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A Fuchs

Publications and source records attributed to A Fuchs.

At least 55 records · Page 3Linked to original sources
PubMed1998

Connecting cortical and behavioral dynamics: bimanual coordination.

For the paradigmatic case of bimanual coordination, we review levels of organization of behavioral dynamics and present a description in terms of modes of behavior. We briefly review a recently developed model of spatiotemporal brain activity that is based on short- and long-range connectivity of neural ensembles. This model is specified for the case of motor and sensorimotor units embedded in the neural sheet. Focusing on the cortical left-right symmetry, we derive a bimodal description of the brain activity that is connected to behavioral dynamics. We make predictions of global features of brain dynamics during coordination tasks and test these against experimental magnetoencephalogram (MEG) results. A key feature of our approach is that phenomenological laws at the behavioral level can be connected to a field-theoretical description of cortical dynamics.

Brain↗
PubMed1998

p40(phox) is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase. Implication of a protein kinase c-type kinase in the phosphorylation process.

The superoxide-generating NADPH oxidase complex of phagocytic cells is a multicomponent system containing a membrane-bound flavocytochrome b and a small G protein Rac as well as cytosolic factors p67(phox) (phagocyte oxidase), p47(phox), and p40(phox), which translocate to the membrane upon activation. In a previous paper, we reported that p40(phox) undergoes phosphorylation on multiple sites upon stimulation of the NADPH oxidase by either phorbol 12-myristate 13-acetate or by formyl peptide with a time course that is strongly correlated with that of superoxide production (Fuchs, A., Bouin, A. P., Rabilloud, T., and Vignais, P. V. (1997) Eur. J. Biochem. 249, 531-539). In this study, through phosphoamino acid and tryptic peptide maps of in vivo and in vitro phosphorylated p40(phox), we show that p40(phox) is phosphorylated on serine and threonine residues during activation of the NADPH oxidase in dimethyl sulfoxide-differentiated HL60 promyelocytes as well as in isolated human neutrophils. In vitro phosphorylation studies using casein kinase II and protein kinase C (PKC) as well as the effect of various protein kinase inhibitors on the isoelectric focusing pattern of p40(phox) in whole cell lysates point to a role of a PKC type kinase in the phosphorylation of p40(phox). Directed mutagenesis of all PKC consensus sites enable us to conclude that Thr154 and Ser315 in p40(phox) are phosphorylated during activation of the NADPH oxidase.

Amino Acid Substitution↗
PubMed1998

Dynamic cortical activity in the human brain reveals motor equivalence.

That animals and humans can accomplish the same goal using different effectors and different goals using the same effectors attests to the remarkable flexibility of the central nervous system. This phenomenon has been termed 'motor equivalence', an example being the writing of a name with a pencil held between the toes or teeth. The idea of motor equivalence has reappeared because single-cell studies in monkeys have shown that parameters of voluntary movement (such as direction) may be specified in the brain, relegating muscle activation to spinal interneuronal systems. Using a novel experimental paradigms and a full-head SQUID (for superconducting quantum interference device) array to record magnetic fields corresponding to ongoing brain activity, we demonstrate: (1), a robust relationship between time-dependent activity in sensorimotor cortex and movement velocity, independent of explicit task requirements; and (2) neural activations that are specific to task demands alone. It appears, therefore, that signatures of motor equivalence in humans may be found in dynamic patterns of cortical activity.

Brain↗
PubMed1998

Flow cytometry with or without cytochemistry for the diagnosis of acute leukemias?

