the pheochromocytomas were sporadic and histologically typical, except for a focal spindle cell configuration in one. It is believed that the morphologic appearance of these tumors represents divergent differentiation from neural crest, expressing typical pheochromocytoma (polygonal cells) and melanocytic features (melanin pigment).

Adrenal Gland Neoplasms↗
PubMed1990

Differentiation inhibiting activity is produced in matrix-associated and diffusible forms that are generated by alternate promoter usage.

The differentiation of embryonic stem (ES) cells is controlled by the regulatory factor differentiation inhibiting activity/leukemia inhibitory factor (DIA/LIF). Examination of feeder cell-mediated suppression of ES cell differentiation revealed that DIA/LIF is produced both as a diffusible protein and in an immobilized form associated with the extracellular matrix. This alternative localization arises from the expression of alternate transcripts that diverge throughout exon 1. The effect of alternate first exon usage is to change the amino terminus of the primary translation product and to direct incorporation of mature, biologically active DIA/LIF into the extracellular matrix. The production of a potent regulatory factor in both diffusible and immobilized forms may be an important element of developmental control mechanisms.

Amino Acid Sequence↗
PubMed2004

Rosacea: II. Therapy.

Despite an incomplete understanding of the pathogenesis of rosacea, therapeutic modalities continue to expand. The principal subtypes of rosacea include erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea. These phenotypic expressions are probably caused by divergent pathogenic factors and consequently respond to different therapeutic regimens. A subtype-directed approach to therapy is discussed in part II of this review. We provide an overview of the available topical, oral, laser, and light therapies in the context of these cutaneous subtypes, review the evidence that supports their use, and outline their therapeutic approach. Suggestions for future areas of study also are provided. Learning objective At the completion of this learning activity, participants should be familiar with the subtype-directed approach to therapy for rosacea including available topical, oral, laser, and light therapies.

Anti-Infective Agents↗
PubMed2006

Post-translational modifications of Trypanosoma cruzi histone H4.

Histone tails provide sites for a variety of post-translational modifications implicated in the control of gene expression and chromatin assembly. As both histones and control of gene expression in trypanosomes are highly divergent compared to most eukaryotes, post-translational modifications of Trypanosoma cruzi histones were investigated. After in vivo incubation of live parasites with radiolabeled precursors, histone H4 mainly incorporates [(3)H]-acetyl, and to a lesser extent [(3)H]-methyl residues. In contrast, histone H3 preferentially incorporates [(3)H]-methyl residues. The modifications of histone H4 were further characterized by mass spectrometry. MALDI-TOF-TOF-MS analysis revealed that peptides from histone H4 amino-terminus, obtained by either endoproteinase Glu-C or endoproteinase Arg-C digestion, contain isoforms with 14 and 42Da additions, suggesting the presence of simultaneous acetylations and/or methylations. Tandem mass spectrometry analysis demonstrated that the N-terminal alanine is methylated, and lysine residues at positions 4, 10, 14 and 57 are acetylated; lysine at position 18 is mono-methylated, while arginine at position 53 is dimethylated. Immunoblotting analyses using specific antibodies raised against synthetic and acetylated peptides of T. cruzi histone H4 indicate that lysine 4 is acetylated in the majority of histone H4, while other acetylations at the N-terminus portion of histone H4 are less abundant.

Acetylation↗
PubMed2004

Telephone or surgery asthma reviews? Preferences of participants in a primary care randomised controlled trial.

263 participants completing a randomised controlled trial comparing telephone vs. face-to-face asthma consultations were asked about preferences for future reviews. Qualitative analysis of data from 209 respondents identified divergent views. Clear opinions were expressed about the respective roles of the two modes of consulting; telephone consultations were considered convenient for reviewing 'well controlled' asthma, whereas face-to-face consultations were perceived as allowing in-depth assessment of problems in those with more symptomatic asthma. Practices may consider offering patients the choice of a telephone or face-to-face review.

Journal Article↗
PubMed1985

Classification and pathogenesis of vulvovaginal candidiasis.

