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PubMed1986

Functions of mononuclear phagocytes in mice exposed to diethylstilbestrol: a model of aberrant macrophage development.

Administration of the synthetic estrogen diethylstilbestrol (DES) lowers the systemic resistance of mice to challenge with either tumor cells or the facultative intracellular parasite Listeria monocytogenes. To assess the potential role of impaired mononuclear phagocyte system (MPS) function in this depression of host resistance, we addressed the question of systemic perturbations of the MPS induced by administration of DES. A panel of objective quantitative markers which have been previously shown to identify and characterize macrophages in the several stages of development of activation was employed. DES perturbed the resident population of peritoneal macrophages by increasing their number approximately twofold and by enhancing their competence for phagocytosis, cytostasis of tumor cells, and secretion of plasminogen activator. When we examined the competence of the MPS in DES-treated mice to respond to challenge with activating stimuli, we found that DES systemically suppressed the development of macrophages, in response to either pyran copolymer or BCG, to develop tumoricidal function and to gain competence for secretion of reactive oxygen intermediates such as H2O2. Since these data suggested that DES inhibited the development of macrophages from a precursor stage (i.e., responsive macrophages) to activated macrophages in vivo, we tested this possibility directly by applying known activating signals in vitro to responsive macrophages. Responsive macrophages from DES-treated mice did not become activated in response to the application of two known potent activating signals (i.e., MAF + LPS). Taken together, the data indicate that DES systemically perturbs the MPS and does so by enhancing development of the early stages of maturation and suppressing subsequent development.

Animals↗
PubMed1982

Testing for cis' proline with alpha-aminoisobutyric acid substitution. N.m.r. studies of AIB substituted bradykinins.

Substitution of Pro residues with AIB (alpha-aminoisobutyric acid) residues in peptides provides a means of evaluating the presence of cis' proline conformations both in solution and, using bioassay data, in a receptor complex. 1H n.m.r. has been used to probe the DMSO solution conformation of all seven of the possible AIB/Pro isomers of bradykinin. AIB substitution for Pro2 and/or Pro3 appears to stabilize a type III beta-turn involving the N-terminal residues, but not an incipient 3(10) helix suggested by model peptides. These substitutions are correlated with low biological potencies, suggesting that such conformational features may be incompatible with receptor complexation. Alternatively, AIB7 -bradykinin analogs exhibit a variety of long range shift perturbations relative to bradykinin. The data suggests that bradykinin can adopt several folded conformations, including beta-turns involving both Ser6-Pro7-Phe8-Arg9 and Phe5-Ser6-Pro7-Phe8. The relatively high biological activities of the AIB7-BK suggest that the complexed form of the peptide is characterized by a cis' Pro7 conformation.

Amino Acid Sequence↗
PubMed1990

Effects of cholesterol on the structural transitions induced by diacylglycerol in phosphatidylcholine and phosphatidylethanolamine bilayer systems.

The transient membrane lipid diacylglycerol (DG) is known to modify and destabilize phospholipid bilayers and can lead to the formation of nonbilayer structures. Since cholesterol forms a major fraction of many plasma membranes, we have investigated how it modifies the structural effects of DG on bilayers of egg phosphatidylcholine (PC) and egg phosphatidylethanolamine (PE). We view these systems as modelling the behaviour of local, DG-containing sites in membranes. Using X-ray diffraction, we have characterized the lamellar (L alpha) and inverse hexagonal (HII) structures that these ternary lipid mixtures form in excess aqueous solution. As the DG level increases, the lipid progresses from a single L alpha structure to a mixture of L alpha and HII, and then to a pure HII structure. This allows determination of the DG levels at which the HII transition begins, which we interpret as those levels that destabilize bilayers. In both PC and PE bilayers, the presence of 30 mol% cholesterol reduces the amounts of DG required to destabilize the bilayer structure. The destabilization can be translated into the number of neighbouring lipid molecules that a DG molecule perturbs, and of bilayer areas that it affects. The data show that the presence of cholesterol greatly enhances the perturbing effects of DG. We examine the possible role of DG in enzyme activation and membrane fusion.

Cholesterol↗
PubMed2025

Mapping transcriptional responses to cellular perturbation dictionaries with RNA fingerprinting.

