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Biomedical subjects

A Blondel

Publications and source records attributed to A Blondel.

At least 19 recordsLinked to original sources
PubMed2006

Improved search for nu(mu) --> nu(e) oscillation in a long-baseline accelerator experiment.

We performed an improved search for nu(mu) --> nu(e) oscillation with the KEK to Kamioka (K2K) long-baseline neutrino oscillation experiment, using the full data sample of 9.2 x 10(19) protons on target. No evidence for a nu(e) appearance signal was found, and we set bounds on the nu(mu) --> nu(e) oscillation parameters. At Deltam(2)=2.8 x 10(-3) eV(2), the best-fit value of the K2Knu(mu) disappearance analysis, we set an upper limit of sin(2)2theta(mue) < 0.13 at a 90% confidence level.

Journal Article↗
PubMed2005

Search for coherent charged pion production in neutrino-carbon interactions.

We report the result from a search for charged-current coherent pion production induced by muon neutrinos with a mean energy of 1.3 GeV. The data are collected with a fully active scintillator detector in the K2K long-baseline neutrino oscillation experiment. No evidence for coherent pion production is observed, and an upper limit of is set on the cross section ratio of coherent pion production to the total charged-current interaction at 90% confidence level. This is the first experimental limit for coherent charged pion production in the energy region of a few GeV.

Journal Article↗
PubMed2005

Evidence for muon neutrino oscillation in an accelerator-based experiment.

We present results for nu(mu) oscillation in the KEK to Kamioka (K2K) long-baseline neutrino oscillation experiment. K2K uses an accelerator-produced nu(mu) beam with a mean energy of 1.3 GeV directed at the Super-Kamiokande detector. We observed the energy-dependent disappearance of nu(mu), which we presume have oscillated to nu(tau). The probability that we would observe these results if there is no neutrino oscillation is 0.0050% (4.0 sigma).

Journal Article↗
PubMed2001

Disorders in intentional gestural organization in Alzheimer's disease: combined or selective impairment of the conceptual and production systems?

This study examines disorders which affect the intentional gestural organization in Alzheimer's disease. An original and prospective protocol which assessed both the conceptual and production systems (with reference to the Roy and Square model 1985) was presented to 16 patients with Alzheimer's disease (mild to moderate dementia) and 40 healthy elderly subjects. Our study showed impairment of both systems in the Alzheimer's patients group. Two patients presented reverse performance profiles, which were characterized in one case by preservation of the conceptual system and impairment of the production system and in the other by the reverse dissociation. The findings demonstrated that disorders in the intentional gestural organization in Alzheimer's disease usually affect both the conceptual and production systems. The hypothesis concerning the existence of two functionally distinct systems underlying the organization of intentional body movement was corroborated (1) by a lack of significant correlation between the scores obtained in the assessment of the two systems and (2) by the demonstration of the double dissociation.

Aged↗
PubMed2000

Complementation between dimeric mutants as a probe of dimer-dimer interactions in tetrameric dihydrofolate reductase encoded by R67 plasmid of E. coli.

The effect of mutations on the interactions between dimers in R67 dihydrofolate reductase (R67 DHFR), a tetrameric enzyme conferring resistance to trimethoprim, was investigated by site-directed mutagenesis combined with phenotypic, enzymatic, and biochemical analysis. Some 14 mutants at two positions involved in a hydrogen bond between dimers were constructed. All were shown to be dimers. However, complementation between pairs of dimeric mutated proteins resulted in the restoration of the enzymatic activity and heterotetramer formation. A combinatorial approach was set up to create efficiently such heterotetramers and identify the complementing pairs of mutations. A dozen of such pairs were found. An accurate method was set up to measure the association of the complementing dimers in a "quasi-isologous" heterotetramer and used to study the effects of mutations and pH on the association. Thus, the pair of proteins bearing respectively the S59A and H62L mutations was shown to form heterotetramers with catalytic properties close to those of the wild-type protein. Its association was as strong as that of the wild-type protein at cytoplasmic pH (6. 5), and was more stable at lower pH values.A double-mutant protein bearing simultaneously the S59A and H62L mutations was produced and analyzed. Its association was weakened by 1.2 kcal/mol as compared to the wild-type enzyme at pH 6.5 but was insensitive to pH. Comparing the energy of association between dimers in the wild-type protein, the heterotetramer and the double mutant allowed us to dissect the effects of the pH and of the molecular context on a subset of interactions between the R67 DHFR subunits.