Ninety-three (93) cases of acute leukemia were assessed using flow cytometry and cytochemistry and assigned to one of four categories: myeloid, lymphoid, biphenotypic, and non-diagnostic. In leukemias designated as ALL or AML by both methodologies, there was lineage agreement in all but 3 of 71 cases (95.8%). However, when nondiagnostic or biphenotypic diagnoses made by either methodology were included, complete agreement occurred in only 77.4% of cases. Of 37 cases designated myeloid origin by flow cytometry, 33 (89.2%) were read as myeloid by cytochemistry. The four discordant diagnosis were read as lymphoid (2) or as non-diagnostic (2). Eighty percent of lymphoid leukemias were diagnosed as such by both flow cytometry and cytochemistry; one early B cell ALL was diagnosed as myeloid and 8 as non-diagnostic. Fifty percent (50%) of flow cytometry defined T-cell ALL were considered non-diagnostic by cytochemistry as compared to 17% of the total ALL group. Of the remaining four designated non-T cell ALL by flow cytometry and non-diagnostic by cytochemistry, three were read by flow cytometry to be standard pre-B ALL and one an early B-cell ALL. Only 2/9 leukemias considered biphenotypic by flow were identified as such by cytochemistry. Given (1) the potential importance of non-lineage expression in the prognosis of myeloid and lymphoid leukemias, (2) cytochemistry's impaired ability to diagnose biphenotypic, T-cell, and promyelocytic leukemias, and (3) the increased costs incurred in diagnosis when both modalities are used, perhaps it is time to re-examine the utility of performing both flow cytometry and cytochemistry as initial testing for leukemia categorization.

Adolescent↗
PubMed1998

Fine mapping and regulation of the association of p53 with p34cdc2.

In vivo p53 is multiply phosphorylated by different protein kinases suggesting a central role for phosphorylation in modulating p53 function. In addition, p53 was found to be associated with two protein kinases, p34cdc2 and protein kinase CK2. Here we report the precise mapping of the interaction sites of p53-p34cdc2 complexes. The p34cdc2 binding site on human p53 maps to one distinct C-terminal site LQIRGRERFE (aa 330-339) close to the corresponding phosphorylation site at serine 315. In order to test whether phosphorylation of p53 might influence the binding of p53 to p34cdc2 phosphorylation mutants of the C-terminus of p53, which mimick permanent phosphorylation, were tested on their ability to bind to p34cdc2 in vitro. Substitution of serine 315 (the p34cdc2 phosphorylation site) with aspartic acid had only little effect on complex formation whereas an exchange of serine 392 (the protein kinase CK2 phosphorylation site) to aspartic acid resulted in a significant reduced relative binding affinity of p53 to p34cdc2. The same result was obtained when the C-terminus of p53 was phosphorylated by purified protein kinase CK2 prior to examination of complex formation. In addition, the specificity of the complex formation has been checked by competition experiments with full length p53 proteins and the influence of cyclin B on complex formation was examined.

Amino Acid Sequence↗
PubMed1998

New zwitterionic detergents improve the analysis of membrane proteins by two-dimensional electrophoresis.

Severe quantitative loss of protein is often observed in high-resolution two-dimensional electrophoresis of membrane proteins, while the resolution is usually not affected. To improve the solubility of proteins in this technique, we tested denaturing cocktails containing various detergents and chaotropes. Best results were obtained with a denaturing solution containing urea, thiourea, and zwitterionic detergents, synthesized for this purpose. Among the dozen detergents synthesized and tested, amidosulfobetaines with an alkyl tail containing 14-16 carbons proved most efficient, solubilizing previously undetected membrane proteins.

Animals↗
PubMed1998

Probing the mechanism of the carcinogenic activation of N-nitrosodiethanolamine with deuterium isotope effects: in vivo induction of DNA single-strand breaks and related in vitro assays.

A series of bioassays, including in vivo induction of DNA single-strand breaks (SSB) and cytotoxicity in cytochrome P450 2E1-transfected cells, were utilized with N-nitrosodiethanolamine (NDELA), its deuterated isotopomers (alpha-D4NDELA and beta-D4NDELA), N-nitroso-2-hydroxymorpholine (NHMOR), and two of its deuterated isotopomers (2-D-NHMOR and 5,5-D2-NHMOR) to probe the mechanism of carcinogenic activation of NDELA and the role of its metabolite NHMOR. DNA samples, taken from the livers of male Wistar rats 4 h after the administration of NDELA, exhibited dose-dependent DNA SSB levels over the range of 0.08-0.75 mmol/kg (body weight), with the greatest SSB level at the highest dose. Deuterium isotope effects on DNA SSB levels were inversely dependent on dose: alpha-D4NDELA, 3. 22-1.37; and beta-D4NDELA, 1.38-0.79. At the lowest dose of 0.15 mmol/kg (body weight), 5,5-D2-NHMOR gave an isotope effect for DNA SSB of 2.8 while that for 2-D-NHMOR was 0.7. NDELA and beta-D4NDELA were equally cytotoxic to human P450 2E1-transfected V79 Chinese hamster cells, while alpha-D4NDELA was not. Significant DNA SSB levels were observed in these cells for NDELA and beta-D4NDELA but not for alpha-D4NDELA. A kinetic deuterium isotope effect of 2.6 for Vmax/Km was observed for the horse liver alcohol dehydrogenase-mediated oxidation of beta-D4NDELA to NHMOR, while kH/kD for alpha-D4NDELA was 1.05. These data provide the first definitive evidence for the activation of NDELA by a pathway involving the scission of the alpha-CH bond and are consistent with P450 2E1-mediated alpha-hydroxylation of NDELA producing the corresponding reactive alpha-hydroxynitrosamine.