Although candidiasis of the female genital tract is one of the most common of the vaginitides, it is a poorly understood disease entity. Vulvovaginal candidiasis is a monoetiologic disease, but the pathways by which pathogenic expression is attained are sufficiently divergent to constitute a classification schema that influences therapy. For selection of appropriate therapy, the following three broad categories are proposed: (1) primary candidiasis, (2) antibiotic-induced candidiasis, and (3) systemically induced candidiasis.

Anti-Bacterial Agents↗
PubMed1996

Human TAFII 105 is a cell type-specific TFIID subunit related to hTAFII130.

We previously characterized Drosophila and human TAF subunits that make up the core TFIID complex found in all cells. Here, we report that differentiated B cells contain a novel substoichiometric TAF of 105 kDa not found associated with TFIID isolated from other cell types. The cDNA encoding hTAFII105 reveals a highly conserved C-terminal domain shared by hTAFII130 and oTAFII110, while the N-terminal coactivator domain has diverged significantly. All cells tested express TAFII105 mRNA, but only B cells contain significant levels of protein associated with TFIID. Transient overexpression of hTAFII105 selectively squelches the transcription of some genes in B cells. These properties suggest that TAFII105 is a cell type-specific subunit of TFIID that may be responsible for mediating transcription by a subset of activators in B cells.

Amino Acid Sequence↗
PubMed2000

Parathyroid hormone-related peptide and bone: pathological and physiological aspects.

Parathyroid hormone-related peptide (PTHrP) was initially discovered as a tumor-derived systemic factor which causes humoral hypercalcemia of malignancy. When overproduced and secreted by tumor cells, PTHrP acts on target organs such as bone and kidney to cause hypercalcemia through its 'PTH-like effects'. The hypercalcemic effects of PTHrP are attributed to its N-terminal portion (1-36) which shows a limited homology with PTH and is able to bind to the common PTH/PTHrP receptor. In contrast to such pathological effects as a humoral factor, PTHrP is now recognized as a locally active cytokine produced by a variety of tissues and cell types. Gene knockout experiments have revealed critical roles for PTHrP in a wide spectrum of physiological processes including chondrogenesis. It also significantly contributes to various pathological processes such as tumor metastasis to bone and bone destruction in arthropathies, acting as a bone-resorbing cytokine. Consistent with its divergent roles, regulation of PTHrP expression as well as its mode of action seems to be much more complex than its hormonal counterpart, PTH. In this article, we will briefly review the recent progress in our understanding of both physiological and pathological aspects of PTHrP biology, with a particular focus on its roles as a bone cytokine.

Bone Diseases↗
PubMed2003

Lymphocyte populations in human lymph nodes. Alterations in CD4+ CD25+ T regulatory cell phenotype and T-cell receptor Vbeta repertoire.

Here we provide a description of lymphocyte populations in human lymph nodes (LN) with a special emphasis on the CD4+ lymphocyte population constitutively expressing CD25 at a high level and endowed with immunoregulatory properties [T regulatory (Treg) cells]. Lymph nodes were analysed by multicolour flow cytometry in parallel with correspondent peripheral blood (PB). Immunomagnetically purified Treg cells were tested for anergy and suppressive activity in a CD3/T-cell receptor (TCR)-driven proliferation assay. Compared to PB, there was a reduced T/B lymphocyte ratio in LN. Both LN and PB contained a similar proportion of CD4+ lymphocytes but, conversely, CD8+ lymphocytes were less represented in PB, with a consequent increase in the ratio of CD4+/CD8+ natural killer cells were <2% (PB range 6-22%). No significant differences existed in the frequency of the other lymphocyte subpopulations examined (naïve-type CD4+ and CD8+ lymphocytes, activated B and CD4+ lymphocytes, and effector-type CD8+ lymphocytes). LN and PB contained similar percentages of CD4+ lymphocytes constitutively expressing intermediate or high levels of CD25. CD4+ CD25++ cells constitutively coexpressed high levels of CD152 and were therefore identified as Treg cells. Treg cells in LN and PB differed in terms of CD45RB, HLA-DR, CD45RO, and CD62L expression. Also the TCRVbeta repertoire diverged between Treg cells from LN and PB. Similar to Treg cells from PB, Treg cells from LN were anergic and efficiently inhibited other CD4+ and CD8+ lymphocyte proliferation. This study extends the information on the diversities in lymphocyte composition between human LN and PB, and reports for the first time a description of the phenotypic and functional characteristics of Treg cells in human LN, highlighting the importance of the LN microenvironment in shaping the surface phenotype of Treg cells.