Amino Acid Substitution↗
PubMed2000

Characterisation of the effects of nicotine in the five-choice serial reaction time task in rats: antagonist studies.

RATIONALE: Nicotine has been shown to decrease reaction time and increase anticipatory responses in a five-choice serial reaction time task (5-CSRTT) in rats, but the receptor mechanisms mediating this effect remain unknown. OBJECTIVES: To evaluate further the effects of nicotine in this task and to characterise the receptors mediating these effects. METHODS: Using a standard 5-CSRTT protocol, rats were trained to respond to a 0.5-s visual stimulus, which was reduced to 0.25 s for experimental sessions to induce a performance decrement. The effects of acute (0.03-0.3 mg/kg IP) and repeated (0.1 and 0.3 mg/kg IP for 5 days) nicotine were studied, as was the ability of mecamylamine (1 mg/kg IP), hexamethonium (5 mg/kg IP), dihydro-beta-erythroidine (6 mg/kg IP) and methyllycaconitine (10 mg/kg IP) to antagonise the effects of acute nicotine. RESULTS: Nicotine had no effect on accuracy, but decreased response latencies, improved performance in the less-well attended stimulus locations and increased inappropriate responding after both acute and repeated treatment. The data suggest that nicotine improves readiness to respond and improves target scanning, and decreases the ability to withhold premature responses (i.e. increased impulsivity). Except for the reduction in error latency, all of the effects of nicotine were antagonised by the non-selective, centrally acting antagonist mecamylamine, whereas the peripheral antagonist hexamethonium had no effect, demonstrating that nicotine's actions are central in origin. Dihydro-beta-erythroidine, a competitive nicotinic antagonist, antagonised all of the effects of nicotine. In contrast, the alpha7 antagonist methyllycaconitine had no significant effects against nicotine. CONCLUSIONS: These results demonstrate that the alpha7 receptor subtype is not involved in the effects of nicotine in the 5-CSRTT and that its effects are more likely to be mediated by a receptor(s) such as alpha4beta2, alpha4beta4 and/or alpha3beta2 which is sensitive to antagonism by dihydro-beta-erythroidine.

Aconitine↗
PubMed1999

Retinoic acid receptor: a simulation analysis of retinoic acid binding and the resulting conformational changes.

The binding/escape mechanism of all- trans retinoic acid with respect to the ligand-binding domain of the nuclear receptor RARgamma has been studied by molecular dynamic simulations. The entry/exit channel was shown to be on the side of the activation helix by the use of multiple copy dynamics. Three independent minimum energy paths from the liganded structure to a model for the unliganded structure were calculated with the conjugate peak refinement method. Ligand escape takes place in the early steps of the transition during rearrangement of the binding pocket; the latter involves inward motion of the beta-sheet and outward motions of the Omega-loop and helix H6. The correlated rearrangements involved in the escape phase are similar and occur in the same order for the different paths. After the escape phase, the conformational changes affect primarily the C-terminal helices H11-H12 and the Omega-loop. The three paths are significantly different for this reorganization phase and reveal a multiplicity of possibilities, in agreement with the idea that the apo state is structurally less constrained. The present calculations extend the crystallographic results, confirming the "mouse trap" mechanism and stressing the importance of the helix H3 conformation and of the contacts between the Omega-loop and helices H11 and H6. They are in good agreement with known mutants and point to other functionally important residues, especially in helices H3 and H11, suggesting mutations that may affect the ligand-binding function and the associated conformational changes.

Computer Simulation↗
PubMed1999

Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck.