Animals↗
PubMed1998

Lectin-mediated drug targeting: preparation, binding characteristics, and antiproliferative activity of wheat germ agglutinin conjugated doxorubicin on Caco-2 cells.

PURPOSE: To investigate the usefulness of wheat germ agglutinin as a targeting carrier protein for an acid-labile chemotherapeutic prodrug directed against colon carcinoma cells in vitro. METHODS: Cis-aconityl-linked doxorubicin-wheat germ agglutinin was prepared by a two step procedure and the conjugate-binding capacity of target- and non-target cells was assayed by flow cytometry. The antiproliferative activity of the prodrug on Caco-2 and MOLT-4 cells was determined by the XTT- and BrdU-test and compared with that of the parent drug and the lectin alone. RESULTS: At pH 4.0, about 50% of the conjugated doxorubicin were released within 24 h from the water soluble prodrug exhibiting a conjugation number of 24 (mol doxorubicin/mol WGA). The prodrug-binding capacity of colon carcinoma cells exceeded that of human colonocytes and lymphoblastic MOLT-4 cells 4.5-fold. Additionally, the antiproliferative effect of the conjugate on Caco-2 cells was 39% as opposed to 5% in case of MOLT-4 cells. As the unmodified carrier protein inhibited or stimulated Caco-2 cell growth in a concentration-dependent manner, the cytostatic activity of the conjugate was determined at WGA concentrations without an effect on cell-proliferation. Considering 50% release of conjugated drug at the most, the prodrug yielded 160% of the cytostatic activity of free doxorubicin. CONCLUSIONS: WGA-prodrug targeting offers new perspectives for site-specific, cytoinvading drug delivery in colon cancer chemotherapy.

Aconitic Acid↗
PubMed1998

Detecting acute graft rejection in patients after orthotopic heart transplantation: analysis of heart rate variability in the frequency domain.

BACKGROUND: Acute transplant rejection is a major complication after heart transplantation. To treat patients with rejection, early detection is necessary before fatal heart dysfunction. Because of its invasive aspect, endomyocardial biopsy is limited with respect to its frequency and complication rate. Little work has been done so far to develop noninvasive methods for detecting rejection, and, hence, investigation for such methods would seem to be of considerable value. METHODS: After routine endomyocardial biopsy in 117 heart transplant recipients (age 49 +/- 13 years time after transplantation 6 to 48 months), electrocardiography results were recorded with the patient in a supine position at a controlled respiratory rate (0.25 Hz) over 10 minutes. Patients with an artificial pacemaker or severe arrhythmia were excluded. On the basis of endomyocardial biopsy reports, two groups of patients were defined: patients without rejection (AR0, n = 73) and patients with severe rejection (AR1b to AR4, n = 32). The spectra of R-wave to R-wave intervals were calculated, and different spectral components were evaluated: low frequency (LF, 0.05 to 0.18 Hz), high frequency (HF, 0.18 to 0.5 Hz), LF + HF, LF + HF minus the respiratory peak (RP) (LF + HF - RP), and the total power (0 to 0.5 Hz). RESULTS: All frequency domain parameters except HF were significantly higher in patients with severe rejection than in patients without rejection. By means of the calculation of receiver operating characteristic curves, LF + HF - RP was the most reliable frequency domain parameter for the detection of severe rejection. Setting its threshold value to 5 msec2, 77% sensitivity, and 76% specificity could be achieved. CONCLUSIONS: Spectral analysis of heart rate variability may be used as a noninvasive tool to detect severe rejection episodes.

