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PubMed2000

Sequence-specific NMR assignment of proteins by global fragment mapping with the program MAPPER.

A new program, MAPPER, for semiautomatic sequence-specific NMR assignment in proteins is introduced. The program uses an input of short fragments of sequentially neighboring residues, which have been assembled based on sequential NMR connectivities and for which either the 13C(alpha) and 13C(beta) chemical shifts or data on the amino acid type from other sources are known. MAPPER then performs an exhaustive search for self-consistent simultaneous mappings of all these fragments onto the protein sequence. Compared to using only the individual mappings of the spectroscopically connected fragments, the global mapping adds a powerful new constraint, which results in resolving many otherwise intractable ambiguities. In an initial application, virtually complete sequence-specific assignments were obtained for a 110 kDa homooctameric protein, 7,8-dihydroneopterin aldolase from Staphylococcus aureus.

Aldehyde-Lyases↗
PubMed1994

MAP kinase kinase kinase, MAP kinase kinase and MAP kinase.

Signal transduction pathways that respond to external signals through the MAP kinase family of protein kinases are involved in diverse responses in eukaryotic cells. MAP kinases are one element in a series of kinases that serve to connect the plasma membrane with cytoplasmic and nuclear events. MAP kinases have the unusual feature that their activation requires threonine and tyrosine phosphorylation carried out by a dual specificity protein kinase. Recent advances have shown that in two MAP kinase pathways (the mating response pathway in the fission yeast Schizosaccharomyces pombe, and receptor tyrosine kinase signalling), the small GTP binding protein ras p21 links membrane events to kinase pathway activation.

Animals↗
PubMed1986

Visuomotor fields of the superior colliculus: a quantitative model.

Electrophysiological and electrical stimulation studies in the monkey have disclosed that both the retinal surface and the metrics of saccades are topographically represented in the superior colliculus. This mapping of sensory and motor space onto the colliculus is nonhomogeneous in that the central region is over-represented in both the visual and the motor map. Single unit studies have revealed that visual receptive fields of collicular neurons are typically quite large and are characterized by a skewed (asymmetrical) sensitivity profile. Analyses by McIlwain [J. Neurophysiol. 38, 219-230 (1975)] in the cat have suggested that this skewness property reflects mainly the spatial distortion inherent in the afferent mapping. In this paper we describe a quantitative model, based on a logarithmic mapping function combined with a Gaussian connectivity function in the colliculus, which can account for the extent and the shape of collicular receptive fields. Collicular neurons in the deeper layers have movement-related bursts of activity for saccades in a limited amplitude and direction range related to their location in the collicular map. These movement fields, like visual receptive fields, may be quite extensive and typically have a skewed profile. In our model, an efferent-mapping function is defined, which relates the locus of a population of recruited cells to the metrics of the ensuing saccade. The parameters of this function, which was taken to be identical with the afferent mapping function, were estimated from Robinson's [Vision Res. 12, 1795-1808 (1972)] electrical stimulation data. Based on the assumption that the population-activity profile resembles a two-dimensional Gaussian function, the shape and the size of movement fields can then be described with just 2 or 3 free parameters. Electrophysiological data recorded from a small sample of collicular visuomotor neurons were used to illustrate the procedure, which we designed to enable application of our model to the experimental data. The best fit was obtained when the mapping function was slightly anisotropic. Suggestions on how the model could be improved and extended are offered in the Discussion.

Action Potentials↗
PubMedDate not supplied

The anatomy and clinical significance of the collateral circulation between the internal and external carotid arteries through the ophthalmic artery.

