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PubMed1993

A protein kinase similar to MAP kinase activator acts downstream of the raf kinase in Drosophila.

D-raf, a Drosophila homolog of Raf-1, plays key roles in multiple signal transduction pathways. Dsor1, a putative factor downstream of D-raf, was genetically identified by screening of dominant suppressors of D-raf. Dsor1Su1 mapped on X chromosome significantly suppressed the D-raf mutant phenotypes, and the loss-of-function mutations of Dsor1 showed phenotypes similar to those of the D-raf null mutations. Dsor1Su1 also significantly suppressed the mutations of other terminal class genes acting further upstream of D-raf. Molecular cloning of Dsor1 revealed its product with striking similarity to the microtubule-associated protein (MAP) kinase activator and yeast PBS2, STE7, and byr1. Our genetic results demonstrate the connection between raf and the highly conserved protein kinase cascade involving MAP kinase in vivo.

Amino Acid Sequence↗
PubMed1995

Effects of channel-to-electrode mappings on speech reception with the ineraid cochlear implant.

OBJECTIVE: Research was conducted to assess multichannel saliency with the Ineraid cochlear prosthesis. The goal was to determine whether tonotopically ordered stimulation benefits speech reception. DESIGN: In a single high-performing subject, changes in speech reception were studied during two dramatic alterations to the normal (tonotopic) mapping between the sound-processors's four filter channels and the intracochlear electrode array: In one alteration, the four filter outputs were summed and delivered to one electrode; this single-channel mapping was worn for 7 days. In another alteration, the four filter outputs were connected in reverse tonotopic order to four intracochlear electrodes; this reversed mapping was worn for 3 days. RESULTS: When using the implant in conjunction with speechreading, all three mappings provided large gains over speechreading alone on the recognition of words in sentences. When using the implant alone (without speechreading), tests of consonant and vowel recognition, and the recognition of words in isolation and in sentences all showed substantial decreases in performance across the three mapping conditions: normal > single-channel > reversed. The patterns of segmental confusions and the relations among scores on different tests were highly consistent. Finally, the performance with the altered mappings was, in some ways, remarkably good. With single-channel mapping, 15% word recognition was obtained, much less than the 54% obtained with the normal mapping, but demonstrative of some open-set speech reception. With the reversed mapping, high levels of consonantal voicing and manner information were received, indicating good reception of time-intensity cues, but open-set word recognition was near zero. CONCLUSIONS: Despite the extensive spread of current associated with monopolar intracochlear stimulation, the Ineraid electrode array affords a degree of perceptual selectivity that substantially aids speech reception.

Adult↗
PubMed2000

Direct visualisation of conformational changes in EF(0)F(1) by electron microscopy.

The isolated H(+)-ATPase from Escherichia coli (EF(0)F(1)) was investigated by electron microscopy of samples of negatively stained monodisperse molecules, followed by single-particle image processing. The resulting three-dimensional maps showed that the F(1)-part is connected by a prominent stalk to a more peripheral part of F(0). The F(1)-part showed stain-accessible cavities inside. In three-dimensional maps from selected particles, a second stalk could be detected which was thinner than the main stalk and is thought to correspond to the stator.Three-dimensional maps of the enzyme in the absence and in the presence of the substrate analogue adenyl-beta, gamma-imidodiphosphate (AMP-PNP) were calculated. Upon binding of AMP-PNP the three-dimensional maps showed no significant changes in the F(0)-part of EF(0)F(1), whereas a major conformational change in the F(1)-part was observed. (1) The diameter of the F(1)-part decreased upon binding of AMP-PNP mainly in the upper half of F(1). (2) Enzyme particles prepared in the presence of AMP-PNP had a pointed cap at the top of the F(1)-part which was missing in its absence. (3) The stain-accessible cavity inside the F(1)-part altered its pattern significantly.

Adenylyl Imidodiphosphate↗
PubMed1972

The three-dimensional structure of yeast phenylalanine transfer RNA: shape of the molecule at 5.5-A resolution.

