RESUMEN
The alpha rhythm is the longest-studied brain oscillation and has been theorized to play a key role in cognition. Still, its physiology is poorly understood. In this study, we used microelectrodes and macroelectrodes in surgical epilepsy patients to measure the intracortical and thalamic generators of the alpha rhythm during quiet wakefulness. We first found that alpha in both visual and somatosensory cortex propagates from higher-order to lower-order areas. In posterior cortex, alpha propagates from higher-order anterosuperior areas toward the occipital pole, whereas alpha in somatosensory cortex propagates from associative regions toward primary cortex. Several analyses suggest that this cortical alpha leads pulvinar alpha, complicating prevailing theories of a thalamic pacemaker. Finally, alpha is dominated by currents and firing in supragranular cortical layers. Together, these results suggest that the alpha rhythm likely reflects short-range supragranular feedback, which propagates from higher- to lower-order cortex and cortex to thalamus. These physiological insights suggest how alpha could mediate feedback throughout the thalamocortical system.
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Ritmo alfa , Corteza Cerebral/fisiología , Electrodos , Electroencefalografía , Humanos , Tálamo/fisiologíaRESUMEN
This study exemplifies the use of three ADHD-relevant methodological innovations. (1) The use of novel, patented, computational peptide design techniques to generate peptides targeting the extra-cellular and para-transmembrane amino acid loops of the putatively ADHD-involved, D(2) dopamine receptor, D(2)DAR; (2) experimental evidence that these peptides in L-amino acid/ortho ordered or D-amino acid/reverse ordered (retro-inverso), D(2)DAR, hydrophobic eigenmode matched forms, evoked positive allosteric and indirect agonist influences on in vitro stably receptor transfected CHO and LtK cells and on in vivo, brain mediated activity; (3) a representative 15 residue all-D-amino acid, D(2) mode matched peptide, given parenterally, was found to "repair" a key aberrant ADHD behavioral characteristic in a standard animal model of ADHD, the Spontaneously Hypertensive Rat, SHR, relative to its progenitor species control, the Wistar-Kyoto rat, WKY. The representative, retro-inverso peptide, all-D-LLYKNKPRYPKRNRE, reversed SHR's relative deficiency in sensory motor gating (pre-pulse inhibition, PPI) while leaving SHR's nonselective attention (rearings), impulsive behavior (time in center), and activity level (timed total motor behavior) unchanged. Amphetamine also reversed SHRs sensory gating defect, but with significant increases in nonselective attention, impulsivity and hyperactivity. These preliminary results suggest the possibility of a new, "softer" pharmacological approach to ADHD: hydrophobic mode matched peptide allosteric augmentation of the activity of indigenous dopamine with respect to D(2)DAR mediated function, in place of stimulant drug-induced presynaptic dopamine release or impairment of dopamine uptake.
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Algoritmos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Diseño Asistido por Computadora , Trastornos Mentales/tratamiento farmacológico , Péptidos/química , Péptidos/uso terapéutico , Estimulación Acústica/efectos adversos , Sitio Alostérico/efectos de los fármacos , Anfetamina/uso terapéutico , Animales , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Conducta Animal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/uso terapéutico , Modelos Animales de Enfermedad , Dopamina/química , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Masculino , Trastornos Mentales/etiología , Inhibición Neural/efectos de los fármacos , Ratas , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Reflejo de Sobresalto/fisiología , Reflejo de Sobresalto/efectos de la radiación , Especificidad de la Especie , Factores de TiempoRESUMEN
Patterns in G-protein-coupled receptors' hydrophobically transformed amino-acid sequences can be computationally characterized as hierarchies of autocorrelation waves, "hydrophobic eigenmodes", using autocovariance matrix decomposition and all poles power spectral and wavelet transformations. L- or D-amino acid (retro-inverso) 12-18 residue peptides targeting these modes can be designed using eigenvector templates derived from these computations. In all, 12 human long-form D(2) dopamine receptor eigenmode-targeted 15 mer peptides were designed, synthesized, and shown to modulate and/or indirectly activate the extracellular acidification response, EAR, in stably receptor-transfected CHO and LtK cells, with an 83% hit rate. Representative L- and D-amino-acid retro-inverso peptides injected bilaterally in the nucleus accumbens demonstrated changes in rat exploratory behavior and prepulse inhibition similar to those observed following parenteral amphetamine. In contrast with geometric models used for ligand design, such as pharmacophores, the hydrophobic eigenmode approach to lead modulatory peptide design targets hydrophobic eigenmode-bearing subsequences, including those not visible from X-ray and NMR studies such as extracellular segments and loops.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Conducta Exploratoria/fisiología , Péptidos/metabolismo , Receptores de Dopamina D2/metabolismo , Secuencia de Aminoácidos , Animales , Cricetinae , Dopamina/metabolismo , Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Datos de Secuencia Molecular , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Péptidos/administración & dosificación , Péptidos/genética , Ratas , Ratas Sprague-DawleyRESUMEN
That the topological entropy, h(T(&mgr;) ), of a C(1
RESUMEN
What are the functional neuroimaging measurements required for more fully characterizing the events and locations of neocortical activity? A prime assumption has been that modulation of cortical activity will inevitably be reflected in changes in energy utilization (for the most part) changes of glucose and oxygen consumption. Are such a measures complete and sufficient? More direct measures of cortical electrophysiological activity show event or task-related modulation of amplitude or band-limited oscillatory power. Using magnetoencephalography (MEG), these measures have been shown to correlate well with energy utilization sensitive BOLD fMRI. In this paper, we explore the existence of state changes in electrophysiological cortical activity that can occur independently of changes in averaged amplitude, source power or indices of metabolic rates. In addition, we demonstrate that such state changes can be described by applying a new measure of complexity, rank vector entropy (RVE), to source waveform estimates from beamformer-processed MEG. RVE is a non-parametric symbolic dynamic informational entropy measure that accommodates the wide dynamic range of measured brain signals while resolving its temporal variations. By representing the measurements by their rank values, RVE overcomes the problem of defining embedding space partitions without resorting to signal compression. This renders RVE-independent of absolute signal amplitude. In addition, this approach is robust, being relatively free of tunable parameters. We present examples of task-free and task-dependent MEG demonstrating that RVE provides new information by uncovering hidden dynamical structure in the apparent turbulent (or chaotic) dynamics of spontaneous cortical activity.