Complete occlusion of the internal carotid artery is not necessarily associated with total disruption of cerebral blood flow distal to the site of the arterial obstruction. In fact, the flow of blood may be sufficient to maintain cerebral perfusion. This is accomplished by the shunting of blood from the external to the internal carotid artery by means of collateral circuits. While several major branch arteries of the external carotid artery may be recruited in this process, the ophthalmic artery is often the final common pathway before the anastomosis with the internal carotid artery. With the aim of elucidating these collateral circles, digital subtraction angiography was used to examine 100 patients with total occlusion of the internal carotid artery. These data were compared with those obtained using Doppler ultrasound, duplex scanning, and transcranial Doppler. Forty patients were excluded because there was no demonstrable collateral circulation, because the collateral circulation used the communicating arteries, or because the ophthalmic artery arose from the middle meningeal artery. Dynamic data were obtained by compressing the branches of the two external and common carotid arteries, and the blood vessels were identified by comparison with previous anatomic studies. We have constructed a precise map of the intra- and extracranial circles that connect the internal and external carotid arteries through the pathways that include the ophthalmic artery. This map demonstrates why apparently identical vascular occlusions may have divergent symptomatologies and clinical outcomes, which may range from the complete absence of symptoms to cerebral infarction.

Aged↗
PubMed2001

The topology of the possible: formal spaces underlying patterns of evolutionary change.

The current implementation of the Neo-Darwinian model of evolution typically assumes that the set of possible phenotypes is organized into a highly symmetric and regular space equipped with a notion of distance, for example, a Euclidean vector space. Recent computational work on a biophysical genotype-phenotype model based on the folding of RNA sequences into secondary structures suggests a rather different picture. If phenotypes are organized according to genetic accessibility, the resulting space lacks a metric and is formalized by an unfamiliar structure, known as a pre-topology. Patterns of phenotypic evolution-such as punctuation, irreversibility, modularity--result naturally from the properties of this space. The classical framework, however, addresses these patterns by exclusively invoking natural selection on suitably imposed fitness landscapes. We propose to extend the explanatory level for phenotypic evolution from fitness considerations alone to include the topological structure of phenotype space as induced by the genotype-phenotype map. We introduce the mathematical concepts and tools necessary to formalize the notion of accessibility pre-topology relative to which we can speak of continuity in the genotype-phenotype map and in evolutionary trajectories. We connect the factorization of a pre-topology into a product space with the notion of phenotypic character and derive a condition for factorization. Based on anecdotal evidence from the RNA model, we conjecture that this condition is not globally fulfilled, but rather confined to regions where the genotype-phenotype map is continuous. Equivalently, local regions of genotype space on which the map is discontinuous are associated with the loss of character autonomy. This is consistent with the importance of these regions for phenotypic innovation. The intention of the present paper is to offer a perspective, a framework to implement this perspective, and a few results illustrating how this framework can be put to work. The RNA case is used as an example throughout the text.

Animals↗
PubMed1987

Projection from the pretectal nuclei to the dorsal lateral geniculate nucleus in the cat: a wheat germ agglutinin-horseradish peroxidase study.

To study the projection from the pretectum to the dorsal lateral geniculate nucleus (LGNd) in the cat, we used anterograde and retrograde transport of wheat germ agglutinin-horseradish peroxidase (WGA-HRP). Special attention was directed to the retinotopic maps of the pretectum and LGNd. Multiple restricted injections were made into different parts of the pretectum or LGNd. The pretectogeniculate pathway terminates mostly in the medial interlaminar nucleus (MIN) and layers A and A1, and to some extent in the lamina C within the ipsilateral LGNd. The lateral part of the nucleus of the optic tract (NTO) receives afferents from the superior retina, and the medial part of NTO and posterior pretectal nucleus (NPP) receives afferents from the inferior retina. There is no topographic organization in the retinal projection to the olivary pretectal nucleus (NOL). The lateral part of NTO projects ipsilaterally to the rostral portion of LGNd, which receives afferents from the superior retina. The medial part of NTO projects ipsilaterally to the caudal portion of LGNd, which receives afferents from the inferior retina. The NOL projects to all laminar parts of LGNd, ipsilaterally. The NPP projects largely to the ipsilateral MIN, which receives afferents from the pericentral and peripheral retina. These results suggest that similar parts of the retinotopic maps present in the pretectum and LGNd are connected.

Animals↗
PubMed1987

Organization of intracortical and commissural connections in somatosensory cortical areas I and II in the raccoon.