Three isomorphous heavy-atom derivatives have been obtained of orthorhombic crystals of phenylalanine transfer RNA from yeast. These derivatives contain osmium, samarium, and platinum. The positions of the heavy atoms have been determined; these have been used to calculate a three-dimensional electron-density map of transfer RNA at a resolution of 5.5 A. The map shows a high contrast between the molecular boundaries and the solvent areas, so that most of the external shape of the molecule can be determined. The molecule appears to be 92 A long and to have a width varying from 16 A to 34 A. There are some narrow regions in the molecule that connect more globular regions. The electron density map shows chains of dense objects approximately 6 A apart that are probably due to adjacent phosphate groups on the polynucleotide chain. At the present stage of the analysis it is not possible to trace the entire backbone unambiguously; however, the data at this resolution suggest no apparent similarity between the folding of the molecule and any of the tertiary structure models proposed for transfer RNA.

Models, Structural↗
PubMed2005

The chronoarchitecture of the cerebral cortex.

We review here a new approach to mapping the human cerebral cortex into distinct subdivisions. Unlike cytoarchitecture or traditional functional imaging, it does not rely on specific anatomical markers or functional hypotheses. Instead, we propose that the unique activity time course (ATC) of each cortical subdivision, elicited during natural conditions, acts as a temporal fingerprint that can be used to segregate cortical subdivisions, map their spatial extent, and reveal their functional and potentially anatomical connectivity. We argue that since the modular organisation of the brain and its connectivity evolved and developed in natural conditions, these are optimal for revealing its organisation. We review the concepts, methodology and first results of this approach, relying on data obtained with functional magnetic resonance imaging (fMRI) when volunteers viewed traditional stimuli or a James Bond movie. Independent component analysis (ICA) was used to identify voxels belonging to distinct functional subdivisions, based on their differential spatio-temporal fingerprints. Many more regions could be segregated during natural viewing, demonstrating that the complexity of natural stimuli leads to more differential responses in more functional modules. We demonstrate that, in a single experiment, a multitude of distinct regions can be identified across the whole brain, even within the visual cortex, including areas V1, V4 and V5. This differentiation is based entirely on the differential ATCs of different areas during natural viewing. Distinct areas can therefore be identified without any a priori hypothesis about their function or spatial location. The areas we identified corresponded anatomically across subjects, and their ATCs showed highly area-specific inter-subject correlations. Furthermore, natural conditions led to a significant de-correlation of interregional ATCs compared to rest, indicating an increase in regional specificity during natural conditions. In contrast, the correlation between ATCs of distant regions of known substantial anatomical connections increased and reflected their known anatomical connectivity pattern. We demonstrate this using the example of the language network involving Broca's and Wernicke's area and homologous areas in the two hemispheres. In conclusion, this new approach to brain mapping may not only serve to identify novel functional subdivisions, but to reveal their connectivity as well.

Brain Mapping↗
PubMed2001

Minimal vertex covers on finite-connectivity random graphs: a hard-sphere lattice-gas picture.

The minimal vertex-cover (or maximal independent-set) problem is studied on random graphs of finite connectivity. Analytical results are obtained by a mapping to a lattice gas of hard spheres of (chemical) radius 1, and they are found to be in excellent agreement with numerical simulations. We give a detailed description of the replica-symmetric phase, including the size and entropy of the minimal vertex covers, and the structure of the unfrozen component which is found to percolate at a connectivity c approximately 1.43. The replica-symmetric solution breaks down at c=e approximately 2.72. We give a simple one-step replica-symmetry-broken solution, and discuss the problems in the interpretation and generalization of this solution.

Journal Article↗
PubMed1975

The arrangement of germ cells in the rat seminiferous tubule: an electron-microscope study.

The spermatogonia and early spermatocytes of 13 samples of rat seminiferous epithelium (about 0-05 mm2 each) were mapped from electron micrographs of serial sections. Clones of cells, connected by cytoplasmic bridges (syncytia of 2-100 cells), in various stages of spermatogenic development were identified. Maps of 7 separate areas are illustrated. It is concluded that, contrary to the models of spermatogonial proliferation based on light-microscope observations, regions of seminiferous epithelium which are identical in terms of spermatid and spermatocyte criteria have, in fact, quantitative and qualitative differences in their spermatogonial population. The data are interpreted that for a given epithelial area there is a periodic build-up of spermatogonia which then produce several successive quanta of spermatocytes and when the spermatogonia are depleted the process repeats. That cell numbers less than double following a mitotic cycle has generally been attributed to systematic degeneration. Evidence from electron microscopy indicates, however, that at the mitotic peaks not all the syncytia undergo division but that some remain arrested. Similarly, within a dividing syncytium a few cells do not divide while they advance developmentally with the syncytium as a whole. The observed large size of spermatocyte syncytia further argues against systematic degeneration with its attendant fragmentation of syncytia.

