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K Abel

Publications and source records attributed to K Abel.

At least 37 records · Page 2Linked to original sources
PubMed1996

Generation of an integrated transcription map of the BRCA2 region on chromosome 13q12-q13.

An integrated approach involving physical mapping, identification of transcribed sequences, and computational analysis of genomic sequence was used to generate a detailed transcription map of the 1. 0-Mb region containing the breast cancer susceptibility locus BRCA2 on chromosome 13q12-q13. This region is included in the genetic interval bounded by D13S1444 and D13S310. Retrieved sequences from exon amplification or hybrid selection procedures were grouped into physical intervals and subsequently grouped into transcription units by clone overlap. Overlap was established by direct hybridization, cDNA library screening, PCR cDNA linking (island hopping), and/or sequence alignment. Extensive genomic sequencing was performed in an effort to understand transcription unit organization. In total, approximately 500 kb of genomic sequence was completed. The transcription units were further characterized by hybridization to RNA from a series of human tissues. Evidence for seven genes, two putative pseudogenes, and nine additional putative transcription units was obtained. One of the transcription units was recently identified as BRCA2 but all others are novel genes of unknown function as only limited alignment to sequences in public databases was observed. One large gene with a transcript size of 10.7 kb showed significant similarity to a gene predicted by the Caenorhabditis elegans genome and the Saccharomyces cerevisiae genome sequencing efforts, while another contained a motif sequence similar to the human 2',3' cyclic nucleotide 3' phosphodiesterase gene. Several retrieved transcribed sequences were not aligned into transcription units because no corresponding cDNAs were obtained when screening libraries or because of a lack of definitive evidence for splicing signals or putative coding sequence based on computational analysis. However, the presence of additional genes in the BRCA2 interval is suggested as groups of putative exons and hybrid selected clones that were transcribed in consistent orientations could be localized to common physical intervals.

BRCA2 Protein↗
PubMed1996

Identification and mapping of a putative bombesin receptor gene on human chromosome 17q21.3+.

A mouse bombesin receptor cDNA was used as a probe to screen a human P1 genomic library. Clone HBR1 was isolated and used to localize a putative human bombesin receptor gene (HBRKS) on human chromosome 17q21.3 by fluorescent in situ hybridization (FISH). HBRKS was identified and mapped by polymerase chain reaction (PCR) amplification from a Yeast artificial chromosome (YAC) contig spanning 17q21-q23. In addition, a few candidate genes were found by exon-trapping from HBR1.

Animals↗
PubMed1995

Dephosphorylation of the focal adhesion protein VASP in vitro and in intact human platelets.

The focal adhesion protein VASP, a possible link between signal transduction pathways and the microfilament system, is phosphorylated by both cAMP- and cGMP-dependent protein kinases in vitro and in intact cells. Here, the analysis of VASP dephosphorylation by the serine/threonine protein phosphatases (PP) PP1, PP2A, PP2B and PP2C in vitro is reported. The phosphatases differed in their selectivity with respect to the dephosphorylation of individual VASP phosphorylation sites. Incubation of human platelets with okadaic acid, a potent inhibitor of PP1 and PP2A, caused the accumulation of phosphorylated VASP indicating that the phosphorylation status of VASP in intact cells is regulated to a major extent by serine/threonine protein phosphatases. Furthermore, the accumulation of phosphorylated cAMP-dependent protein kinase substrate(s) appears to account for inhibitory effects of okadaic acid on platelet function.

Amino Acid Sequence↗
PubMed1995

The proline-rich focal adhesion and microfilament protein VASP is a ligand for profilins.