Adolescent↗
PubMed1998

Single-center randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of acute myocardial rejection.

BACKGROUND: To compare the efficacy and safety of tacrolimus and cyclosporine in heart transplantation, this single-center, prospective, randomized, open-label clinical trial was undertaken. METHODS: Seventy-three adult patients were randomly assigned at the time of transplantation to receive either tacrolimus (n=43) or cyclosporine (n=30) as the primary immunosuppressant. Ten of the 43 patients in the tacrolimus group received the drug intravenously in the perioperative period; all other patients received only oral tacrolimus. RESULTS: With a mean follow-up of 27 months, patient survival rates (tacrolimus 83%, cyclosporine 81%) were similar. Fewer patients experienced acute rejection in the tacrolimus group (79%) than in the cyclosporine group (100%), but the difference was not statistically significant. The number of infections and dialysis and insulin requirements were similar for the 2 treatment groups, but the proportion of patients requiring multidrug antihypertensive regimens was lower in the tacrolimus group (12.5% vs 50.0% at month 6; p=.025). The interpatient variance in pharmacokinetic parameters in a subset of 10 patients was much higher after the first oral dose of tacrolimus than at steady-state (eg, first-dose time at which maximal concentration is reached (t(max)): 3.5+/-2.5h, steady-state t(max): 2.0+/-0.7h), and patients treated with intravenous tacrolimus (n=13) rather than oral tacrolimus (n=30) reached target concentrations faster and with less interpatient variability (eg, at day 0: 9.72+/-10.9 ng/mL intravenously vs 3.31+/-8.1 orally). CONCLUSIONS: Tacrolimus was associated with similar efficacy and safety profiles compared with cyclosporine. The higher interpatient variance in absorption associated with oral tacrolimus during the first few days after transplantation would suggest that intravenous tacrolimus should be used during the perioperative period.

Administration, Oral↗
PubMed1997

Particulate matter less than 10 microns (PM10) and fine particles less than 2.5 microns (PM2.5): relationships between indoor, outdoor and personal concentrations.

Among 17 homes in Switzerland, the relationship between indoor and outdoor levels for particulate matter less than 10 microns (PM10), particulate matter less than 2.5 microns (PM2.5) and NO2 was investigated. In 10 homes, the inhabitants also participated in conducting personal measurements. All homes were naturally ventilated. In homes without any indoor sources and where human activity was low, PM10 I/O ratios amounted to approximately 0.7. Of the indoor sources, smoking had the highest influence on I/O ratios (> 1.8). In homes not containing any apparent source, 'human activity' was an important factor accounting for high indoor levels. However, this factor is difficult to quantify. Personal exposure was in most cases higher than the indoor and the corresponding home outdoor levels. For NO2, gas-cooking was found to have the strongest influence on elevated I/O ratios (> 1.2) whilst for other homes, the I/O ratio was less than 1.

Air Pollution, Indoor↗
PubMed1997

The 40-kDa component of the phagocyte NADPH oxidase (p40phox) is phosphorylated during activation in differentiated HL60 cells.

The superoxide-generating NADPH oxidase complex of phagocytic cells is a multicomponent system containing a membrane-bound flavocytochrome b and a small G protein Rac as well as cytosolic factors p67phox, p47phox and p40phox which translocate to the membrane upon activation. Known mechanisms underlying the translocation of these proteins include polyphosphorylation of p47phox and specific Src homology 3/polyproline motif interactions. In this study, through two-dimensionnal electrophoresis and immunoprecipitation experiments, we show using dimethylsulfoxide-differentiated HL60 promyelocytes that p40phox is in a basal phosphorylated state in resting cells and undergoes further phosphorylation on multiple sites upon stimulation of the NADPH oxidase by either phorbol myristate acetate or by the formyl peptide fMet-Leu-Phe-Lys. Moreover, the extent of phosphorylation is strongly correlated with the level of superoxide production. Typically, in cells transiently activated by fMet-Leu-Phe-Lys, onset of superoxide production coincides with the appearance of new phosphorylated species of p40phox and, at the end of the respiratory burst, dephosphorylation of p40phox is observed. In vitro assays show that the kinase(s) involved in the phosphorylation of p40phox differ from those which participate in the phosphorylation of p47phox. This suggests that, in the cell, the phosphorylation of p40phox and of p47phox are under the control of two different kinase pathways.

