Local thermal unpleasantness and discomfort prediction in the vicinity of thermoneutrality

This work emphasizes a better understanding of the origin of human thermal discomfort under heterogeneous but steady environments, in subjects in the vicinity of physiological and sensory thermoneutrality. The knowledge of skin temperatures allows a psychophysiological study aiming at linking the body thermal state (local and global) to thermal sensation (perceptive and affective judgements). By using two driving simulators, 345 subjects were exposed to different thermal environments, modulated by factors such as the air distribution in the automotive cockpit or the clothing insulation (winter or summer). This work shows that consideration of the local thermal state is essential for the evaluation of thermal comfort in the case of non-uniform environments. Our experimental conditions point out that the overall sensation of discomfort is quantitative, with local unpleasantness needing to be felt for a certain number of body surfaces. A local origin is suggested for cold discomfort, in opposition to the global characteristics of warm discomfort.     

IgE-mediated anaphylaxis caused by bites of the pigeon tick Argas reflexus: cloning and expression of the major allergen Arg r 1

BACKGROUND: Anaphylactic reactions caused by bites of the European pigeon tick Argas reflexus are repeatedly reported. This soft-backed tick is a parasite of wild pigeons colonizing urban buildings and houses. Occasionally the ticks can bite human beings, inducing anaphylactic reactions in sensitized patients. OBJECTIVE: Our aim was to characterize the major allergen implicated in a series of anaphylactic reactions caused by Argas bites and to produce the allergen as recombinant protein for diagnostic purposes. METHODS: Protein extracts were prepared from whole A reflexus bodies, and IgE immunoblots were performed with sera from 13 patients who had an anaphylactic reaction with pigeon tick bites. A cDNA expression library was constructed from whole ticks and screened with a polyclonal rabbit antiserum raised against the major allergen. RESULTS: The cDNA coding for the dominant allergen Arg r 1 could be isolated. It encodes a protein belonging to the lipocalin family. Allergenicity of the recombinant Arg r 1 was confirmed by immunoblot, ELISA, and intradermal skin tests. CONCLUSION: The dominant allergen of A reflexus has been isolated and the corresponding cDNA cloned. The recombinant protein, a lipocalin, was expressed in Escherichia coli and was shown to be immunoreactive in vitro and in vivo. Recombinant Arg r 1 was used as a diagnostic tool in a series of anaphylactic reactions caused by pigeon tick bites.     

Analysis of the spontaneous in vitro anti-HIV-1 antibody secretion by peripheral blood mononuclear cells in HIV-1 infection.

We studied the spontaneous in vitro secretion of anti-HIV-1 antibodies by peripheral blood mononuclear cells (PBMC) from HIV-1-infected patients. Specific antibody production was detected in supernatants of PBMC cultures using an ELISA; HIV-1 specificity was confirmed by antigen adsorption and Western blotting. This antibody secretion was found to be an active phenomenon and was not due to a release of plasma antibodies passively adsorbed onto the cell membranes. In all positive supernatants, anti-HIV-1-secreted antibodies were directed against env-encoded antigens and many supernatants also contained antibodies to pol- and gag-encoded antigens. PBMC from all HIV-1-infected patients tested (140 adults and 18 infants) secreted anti-HIV-1 antibodies. This production was found during all the clinical stages of HIV-1 infection. Our results suggest that this spontaneous HIV-1-specific antibody secretion represents a marker of HIV-1 infection. Detection of these antibodies could be a valuable tool for early confirmation of HIV-1 infection in neonates born to HIV-1-seropositive mothers.     

Sequence analysis of cDNAs for the human and bovine ATP synthase β subunit: mitochondrial DNA genes sustain seventeen times more mutations

We have cloned and sequenced human and bovine cDNAs for the subunit of the ATP synthase (ATP-synß), a nuclear DNA (nDNA) encoded oxidative phosphorylation (OXPHOS) gene. The two cDNAs were found to share 99% amino acid homology and 94% nucleotide homology. The evolutionary rate of ATPsynß was then compared with that of two mitochondrial DNA (mtDNA) ATP synthase genes (ATPase 6 and 8), seven other mtDNA OXPHOS genes, and a number of nuclear genes. The synonymous substitution rate for ATPsynß proved to be 1.9 × 10^–9 substitutions per site per year (substitutions × site^–1 × year^–1) (SSY). This is less than 1/2 that of the average nDNA gene, 1/12 the rate of ATPase 6 and 8, and 1/17 the rate of the average mtDNA gene. The synonymous and replacement substitution rates were used to calculate a new parameter, the selective constraint ratio. This revealed that even the most variable mtDNA protein was more constrained than the average nDNA protein. Thus, the high substitution mutation rate and strong selective constraints of mammalian mtDNA proteins suggest that mtDNA mutations may result in a disproportionately large number of human hereditary diseases of OXPHOS.     