Profilins are small proteins that form complexes with G-actin and phosphoinositides and are therefore considered to link the microfilament system to signal transduction pathways. In addition, they bind to poly-L-proline, but the biological significance of this interaction is not yet known. The recent molecular cloning of the vasodilator-stimulated phosphoprotein (VASP), an established in vivo substrate of cAMP- and cGMP-dependent protein kinases, revealed the presence of a proline-rich domain which prompted us to investigate a possible interaction with profilins. VASP is a microfilament and focal adhesion associated protein which is also concentrated in highly dynamic regions of the cell cortex. Here, we demonstrate that VASP is a natural proline-rich profilin ligand. Human platelet VASP bound directly to purified profilins from human platelets, calf thymus and birch pollen. Moreover, VASP and a novel protein were specifically extracted from total cell lysates by profilin affinity chromatography and subsequently eluted either with poly-L-proline or a peptide corresponding to a proline-rich VASP motif. Finally, the subcellular distributions of VASP and profilin suggest that both proteins also interact within living cells. Our data support the hypothesis that profilin and VASP act in concert to convey signal transduction to actin filament formation.

Amino Acid Sequence↗
PubMed1995

Signal requirements for production of luteinizing hormone releasing-hormone by human T cells.

We have previously demonstrated that both human CD4+ and CD8+ T lymphocytes produce enhanced levels of luteinizing hormone-releasing hormone (LHRH) mRNA and peptide upon stimulation with monoclonal antibody directed at the CD3 component of the T cell receptor for antigen (TCR) or mitogenic lectin. In the current study, we define the signaling pathways that control TCR-mediated LHRH production by using agents known to affect distinct signals, and compare the messenger systems required for LHRH response to other T-cell-associated activation responses, such as expression of CD69 and interleukin-2 receptor (IL-2R) molecules and production of interleukin-2 (IL-2). Results indicate that the activation of protein kinase C (PKC) is essential for LHRH production by previously nonstimulated T cells, not increased concentration of cytosolic-free calcium ([Ca2+]i). Phorbol ester (PMA), a direct activator of PKC, provoked LHRH production and cell surface expression of CD69 and IL-2R molecules by T cells, but not IL-2 synthesis. The synthesis of IL-2 by T cells required costimulation with PMA and ionomycin, a Ca2+ ionophore. Consistent with these observations, H7, an inhibitor of PKC, prevented T cells from producing LHRH upon activation with mitogen. However, LHRH production was not suppressed by HA1004, which inhibits all cyclic nucleotide-dependent protein kinases except for PKC. Genistein, a selective inhibitor of protein tyrosine kinase, blocked PMA-induced increase in LHRH production, but not CD69 and IL-2R expression, suggesting that protein tyrosine phosphorylation events distal from PKC activation may play a role in regulating LHRH response.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Microdissection and microcloning of chromosomal alterations in human breast cancer.

The recognition of recurring sites of chromosome changes in malignancies has greatly facilitated the identification of genes implicated in the pathogenesis of human cancers. Based especially upon recent studies [1-4], it appears increasingly likely that a subset of recurring chromosome alterations will be recognized in human breast cancer. Currently recognized chromosome changes characterizing breast carcinoma include the recognition of cytologic features of gene amplification (e.g. double minutes [dmins] and homogeneously staining regions [HSRs]) [5-8]. As these and other chromosome regions are implicated in recurring abnormalities in breast cancer, it will become increasingly important to have band- or region-specific genomic libraries and probes in order to facilitate high resolution physical mapping and ultimately to clone breast cancer related genes [9]. Toward this end an important recent development in physical mapping has been the establishment of chromosome microdissection as a rapid and reproducible approach to rapidly isolate and characterize chromosome region-specific DNA, greatly facilitating the initial steps in positional cloning of disease-related genes [10-13]. In this brief report, we will highlight the application of chromosome microdissection to the generation of region-specific probes for both fluorescent in situ hybridization (FISH) and the generation of genomic microclone libraries. Additionally, efforts using this methodology to generate a microclone library encompassing the early onset breast/ovarian cancer (BRCA1) gene will be presented.

Breast Neoplasms↗
PubMed1995

Gender differences in schizophrenia: hormonal effect or subtypes?

