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PubMed1997

Consciousness and cognition may be mediated by multiple independent coherent ensembles.

Short-term or working memory (WM) provides temporary storage of information in the brain after an experience and is associated with conscious awareness. Neurons sensitive to the multiple stimulus attributes comprising an experience are distributed within many brain regions. Such distributed cell assemblies, activated by an event, are the most plausible system to represent the WM of that event. Studies with a variety of imaging technologies have implicated widespread brain regions in the mediation of WM for different categories of information. Each kind of WM may thus be expected to involve many brain regions rather than a local, uniquely dedicated set of cells. Neurons in a distributed "cell assembly" may be self-selected by their temporally coherent activations. The process by which this fragmented representation of the recent past is reassembled to accomplish essentially automatic and reliable recognition of a recurrent event constitutes an important problem. One plausible mechanism to achieve the identification of past with previous events would require that the representational system mediating WM must coexist in spatial extent and somehow overlap in temporal activation with cell ensembles registering input from subsequent events. The detection of such a postulated mechanism required an experimental approach which would focus upon spatial patterns of coherent activation while information about different events was stored in WM and retrieved, rather than focusing upon the temporal sequences of activation in localized regions of interest. For this purpose, the familiar delayed matching from sample (DMS) task was modified. A series of information-free flashes, or "noncontingent probes," was presented before an initial series of visual information items, the Priming Sample, which were to be held in WM during a Delay Period. A second series of visual information items were then presented, the Matching Sample. The task required detection of any item in the second series which had been absent from the initial series. Thirty such trials with a particular category of visual information constituted a single task. Several DMS tasks with this standardized design, but with different categories of visual information, were presented within each test session. The information categories included letters of the alphabet, single digit numbers, or faces from a school yearbook. Event-related potentials (ERPs), were computed from 21 standardized electrode placements, separately for information-free probes and for information items in each interval of the trials within a task. Because each electrode is particularly sensitive to coherent activation of neurons in the immediately underlying brain regions, topographic maps were constructed and interpolated across the surface of the scalp. The momentary fluctuations of the resulting voltage "landscapes" throughout the task were then subjected to quantitative analysis. Distinctive landscapes sometimes persisted for prolonged periods, implying sustained engagement of very large populations of neurons. "Difference landscapes" were constructed by subtraction of topographic maps evoked by noncontingent probes during the Delay Period from maps of probe ERPs before the presentation of the initial information in the Priming Sample. Such probe difference landscapes displayed recurrent high similarity to momentary landscapes elicited during subsequent presentation of the information items in the Matching Sample. It seemed as if the distributed cell assembly continuously engaged by mediation of WM of the diverse attributes of the initial stimuli was being dynamically compared to the ensembles engaged by registration of the subsequent stimuli. Spatial Principal Component Analysis was applied to the sequences of momentary voltage landscapes observed throughout trials of each task. This method sought a small number of spatial patterns with which these large sets of inhomogeneous spatial distributions of voltage co

Adult↗

PubMed1999

Using the Lac repressor system to identify interacting proteins.

The present protocol describes a series of procedures to identify peptides interacting with PDZ domains. It is conceivable that the procedures can be applied to other purified protein modules or intact proteins without substantial modifications. With the deduced consensus combined with sequence information, it is possible to identify proteins present in the database with compatible sequences. If the expression of target protein and potential interacting candidate overlap temporally and spatially, biochemical and molecular experiments can be designed to study their physical and functional interactions.

Animals↗

PubMed2000

C-terminal domains of Escherichia coli topoisomerase I belong to the zinc-ribbon superfamily.

Detection of remote evolutionary connections is increasingly difficult with sequence and structural divergence. A combination of sequence and structural analysis, in which statistically supported sequence similarity had a crucial impact, revealed that Escherichia coli topoisomerase I C-terminal fragment is evolutionarily related to the three tetracysteine zinc-binding domains of the enzyme. Spatial structure analysis of this C-terminal fragment indicates that it consists of two structurally similar domains and suggests homology between them. Sequence similarity between the zinc-binding domains of type Ia topoisomerases and transcription regulators of known spatial structure helps to conclude that E. coli topo I contains five copies of a zinc ribbon domain at the C terminus. Two of these domains, corresponding to the C-terminal fragment, lost their cysteine residues and are probably not able to bind zinc. Present analyses lead to the classification of the C-terminal fragment of E. coli topoisomerase I as a member of zinc ribbon superfamily, despite the absence of zinc-binding sites.