What determines the frequency of fast network oscillations with irregular neural discharges? I. Synaptic dynamics and excitation-inhibition balance

When the local field potential of a cortical network displays coherent fast oscillations ( approximately 40-Hz gamma or approximately 200-Hz sharp-wave ripples), the spike trains of constituent neurons are typically irregular and sparse. The dichotomy between rhythmic local field and stochastic spike trains presents a challenge to the theory of brain rhythms in the framework of coupled oscillators. Previous studies have shown that when noise is large and recurrent inhibition is strong, a coherent network rhythm can be generated while single neurons fire intermittently at low rates compared to the frequency of the oscillation. However, these studies used too simplified synaptic kinetics to allow quantitative predictions of the population rhythmic frequency. Here we show how to derive quantitatively the coherent oscillation frequency for a randomly connected network of leaky integrate-and-fire neurons with realistic synaptic parameters. In a noise-dominated interneuronal network, the oscillation frequency depends much more on the shortest synaptic time constants (delay and rise time) than on the longer synaptic decay time, and approximately 200-Hz frequency can be realized with synaptic time constants taken from slice data. In a network composed of both interneurons and excitatory cells, the rhythmogenesis is a compromise between two scenarios: the fast purely interneuronal mechanism, and the slower feedback mechanism (relying on the excitatory-inhibitory loop). The properties of the rhythm are determined essentially by the ratio of time scales of excitatory and inhibitory currents and by the balance between the mean recurrent excitation and inhibition. Faster excitation than inhibition, or a higher excitation/inhibition ratio, favors the feedback loop and a much slower oscillation (typically in the gamma range).     

Comparison of HLA-DR1-restricted T cell response induced in HLA-DR1 transgenic mice deficient for murine MHC class II and HLA-DR1 transgenic mice expressing endogenous murine MHC class II molecules

Transgenic mice expressing human HLA class II molecules provide a useful model for identifying HLA-restricted CD4+ epitopes. However, the influence of endogenous murine H-2-restricted T cell responses on HLA-restricted responses is not known. In the present study, we show that HLA-DR1 transgenic mice deficient for H-2 class II expression (HLA-DR1+/+/IAbeta0/0) exhibit an equivalent expression level of the transgene HLA-DR1 and a similar diversity in the TCR repertoire, but a slightly different number of CD4+ peripheral T cells, when compared to HLA-DR1 transgenic mice in which H-2 class II molecules were retained (HLA-DR1+/+/IAbeta+/+). More importantly, a strong antigen-specific HLA-DR1-restricted response was observed in nearly all HLA-DR1+/+/IAbeta0/0 mice immunized with HBV envelope protein (HBs) or capsid protein (HBc), whereas weak HBs- or HBc-specific HLA-DR1-restricted responses were detected in half of the immunized HLA-DR1+/+/IAbeta+/+ mice. Conversely, strong HBs- or HBc-specific H-2-restricted T cell responses were detected in HLA-DR1+/+/IAbeta+/+ mice but not in HLA-DR1+/+/IAbeta0/0 mice. Our results indicate that the coexpression of endogenous H-2 class II molecules reduces the intensity of HLA-DR1-restricted antigen-specific responses in transgenic mice, by favoring murine over human MHC recognition and education. Thus, HLA-DR1+/+/IAbeta0/0 mice represent a better model for identifying and characterizing HLA-DR1-restricted epitopes relevant for human disease.     

Three highly polymorphic microsatellites at the human myelin oligodendrocyte glycoprotein locus, 100 kb telomeric to HLA-F : Characterization and relation to HLA haplotypes

The MOG locus, located on chromosomal bands 6p21.3-p22 and mapped about 100 kb telomeric to HLA-F, was isolated from cosmid ICRFcl09A2434 and shown to contain three microsatellites. These CA-repeat polymorphic markers were characterized in a sample of 173 healthy unrelated individuals and 84 DNAs from the HLA Workshop reference panel, by a method combining fluorescence labeling of PCR products and use of an automated DNA sequencer. For the three markers, frequencies of heterozygotes are well predicted from allele frequencies by the Hardy—Weinberg rule, which suggests that problems of allele nonamplification are unlikely. Typing of cell lines homozygous in the HLA region allowed unambiguous definition of 81 HLA-MOG haplotypes and showed that several HLA ancestral haplotypes extended to the MOG region. The high degree of polymorphism (59%, 51%, and 81% at the three loci, respectively, and 87% at the haplotype level) makes these new markers informative for association or linkage studies with diseases such as hemochromatosis or multiple sclerosis, and for studies aimed at precisely delineating the site of crossover in chromosomes in which recombination occurred in the distal part of the HLA class I region.     

Integration from proteins to organs: the IUPS Physiome Project

The IUPS Physiome Project is an internationally collaborative open source project intended to provide a public domain framework for computational physiology, including the development of modeling standards, computational tools and web-accessible databases of models of structure and function at all spatial scales and across all organ systems. Here, we illustrate the application of this multi-scale modeling approach to three organ systems: the heart, the lungs and the musculo-skeletal system, and in each case we show how the organ level models incorporate tissue and cell-level physiology. Although the computational physiology framework presented here does not yet incorporate models of ageing processes, the model-based approach is certainly capable of describing ageing and disease-related processes both via parameter changes within the models of normal physiological processes and via models of additional processes added to the framework.