Compared with their male counterparts, females with schizophrenia, on average, show better premorbid functioning, later onset, and a more benign course of illness. They are also more likely to have a family history of schizophrenia and/or affective illness, to exhibit "atypical" and affective features, and to show a seasonal pattern of hospital admission that mimics that of patients with mania. However, there exists a paradox. Although schizophrenia in females has much in common with affective disorder, the "schizophrenogenic" effect of maternal influenza also appears to be more significant in female than in male schizophrenia. Perhaps females with a predisposition to affective psychosis who have also been subject to the effects of maternal viral infection during gestation develop some subtle neurodevelopmental damage that renders their psychosis schizophrenia-like.

Female↗
PubMed1994

Growth hormone responses to pyridostigmine in schizophrenia: evidence for cholinergic dysfunction.

The hypothesis that increased central cholinergic neurotransmitter function may be present in schizophrenic illness and may underlie negative symptoms was tested using a neuroendocrine challenge approach. The cholinergic challenge used was the anticholinesterase pyridostigmine, thought to cause the release of growth hormone (GH) from the anterior pituitary by diminishing inhibitory somatostatin tone. Eleven patients, six neuroleptic-naive and five neuroleptic-free, satisfying DSM-III-R criteria for schizophrenia and 11 matched controls took part. Subjects received pyridostigmine (120 mg orally) and blood was sampled at 0, 60, 90, 120, and 180 min for GH estimation. Peak GH responses were significantly increased in the schizophrenic group compared to controls. There was no relationship between individual peak GH values and negative symptom ratings (Scale for the Assessment of Negative Symptoms). Neither could a relationship be established between other aspects of psychopathology or dyskinesias and GH responses. An increased pyridostigmine/GH response is also found in affective disorders and could be related to nonspecific symptoms common to all these diagnostic groups. This study suggests that schizophrenia may be associated with increased cholinergic neurotransmitter function but the relationship between this cholinergic dysfunction and schizophrenia may involve psychopathology not specific to schizophrenia.

Adult↗
PubMed1994

cAMP- and cGMP-dependent protein kinase phosphorylation sites of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) in vitro and in intact human platelets.

The vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cAMP-dependent- (cAK) and cGMP-dependent protein kinase (cGK) in human platelets and other cardiovascular cells. To identify the VASP phosphorylation sites, purified VASP was phosphorylated by either protein kinase and subjected to trypsin, V8 and Lys-C proteolysis. The phosphorylated proteolytic fragments obtained were separated by reversed phase high performance liquid chromatography. Sequence analysis of the phosphorylated peptides and 32P measurement of the released 32P-labeled amino acids revealed three phosphorylation sites: a serine 1-containing site (LRKVSKQEEA), a serine 2-containing site (HIERRVSNAG), and a threonine-containing site (MNAVLARRRKATQVGE). Additional experiments with purified VASP demonstrated that both cAK and cGK phosphorylated serine 2 rapidly and the threonine residue slowly, whereas cGK phosphorylated the serine 1 residue more rapidly than the cAK. These differences in the phosphorylation rates of VASP by the two protein kinases were also observed with synthetic peptides corresponding to the sequences of the three identified phosphorylation sites. These experiments also established the synthetic peptide serine 1 as one of the best in vitro cGK substrates and the serine 2-containing site as the site responsible for the phosphorylation-induced mobility shift of VASP in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Experiments with 32P-labeled platelets provided evidence that VASP is phosphorylated at the same three identified sites also in intact cells and that selective activation of cAK or cGK primarily increased the phosphorylation of both serine 2 and serine 1 but not threonine. Our results demonstrated overlapping substrate specificities of cAK and cGK in vitro and in intact cells. However, important quantitative and qualitative differences between cAK- and cGK-mediated phosphorylation of the focal adhesion protein VASP in human platelets were also observed, suggesting distinct functions of the two types of cyclic nucleotide-mediated VASP phosphorylation.

Amino Acid Sequence↗
PubMed1994

Basic experimental studies on corpus cavernosum electromyography and smooth-muscle electromyography of the urinary bladder.