Amino Acid Sequence↗

PubMed1999

Do hippocampal pyramidal cells signal non-spatial as well as spatial information?

It is generally agreed that the rat hippocampus is involved in spatial memory. Whether this is its sole or primary function, or merely one component of a broader function, is still debated. It has been suggested, for example, that the hippocampus stores information about flexible relations between stimuli, both spatial and non-spatial. In this paper, I reiterate the basic tenet of the cognitive map theory that the processing and storage of spatial information is the primary and perhaps the exclusive role of the hippocampus in the rat, and that data that appear to contradict this have been misinterpreted. These data are found in reports of non-spatial correlates of unit activity recorded in the awake animals and reports of deficits on non-spatial tasks following hippocampal lesions. In this paper, I examine both claims and suggest alternative explanations of the data. The first part of the paper contains a review of some of the properties of hippocampal place cells, which might be misinterpreted as non-spatial in "non-spatial" tasks. For example, if an animal is trained to carry out a sequence of stereotyped actions in different parts of an environment, there will be a strong correlation between the performance of each behaviour and the animal's location, and it is necessary to rule out the locational correlate as the cause of the firing pattern. The second part of the paper looks at the results of experiments on conditioning and non-spatial discrimination tasks and concludes that the results are less supportive of a more general relational theory of hippocampal function than has been suggested. Furthermore, there is often a discrepancy between the correlates of unit firing in non-spatial tasks and the absence of an effect of hippocampal damage on these same or similar tasks. It is concluded that, contrary to the claims of its detractors, the cognitive map theory is still the theory of hippocampal function that is most clearly specified, makes the most testable predictions, and for which there is the strongest experimental support.

Animals↗

PubMed2004

Decoding randomly ordered DNA arrays.

We have developed a simple and efficient algorithm to identify each member of a large collection of DNA-linked objects through the use of hybridization, and have applied it to the manufacture of randomly assembled arrays of beads in wells. Once the algorithm has been used to determine the identity of each bead, the microarray can be used in a wide variety of applications, including single nucleotide polymorphism genotyping and gene expression profiling. The algorithm requires only a few labels and several sequential hybridizations to identify thousands of different DNA sequences with great accuracy. We have decoded tens of thousands of arrays, each with 1520 sequences represented at approximately 30-fold redundancy by up to approximately 50,000 beads, with a median error rate of <1 x 10(-4) per bead. The approach makes use of error checking codes and provides, for the first time, a direct functional quality control of every element of each array that is manufactured. The algorithm can be applied to any spatially fixed collection of objects or molecules that are associated with specific DNA sequences.

Algorithms↗

PubMed1994

Head movement in normal subjects during simulated PET brain imaging with and without head restraint.

UNLABELLED: Head movement during brain imaging is recognized as a source of image degradation in PET and most other forms of medical brain imaging. However, little quantitative information is available on the kind and amount of head movement that actually occurs during these studies. We sought to obtain this information by measuring head movement in normal volunteers. METHODS: Head position data were acquired for 40 min in each of 13 supine subjects with and without head restraint. These data were then used to drive a mathematically simulated head through exactly the same set of movements. The positions of point sources embedded in this head were computed at each location and these data summarized as movement at FWHM in each of the three coordinate directions. RESULTS: Head movement increased with the length of the sampling interval for studies of either type (with or without head restraint), but the amount and rate of increase with restraint was much smaller. In contrast, head movement during consecutive, short sampling intervals was small and did not increase with time. Spatial gradients in head movement were detected within each study type, and significant spatial differences in head movement were found between study types. CONCLUSIONS: Head movements in normal, supine subjects, though small, can cause the effective resolution of a brain imaging study to appear to vary in space and time. These effects can be reduced significantly with head restraint and may also be reduced by dividing the acquisition of a single image into a sequence of short images (instead of a single long image), aligning these images spatially and summing the result.