The organization of intracortical and callosal projecting cell bodies was examined in somatosensory representation areas I (SI) and II (SII) of the raccoon by use of horseradish peroxidase (HRP) or horseradish peroxidase-wheat germ agglutin (HRP-WHA). HRP and HRP-WHA were injected into commissurally and noncommissurally connected subdivisions of SI and SII. Injection sites in SII were identified electrophysiologically. Results were obtained from transverse sections in which the HRP was visualized with the aid of the substrates dihydrochlorobenzidine or tetramethyl benzidine in the presence of hydrogen peroxidase. The principal findings were the following: (1) there are reciprocal connections between SI and SII; (2) in SI the intracortically projecting cell bodies and terminals are located primarily in sulcal cortex; (3) intracortically projecting neurons in SI are located primarily in layers III whereas in SII they are located principally in layers III and V; (4) there are connections between disparate areas within SI; and (5) there are intracortical connections between callosum-connected and acallosal regions in SII. These results are discussed with regard to the results of mapping studies of the SI, the significance of intracortical connections to the formation of sulci in SI, and the possible roles of nonhomotopic connections in the intermanual transfer of learning.

Animals↗
PubMed2005

Ipsilateral cortical connections of motor, premotor, frontal eye, and posterior parietal fields in a prosimian primate, Otolemur garnetti.

The ipsilateral connections of motor areas of galagos were determined by injecting tracers into primary motor cortex (M1), dorsal premotor area (PMD), ventral premotor area (PMV), supplementary motor area (SMA), and frontal eye field (FEF). Other injections were placed in frontal cortex and in posterior parietal cortex to define the connections of motor areas further. Intracortical microstimulation was used to identify injection sites and map motor areas in the same cases. The major connections of M1 were with premotor cortex, SMA, cingulate motor cortex, somatosensory areas 3a and 1, and the rostral half of posterior parietal cortex. Less dense connections were with the second (S2) and parietal ventral (PV) somatosensory areas. Injections in PMD labeled neurons across a mediolateral belt of posterior parietal cortex extending from the medial wall to lateral to the intraparietal sulcus. Other inputs came from SMA, M1, PMV, and adjoining frontal cortex. PMV injections labeled neurons across a large zone of posterior parietal cortex, overlapping the region projecting to PMD but centered more laterally. Other connections were with M1, PMD, and frontal cortex and sparsely with somatosensory areas 3a, 1-2, S2, and PV. SMA connections were with medial posterior parietal cortex, cingulate motor cortex, PMD, and PMV. An FEF injection labeled neurons in the intraparietal sulcus. Injections in posterior parietal cortex revealed that the rostral half receives somatosensory inputs, whereas the caudal half receives visual inputs. Thus, posterior parietal cortex links visual and somatosensory areas with motor fields of frontal cortex.

Animals↗
PubMed1987

Computational model of the motor program generator for pursuit.

A parallel processing neural network model of a motor program generator (MPG) for pursuit eye movements (PEM) was developed. The MPG model consists of two neural networks (velocity maps), which represent velocity values theta R and theta L respectively, as eccentric locations on the map with zero in the center. Neurons are arranged in a circular layer and connected only to their immediate neighbors. The potential field P of all neurons is analogous to a flat circular membrane whose center can be pushed up or down. During PEM one of the two maps, which are connected in a push-pull fashion, always features an activity peak (AP) which travels with constant velocity vT from one neuron to the next. The shape of P defines whether AP travels in a circle (theta = constant), towards the periphery (theta increase) or towards the center (theta decrease). Such a model provides a novel approach for understanding neural generators of non-periodical motor programs.

Animals↗
PubMed1993

Mapping of epitopes on the SmD molecule: the use of multiple antigen peptides to measure autoantibodies in systemic lupus erythematosus.

Autoantibodies against the ribonucleoproteins B, B' and D are a serological marker of systemic lupus erythematosus (SLE). We mapped the epitopes recognized by autoantibodies on the SmD molecule by means of 7 synthetic peptides corresponding to the entire length of the protein. By ELISA assay, 25% of the lupus sera contained IgG antibodies specific for the C-terminal SmD sequence 95-119. This reactivity was confirmed by synthesizing the sequence as a multiple antigen peptide (MAP): antibodies reactive with the MAP 95-119 were present only in SLE and not in other connective tissue disorders. Sera containing high titers of anti-MAP 95-119 antibodies reacted in immunoblot with the SmD protein. These results indicate the presence of a dominant epitope in the C-terminal region of SmD, which is highly homologous to the Epstein-Barr virus induced nuclear protein EBNA I.

