Terminology for early pregnancy loss must be changed.
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Abortion, Spontaneous↗
Biomedical subjects
S Cooper
Publications and source records attributed to S Cooper.
Interaction of p59fyn kinase with the dynein light chain, Tctex-1, and colocalization during cytokinesis.
The protein tyrosine kinase p59fyn (Fyn) plays important roles in both lymphocyte Ag receptor signaling and cytokinesis of proB cells. We utilized yeast two-hybrid cloning to identify the product of the tctex-1 gene as a protein that specifically interacts with Fyn, but not with other Src family kinases. Tctex-1 was recently identified as a component of the dynein cytoskeletal motor complex. The capacity of a Tctex-1-glutathione S-transferase fusion protein to effectively bind Fyn from cell lysates confirmed the authenticity of this interaction. Tctex-1 binding required the first 19 amino acids of Fyn and integrity of two lysine residues within this sequence that were previously shown to be important for Fyn interactions with the immunoreceptor tyrosine-based activation motifs (ITAMs) of lymphocyte Ag receptors. Expression of tctex-1 mRNA and protein was observed in all lymphoma lines analyzed, and immunofluorescence confocal microscopy localized the protein to the perinuclear region. Analysis of a T cell hybridoma revealed prominent colocalization of Tctex-1 and Fyn at the cleavage furrow and mitotic spindles in cells undergoing cytokinesis. Our results provide a unique insight into a mechanism by which Tctex-1 might mediate specific recruitment of Fyn to the dynein complex in lymphocytes, which may be a critical event in mediating the previously defined role of Fyn in cytokinesis.
Animals↗
Cycle-specific replication of chromosomal and F-plasmid origins.
There have been various proposals for the pattern of F-plasmid replication during the division cycle. Here we show that the recent studies of Gordon et al. (Cell 90, 1113-1121, 1997) on the duplication and segregation of green fluorescent protein (GFP) labeled replication origins of the Escherichia coli chromosome and the F plasmid during the division cycle support the proposal that the F plasmid replicates with a cell-cycle-specific (artiocyclic) pattern.
Cell Cycle↗
Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac-/- mice.
We used a murine model containing a disruption of the murine homologue (Fac) of Fanconi Anemia group C (FAC) to evaluate the role of Fac in the pathogenesis of bone marrow (BM) failure. Methylcellulose cultures of BM cells from Fac-/- and Fac+/+ mice were established to examine the growth of multipotent and lineage-restricted progenitors containing inhibitory cytokines, including interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-1alpha (MIP-1alpha). Clonogenic growth of Fac-/- progenitors was reduced by 50% at 50- to 100-fold lower concentrations of all inhibitory cytokines evaluated. We hypothesized that the aberrant responsiveness to inhibitory cytokines in clonogenic cells may be a result of deregulated apoptosis. To test this hypothesis, we performed the TUNEL assay on purified populations of primary BM cells enriched for hematopoietic progenitors or differentiated myeloid cells. After stimulation with TNF-alpha, accentuated apoptosis was observed in both populations of Fac-/- cells. In addition, deregulated apoptosis was also noted in the most immature phenotypic population of hematopoietic cells after stimulation with MIP-1alpha. Together these data suggest a role of Fac in affecting the signaling of multiple cytokine pathways and support cytokine-mediated apoptosis as a major mechanism responsible for BM failure observed in FA patients.
Animals↗
Characterization of CKbeta8 and CKbeta8-1: two alternatively spliced forms of human beta-chemokine, chemoattractants for neutrophils, monocytes, and lymphocytes, and potent agonists at CC chemokine receptor 1.
Two new members of human beta-chemokine cDNA were isolated based on structural and functional similarities to human leukotactin-1. One of these clones was identical to the previously isolated human beta-chemokine, CKbeta8, whereas the other is a splicing variant of CKbeta8, therefore named CKbeta8-1. CKbeta8 was short in 51 nucleotides (17 amino acids) compared with CKbeta8-1. The mature proteins of CKbeta8-1 and CKbeta8 consisted of 116 and 99 amino acids with calculated molecular weights of 12,500 and 10,950, respectively. Both CKbeta8-1 and CKbeta8 were potent agonists at CCR1. These chemokines chemoattracted neutrophils, monocytes, and lymphocytes. They also significantly suppressed colony formation by human bone marrow, granulocyte-macrophage, erythroid, and multipotential progenitor cells stimulated by combinations of growth factors. To our knowledge, this is the first example that an alternative splicing produces two active beta-chemokines from a single gene.