Animals↗
PubMed2004

C-peptide stimulates Na+, K+-ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells.

Proinsulin-connecting peptide (C-peptide) exerts physiological effects partially via stimulation of Na(+), K(+)-ATPase. We determined the molecular mechanism by which C-peptide stimulates Na(+), K(+)-ATPase in primary human renal tubular cells (HRTCs). Incubation of the cells with 5 nM human C-peptide at 37 degrees C for 10 min stimulated (86)Rb(+) uptake by 40% (p<0.01). The carboxy-terminal pentapeptide was found to elicit 57% of the activity of the intact molecule. In parallel with ouabain-sensitive (86)Rb(+) uptake, C-peptide increased alpha subunit phosphorylation and basolateral membrane (BLM) abundance of the Na(+), K(+)-ATPase alpha(1) and beta(1) subunits. The increase in BLM abundance of the Na(+), K(+)-ATPase alpha(1) and beta(1) subunits was accompanied by depletion of alpha(1) and beta(1) subunits from the endosomal compartments. C-peptide action on Na(+), K(+)-ATPase was ERK1/2-dependent in HRTCs. C-peptide-stimulated Na(+), K(+)-ATPase activation, phosphorylation of alpha(1)-subunit and translocation of alpha(1) and beta(1) subunits to the BLM were abolished by a MEK1/2 inhibitor (20 muM PD98059). C-peptide stimulation of (86)Rb(+) uptake was also abolished by preincubation of HRTCs with an inhibitor of PKC (1 muM GF109203X). C-peptide stimulated phosphorylation of human Na(+), K(+)-ATPase alpha subunit on Thr-Pro amino acid motifs, which form specific ERK substrates. In conclusion, C-peptide stimulates sodium pump activity via ERK1/2-induced phosphorylation of Thr residues on the alpha subunit of Na(+), K(+)-ATPase.

Amino Acid Sequence↗
PubMed2001

Slow IPSC kinetics, low levels of alpha1 subunit expression and paired-pulse depression are distinct properties of neonatal inhibitory GABAergic synaptic connections in the mouse superior colliculus.

Remodelling of visual maps in the superior colliculus (SC) depends on neuronal activity. Synaptic inhibition could contribute to this process because spontaneous spike discharge in the SC was modulated by GABA(A) receptor activation at postnatal days (P) 1-3. To investigate the functional capacity of GABAergic synaptic transmission at this early stage of development, whole-cell patch-clamp recordings were made from wide field neurons (WFNs) in horizontal slices comprising the superficial grey layer of the SC. Focal stimulation in the vicinity of WFNs evoked tetrodotoxin-sensitive stimulus-locked inhibitory postsynaptic currents (eIPSCs). The failure rate of eIPSCs was low ( approximately 0.2), and the maximal amplitude of evoked unitary eIPSCs exceeded the amplitude of average miniature IPSCs (mIPSCs) by a factor of 4-5, suggesting that action potential-mediated GABA release was more effective than spontaneous release. Some of the properties of GABAergic synaptic transmission in the neonatal SC were age-specific. In contrast with eIPSCs in the more mature SC at P20-22, neonatal eIPSCs decayed more slowly, preferentially fluctuated in duration, not amplitude, and mostly lacked temporal summation, due to depression at shorter intervals. The paired-pulse ratio (eIPSC2 : eIPSC1) was inversely related to the duration of eIPSCs. PCR analysis showed, in addition, that the ratio of alpha1 : alpha3 subunit expression was lower in the neonatal SC. Together, these results suggest that, at a young age, efficacy of GABAergic synaptic transmission is primarily constrained by the slow kinetics and the saturation of postsynaptic GABA(A) receptors.

Action Potentials↗
PubMed2000

Growth of new brainstem connections in adult monkeys with massive sensory loss.