Single-cell perturbation dictionaries provide systematic measurements of how cells respond to genetic and chemical perturbations, and create the opportunity to assign causal interpretations to observational data. Here, we introduce RNA fingerprinting, a statistical framework that maps transcriptional responses from new experiments onto reference perturbation dictionaries. RNA fingerprinting learns denoised perturbation "fingerprints" from single-cell data, then probabilistically assigns query cells to one or more candidate perturbations while accounting for uncertainty. We benchmark our method across ground-truth datasets, demonstrating accurate assignments at single-cell resolution, scalability to genome-wide screens, and the ability to resolve combinatorial perturbations. We demonstrate its broad utility across diverse biological settings: identifying context-specific regulators of p53 under ribosomal stress, characterizing drug mechanisms of action and dose-dependent off-target effects, and uncovering cytokine-driven B cell heterogeneity during secondary influenza infection in vivo. Together, these results establish RNA fingerprinting as a versatile framework for interpreting single-cell datasets by linking cellular states to the underlying perturbations which generated them.

Journal Article↗
PubMed1988

Tertiary structure of Escherichia coli tRNA(3Thr) in solution and interaction of this tRNA with the cognate threonyl-tRNA synthetase.

The solution structure of Escherichia coli tRNA(3Thr) (anticodon GGU) and the residues of this tRNA in contact with the alpha 2 dimeric threonyl-tRNA synthetase were studied by chemical and enzymatic footprinting experiments. Alkylation of phosphodiester bonds by ethylnitrosourea and of N-7 positions in guanosines and N-3 positions in cytidines by dimethyl sulphate as well as carbethoxylation of N-7 positions in adenosines by diethyl pyrocarbonate were conducted on different conformers of tRNA(3Thr). The enzymatic structural probes were nuclease S1 and the cobra venom ribonuclease. Results will be compared to those of three other tRNAs, tRNA(Asp), tRNA(Phe) and tRNA(Trp), already mapped with these probes. The reactivity of phosphates towards ethylnitrosourea of the unfolded tRNA was compared to that of the native molecule. The alkylation pattern of tRNA(3Thr) shows some similarities to that of yeast tRNA(Phe) and mammalian tRNA(Trp), especially in the D-arm (positions 19 and 24) and with tRNA(Trp), at position 50, the junction between the variable region and the T-stem. In the T-loop, tRNA(3Thr), similarly to the three other tRNAs, shows protections against alkylation at phosphates 59 and 60. However, tRNA(3Thr) is unique as far as very strong protections are also found for phosphates 55 to 58 in the T-loop. Compared with yeast tRNA(Asp), the main differences in reactivity concern phosphates 19, 24 and 50. Mapping of bases with dimethyl sulphate and diethyl pyrocarbonate reveal conformational similarities with yeast tRNA(Phe). A striking conformational feature of tRNA(3Thr) is found in the 3'-side of its anticodon stem, where G40, surrounded by two G residues, is alkylated under native conditions, in contrast to other G residues in stem regions of tRNAs which are unreactive when sandwiched between two purines. This data is indicative of a perturbed helical conformation in the anticodon stem at the level of the 30-40 base pairs. Footprinting experiments, with chemical and enzymatic probes, on the tRNA complexed with its cognate threonyl-tRNA synthetase indicate significant protections in the anticodon stem and loop region, in the extra-loop, and in the amino acid accepting region. The involvement of the anticodon of tRNA(3Thr) in the recognition process with threonyl-tRNA synthetase was demonstrated by nuclease S1 mapping and by the protection of G34 and G35 against alkylation by dimethyl sulphate. These data are discussed in the light of the tRNA/synthetase recognition problem and of the structural and functional properties of the tRNA-like structure present in the operator region of the thrS mRNA.

Affinity Labels↗
PubMed1986

Intraoral air pressure and oral air flow under different bleed and bite-block conditions.

Intraoral pressures and oral flows were measured as normal talkers produced /p lambda/ and /si/ under experimental conditions that perturbed the usual aeromechanical production characteristics of the consonants. A translabial pressure-release device was used to bleed off intraoral pressure during /p/. Bite-blocks were used to open the anterior bite artificially during /s/. For /p/, intraoral pressure decreased and translabial air leakage increased as bleed orifice area increased. For /s/, flow increased as the area of sibilant constriction increased, but differential pressure across the /s/ oral constriction did not vary systematically with changes in its area. Flow on postconsonantal vowels /lambda/ and /i/ did not vary systematically across experimental conditions. The data imply that maintenance of perturbed intraoral pressure was more effective when compensatory options included opportunity for increased respiratory drive and structural adjustments at the place of consonant articulation rather than increased respiratory drive alone.