Alternative Splicing↗
On the interpretation of the shortening of the G1-phase by overexpression of cyclins in mammalian cells.
Increasing the concentration of cyclins in mammalian cells leads to a shortening of the G1-phase of the division cycle. This observation has been interpreted as indicating that these cyclins act during, and are rate limiting for, passage through the G1-phase. Here it is argued that it is not possible to interpret experiments involving cyclin overexpression-induced changes in the lengths of individual cell cycle phases without considering changes in the overall cellular growth rate. A rigorous reanalysis of these experiments demonstrates that the results are consistent with the proposal that the shortening of the G1-phase is merely due to an increase in the rate of mass synthesis in all phases of the cell cycle. Increased cyclin concentrations leads to a faster rate of mass synthesis and a concomitant shortening of the G1-phase. Cyclins can also affect the length of the S- and G2-phases, which leads to the observed shortening of the G1-phase. Thus, the experiments on cyclin overexpression and their effect on G1-phase length cannot be used to support the proposal that cyclins act specifically during the G1-phase of the division cycle.
Animals↗
A positive effect of p21cip1/waf1 in the colony formation from murine myeloid progenitor cells as assessed by retroviral-mediated gene transfer.
p21cip1/waf1 is a cyclin dependent kinase inhibitor. We have previously reported stimulation of p21cip1/waf1 by steel factor and GM-CSF in a factor dependent cell line and of p21cip1/waf1 involvement in hematopoiesis in vivo in p21cip1/waf1 gene knockout (-/-) mice. To further assess a role for increased p21cip1/waf1 in hematopoietic progenitor cells, we developed the retroviral vector L(p21cip1)SN to transcriptionally regulate p21cip1/waf1 from the Mo-MLV LTR. L(p21cip1)SN and the control vector LXSN were used to transduce murine bone marrow progenitor cells from p21cip1/waf1 (-/-) and littermate control (+/+) mice, as well as from other mouse strains. Hematopoietic colony formation by transduced cells was assessed in semi-solid culture medium with multiple growth factors. Myeloid colony formation by bone marrow cells from p21cip1/waf1 (-/-) mice was significantly lower than that by (+/+) mouse cells. Transduction of cells with LXSN had no effect on colony formation: however, (-/-) cells transduced with L(p21cip1)SN formed significantly greater numbers of colonies than either LXSN-transduced (-/-) or (+/-) cells. Moreover, L(p21cip1)SN-transduced (+/+) cells formed significantly more colonies than LXSN-transduced (+/+) cells. Increased cloning efficiency of progenitors from normal strains of mice induced by L(p21cip1)SN compared to LXSN-transduced cells was seen whether unseparated or highly purified populations of Sca1+ Lin- marrow cells were used. Gene transfer of L(p21cip1)SN increased the size and number of cells per colony, as well as the number of colonies compared to LXSN gene transfer. No colonies grew from non-transduced, LXSN-, or L(p21cip1)SN-transduced cells when no growth factors were added to the cultures. These results document the positive effect of p21cip1/waf1 in the proliferation and/or differentiation of the murine myeloid progenitor cells that lead to colony formation.
Animals↗
A major histocompatibility complex class I allele shared by two species of chimpanzee.
Little is known regarding the rates at which natural selection can modify or retain antigen presenting alleles at the major histocompatibility complex (MHC). Discovery of identical [1101 base pairs (bp)] coding regions at the MHC class I C locus in Pan troglodytes and Pan paniscus, chimpanzee species that diverged approximately 2.3 million years ago, now indicates that a class I allotype can survive for at least this period. Remarkable conservation was also reflected in the (1799 bp) introns where a maximum of only six substitutions distinguished five alleles (three from P. troglodytes and two from P. paniscus) that encoded the identical heavy chain allotype. Analysis of a more distantly related human allele, HLA-Cw*0702, corroborated that intron variation was non-uniform along the gene. Thus we provide a clear reference frame for the lifetime of an MHC class I allotype, a direct estimate of allelic substitution rates, and evidence for an unusual evolution of MHC class I introns.
Alleles↗
Mammalian cells are not synchronized in G1-phase by starvation or inhibition: considerations of the fundamental concept of G1-phase synchronization.