Somatotopic maps in the cortex and the thalamus of adult monkeys and humans reorganize in response to altered inputs. After loss of the sensory afferents from the forelimb in monkeys because of transection of the dorsal columns of the spinal cord, therapeutic amputation of an arm or transection of the dorsal roots of the peripheral nerves, the deprived portions of the hand and arm representations in primary somatosensory cortex (area 3b), become responsive to inputs from the face and any remaining afferents from the arm. Cortical and subcortical mechanisms that underlie this reorganization are uncertain and appear to be manifold. Here we show that the face afferents from the trigeminal nucleus of the brainstem sprout and grow into the cuneate nucleus in adult monkeys after lesions of the dorsal columns of the spinal cord or therapeutic amputation of an arm. This growth may underlie the large-scale expansion of the face representation into the hand region of somatosensory cortex that follows such deafferentations.

Afferent Pathways↗
PubMedDate not supplied

Non-homogenous neural networks with chaotic recursive nodes: connectivity and multi-assemblies structures in recursive processing elements architectures.

This paper addresses recurrent neural architectures based on bifurcating nodes that exhibit chaotic dynamics, with local dynamics defined by first order parametric recursions. In the studied architectures, logistic recursive nodes interact through parametric coupling, they self organize, and the network evolves to global spatio-temporal period-2 attractors that encode stored patterns. The performance of associative memories arrangements is measured through the average error in pattern recovery, under several levels of prompting noise. The impact of the synaptic connections magnitude on architecture performance is analyzed in detail, through pattern recovery performance measures and basin of attraction characterization. The importance of a planned choice of the synaptic connections scale in RPEs architectures is shown. A strategy for minimizing pattern recovery degradation when the number of stored patterns increases is developed. Experimental results show the success of such strategy. Mechanisms for allowing the studied associative networks to deal with asynchronous changes in input patterns, and tools for the interconnection between different associative assemblies are developed. Finally, coupling in heterogeneous assemblies with diverse recursive maps is analyzed, and the associated synaptic connections are equated.

Algorithms↗
PubMed1982

Topography between the entorhinal cortex and the dentate septotemporal axis in rats: I. Medial and intermediate entorhinal projecting cells.

Retrograde tracing experiments were performed to clarify the topographic projection from medial (area 28m) and intermediate (area 28i) divisions of the entorhinal cortex to the dentate gyrus. Pipets filled with horseradish peroxidase (HRP) were positioned by electrophysiologic guidance at one of several septotemporal (S-T) levels in the dentate molecular layer of anesthetized rats; the tracer was expelled iontrophoretically to minimize its spread. Retrograde labeling of neurons within areas 28m and 28i was analyzed in relation to cytoarchitectonic as well as spatial features of the region (obtained by histologic reconstruction). Regardless of the S-T level, ejections of HRP which were confined to the dentate gyrus labeled only layer II neurons of each area. Following septal pole ejections, labeled neurons were located in the posterolateral, extreme posterior, and posteromedial parts of both areas 28m and 28i. Mid S-T ejections produced not only a ventral, but also an anteromedial, shift in the location of entorhinal projection cells; no cells were labeled posterolaterally. After temporal dentate ejections labeled neurons occupied the most anteromedial part of these entorhinal areas. For both areas, but especially for area 28i, convergence of entorhinal efferents upon a single S-T level in the dentate gyrus occurred from neurons which lay in a dorsoventral (i.e., frontal), and to a lesser extent a rostrocaudal, plane. The efferent axes of both areas 28m and 28i thus appear to be curved and are therefore best described in three dimensions. The entorhinal axes begin in a posterodorsolateral location, wrap around the posterior cortical convexity, and end in an anteroventromedial position. The results provide a useful map for in situ exploration of entorhinodentate connections in the rat, emphasize the parallel innervation of the dentate gyrus by distinct entorhinal fiber systems, and reflect the importance of the S-T axis as a framework for interpreting hippocampal organization.

Animals↗
PubMed1999

Specificity and strength of retinogeniculate connections.