T-cell antigen receptor-induced signaling requires both ZAP-70 and Lck protein-tyrosine kinases. One essential function of Lck in this process is to phosphorylate ZAP-70 and up-regulate its catalytic activity. We have previously shown that after T-cell antigen receptor stimulation, Lck binds to ZAP-70 via its Src homology 2 (SH2) domain (LckSH2) and, more recently, that Tyr319 of ZAP-70 is phosphorylated in vivo and plays a positive regulatory role. Here, we investigated the possibility that Tyr319 mediates the SH2-dependent interaction between Lck and ZAP-70. We show that a phosphopeptide encompassing the motif harboring Tyr319, YSDP, interacted with LckSH2, although with a lower affinity compared with a phosphopeptide containing the optimal binding motif, YEEI. Moreover, mutation of Tyr319 to phenylalanine prevented the interaction of ZAP-70 with LckSH2. Based on these results, a gain-of-function mutant of ZAP-70 was generated by changing the sequence Y319SDP into Y319EEI. As a result of its increased ability to bind LckSH2, this mutant induced a dramatic increase in NFAT activity in Jurkat T-cells, was hyperphosphorylated, and displayed a higher catalytic activity compared with wild-type ZAP-70. Collectively, our findings indicate that Tyr319-mediated binding of the SH2 domain of Lck is crucial for ZAP-70 activation and consequently for the propagation of the signaling cascade leading to T-cell activation.

Amino Acid Sequence↗
PubMed1999

The effect of repeated nicotine administration on the performance of drug-naive rats in a five-choice serial reaction time task.

Nicotine improves cognitive performance both in animals and in humans, particularly in tests involving attentional processes. The five-choice serial reaction time task (5-CSRTT) is widely used as a model of attentional performance in rats, and previous studies have demonstrated effects of nicotine in this task on measures such as improved reaction time. Using a modified version of this task (in which rats were required to respond to the disappearance of one of five stimulus lights), we evaluated the effects of repeated nicotine administration (0.3 mg/kg, intraperitoneally, on three occasions over 7 days) in drug-naive rats. After the first administration, nicotine increased accuracy and reduced inappropriate responding (anticipatory responses and responses during time-out) compared to performance following vehicle administration on the preceding day. However, with repeated administration the improvement in accuracy disappeared, and other effects became apparent. Thus, after the third administration the main effects of nicotine were to increase inappropriate responding and to reduce reaction times. A fourth administration 1-2 weeks later produced similar results to the third administration, suggesting that the effects of nicotine were now constant. Despite the general increase in inappropriate responding, there was no impairment in accuracy. In contrast to the response to repeated nicotine, the performance of the rats on the 3 vehicle days remained constant. These data demonstrate that the administration of nicotine to drug-naive subjects improves performance in the 5-CSRTT but that with repeated administration this effect disappears and is replaced by a profile in which inappropriate and impulsive responding predominate.

Animals↗
PubMed1997

[Clinical and cognitive study of apraxia in cortico-basal atrophy. A selective disorder of the production system].

The aim of this study was to characterize the different processes underlying apraxic disorders in cortico-basal degeneration. Three patients were submitted to a prospective paradigm elaborated in the theoretical framework proposed by Roy and Square (1985). This cognitive model postulates a two-steps system in the control mechanisms in limb praxis: the conceptual system and the production system. Our results, strictly similar for the three patients, showed a sparing of the conceptual system and an impairment of the production system with a dramatic lack in the control of the temporal and spatial aspects of the gestures. These results suggest a dysfunction of the premotor cortex including the supplementary motor area.

Aged↗
PubMed1996

Destabilizing interactions between the partners of a bifunctional fusion protein.

Hybrid MalE-GVP is a bifunctional protein in vitro since it binds maltose as protein MalE of Escherichia coli and since it is dimeric and specifically binds single-stranded DNA as protein GVP of phage M13. The oxidation rate of a unique cysteine residue was used to compare the stabilities of GVP in its free and hybrid forms, under conditions where MalE was either folded or unfolded by a denaturing agent. The results showed that both the covalent link and tertiary non-covalent interactions between MalE and GVP destabilized GVP in MalE-GVP. To test whether GVP had identical structures in its free and hybrid forms, mutations were used as local conformational probes. The effects of these mutations on the capabilities of MalE-GVP to dimerize and to bind single-stranded DNA were assayed in vitro. They were compatible with the effects of the same mutations on the global activity of free GVP in vivo and with the effects that could be predicted from the known data on free GVP, in particular its crystal structure. Thus, one partner of a hybrid protein can be destabilized by the other partner while maintaining its structural and functional characteristics.