Cell Differentiation↗
PubMed1997

Expression of interleukin-1beta in human breast carcinoma.

BACKGROUND: Interleukin 1beta (IL-1beta) is a multifunctional cytokine that up-regulates the inflammatory response. It is not known whether IL-1beta plays a major role in human malignancy. To determine whether IL-1beta might be involved in breast carcinoma progression, the authors measured the IL-1beta content in tissue extracts from >200 invasive breast carcinomas and smaller numbers of ductal carcinoma in situ (DCIS) and benign lesions. METHODS: IL-1beta content was measured by an enzyme-linked immunoadsorbent assay and analyzed to determine whether these values were correlated with the contents of scatter factor (SF) (an invasogenic and angiogenic cytokine), von Willebrand's factor (VWF) (a marker of endothelium), thrombospondin-1 (TSP1) (an antiadhesive and antiangiogenic glycoprotein), and tumor necrosis factor-alpha (TNF alpha) (another proinflammatory cytokine). Studies were also performed to determine whether IL-1beta content was correlated with other pathologic and immunochemical variables that have been utilized or proposed as prognostic indicators for breast carcinoma. RESULTS: The most important findings of these studies were: 1) immunoreactive IL-1beta was detected in approximately 90% of invasive breast carcinomas; 2) IL-1beta levels were significantly higher in invasive carcinomas than in a group of DCIS and benign lesions; 3) high IL-1beta content in invasive carcinomas was significantly associated with higher contents of SF, VWF, and TSP1, but not TNF alpha; and 4) there was a trend toward higher IL-1beta content in invasive carcinomas with a group of other parameters that suggest a biologically more aggressive tumor (estrogen receptor negativity, high tumor grade, p53 positivity, and bcl-2 negativity); and the proportion of invasive tumors with these characteristics was significantly increased in a subgroup of tumors having very high IL-1beta content. The authors also found a correlation between high IL-1beta content and CD68 positivity, suggesting that macrophages may account for some of the IL-1beta present in human breast carcinoma tissue. CONCLUSIONS: These findings suggest that significant titers of IL-1beta are present within the microenvironment of most breast carcinomas and that a high IL-1beta content is often associated with tumor invasiveness and with other pathologic features suggestive of an aggressive tumor biology.

Biomarkers↗
PubMed1997

Antitumor activity of the novel human breast cancer growth inhibitor, mammary-derived growth inhibitor-related gene, MRG.

A novel human tumor growth inhibitor was identified by differential cDNA sequencing. The predicted amino acid sequence of this tumor-suppressing factor has a significant sequence homology to mouse mammary-derived growth inhibitor and thus was named mammary-derived growth inhibitor-related gene (MRG). MRG was found to be expressed in normal and benign human breast tissues but not in breast carcinomas. In situ hybridization analysis demonstrated a stage-specific MRG expression as follows. MRG was barely detectable in breast carcinomas, showed partial and weak expression in benign hyperplasia, but was expressed at a high level in normal breast epithelial cells. To determine if MRG can modulate in vivo growth of human breast cancers, we transfected a full-length MRG cDNA into MDA-MB-231 human breast cancer cells and studied the orthotopic growth of MRG transfectants versus control transfectants in the mammary fat pad of athymic nude mice. Overexpression of MRG in human breast cancer cells significantly suppressed cell proliferation in vitro and tumor growth in an orthotopic nude mouse model. These results suggest that MRG has tumor-suppressing activity, and the loss of MRG expression may be involved in the development and progression of breast cancer.

Amino Acid Sequence↗
PubMed1997

Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4.

We recently identified, cloned, and characterized a novel human tissue inhibitor of metalloproteinases-4, TIMP-4 (Greene et al., 1996). To determine if TIMP-4 can modulate the in vivo growth of human breast cancers, we transfected a full-length TIMP-4 cDNA into MDA-MB-435 human breast cancer cells and studied the orthotopic growth of TIMP-4-transfected (TIMP4-435) versus control (neo-435) clones in the mammary fat pad of athymic nude mice. TIMP4-435 clones expressed TIMP-4 mRNA and produced anti-metalloproteinase (MMP) activity, while neo-435 clones did not express TIMP-4 mRNA or produce detectable anti-MMP activity. Overexpression of TIMP-4 inhibited the invasion potential of the cells in the in vitro invasion assay. When injected orthotopically into nude mice, TIMP-4 transfectants were significantly inhibited in tumor growth by 4-10-fold in primary tumor volumes; and in an axillary lymph node and lung metastasis as compared with controls. These results suggest the therapeutic potential of TIMP-4 in treating cancer malignant progression.