In contrast to the extensive work on in vitro experiments for elucidation of the electrical properties of smooth musculature, the acquisition of knowledge on electrical signal behaviour from smooth-muscle cells in an in vivo situation remains very limited and rare. Smooth-muscle electromyographic recording from the smooth musculature of the genitourinary tract, in particular from the penile cavernous bodies and the urinary bladder, has recently become one of the most interesting issues in both impotence research as well as neurophysiological assessment of the urinary bladder. However, the inadequate available data on corpus cavernosum and EMG recordings remains controversial due to the significant discrepancy between basic physiology of the smooth musculature, technical prerequisites and the expected clinical impact from the smooth-muscle EMG of genitourinary organs. This article is an attempt to describe the fundamentals of smooth-muscle EMG signal behaviour and the technical prerequisites for data acquisition and analysis of electrical activity from smooth-muscle cells of the cavernous bodies and urinary bladder. A description is given of the technical aspects, including methodology and interpretation of the recorded data, and also of the possible interference by artefacts (endogeneous and exogeneous) that might limit the clinical relevance of this encouraging method. The advantages, pitfalls and limitations of online analogous data registration and the possibility of computer-assisted smooth-muscle electrical activity recording and analysis are demonstrated by basic in vivo studies on cavernous bodies and also the detrusor muscle.

Animals↗
PubMed1993

Reconstitution of Mycobacterium leprae immunity in severe combined immunodeficient mice using a T-cell line.

To test whether Mycobacterium leprae-immune T cells can confer protection against infection with leprosy bacilli, severe combined immunodeficient (SCID) mice were reconstituted with a BALB/c-derived, M. leprae-responsive, T-cell line. Flow cytometric analysis of spleen and peripheral blood cells confirmed reconstitution with T cells. In vitro lymphokine production and the proliferation of spleen cells from the reconstituted animals established that the donor cells had maintained their functional activity for the duration of the study (275 days). The transfer of immune T cells 24 hr before foot pad infection with leprosy bacilli resulted in a profound reduction in M. leprae multiplication, as compared to the nonreconstituted SCID mice. The yield of acid-fast bacilli in the foot pads of SCID mice reconstituted with the M. leprae-immune T cells also was significantly lower than that found in naive BALB/c mice, and at levels previously found only in BALB/c mice that had been immunized effectively. These experiments demonstrate that M. leprae-immune T cells home effectively and control M. leprae infection in SCID mice.

Animals↗
PubMed1991

An audit of rectal examination on general/geriatric wards in a district general hospital.

A study of 187 in-patients on designated medical/geriatric wards revealed that rectal examination was performed as part of physical examination in only 25% of patients. In the elderly (118 patients) it was performed in 36%. A prospective analysis of 100 elderly patients, in whom digital rectal examination was performed, revealed that 46 patients had significant findings. In only 33 of these were there any gastrointestinal or genitourinary symptoms or signs. As a result of these findings it is recommended that digital rectal examination be considered mandatory in the elderly admitted into hospital.

Adult↗
PubMed1989

Genetic and tissue-specific variation in the expression of a closely linked murine multigene family on chromosome 15 that encodes salivary and lacrimal proteins.

The murine submandibular gland (SMG) produces a novel class of highly acidic salivary proteins encoded by one or more highly abundant mRNA transcripts. In inbred mice, these transcripts are encoded by members of a multigene family comprising approximately 8-12 homologues. Most, and probably all, of these homologues are clustered at a new locus near belted (bt) on chromosome 15, which we designate Spt (salivary protein). Although physically closely linked, Spt genes differ in their patterns of expression both in strains of mice and in their tissues. One gene, Spt-1, is expressed at high levels in the SMG of all inbred strains examined. This gene is also expressed at significant levels in the lacrimal gland. A second gene, Spt-2, appears to be present as a single copy in some strains and as two copies in others. This gene is expressed at high levels only in the SMG of those strains carrying two copies, and Spt-2 mRNA is not detectable in the SMG of strains carrying only one copy. In contrast to Spt-1, the Spt-2 gene is not expressed at detectable levels in the lacrimal gland.

Animals↗