Adult↗

PubMed2000

[19F-MRT of pulmonary ventilation in the breath-hold technic using SF6 gas].

OBJECTIVE: Development of a method to analyze lung ventilation by 19F-magnetic resonance imaging (MRI) of inspired SF6 gas during breath hold. MATERIAL AND METHODS: Measurements were performed with a Siemens Magnetom Vision 1.5 T scanner using the conventional gradient overdrive. Coronal images of the lung were acquired using ultrafast gradient-echo pulse sequences with TR/TE/alpha = 1.4 ms/0.48 ms/40 degrees without slice selection. With NEX = 200 averages and MA = 32 x 64 raw data matrix, the acquisition time was 9 s/image. Higher spatial resolution of 4.7 x 6.3 x 15 mm3 was obtained with a three-dimensional pulse sequence (TR/TE/alpha = 1.6 ms/0.48 ms/65 degrees, NEX = 20) running for 49 s. Measurements wer performed in three anesthetized and ventilated pigs (18 kg). RESULTS: A nearly linear relation between SF6 concentration and 19F signal intensity was observed. The signal-to-noise ratio in images obtained without slice selection was 30.9, with slice selection it was 14.9. No differences between SF6 distribution to both lungs were observed in the animals. CONCLUSION: Breath-hold MRI of SF6 gas distribution in the lung was demonstrated for the first time. The low spin-density was compensated for by highly repetitive signal averaging. Breath-hold 19F-MR imaging of ventilated airspaces to assess SF6 distribution in the human lung appears to be an interesting new method, which can be implemented with little technical efforts, and does not rely on radioactive isotopes.

Animals↗

PubMedDate not supplied

MR measurement of spinal CSF flow with the RACE technique.

The purpose of our study was the application and validation of a phase-sensitive pulse sequence that allowed real time CSF flow measurement without need for electrocardiographic (ECG) synchronization. After excitation of a slice perpendicular to the axis of the spine, projective data were obtained with a gradient echo sequence [contrast enhanced Fourier acquired steady-state technique (CE-FAST)] without spin warp gradient [real time acquisition and evaluation of motion technique (RACE)], allowing one-dimensional spatial resolution across the region of interest with a total sampling time of 20-30 ms. The sequence was calibrated with a spinal CSF phantom with oscillatory fluid motion. The calculated mean pulsation amplitudes of 20 healthy volunteers in the cervical region were 16 mm (range 9-36 mm), in the thoracic region 11 mm (5-21 mm), and in the lumbar region 3 mm (1-6 mm). The technique was capable of demonstrating physiologic alterations of CSF flow during respiratory maneuvers and may provide a tool to evaluate the altered CSF dynamics resulting from spinal block, inflammatory processes, or hemorrhage.

Adolescent↗

PubMed1992

Development of binocular vision in the kitten's striate cortex.

Studies of the development and plasticity of the visual pathway are well documented, but a basic question remains open: what is the physiological status of the system prior to extensive visual experience? Somewhat conflicting answers have been put forward, and in a major area, binocular vision, reports have ranged from severe immaturity to well-developed maturity. This is an important question to resolve since binocular cells in the visual cortex are thought to be the neural substrate for stereoscopic depth perception. We have addressed this question by recording from single cells in the striate cortex of kittens at postnatal ages 2, 3, and 4 weeks and from adults for comparison. Gratings with sinusoidal luminance distribution are presented to left, right, or both eyes. For each cell, we determine optimal values for orientation and spatial frequency. Relative phase (retinal disparity) is then varied in a dichoptic sequence so that binocular interaction may be studied. Results are as follows. In the normal adult, we have shown in previous work that most binocular interaction in the visual cortex can be accounted for on the basis of linear summation. Results from 3 and 4 week postnatal kittens are closely similar to those from adults. All types of binocular interaction found in adults are present in kittens. This includes phase-specific and non-phase-specific suppression or facilitation. Furthermore, monocular and binocular tuning characteristics are comparable in kittens and adults. The clear changes that occur with age are optimal spatial frequencies and peak responses. In addition, at 2 weeks, there is a substantially higher proportion of monocular cells compared to other ages and correspondingly, lower relative numbers of cells that exhibit phase-specific or suppressive binocular interactions. From increases in optimal spatial frequency and interpupillary distance with age, we calculated predicted changes in binocular disparity thresholds (stereo acuity) with age. Although there are methodological limits with respect to the behavioral testing of young kittens, the predicted results are comparable to some of the values obtained. Considered together, our results show that the physiological apparatus for binocular vision is functional at an early stage in postnatal development. It is possible that the connections that underlie this function are developed rapidly during early postnatal experience. An alternative possibility is that there is an elaborate genetic organization of binocular vision, but our study does not address this issue directly. A combination of these factors may be applicable.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