Synchronization of mammalian cells by starvation-refeeding or by inhibition-release are among the most commonly used techniques for division cycle analysis. An alternative analysis--in the form of a Gedanken or thought experiment--is presented, casting doubt on the utility of this synchronization method. Arresting cell growth produces a culture where all cells contain a G1 amount of DNA. However, these cells are not arrested at a particular point in the G1-phase. Analysis of 'G1 arrested cells' suggests that, upon resumption of growth, the cells are not synchronized.
3T3 Cells↗
On the proposal of a G0 phase and the restriction point.
Zetterberg and Larsson proposed that the restriction point divides the G1 phase into two parts. Cells before this point are able to leave the division cycle and enter a G0 phase; cells past this point are unaffected by a short period of low serum. Additional results of Zetterberg and Larsson--1) cycloheximide treatment affects cells in the same way as low serum, and 2) a delay in the second division after serum starvation in the cells not initially affected in their first division--indicate that their experiments are consistent with serum removal affecting cells in all phases of the cell cycle equally. Their experiments are consistent with the continuum model of the mammalian division cycle. There is no need to postulate a restriction point or a G0 phase to explain the serum starvation results.
Cell Cycle↗
Inverted deepithelialized latissimus dorsi flap for the correction of lumpectomy defects in the irradiated breast.
Deformities following lumpectomy and radiation can provide reconstructive challenges for the plastic surgeon. With the increasing incidence of breast conservation therapy, these problems are likely to become more frequent in the future. The use of autologous tissue, particularly the latissimus dorsi, provides an excellent option for correcting these tissue deformities. We propose using an inverted latissimus with a deepithelialized skin paddle to correct these defects when there is no shortage of overlying skin. Additionally, this technique provides a softer texture to the entire radiated breast.
Aged↗
Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells.
Shp-2 is a cytoplasmic tyrosine phosphatase that contains two Src homology 2 (SH2) domains at the N terminus. Biochemical data suggests that Shp-2 acts downstream of a variety of receptor and cytoplasmic tyrosine kinases. A targeted deletion mutation in the N-terminal SH2 (SH2-N) domain results in embryonic lethality of homozygous mutant mice at midgestation. In vitro embryonic stem (ES) cell differentiation assays suggest that Shp-2 might play an important role in hematopoiesis. By aggregating homozygous mutant (Shp-2(-/-)) ES cells and wild-type (WT) embryos, we created Shp-2(-/-)-WT chimeric animals. We report here an essential role of Shp-2 in the control of blood cell development. Despite the widespread contribution of mutant cells to various tissues, no Shp-2(-/-) progenitors for erythroid or myeloid cells were detected in the fetal liver and bone marrow of chimeric animals by using the in vitro CFU assay. Furthermore, hematopoiesis was defective in Shp-2(-/-) yolk sacs. In addition, the Shp-2 mutation caused multiple developmental defects in chimeric mice, characterized by short hind legs, aberrant limb features, split lumbar vertebrae, abnormal rib patterning, and pathological changes in the lungs, intestines, and skin. These results demonstrate a functional involvement of Shp-2 in the differentiation of multiple tissue-specific cells and in body organization. More importantly, the requirement for Shp-2 is more stringent in hematopoiesis than in other systems.
Animals↗
Regarding "Prospective randomized comparison of surgical versus endovascular management of thrombosed dialysis access grafts".
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Angioplasty, Balloon↗
Isolation and characterization of Exodus-2, a novel C-C chemokine with a unique 37-amino acid carboxyl-terminal extension.
Chemokines are a group of small, homologous proteins that regulate leukocyte migration, hemopoiesis, and HIV-1 absorption. We report here the cloning and characterization of a novel murine and human C-C chemokine termed Exodus-2 for its similarity to Exodus-1/MIP-3alpha/LARC, and its chemotactic ability. This novel chemokine has a unique 36 or 37 (murine and human, respectively) amino acid carboxyl-terminal extension not seen in any other chemokine family member. Purified recombinant Exodus-2 was found to have two activities classically associated with chemokines: inhibiting hemopoiesis and stimulating chemotaxis. However, Exodus-2 also had unusual characteristics for C-C chemokines. It selectively stimulated the chemotaxis of T-lymphocytes and was preferentially expressed in lymph node tissue. The combination of these characteristics may be a functional correlate for the unique carboxyl-terminal structure of Exodus-2.
Amino Acid Sequence↗
Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1.