Adult↗
PubMed1992

Effects of 4-hydroperoxycyclophosphamide (4-OOH-CP) and 4-hydroperoxydechlorocyclophosphamide (4-OOH-deCICP) on the cell cycle of post implantation rat embryos.

In this study, we used preactivated forms of cyclophosphamide (CP) and dechlorocyclophosphamide (deClCP) to examine the effects of phosphoramide mustard (PM) and acrolein, respectively, on the cell cycle of postimplantation rat embryos. The percentage distribution of cells in the G1/G0, S, and G2/M phases of the cell cycle was determined by flow-cytometric analysis. At embryotoxic concentrations, 4-OOH-CP (PM) induced major cell cycle perturbations whereas 4-OOH-deClCP (acrolein) caused no major perturbation of the cell cycle. These data support the hypothesis that the mechanism of the embryotoxic action of PM involves alkylation of DNA, whereas the mechanism of action of acrolein does not. The primary effect of PM on the cell cycle was an initial delay in the S phase followed by a G2/M arrest. At low embryotoxic concentrations of 4-OOH-CP, there was apparent reversal of the G2/M arrest; at higher embryotoxic concentrations there was little recovery from the G2/M arrest. The high level of cell death found at higher drug concentrations suggests that prolonged G2/M arrest leads to cell death. Using radiolabeled CP and cell sorting, it was determined that PM predominantly alkylated DNA in the S phase of the cell cycle. Overall, the data from this study support the hypothesis that DNA cross-links, induced by the alkylation of DNA by PM, induce cell cycle perturbations. Furthermore, these cell cycle alterations may be one of the early steps in the mechanism leading to the embryotoxicity of PM.

Abnormalities, Drug-Induced↗
PubMed2005

Microtubule-associated protein MAP1A, MAP1B, and MAP2 proteolysis during soluble amyloid beta-peptide-induced neuronal apoptosis. Synergistic involvement of calpain and caspase-3.

A growing body of evidence supports the notion that soluble oligomeric forms of the amyloid beta-peptide (Abeta) may be the proximate effectors of neuronal injuries and death in the early stages of Alzheimer disease. However, the molecular mechanisms associated with neuronal apoptosis induced by soluble Abeta remain to be elucidated. We recently demonstrated the involvement of an early reactive oxygen species-dependent perturbation of the microtubule network (Sponne, I., Fifre, A., Drouet, B., Klein, C., Koziel, V., Pincon-Raymond, M., Olivier, J.-L., Chambaz, J., and Pillot, T. (2003) J. Biol. Chem. 278, 3437-3445). Because microtubule-associated proteins (MAPs) are responsible for the polymerization, stabilization, and dynamics of the microtubule network, we investigated whether MAPs might represent the intracellular targets that would enable us to explain the microtubule perturbation involved in soluble Abeta-mediated neuronal apoptosis. The data presented here show that soluble Abeta oligomers induce a time-dependent degradation of MAP1A, MAP1B, and MAP2 involving a perturbation of Ca2+ homeostasis with subsequent calpain activation that, on its own, is sufficient to induce the proteolysis of isoforms MAP2a, MAP2b, and MAP2c. In contrast, MAP1A and MAP1B sequential proteolysis results from the Abeta-mediated activation of caspase-3 and calpain. The prevention of MAP1A, MAP1B, and MAP2 proteolysis by antioxidants highlights the early reactive oxygen species generation in the perturbation of the microtubule network induced by soluble Abeta. These data clearly demonstrate the impact of cytoskeletal perturbations on soluble Abeta-mediated cell death and support the notion of microtubule-stabilizing agents as effective Alzheimer disease drugs.

Amyloid beta-Peptides↗
PubMed1985

Transmembrane signalling by the T cell antigen receptor. Perturbation of the T3-antigen receptor complex generates inositol phosphates and releases calcium ions from intracellular stores.