PubMed2006

Short-term impact of 1997/1998 ENSO-induced disturbance on abundance and genetic variation in a tropical butterfly.

In order to assess the short-term impact of habitat loss after disturbance, we studied Arhopala epimuta (Lepidoptera: Lycaenidae) populations in 5 landscapes in Borneo that were differentially affected by the 1997/1998 El Niño Southern Oscillation-induced drought and fire. Sampling was conducted before (1997) and after (1998 and 2000) disturbance. This study combined demographic and genetic data inferred from the analysis of 5 microsatellite loci and mitochondrial DNA (mtDNA) control region sequences. Over all 5 landscapes, a total of 313 A. epimuta were sampled over the 3-year survey. Butterfly abundance varied greatly both spatially and temporally (within disturbed landscapes). After the disturbance, a 4-fold population expansion was observed in a small unburned isolate, whereas population extinction was observed in one of the severely burned areas. The analysis of mtDNA sequences in a subsample of 106 A. epimuta revealed no significant spatial or temporal genetic structure. The analysis of 5 microsatellite loci revealed high frequencies of null alleles. Genetic evidence of recent change in population size was found in all 3 unburned landscapes using microsatellites. Congruent to mtDNA, microsatellites failed to detect significant genetic structure according to sampling year or landscapes. Our results suggest that, for mobile species within recently fragmented habitat, habitat loss after disturbance may lead to local population extinction but may augment genetic diversity in remnant local populations because of increased gene flow.

Animals↗

PubMed2001

Nucleotide polymorphism and natural selection at the pantophysin (Pan I) locus in the Atlantic cod, Gadus morhua (L.).

Molecular studies of nucleotide sequence variation have rarely attempted to test hypotheses related to geographically varying patterns of natural selection. The present study tested the role of spatially varying selection in producing significant linkage disequilibrium and large differences in the frequencies of two common alleles at the pantophysin (Pan I) locus among five populations of the Atlantic cod, Gadus morhua. Nucleotide sequences of 124 Pan I alleles showed strong evidence for an unusual mix of balancing and directional selection but no evidence of stable geographically varying selection. The alleles were highly divergent at both the nucleotide level (differing on average by 19 mutations) and at amino acid level (each having experienced three amino acid substitutions since diverging from a common ancestral allele). All six amino acid substitutions occurred in a 56-residue intravesicular loop (IV1 domain) of the vesicle protein and each involved a radical change. An analysis of molecular variation revealed significant heterogeneity in the frequencies of recently derived mutations segregating within both allelic classes, suggesting that two selective sweeps may be presently occurring among populations. The dynamic nature of the Pan I polymorphism in G. morhua and clear departure from equilibrium conditions invalidate a simple model of spatially varying selection.

Alleles↗

PubMed2002

Identification of a novel cis-regulatory element involved in the heat shock response in Caenorhabditis elegans using microarray gene expression and computational methods.