Adult↗
PubMed2001

Developmental changes in the mRNA levels of IGF-I and its related genes in the reproductive organs of Japanese quail (Coturnix coturnix japonica).

Summary Insulin-like growth factor-I (IGF-I) is involved in the regulation of growth and differentiation of a variety of vertebrate tissues. The biological actions of IGF-I are mediated mainly by the IGF-I receptor (IGF-IR) and partly by the insulin receptor (IR) and modulated by IGF binding proteins (IGFBP). We conducted studies designed to clarify the possible roles of IGF system in the development of the avian reproductive organs. We cloned cDNAs of IGF-I, IGF-IR, IR and IGFBP-2 of Japanese quail and simultaneously measured the expression of these genes in the quail liver, testis and oviduct at different ages using a lysate RNase protection assay. Hepatic IGF-I mRNA levels increased rapidly and remained elevated during the rapid-growing period, which coincided with the period of rapid increase in testicular weight. IGF-I mRNA was detected at each stage of developing testis examined. Its level was high at the early stage and decreased with age. IGFBP-2 mRNA in testis exhibited a similar expression pattern to that of IGF-I, whereas a divergence in IGF-I and IGF-IR gene expression was observed. Both IGF-IR and IR mRNAs increased when the testis grew rapidly and decreased when sexual maturation was almost completed. These results suggest that IGF-I may serve as an autocrine/paracrine regulator as well as an endocrine regulator in the testicular development and function of Japanese quail. In the oviduct, IGF-I, IGF-IR, IR and IGFBP-2 mRNAs were also developmentally regulated. A rapid growth of the oviduct was accompanied by a significant increase in the level of IGF-I mRNA. The expression of genes encoding IGF-IR, IR and IGFBP-2 in the oviduct exhibited a similar developmental change to that of IGF-I. These results suggest that IGF-I mainly works in an autocrine and/or paracrine manner in the oviduct during the development of this organ. The findings of the present study provide further evidence of an important role for IGF system in the development and function of the avian reproductive system.

Animals↗
PubMed1989

CD4-Pseudomonas exotoxin hybrid protein blocks the spread of human immunodeficiency virus infection in vitro and is active against cells expressing the envelope glycoproteins from diverse primate immunodeficiency retroviruses.

We previously described an unusual recombinant protein, designated CD4(178)-PE40, containing the gp120 binding region of human CD4 linked to active regions of Pseudomonas exotoxin A. The ability of this molecule to selectively inhibit protein synthesis in cells expressing the surface envelope glycoprotein of human immunodeficiency virus (HIV) suggested this molecule may be useful in treating infected individuals. To further evaluate its therapeutic potential, several in vitro properties of this hybrid toxin were examined. CD4(178)-PE40 was found to be an extremely potent cytotoxic agent, selectively killing HIV-infected cells with IC50 values around 100 pM. In a coculture system employing mixtures of HIV-infected and -uninfected cells, the hybrid toxin inhibited spread of the infection, as judged by a delay in HIV-induced cell killing and a dramatic suppression of free virus production. Experiments with control recombinant proteins indicated that this protective effect was primarily due to selective killing of the HIV-infected cells, rather than to a simple blocking effect of the CD4 moiety of the hybrid toxin. Using recombinant vaccinia viruses as expression vectors, we found the hybrid toxin to be active against cells expressing the envelope glycoproteins of divergent isolates of HIV-1, as well as HIV-2 and simian immunodeficiency virus. These results provide further support for the therapeutic potential of CD4(178)-PE40 in the treatment of HIV-infected individuals.

Antiviral Agents↗