Antibodies against the T3-antigen receptor complex can activate the human T cell line, Jurkat, to produce interleukin 2 (2-5). This activation is initiated by a receptor-mediated increase in the concentration of free cytoplasmic calcium ions [Ca2+]i (3, 4). In this communication, we investigate the mechanism by which the receptor complex increases [Ca2+ )i in Jurkat cells. The initial receptor-mediated change in [Ca2+]i can occur when extracellular Ca2+ is depleted by EGTA. Perturbation of the T cell antigen receptor, therefore, generates a signal which mobilizes Ca2+ from intracellular stores. As inositol trisphosphate appears to function as such a signal for certain hormone receptors, we measured the levels of inositol trisphosphate and of the other inositol phosphate compounds in Jurkat. Antibodies to either the antigen receptor heterodimer or T3 determinants result in marked elevations of all three inositol phosphates. These changes in inositol phosphates are not secondary to the receptor-mediated increases in [Ca2+]i as demonstrated by the inability of the Ca2+ ionophore, ionomycin, to affect the levels of any of these compounds. In concentrations between 0.1 and 1 microM, purified inositol trisphosphate releases Ca2+ from permeabilized Jurkat cells. Taken together, these data indicate that, during activation, perturbation of the T3-antigen receptor complex generates inositol trisphosphate. This compound functions as an intracellular signal to release Ca2+ from intracellular stores, leading to increases in [Ca2+]i.

Aminoquinolines↗
PubMed1992

Impedances of thin and layered systems: cells with even or odd numbers of interfaces.

Impedance data, e.g., system responses, from perturbing small amplitude applied sinusoid signals of near DC to high kilohertz frequencies, give chemical information. Analysis of frequency-dependent imaginary and real impedance proceeds from equivalent analog circuit elements to chemical and physical significance determined from many model systems. Already, it is possible to interpret bulk transport processes, surface kinetic effects, diffusion phenomena, and dependencies on the type of contacts: symmetric ion contact, symmetric metal contact or asymmetric metal-ion interfaces, and cell design; even (battery or sensor) and odd numbered (constrained junction or immiscible liquid) interfaces in a system. These analyses cover the chemical origins, locations and meanings of the lumped resistances, capacitances and transmission lines that are introduced by engineers in their strict analog interpretations of the impedance data. Examples cover simple ohmic, simple diffusive behavior, complex behavior with surface interfacial kinetics or surface resistances, and with finite (nonblocking) or infinite (blocking) DC impedance. High and low frequency responses may show so-called constant phase element character that suggests fractal behavior. Low frequency data occasionally appear in the second quadrant of impedance plane plots. These results are caused by negative capacitances and resistances. In this paper, chemical interpretations of analog circuit elements are mainly based on theory and observations of thin cells of electrolytes and solid and liquid films (membranes) that are ionic or mixed ionic/electronic conductors. The information should carry over into thickened, gelled, and tissue electrolyte phases and serve as a basis for medically-oriented, perhaps diagnostic impedance measurement applications already pioneered by Herman Schwan.

Electric Conductivity↗
PubMed1989

Physical studies of 5S RNA variants at position 66.

Two variants of the 5S RNA of E. coli have been examined by imino proton NMR spectroscopy, one of them a deletion of A66 (Christiansen, J., Douthwaite, S.R., Christensen, A. and Garrett, R.A. (1985) EMBO J. 4, 1019-1024) and the other a replacement of A66 with a C (Goringer, H.U. and Wagner, R. (1986) Biol. Chem. Hoppe-Seyler 367, 769-780). Both are of interest because the role the bulged A in helix II of 5S RNA is supposed to play in interactions with ribosomal protein L18. The data show that the structural perturbations that result from these mutations are minimal, and assign the resonances of some of the imino protons around position 66. Some mutations at or near position 66 greatly reduce the L18-dependent increase in the circular dichroism of 5S RNA at 267 nm first observed by Bear and coworkers (Bear, D.G., Schleich, T., Noller, H.F. and Garrett, R.A. (1977) Nucl. Acids Res. 4, 2511-2526).

Base Sequence↗
PubMed2006

Perturbation of polyamine metabolism and its relation to cell death in human colon cancer cells treated by 7beta-hydroxycholesterol and 7beta-hydroxysitosterol.