Retinal ganglion cells and their target neurons in the principal layers of the lateral geniculate nucleus (LGN) of the thalamus have very similar, center-surround receptive fields. Although some geniculate neurons are dominated by a single retinal afferent, others receive both strong and weak inputs from several retinal afferents. In the present study, experiments were performed in the cat that examined the specificity and strength of monosynaptic connections between retinal ganglion cells and their target neurons. The responses of 205 pairs of retinal ganglion cells and geniculate neurons with overlapping receptive-field centers or surrounds were studied. Receptive fields were mapped quantitatively using a white-noise stimulus; connectivity was assessed by cross-correlating the retinal and geniculate spike trains. Of the 205 pairs, 12 were determined to have monosynaptic connections. Both the likelihood that cells were connected and the strength of connections increased with increasing similarity between retinal and geniculate receptive fields. Connections were never found between cells with <50% spatial overlap between their centers. The results suggest that although geniculate neurons often receive input from several retinal afferents, these multiple afferents represent a select subset of the retinal ganglion cells with overlapping receptive-field centers.

Animals↗
PubMed1987

Sagittal cytoarchitectonic maps of the Macaca mulatta thalamus with a revised nomenclature of the motor-related nuclei validated by observations on their connectivity.

Cytoarchitectonic atlas plates of the Macaca mulatta thalamus are presented in the sagittal plane of section with a revised nomenclature of the motor thalamic region. The proposed changes in nomenclature are based on the analysis of topographical relationships between nigral, pallidal, and cerebellar projections to the thalamus studied in 13 rhesus monkeys with the use of autoradiography technique. Mapping of the projection zones of these motor-related systems in serial sagittal sections revealed that they are completely segregated with each honoring cytoarchitectonic boundaries of specific nuclear subdivisions. The available data on thalamic connectivity together with the results of the present study allowed us to divide the primate "motor" thalamus into two major territories: (1) the ventral anterior region (VA) and (2) the ventral lateral region (VL). Although the designation of these two areas of the motor thalamus is the same as the classic one, the nuclear subdivisions that compose them differ significantly from those described in previous classifications. As is delineated in the maps, VA represents the basal ganglia territory of the motor thalamus where nigral projections coincide with its magnocellular part (VAmc), and pallidal projections occupy densicellular (VAdc) and parvicellular (VApc) subdivisions. VAdc corresponds closely to VLo of Olszewski; however, we prefer the new term in order to avoid possible conceptual confusions with the ventral lateral region (VL), which does not receive basal ganglia projections. The VL region is characterized as a distinct cytoarchitectonic entity of the motor thalamus that receives cerebellar projections and includes area X, VPLo, VLc, and VLps of Olszewski. The ventral medial region (VM in the present study or VLm in Olszewski terminology) is usually considered together with the basal ganglia territory on a common connectional basis. However, we did not obtain convincing data to support this view, since evidence of terminal labeling was observed only in (or around) fiber bundles passing through the nucleus with other areas free of label. Rather, in this study VM was treated as an intermediate zone between the subthalamus and motor thalamus where fiber bundles from basal ganglia and cerebellum are organized in a topographical manner before reaching their destinations in the VA and VL regions, respectively. Other major thalamic regions represented in the maps were delineated purely on cytoarchitectonic grounds and their traditional nomenclature was maintained.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Components of the signaling pathway linking the 1-methyladenine receptor to MPF activation and maturation in starfish oocytes.

Starfish oocytes are arrested at the G2/M-phase border of meiosis I. Exposure to their natural mitogen, 1-methyladenine (1-MA), leads to the activation of MPF and MAP kinase, resumption of the meiotic cell cycle, and fertilization competency. The 1-MA receptor has not yet been identified, but it is known to be linked functionally to a pertussis toxin-sensitive G-protein. G beta gamma appears to be the major effector of the 1-MA receptor, since injection of G beta gamma, but not activated G alpha i, leads to the activation of MPF, entry into meiosis, and oocyte maturation. The components that connect G beta gamma to MPF and MAP kinase activation in oocytes are unknown. In mammalian cells, a novel phosphatidylinositol 3-kinase, PI-3 kinase-gamma, links G beta gamma to the MAP kinase activation pathway. Here we show that PI-3 kinase is required for starfish oocyte maturation. LY294002 and wortmannin, inhibitors of PI-3 kinase, block MPF and MAP kinase activation and entry into meiosis. Inhibition by LY294002 is reversible and limited to the hormone-dependent period. Neither inhibitor, however, blocks the earliest hormone-induced event, formation of actin spikes at the cell membrane. By contrast, pertussis toxin blocks both actin spiking and later events, arguing that PI-3 kinase functions downstream of G beta gamma. Finally, we show that unlike the well-studied case in Xenopus oocytes, where MAP kinase is an essential component of the MPF activation pathway, MAP kinase is not required for either MPF activation or subsequent oocyte maturation in starfish. Instead, its major role appears to be suppression of DNA synthesis in unfertilized, haploid eggs.