Amino Acid Sequence↗
PubMed1991

Increased recombination adjacent to the Huntington disease-linked D4S10 marker.

Huntington disease (HD) is caused by a genetic defect distal to the anonymous DNA marker D4S10 in the terminal cytogenetic subband of the short arm of chromosome 4 (4p16.3). The effort to identify new markers linked to HD has concentrated on the use of somatic cell hybrid panels that split 4p16.3 into proximal and distal portions. Here we report two new polymorphic markers in the proximal portion of 4p16.3, distal to D4S10. Both loci, D4S126 and D4S127, are defined by cosmids isolated from a library enriched for sequences in the 4pter-4p15.1 region. Physical mapping by pulsed-field gel electrophoresis places D4S126 200 kb telomeric to D4S10, while D4S127 is located near the more distal marker D4S95. Typing of a reference pedigree for D4S126 and D4S127 and for the recently described VNTR marker D4S125 has firmly placed these loci on the existing linkage map of 4p16.3. This genetic analysis has revealed that the region immediately distal to D4S10 shows a dramatically higher rate of recombination than would be expected based on its physical size. D4S10-D4S126-D4S125 span 3.5 cM, but only 300-400 kb of DNA. Consequently, this small region accounts for most of the reported genetic distance between D4S10 and HD. By contrast, it was not possible to connect D4S127 to D4S125 by physical mapping, although they are only 0.3 cM apart. A more detailed analysis of recombination sites within the immediate vicinity of D4S10 could potentially reveal the molecular basis for this phenomenon; however, it is clear that the rate of recombination is not continuously increased with progress toward the telomere of 4p.

Animals↗
PubMed1996

MAD Phasing Strategies Explored with a Brominated Oligonucleotide Crystal at 1.65A Resolution.

The crystal structure of a brominated oligonucleotide d(CGCG(Br)CG), chemical formula C(114)N(48)O(68)P(10)Br(2), has been analysed by multiwavelength anomalous dispersion (MAD) methods. The oligonucleotide crystallizes in space group P2(1)2(1)2(1) with a = 17.97, b = 30.98, c = 44.85 A, alpha = beta = gamma 90 degrees . Data to a resolution of 1.65 A were collected at four wavelengths about the K-absorption edge of the bromine atom (lambda(1) = 0.9323 A, a reference wavelength at the long-wavelength side of the edge; lambda(2) = 0.9192 A, at the absorption-edge inflection point; lambda(3) = 0.9185 A, at the ;white line' absorption maximum; lambda(4) = 0.8983 A, a reference wavelength at the short-wavelength side) using synchrotron radiation at Station PX9.5, SRS, Daresbury. Multiwavelength data could be collected on a single-crystal as the sample was radiation stable. Anomalous and dispersive Patterson maps were readily interpretable to give the bromine anomalous scatterer positions. Phase calculations to 1.65 A, resolution, using all four wavelengths, gave a figure of merit of 0.825 for 2454 reflections. The electron-density map was readily interpretable showing excellent connectivity for the sugar/phosphate backbone and each base was easily characterized. The two nucleotide strands paired up as expected in an antiparallel Watson-Crick-type manner. The structure was refined to 1.65 A using all the data (R-factor = 17.0% based on 3151 reflections, with a data-to-parameter ratio of 2.6). In addition to the four-wavelength analysis, a variety of other phasing strategies, and the associated quality of the resulting electron-density maps, were compared. These included use of either of the reference wavelength data sets in the two possible three-wavelength phasing combinations to assess their relative effectiveness. Moreover, the time dependence upon measuring the Bijvoet differences and its effect upon phasing was also investigated. Finally, the use of only two wavelengths, including Friedel pairs, is demonstrated (the theoretical minimum case); this is of particular interest when considering overall beam time needs and is clearly a feasible experimental strategy, as shown here.