7beta-OHsitosterol and 7beta-OHcholesterol are natural compounds of plant and animal cells with high structural similarity. Recently it was reported that both compounds induced apoptosis on human colon cancer cells by targeting different signalling pathways. Our study aimed at comparing their effects on polyamine metabolism and its relation to apoptosis. When human colon cancer cells were exposed to 7beta-OHsitosterol and to 7beta-OHcholesterol at concentrations inhibiting growth by the same degree, both compounds caused a reduction of polyamine biosynthetic enzyme activity, of the polyamine pools, and an increase of N1-acetylspermidine concentration indicating the enhancement of polyamine catabolism. Exogenous putrescine did not prevent cell death caused by 7beta-OHsitosterol, whereas 7beta-OHcholesterol-induced apoptosis was inhibited. MDL 72527, an inhibitor of polyamine oxidase, an enzyme of the polyamine catabolic pathway, potentiated the antiproliferative effects of 7beta-OHcholesterol by increasing the N1-acetylspermidine pool and enhanced the accumulation of apoptotic cells. In contrast, MDL 72527 did not change the apoptosis rate and the N1-acetylspermidine content in cells treated with 7beta-OHsitosterol. These data indicate that polyamine metabolic perturbations triggered by 7beta-OHcholesterol but not by 7beta-OHsitosterol are related to cell death.

Biogenic Polyamines↗
PubMed1988

Tryptophan sidechain dynamics in hydrophobic oligopeptides determined by use of 13C nuclear magnetic resonance spectroscopy.

Two oligopeptides, t-boc-LAWAL-OMe and t-boc-LALALW-OMe, were synthesized for the purpose of examining the sidechain dynamics of the tryptophan residue in hydrophobic environments by 13C nuclear magnetic resonance and fluorescence spectroscopy. In both peptides, the tryptophan sidechain was greater than 95% enriched with 13C at the C delta 1 position. Spin-lattice relaxation time (T1) and steady-state nuclear Overhauser effect (NOE) data were obtained at 50.3 and 75.4 MHz for both peptides in CD3OD, and at 75.4 MHz for t-boc-LALALW-OMe in lysolecithin-D2O micelles. We have adapted the model-free approach of G. Lipari and A. Szabo (1982, J. Am. Chem. Soc. 104:4546) to interpret the 13C-NMR data. Computer-generated curves based on experimental data obtained at a single frequency demonstrate relationships between an effective correlation time for tryptophan sidechain motion (tau e), a generalized order parameter (sigma) describing the extent of motional restriction, and an overall correlation time for the peptide (tau m). Assuming predominantly dipolar relaxation, least-squares fits of the dual frequency relaxation data provide values for these parameters for both peptides. The contribution of chemical shift anisotropy (CSA), however, is also explicitly assessed in the data analysis, and is shown to perturb the predicted sigma, tau e, and tau m values and to decrease chi(2) values observed in nonlinear least-squares analysis of the data. Because of uncertainty in the contribution of CSA to the relaxation of the indole ring 13C delta 1 atom, nonlinear least-squares analysis of the relaxation data were performed with and without inclusion of a CSA term in the appropriate relaxation equations. Neglecting CSA, an overall peptide correlation time of 0.69 ns is predicted for t-boc-LAWAL-OMe in CD3OD at 20 degrees C compared with 1.28 ns for t-boc-LALALW-OMe. Given these tau m values and taking into account the effect of measurement error in the T1 and NOE data, the internal dynamics of the tryptophan residue of t-boc-LAWAL-OMe in this isotropic environment are described by a range of tau e values from 70 to 112 ps and sigma values between 0.22 and 0.36. Similarly, for t-boc-LALALW-OMe, 68 less than or equal to tau e less than or equal to 93 ps and 0.09 less than or equal to sigma less than or equal to 0.17. The Ch-terminal position of the tryptophan residue in the hexapeptide may account for its lower order parameter. In lysolecithin micelles, the model-free approach applied tot-boc-LALALW-OMe predicts a Te between 0.87 and 1.08 ns, and an order parameter range of 0.72-0.80, assuming an average Tm of 14 ns (Saunders, L. 1966. Biochim. Biophys. Acta. 125:70) for a typical peptide-micelle complex. In this case, measurement of only two 13C relaxation parameters at a single frequency yields sufficient information, plotted in the form of a composite T1-NOE solution curve, to constrain the allowed values of the model-free motional parameters within a relatively narrow range. The predicted range of eV and Te values for the peptide-micelle complex demonstrate that both the rate and spatial mobility of the indole moiety are markedly restrained in the anisotropic micelle environment relative to free methanol solution. Steady-state fluorescence anisotropy measurements made on the peptides dissolved in methanol or with synthetic lysolecithins in water were used to calculate apparent order parameters for tryptophan motion; these values agree well with order parameters calculated from 13C NMR data. The reported results are relevant to the issue of protein dynamic events occurring on the picosecond time scale predicted by molecular dynamics simulations.