We report here the identification of a previously unknown transcription regulatory element for heat shock (HS) genes in Caenorhabditis elegans. We monitored the expression pattern of 11,917 genes from C. elegans to determine the genes that were up-regulated on HS. Twenty eight genes were observed to be consistently up-regulated in several different repetitions of the experiments. We analyzed the upstream regions of these genes using computational DNA pattern recognition methods. Two potential cis-regulatory motifs were identified in this way. One of these motifs (TTCTAGAA) was the DNA binding motif for the heat shock factor (HSF), whereas the other (GGGTGTC) was previously unreported in the literature. We determined the significance of these motifs for the HS genes using different statistical tests and parameters. Comparative sequence analysis of orthologous HS genes from C. elegans and Caenorhabditis briggsae indicated that the identified DNA regulatory motifs are conserved across related species. The role of the identified DNA sites in regulation of HS genes was tested by in vitro mutagenesis of a green fluorescent protein (GFP) reporter transgene driven by the C. elegans hsp-16-2 promoter. DNA sites corresponding to both motifs are shown to play a significant role in up-regulation of the hsp-16-2 gene on HS. This is one of the rare instances in which a novel regulatory element, identified using computational methods, is shown to be biologically active. The contributions of individual sites toward induction of transcription on HS are nonadditive, which indicates interaction and cross-talk between the sites, possibly through the transcription factors (TFs) binding to these sites.

Animals↗

PubMed1978

1H nuclear-magnetic-resonance studies of the molecular conformation of monomeric glucagon in aqueous solution.

Dilute aqueous solutions of glucagon were investigated by high-resolution 1H nuclear magnetic resonance at 360 MHZ. Monomeric glucagon was found to adopt predominantly an extended flexible conformation which contains, however, a local non-random spatial structure involving the fragment--Phe-22--Val-23--Gln-24--Trp-25--. This local conformation is preserved in the partial sequence 22--26 and could thus be characterized in detail. Two interesting conclusions resulted from these experiments. One is that the local spatial structure in the fragment 22--25 of glucagon is identical to that observed in the fragment 20--23 of the human parathyroid hormone. Secondly, the backbone conformation in the C-terminal fragment of glucagon in solution must be different from the alpha-helical structure observed in single crystals of glucagon. These new structural data are analyzed with regard to relationships with glucagon binding to the target cells.

Glucagon↗

PubMed2004

Tracking of V beta 8.2-positive encephalitogenic T cells by complementarity-determining region 3 spectratyping and subsequent Southern blot hybridization in Lewis rats after neuroantigen sensitization.

Pathogenic T cells in organ-specific autoimmune diseases use a limited number of TCR alpha- and beta-chains. In experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats by immunization with myelin basic protein, encephalitogenic T cells mainly use Vbeta8.2 TCR and clonal expansion of the Vbeta8.2 spectratype containing the EAE-specific complementarity-determining region 3 (CDR3) sequence, DSSYEQYFGPG, is found in the spinal cord throughout the course of clinical EAE. In the present study we performed temporal and spatial analyses of Vbeta8.2 spectratype expansion by CDR3 spectratyping and subsequent DNA hybridization with a probe specific for the encephalitogenic CDR3 sequence to elucidate the kinetics of encephalitogenic T cells during the induction phase after neuroantigen sensitization. It was demonstrated that Vbeta8.2 spectratype expansion and/or the positive signal in Southern blot were first detected in the regional lymph nodes as early as day 3 postimmunization and was disseminated over the lymphoid organs by day 6. Because perfusion of immunized rats with PBS erased the positive signals on day 3 postimmunization, the majority of Vbeta8.2-positive encephalitogenic T cells at the very early stage would reside within the lymphatic or blood vessels. Furthermore, removal of the draining lymph node 1, 3, and 6 days after immunization in the foot pad did not ameliorate clinical EAE. These findings strongly suggest that encephalitogenic T cells disseminate throughout the whole body very rapidly after sensitization. Analysis of pathogenic T cells at the clonal level provides useful information for designing effective immunotherapy.

Amino Acid Sequence↗

PubMed2003

Genome-level evolution of resistance genes in Arabidopsis thaliana.