Journal Article↗
PubMed2002

Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice.

The function of the nervous system is a consequence of the intricate synaptic connectivity of its neurons. Our understanding of these highly complex networks has profited enormously from methods used over the past two decades that are based on the mechanical injection of tracer molecules into brain regions. We have developed a genetic system for the mapping of synaptic connections during development of the mammalian central nervous system and in the mature brain. It is based on the transsynaptic transfer of green fluorescent protein (GFP) in the brains of mice using a fusion protein with a nontoxic fragment of tetanus toxin (TTC) expressed in defined neurons. These transgenic mice allowed us to visualize neurons, at single-cell resolution, that are in synaptic contact by the detection of GFP in interconnected circuits. Targeted genetic expression with a specific promoter permitted us to transfer GFP to defined subsets of neurons and brain regions. GFP-TTC is coexpressed with a lacZ reporter gene to discriminate neurons that produce the tracer from cells that have acquired it transneuronally. The marker shows selective transfer in the retrograde direction. We have used electron microscopic detection of GFP to define the ultrastructural features of the system. Our work opens up a range of possibilities for brain slice and in vivo studies taking advantage of the fluorescence of GFP. We point the way toward the use of powerful multiphoton technology and set the stage for the transsynaptic transfer of other proteins in the brains of mice.

Animals↗
PubMed1979

Formation of topographic maps and columnar microstructures in nerve fields.

Topographic connections are found in many parts of the vertebrate nervous systems, known for example as retinotopy. The self-organizing ability of Hebb type modifiable synapses plays an important role in forming, at least in refining, the topographic connections. We present a mathematical analysis of a revised version of the Willshaw-Malsburg model of topographic formation, solving the equations of synaptic self-organization coupled with the field equation of neural excitations. The equilibrium solutions are obtained and their stability is studied. It is proved that two cases exist depending on parameters. In one case, the smooth topographic organization is obtained as a stable equilibrium of the equations. In the other case, this solution becomes unstable, and instead the topographic organization with columnar microstructures appears. This might explain the columnar structures in the cerebrum. The theory is confirmed by computer simulated experiments.

Computers↗
PubMed1985

[Visual cortical areas: topography, connections and function].

The results of the electrophysiological mapping studies in the visual cortex are reviewed, with a special emphasis on the work of Allman and Kaas in the owl monkey. An analysis is given of the topography of the visual field representation within the different visual areas thus defined and comparative elements are given from studies in the visual cortex of cat and macaque monkey. It is shown that the interconnexions between the different cortical visual areas are numerous, especially between adjacent areas. The question of the functional localization in the various areas is discussed. It is proposed that certain aspects of the visual scene are analyzed by a group of interconnected neighbouring areas, whereas the analysis of other aspects involve interconnections between cortical areas which are distributed on the cortical surface.

Animals↗
PubMed2002

Areal organization of the posterior parietal cortex of the ferret (Mustela putorius).

On grounds of electrophysiological mapping, cytoarchitecture, myeloarchitecture and callosal and thalamic connectivity, we have identified two cortical areas in the posterior parietal cortex of the ferret: posterior parietal caudal and rostral (PPc and PPr). These areas occupy the lateral and suprasylvian gyri, from the cingulate sulcus (medially) to the suprasylvian sulcus (laterally) and lie between visual areas 18 and 21 (posteriorly) and the somatosensory areas (anteriorly). Within both areas a coarse representation of the visual field was found and within PPr there was also a representation of the body. Each representation mirrors those within neighboring areas. Cytoarchitectonic and myeloarchitectonic fields within this cortical region did not correspond in any simple way to the physiological representations. The architectonic differences correlate to differential callosal connectivity, with predominant connectivity corresponding to the upper hemifield/head representations. PPr and PPc receive thalamic projections from a different, but overlapping, complement of thalamic nuclei. The superimposition of somatic and visual maps in PPr might relate to the probable role of this area in transforming retinal-centered to body-centered spatial coordinates. The organization of the parietal areas in the ferret resembles that of the flying fox and might unveil a common organizational plan from which the primate posterior parietal cortex evolved.