Carbon Isotopes↗
PubMed1993

Entropy maximization constrained by solvent flatness: a new method for macromolecular phase extension and map improvement.

A practical generally applicable procedure for exponential modeling to maximum likelihood of macromolecular data sets constrained by a moderately large basis set of reliable phases and a molecular envelope is described, based on the computer program MICE [Bricogne & Gilmore (1990). Acta Cryst. A46, 284-297]. Procedures were first tested with simulated data sets. Exact and randomly perturbed amplitudes and phases were generated, together with a known envelope for solvent-free protein and for protein in an electron-dense crystal mother liquor typical of many real protein crystals. These experiments established useful guidelines and values for various parameters. Tests with basis sets chosen from the largest amplitudes indicate that exponential models with considerable correct extrapolated phase and amplitude information can be constructed from as few as 16% of the total number of reflections, with mean phase errors of about 30 degrees, at resolution limits of either 5 or 3 A. When the shape of the solvent channels in macromolecular crystals is known, it offers an important additional source of information. MICE was, therefore, adapted to average the density outside the molecular boundary defined by an input envelope. This flattening process imposes a uniform density distribution in solvent-filled channels as an additional constraint on the exponential model and is analogous to the treatment of solvent in conventional solvent flattening. Experimental data for cytidine deaminase, a structure recently solved by making extensive use of conventional solvent flattening, provides an example of the performance of maximum-entropy methods in a real situation and a compelling comparison of this method to standard procedures. Exponential models of the electron density constrained by the most reliable phases obtained by multiple isomorphous replacement with anomalous scattering (MIRAS) (figure of merit > 0.7, representing 34% of the total number of reflections) and by the envelope give rise to centroid electron-density maps which are quantitatively superior by numerous statistical criteria to conventionally solvent-flattened density. Similarity of these maps to the 2F(obs) - F(calc) map calculated with phases obtained after crystallographic refinement of the model implies that maximum-entropy extrapolation provides better phases for the remaining 66% of the reflections than the original centroid MIRAS distributions. Importantly, the solvent-flattened electron density, although it did permit interpretation of the map which was not readily accomplished with the MIRAS map, contains substantial errors. It is proposed that errors of this sort may account for previously noted deficiencies of the solvent-flattening method [Fenderson, Herriott & Adman (1990). J. Appl. Cryst. 23, 115-131] and for the occasional tendency of incorrect interpretations to be 'locked in' by crystallographic refinement [Brändén & Jones (1990). Nature (London), 343, 687-689, and references cited therein]. Solvent flattening with combined maximization of entropy and likelihood represents a phase-refinement path independent of atomic models, using the experimental amplitudes and the most reliable phases. It should, therefore, become a valuable and generally useful procedure in macromolecular crystal structure determination.

Journal Article↗
PubMed2003

Is there chaos in the brain? II. Experimental evidence and related models.