Animals↗
PubMed1997

Expression of scatter factor and c-met receptor in benign and malignant breast tissue.

BACKGROUND: Scatter factor (SF), also known as hepatocyte growth factor, is an angiogenic cytokine that stimulates epithelial cell motility and invasion. Its receptor is a transmembrane tyrosine kinase encoded by the c-met protooncogene. Several prior experimental and clinical studies have suggested that SF might play a role in the development and progression of breast carcinoma. To investigate the possible involvement of SF and c-met in the evolution of breast carcinoma, the authors studied their expression in sections of human breast tissue. METHODS: A variety of paraffin embedded tissue specimens (of normal breast tissue tissue, benign hyperplasia, ductal carcinoma-in-situ [DCIS], and invasive ductal carcinoma) from 125 patients were immunoperoxidase-stained using specific antisera against SF and c-met. The staining intensities of epithelial mammary cells were scored semiquantitatively, and the staining scores were analyzed as a function of tissue type. In addition, in situ hybridization to detect SF mRNA was performed for a small number of cancer sections. RESULTS: Specific SF staining was observed in tumor cells, normal cell types (epithelium and vascular smooth muscle), and acellular stroma, whereas c- met staining was observed in tumor cells and normal cell types but not in stroma. Analysis of the staining scores of epithelial mammary cells revealed several patterns: (1) SF and c-met staining scores each increased in the following order: normal breast/benign hyperplasias (lowest) --> DCIS (higher) --> invasive carcinoma (highest); (2) normal-appearing mammary ducts and lobules in invasive cancer sections showed less SF and c-met staining than tumor cells in the same specimens but more staining than normal ducts and lobules in sections of normal breast tissue and benign hyperplasia; (3) within the DCIS and invasive cancer groups, SF and c-met staining scores were correlated; and (4) among 40 consecutive cases of DCIS, higher levels of SF and c-met staining showed a trend toward association with other features suggestive of aggressive tumor biology (comedo histology, high nuclear grade, p53 positivity, and bcl-2 negativity). In situ hybridization analysis revealed that the same cell types that expressed SF protein (including tumor cells) also expressed SF mRNA transcripts. CONCLUSIONS: SF and c-met are overexpressed in breast carcinoma as compared with benign breast tissue, and they tend to be coexpressed in cancerous tissue. These findings are consistent with the idea that the SF:c-met ligand:receptor pair may have a role in breast carcinoma progression.

Breast↗
PubMed1997

Oxygen-free radical-mediated injury to cultured rat hepatocytes during cold incubation in preservation solutions.

We have previously shown that the injury to cultured liver endothelial cells during cold incubation in University of Wisconsin (UW) solution is energy-dependent and is mediated by reactive oxygen species. Here we demonstrate that this reactive oxygen-mediated injury is specific neither to endothelial cells nor to UW solution: cultured hepatocytes incubated in cold (4 degrees C) UW solution or histidine-tryptophan-ketoglutarate (HTK) solution were injured under normoxic conditions (loss of viability, 63% +/- 10% after 48 hours of cold incubation in UW solution and 82% +/- 11% after 24 hours of cold incubation in HTK solution), whereas hypoxia was protective (loss of viability, 29% +/- 12% [UW] and 13% +/- 3% [HTK] after the same cold incubation times). The injury under normoxic conditions was also largely decreased by adding either the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) or the flavonoid silibinin to the solutions, or by preincubating the cells with the iron chelator deferoxamine before the hypothermic incubation. Marked lipid peroxidation was observed during cold incubation in both preservation solutions. These results suggest that the injury to cultured hepatocytes during cold incubation in UW and HTK solutions is mediated by reactive oxygen species as is the injury to cultured liver endothelial cells.

Adenosine↗