Pathogen resistance genes represent some of the most abundant and diverse gene families found within plant genomes. However, evolutionary mechanisms generating resistance gene diversity at the genome level are not well understood. We used the complete Arabidopsis thaliana genome sequence to show that most duplication of individual NBS-LRR sequences occurs at close physical proximity to the parent sequence and generates clusters of closely related NBS-LRR sequences. Deploying the statistical strength of phylogeographic approaches and using chromosomal location as a proxy for spatial location, we show that apparent duplication of NBS-LRR genes to ectopic chromosomal locations is largely the consequence of segmental chromosome duplication and rearrangement, rather than the independent duplication of individual sequences. Although accounting for a smaller fraction of NBS-LRR gene duplications, segmental chromosome duplication and rearrangement events have a large impact on the evolution of this multigene family. Intergenic exchange is dramatically lower between NBS-LRR sequences located in different chromosome regions as compared to exchange between sequences within the same chromosome region. Consequently, once translocated to new chromosome locations, NBS-LRR gene copies have a greater likelihood of escaping intergenic exchange and adopting new functions than do gene copies located within the same chromosomal region. We propose an evolutionary model that relates processes of genome evolution to mechanisms of evolution for the large, diverse, NBS-LRR gene family.

Arabidopsis↗

PubMed1995

Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein.

Synapses are highly specialized sites of cell-cell contact involved in signal transfer. The molecular mechanisms modulating the assembly and stability of synapses are unknown. We previously reported the identification of a 90 kDa synapse-associated protein, SAP90, that is localized at the presynaptic termini of inhibitory GABAergic synapses. SAP90 is a mosaic protein composed of three 90 amino acid residue repeats, an SH3 domain and a region homologous to guanylate kinases. SAP90 shares domain specific homology with a family of proteins involved in the assembly and possibly stability of sites of cell contact. These include the product of the lethal(1) discs-large-1 (dlgA) tumor suppressor gene and the zonula occludens proteins ZO-1, ZO-2. The further characterization of cDNA clones encoding components of synaptic junctions has lead to the identification of a 97 kDa protein, called SAP97, that exhibits a strong overall sequence similarity to SAP90. The present study was undertaken to determine the spatial distribution of SAP97, and to reveal further clues to the possible roles of these proteins in synapses. Light and immunoelectron microscopic analysis of the rat hippocampal formation revealed that SAP97 is localized in the presynaptic nerve termini of excitatory synapses. In other brain regions, SAP97 is found in and along bundles of unmyelinated axons. SAP97 is not restricted to the CNS, but is also present at the basal lateral membrane between a variety of epithelial cells. In cultured T84 cells, it is restricted to the cytoplasmic surface of the plasma membranes between adjacent cells, but not at the edges of cells lacking cell-cell contact suggesting a role for SAP97 in cell adhesion. These data suggest that members of the SAP90/SAP97 subfamily may be involved in the site specific assembly, stability or functions of membrane specialization at sites of cell-cell contact.

Adaptor Proteins, Signal Transducing↗

PubMed1998

A technique for determining the spatial relationship between the rotator cuff and the subacromial space in arm abduction using MRI and 3D image processing.

An MR imaging-based technique for three-dimensional determination of subacromial space width in relation to the rotator cuff in arm abduction is presented. Five volunteers were examined in an open MRI in seven arm positions, and coronal images were obtained with a gradient-echo sequence. 3D reconstruction of the bones and the supraspinatus was performed, and the minimal spatial distances between acromion, clavicle, and humerus were calculated. The closest contact between the supraspinatus and the anterior inferior part of the acromion occurred at 90 degrees abduction in internal rotation. The technique presented allows investigation of the morphological basis of the impingement syndrome.

Acromion↗

PubMed1990

Spatial and temporal control elements of the Drosophila engrailed gene.

engrailed (en) is a segmentation gene expressed in a series of stripes throughout embryonic development. Here, I show that regulatory sequences for striped expression are present within the first intron of en. The 1-kb intron is able to confer striped expression early, but not late, in development. This shows that different regulatory sequences are required for en stripes at different times in development. Furthermore, stripes generated by the intron are coincident with en stripes in a wild-type background but behave differently from endogenous engrailed stripes in some segmentation mutant backgrounds. Thus, although the intron can induce apparently normal stripes, it lacks some of the regulatory sequences present within the endogenous gene. These experiments suggest that multiple regulatory programs control an expression in stripes, and each may be able to confer "normal" spatial regulation independently.

Animals↗

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