The search for chaotic patterns has occupied numerous investigators in neuroscience, as in many other fields of science. Their results and main conclusions are reviewed in the light of the most recent criteria that need to be satisfied since the first descriptions of the surrogate strategy. The methods used in each of these studies have almost invariably combined the analysis of experimental data with simulations using formal models, often based on modified Huxley and Hodgkin equations and/or of the Hindmarsh and Rose models of bursting neurons. Due to technical limitations, the results of these simulations have prevailed over experimental ones in studies on the nonlinear properties of large cortical networks and higher brain functions. Yet, and although a convincing proof of chaos (as defined mathematically) has only been obtained at the level of axons, of single and coupled cells, convergent results can be interpreted as compatible with the notion that signals in the brain are distributed according to chaotic patterns at all levels of its various forms of hierarchy. This chronological account of the main landmarks of nonlinear neurosciences follows an earlier publication [Faure, Korn, C. R. Acad. Sci. Paris, Ser. III 324 (2001) 773-793] that was focused on the basic concepts of nonlinear dynamics and methods of investigations which allow chaotic processes to be distinguished from stochastic ones and on the rationale for envisioning their control using external perturbations. Here we present the data and main arguments that support the existence of chaos at all levels from the simplest to the most complex forms of organization of the nervous system. We first provide a short mathematical description of the models of excitable cells and of the different modes of firing of bursting neurons (Section 1). The deterministic behavior reported in giant axons (principally squid), in pacemaker cells, in isolated or in paired neurons of Invertebrates acting as coupled oscillators is then described (Section 2). We also consider chaotic processes exhibited by coupled Vertebrate neurons and of several components of Central Pattern Generators (Section 3). It is then shown that as indicated by studies of synaptic noise, deterministic patterns of firing in presynaptic interneurons are reliably transmitted, to their postsynaptic targets, via probabilistic synapses (Section 4). This raises the more general issue of chaos as a possible neuronal code and of the emerging concept of stochastic resonance Considerations on cortical dynamics and of EEGs are divided in two parts. The first concerns the early attempts by several pioneer authors to demonstrate chaos in experimental material such as the olfactory system or in human recordings during various forms of epilepsies, and the belief in 'dynamical diseases' (Section 5). The second part explores the more recent period during which surrogate-testing, definition of unstable periodic orbits and period-doubling bifurcations have been used to establish more firmly the nonlinear features of retinal and cortical activities and to define predictors of epileptic seizures (Section 6). Finally studies of multidimensional systems have founded radical hypothesis on the role of neuronal attractors in information processing, perception and memory and two elaborate models of the internal states of the brain (i.e. 'winnerless competition' and 'chaotic itinerancy'). Their modifications during cognitive functions are given special attention due to their functional and adaptive capabilities (Section 7) and despite the difficulties that still exist in the practical use of topological profiles in a state space to identify the physical underlying correlates. The reality of 'neurochaos' and its relations with information theory are discussed in the conclusion (Section 8) where are also emphasized the similarities between the theory of chaos and that of dynamical systems. Both theories strongly challenge computationalism and suggest that new models are needed to describe how the external world is represented in the brain.

Animals↗
PubMed2002

Perturbative QCD analysis of local duality in a fixed w2 framework.

We study the Q2 dependence of large x F2 nucleon structure function data, with the aim of providing a perturbative QCD based, quantitative analysis of parton-hadron duality. As opposed to previous analyses at fixed x, we use a framework in fixed W2. We uncover a breakdown of the twist-4 approximation with a renormalon type improvement at O(1/Q(4)) which affects the initial evolution of parton distributions.

Journal Article↗
PubMed2006

Beta-sheet folding mechanisms from perturbation energetics.

Amide backbone and sidechain mutagenesis data can be used in combination with kinetic and thermodynamic measurements to understand the energetic contributions of backbone hydrogen bonding and the hydrophobic effect to the acquisition of beta-sheet structure. For example, it has been revealed that loop 1 of the WW domain forms in the transition state, consistent with the emerging theme that reverse turn formation is rate limiting in beta-sheet folding. A distinct subset of WW domain residues principally influences thermodynamic stability by forming hydrogen bonds and hydrophobic interactions that stabilize the native state. Energetic data and sequence mining reveal that only a small subset of the molecular information contained in sequences or observed in high-resolution structures is required to generate folded functional beta-sheets, consistent with evolutionary robustness.

Animals↗
PubMed2006

Auditory startle alters the response of human subjects exposed to a single whiplash-like perturbation.

STUDY DESIGN: Human volunteers were exposed to a single whiplash-like perturbation. OBJECTIVE: To determine how muscle and kinematic responses are affected by the superposition of a rear-end collision and loud startling noise. SUMMARY OF BACKGROUND DATA: Many whiplash studies use forward perturbations without reproducing the sound of a car crash. Loud sounds are known to evoke startle responses in the neck muscles and therefore could affect whiplash injuries. METHODS: Sixty-five subjects (30 female, 35 male) were exposed to a single forward horizontal perturbation. Head and torso kinematics, and electromyographic activity in the sternohyoid, sternocleidomastoid, scalenus, and cervical paraspinal muscles were measured. Two awareness conditions (deceived and unaware subjects) nested in two startle conditions (with or without a 40 milliseconds, 124 dB sound) were tested. RESULTS: Startle and gender affected the amplitude and timing of numerous kinematic and muscle variables. Awareness affected only one muscle variable. Startled individuals exhibited greater peak head and trunk accelerations, increased activity of the cervical paraspinal muscles, and a reduced head retraction and trunk angle. CONCLUSIONS: An acoustic startle alters the neck muscle and kinematic responses and may be as important as gender in the genesis of whiplash injury.

Acoustic Stimulation↗