ATP-Binding Cassette Transporters↗
PubMed1996

Effect of malnutrition on serum and milk antibodies in Zairian women.

Serum and human milk antimicrobial antibody titers were measured longitudinally in 17 malnourished and 14 control Zairian women during 6 to 18 months of lactation to test whether malnutrition is specifically associated with an impaired secretory antibody response. No decreases in total serum and human milk immunoglobulin concentrations, neutralizing antibody titers against rotavirus, or specific enzyme-linked immunosorbent assay antibody titers against rotavirus, respiratory syncytial virus, Escherichia coli, Streptococcus pneumoniae, and Haemophilus influenzae were detected when malnourished women were compared with control women. Malnutrition had no effect on circulating and secretory antibody concentrations in Zairian women. Daily human milk outputs, however, were about 30% lower in malnourished than in control women, resulting in a correspondingly lower ingestion of immunoglobulins by the children of malnourished women.

Adult↗
PubMed1992

Selenium losses in 10 burned patients.

To determine the selenium (Se) losses and balances, 10 patients with burns of 32 +/- 9% (mean +/- SD) of total body surface and aged 36 +/- 9 years were studied from D1 (first post-injury) unitl D7. Cutaneous losses were extracted from the textiles surrounding the patients. Serum and urine were collected until D20. Exudative losses of nitrogen decreased progressively (mean 8.7 +/- 3.8 g/24H). Se was detectable in wound seepage only during excision-grafting: mean operative loss was 342 +/- 191 mug. Mean urinary Se excretion was 41 +/- 13 mug/24H. Operative cutaneous losses led to some negative balances. Serum Se and glutathione peroxydase (GSHPx) were depressed until D20. Serum Se was related to N intake (p < 0.001). The decreased Se and GSHPx levels reflect a deficiency state, which measured losses did not explain, but limitations of the measurement methods prevented detection of Se cutaneous losses 100 mug/24H.

Journal Article↗
PubMed1991

Engineering the quaternary structure of an exported protein with a leucine zipper.

The leucine zipper of the yeast transcriptional factor GCN4 was grafted to the C-terminal amino acid of the maltose binding protein (MalE) by fusing the malE gene of Escherichia coli to a synthetic gene coding for the leucine zipper. The hybrid protein, MalE-Lzp, was synthesized in large amounts from multicopy plasmids and efficiently exported into the periplasmic space of E. coli, up to 200,000 molecules per cell. Unlike hybrids between MalE and other proteins, MalE-Lzp was quite stable exhibiting only minimal degradation. The hybrid was purified from a periplasmic extract in one step by affinity chromatography on cross-linked amylose. Sedimentation velocity and gel filtration experiments showed that MalE-Lzp existed as a dimer in conditions where MalE was a monomer, at all concentrations tested down to 0.1 microM. Thus, it was possible to engineer the quaternary structure of an exported, monomeric protein by using a structural motif taken from a natural protein.

ATP-Binding Cassette Transporters↗
PubMed1990

Export and purification of a cytoplasmic dimeric protein by fusion to the maltose-binding protein of Escherichia coli.

A hybrid between the maltose-binding protein (MalE) of Escherichia coli and the gene 5 protein (G5P) of phage M13 was constructed at the genetic level. MalE is a monomeric and periplasmic protein while G5P is dimeric and cytoplasmic. The hybrid (MalE-G5P) was synthesized in large amounts from a multicopy plasmid and efficiently exported into the periplasmic space of E. coli. The export was dependent on the integrity of the signal peptide. MalE-G5P was purified from a periplasmic extract by affinity chromatography on cross-linked amylose, with a yield larger than 50,000 molecules/E. coli cell. The hybrid specifically bound denatured but not double-stranded DNA cellulose, as native G5P. Sedimentation velocity and gel-filtration experiments showed that MalE-G5P exists as a dimer. Thus, it was possible to efficiently translocate through the membrane a normally cytoplasmic and dimeric protein, by fusion to MalE. Moreover, the passenger protein kept its activity, specificity and quaternary structure in the purified hybrid. MalE-G5P will enable the study of mutant G5P that no longer binds single-stranded DNA and therefore cannot be purified by DNA-cellulose chromatography.

ATP-Binding Cassette Transporters↗