CC chemokine receptor 1 (CCR1) is expressed in neutrophils, monocytes, lymphocytes, and eosinophils, and binds the leukocyte chemoattractant and hematopoiesis regulator macrophage inflammatory protein (MIP)-1alpha, as well as several related CC chemokines. Four other CCR subtypes are known; their leukocyte and chemokine specificities overlap with, but are not identical to, CCR1, suggesting that CCR1 has both redundant and specific biologic roles. To test this, we have developed CCR1-deficient mice (-/-) by targeted gene disruption. Although the distribution of mature leukocytes was normal, steady state and induced trafficking and proliferation of myeloid progenitor cells were disordered in -/- mice. Moreover, mature neutrophils from -/- mice failed to chemotax in vitro and failed to mobilize into peripheral blood in vivo in response to MIP-1alpha. Consistent with this, -/- mice had accelerated mortality when challenged with Aspergillus fumigatus, a fungus controlled principally by neutrophils. To test the role of CCR1 in granuloma formation, we injected Schistosoma mansoni eggs intravenously, and observed a 40% reduction in the size of lung granulomas in -/- mice compared to +/+ littermates. This was associated with increased interferon-gamma and decreased interleukin-4 production in -/- versus +/+ lung lymph node cells stimulated with egg-specific antigen, suggesting that CCR1 influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1-type 2 cytokine balance. Thus CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation.
Animals↗
Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study.
OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.
Administration, Inhalation↗
Macrophage inflammatory protein-1alpha and interferon-inducible protein 10 inhibit synergistically induced growth factor stimulation of MAP kinase activity and suppress phosphorylation of eukaryotic initiation factor 4E and 4E binding protein 1.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Steel factor (SLF) synergistically stimulate Raf-1 kinase activity, protein synthesis, and proliferation in hematopoietic MO7e cells; synergistic action of these factors is blocked by the suppressive chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and interferon-inducible protein 10 (IP-10; Aronica et al, J Biol Chem 270:21998, 1995). We assessed the potential for both stimulatory and inhibitory factors to act through the MAP kinase signaling pathway by studying the effects of growth factors and chemokines on MAP kinase activation. Also, because activation of kinase signaling pathways and stimulation of protein synthesis by peptide growth factors are associated with increased phosphorylation of eukaryotic initiation factor 4E (elF-4E) and the translational repressor 4E-binding protein 1 (4E-BP1) in some target cells, we investigated whether growth factor treatment could alter eIF-4E or 4E-BP1 phosphorylation state in MO7e cells. We report that treatment of MO7e cells with GM-CSF and SLF stimulated significant, greater-than-additive increases in MAP kinase activity and the phosphorylation of both eIF-4E and 4E-BP1. Increased 4E-BP1 phosphorylation correlated with a decrease in the association of 4E-BP1 with eIF-4E. Growth factor-induced phosphorylation of 4E-BP1 and dissociation of 4E-BP1 from eIF-4E was blocked in cells treated with rapamycin, wortmannin, or PD098059. Treatment of cells with IP-10 or MIP-1alpha blocked the stimulatory effects of GM-CSF and SLF, resulting in suppression of MAP kinase activity, eIF-4E and 4E-BP1 phosphorylation, and eIF-4E/4E-BP1 dissociation. Our results suggest that GM-CSF and SLF exert part of their combined growth-promoting effects on MO7e cells through activation of MAP kinase and enhancement of eIF-4E and 4E-BP1 phosphorylation and dissociation and that suppression of growth factor-induced protein synthesis by MIP-1alpha and IP-10 involves translational repression at the level of eIF-4E.
8-Bromo Cyclic Adenosine Monophosphate↗
Australian bat lyssavirus infection in three fruit bats from north Queensland.
We report the case findings of Australian bat lyssavirus infection in two black flying foxes (Pteropus alecto) and one little red flying fox (Pteropus scapulatus) from north Queensland between January 1995 and August 1996. Although the P. alecto case in January 1995 is the first recognised case of Australian bat lyssavirus infection in Australia, this was a retrospective diagnosis made after identification of the index case at Ballina in May 1996. Eight persons had exposure to the three bats. Serum antibodies to classical rabies virus were measured in six of these persons; the only one seropositive was a veterinarian who had previously been vaccinated against rabies. Six persons received rabies vaccine following exposure. None of the in-contact humans developed signs of lyssavirus infection. For people exposed to Australian bat lyssavirus-positive bats who have not been scratched or bitten or had mucosal contamination by these bats, we suggest a post-exposure regime of five inoculations of the human diploid cell inactivated rabies vaccine.
Animals↗