Animals↗
PubMed2001

Mapping as a method for analysing policy response in the management of health services.

Health services are susceptible to changes in health need, resource allocation, public-health debates and health policies. Service mapping is considered a useful tool for analysing complex issues, monitoring changes over time and facilitating change. It also enables one to describe pathways of care and the relationships between services. This article centres on two projects--a London-wide project 'Service networks for HIV Care' and a local survey 'Mapping of HIV-related services for illicit drug users'--and demonstrates the usefulness of mapping for both studies. Mapping of service networks allowed exploration of a variety of connections between treatment centres, and led to recommendations for a model of HIV service networks across London. The mapping of HIV-related services for illicit drug users confirmed that the service provision was balanced in time, space and target groups, but also identified gaps showing that services were not very successful in attracting women and members of ethnic minority groups. It is clear from both studies that mapping provides an overview of existing services, describing details of services, their target groups or links. It can assist to monitor changes over time, to reconfigure services according to need, and to target resources where need becomes apparent. Mapping exercises also can be useful in identifying new areas for collaboration and interagency work.

Community Health Planning↗
PubMed2001

Tonotopic map of potassium currents in chick auditory hair cells using an intact basilar papilla.

The avian basilar papilla is tonotopically organized such that hair cells along the sensory epithelium respond best to acoustic stimulation at differing frequencies. This specificity arises due to the mechanics of the cochlea itself and intrinsic electrical properties of the hair cells. Tall hair cells show membrane voltage oscillations in response to step current injection that may allow cells to act as electrical resonators, boosting the response at the resonant frequency. These oscillations and the underlying currents have been studied in enzymatically isolated cells. This study uses a whole chick (Gallus domesticus) basilar papilla preparation where the entire epithelium and its afferent connections are intact. With this preparation, a map of changes in potassium currents of tall hair cells was produced. All cells recorded from expressed two K+ currents, a calcium-activated K+ current, I(K(Ca)), and a voltage-activated K+ current, I(K). Also, apical cells expressed an inward rectifier K+ current, I(IR). The amplitude of total outward current increases in a gradient along the tonotopic axis. Pharmacological blockers were used to separate the outward K+ currents. These experiments showed that both currents individually increase in magnitude along a gradient from apex to base. Finally, measurements of oscillation frequency in response to current steps suggest a discontinuous change in the electrical resonances at about 33% from the apex. This study demonstrates a new preparation to study the electrical properties of hair cells in more detail along the tonotopic axis of the chick basilar papilla.

4-Aminopyridine↗
PubMed1997

A computational model of acute focal cortical lesions.

BACKGROUND AND PURPOSE: Determining how cerebral cortex adapts to sudden focal damage is important for gaining a better understanding of stroke. In this study we used a computational model to examine the hypothesis that cortical map reorganization after a simulated infarct is critically dependent on perilesion excitability and to identify factors that influence the extent of poststroke reorganization. METHODS: A previously reported artificial neural network model of primary sensorimotor cortex, controlling a simulated arm, was subjected to acute focal damage. The perilesion excitability and cortical map reorganization were measured over time and compared. RESULTS: Simulated lesions to cortical regions with increased perilesion excitability were associated with a remapping of the lesioned area into the immediate perilesion cortex, where responsiveness increased with time. In contrast, when lesions caused a perilesion zone of decreased activity to appear, this zone enlarged and intensified with time, with loss of the perilesion map. Increasing the assumed extent of intracortical connections produced a wider perilesion zone of inactivity. These effects were independent of lesion size. CONCLUSIONS: These simulation results suggest that functional cortical reorganization after an ischemic stroke is a two-phase process in which perilesion excitability plays a critical role.

Animals↗