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Mapeo Encefálico , Encéfalo/fisiopatología , Magnetoencefalografía , Red Nerviosa/fisiopatología , Esquizofrenia/fisiopatología , Encéfalo/patología , Mapeo Encefálico/métodos , Humanos , Magnetoencefalografía/métodos , Red Nerviosa/patología , Vías Nerviosas/fisiopatología , Esquizofrenia/diagnósticoRESUMEN
Bacillus subtilis spores were immobilized in activated charcoal and tapioca and filled with acacia gum. These formulations were tested for spore stability during storage at temperatures ranging from 40 degrees C to 90 degrees C and for bacterial release. Thermodynamic analysis showed that immobilization of spores in acacia gum significantly increased their viability compared with unprotected spores. The viability was further increased when suspensions of spores in acacia gum were added to granules of charcoal and tapioca. The number of the spores released after storage was also increased when spores were treated with acacia gum prior to immobilization in tapioca and charcoal. Formulations of Bacillus spores with acacia gum and porous carriers (charcoal and tapioca) prolong the anticipated shelf-life of spores even under ambient temperature and provide slow and steady bacterial release consistent with their high viability.
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Bacillus subtilis/fisiología , Materiales Biocompatibles/química , Termodinámica , Acacia/química , Carbón Orgánico/química , Goma Arábiga/química , Manihot/química , Porosidad , Esporas Bacterianas/fisiología , Propiedades de Superficie , Factores de TiempoRESUMEN
Patented signal analytic algorithms applied to hydrophobically transformed, numerical amino acid sequences have previously been used to design short, protein-targeted, L or D retro-inverso peptides. These peptides have demonstrated allosteric and/or indirect agonist effects on a variety of G-protein and tyrosine kinase coupled membrane receptors with 30% to over 80% hit rates. Here we extend these approaches to a globular protein target. We designed eight peptide ligands targeting an ELISA antibody responsive protein, beta-galactosidase, betaGAL. Three of the eight 14mer peptides allosterically activated betaGAL with ELISA methodology. Using Bayesian statistics, this 38% hit rate would have occurred 2 x 10(-9) by chance. These peptides demonstrated binding site competitive or noncompetitive interactions, suggesting allosteric site multiplicity with respect to their betaGAL binding-mediated ELISA signal. Kinetic studies demonstrated the temperature dependence of the betaGAL peptide binding functions. Using the van't Hoff relation, we found evidence for enthalpy-entropy compensation. This relation is often found for hydrophobic interactions in aqueous media, and is consistent with the postulated hydrophobic series encoding underlying our protein-targeted, peptide design methods. It appears that our algorithmic, hydrophobic autocovariance eigenvector template approach to the design of allosteric peptides targeting membrane receptors may also be applicable to the design of peptide ligands targeting nonmembrane involved globular proteins.
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Sitio Alostérico/efectos de los fármacos , Diseño de Fármacos , Péptidos/química , Receptores de Superficie Celular/agonistas , beta-Galactosidasa/química , Secuencia de Aminoácidos , Unión Competitiva , Ligandos , Datos de Secuencia Molecular , Péptidos/farmacología , Pliegue de Proteína , Termodinámica , beta-Galactosidasa/efectos de los fármacosRESUMEN
A new proprietary de novo peptide design technique generated ten 15-residue peptides targeting and containing the leading nontransmembrane hydrophobic autocorrelation wavelengths, "modes", of the human m(1) muscarinic cholinergic receptor, m(1)AChR. These modes were also shared by the m(4)AChR subtype (but not the m(2), m(3), or m(5) subtypes) and the three-finger snake toxins that pseudoirreversibly bind m(1)AChR. The linear decomposition of the hydrophobically transformed m(1)AChR amino acid sequence yielded ordered eigenvectors of orthogonal hydrophobic variational patterns. The weighted sum of two eigenvectors formed the peptide design template. Amino acids were iteratively assigned to template positions randomly, within hydrophobic groups. One peptide demonstrated significant functional indirect agonist activity, and five produced significant positive allosteric modulation of atropine-reversible, direct-agonist-induced cellular activation in stably m(1)AChR-transfected Chinese hamster ovary cells, reflected in integrated extracellular acidification responses. The peptide positive allosteric ligands produced left-shifts and peptide concentration-response augmentation in integrated extracellular acidification response asymptotic sigmoidal functions and concentration-response behavior in Hill number indices of positive cooperativity. Peptide mode specificity was suggested by negative crossover experiments with human m(2)ACh and D(2) dopamine receptors. Morlet wavelet transformation of the leading eigenvector-derived, m(1)AChR eigenfunctions locates seven hydrophobic transmembrane segments and suggests possible extracellular loop locations for the peptide-receptor mode-matched, modulatory hydrophobic aggregation sites.