Animals↗
PubMed1987

Anatomical properties and physiological correlates of the intrinsic connections in cat area 18.

After making a map of response properties of neurons in a roughly 3 X 4 mm region of area 18 in the cat, we injected wheat-germ agglutinin horseradish peroxidase (WGA-HRP) and succinylated concanavalin A (Con A) into physiologically identified regions of the map. We observed up to 10 patches of retrogradely labeled cells surrounding each injection site. The majority of the patches occurred within 1.4 mm of the center of the injection site, but rare patches were found as far as 3.4 mm from the injection site. The mean center-to-center spacing of the intrinsic patches was about 1 mm, while the mean distance between the center of the injection site and the nearest patches was less than 1 mm. The labeled cells included both nonpyramidal and pyramidal types and were found in all layers, although they were usually most dense in layers II-IV. Between 2% and 9% of the cells within a cortical column were labeled after a single injection of WGA-HRP or Con A into area 18. Injections of different tracers into 2 neighboring areas resulted in a uniform and less patchy distribution of labeled cells, which suggests that the patches observed after a single injection were only a portion of a continuous horizontal system of interconnections. The patterns and positions of the intrinsic patches were compared to the distribution of the following receptive-field properties: preferred orientation, receptive-field location, and eye preference. The preferred orientations of the recording sites within the injected and labeled areas were different and, most frequently, orthogonal to each other. This is a highly specific projection, since regions with orientation values like those of the injection site were "within range," yet not labeled. We were unable to detect any relationship between the ocular preferences of the injected and labeled cell regions. Injections into areas predominantly driven by the contralateral eye resulted in labeled regions exhibiting varied eye preference distributions. In some animals they were like the injection site and in others there were equal numbers of contra- and ipsilateral eye-dominated regions. The overall distribution of the patches around the injection site was elongated along the anterior-posterior cortical axis of the brain. The patches extended further in the posterior than the anterior direction. These observations appear to be related to the finding that the cortical magnification factor is greater along the anterior-posterior than the medial-lateral axis of area 18.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2026

Genomic and ecological systems-thinking framework for pathogenic Leptospira in Puerto Rico.

INTRODUCTION: Leptospirosis is a complex zoonotic disease requiring high-resolution surveillance. A systems-thinking framework was used to connect genomic and ecological data and map the geographic and host-based structuring of co-circulating pathogenic Leptospira lineages in Puerto Rico. METHODS: Forty-four core genomes of L. interrogans, L. borgpetersenii, and L. kirschneri from human, domestic, and wildlife hosts were analyzed. Spatiotemporal and landscape metadata were integrated using root-to-tip regression, isolation-by-distance profiling and calibrated single-nucleotide polymorphism (SNP) thresholds (≤1, ≤5, and ≤10 SNPs) to define transmission clusters. RESULTS: Leptospira species exhibited distinct ecological pathways partitioned by geography, explaining 56% of genomic variance for L. interrogans and 91% for L. borgpetersenii (PERMANOVA). L. interrogans displayed high landscape connectivity across multiple hosts, forming localized networks (≤1 to ≤10 SNPs) that capture active spillovers (human-to-rat linkages at ≤1 SNP) and resolved into rodent host-specific lineages (R2 = 0.34). Conversely, L. borgpetersenii showed spatial and temporal genomic homogeneity and a lack of host-associated structure within an unpartitioned transmission pool dominated by Mus musculus. As a result, fixed genomic thresholds yielded disparate outcomes: L. interrogans resolved into 4 to 5 discrete, expanding clusters, whereas L. borgpetersenii grouped into a single uniform population at the ≤10-SNP threshold. CONCLUSION: Co-circulating pathogenic leptospires occupy distinct ecological niches shaped by varying host restriction and environmental persistence. Fixed genomic thresholds lack universal applicability; effective genomic epidemiological surveillance must employ species-specific threshold calibration to accurately map transmission pathways.

Puerto Rico↗