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Axonal processes and neural plasticity. III. Competition for dendrites.

In previous work we have developed a computational framework for topographic map formation and plasticity based on axonal process sprouting and retraction, in which sprouting and retraction are governed by competition for neurotrophic support. Here we show that such an approach can account for certain aspects of the dendritic morphology of cortical maps. In particular, we model the development of ocular dominance columns in the primary visual cortex and show that cortical cells near to column boundaries prefer to elaborate dendritic fields which avoid crossing the boundaries. This emerges as different functional inputs are spatially separated. We predict that afferent segregation occurs before or simultaneously with, but not after, the emergence of dendritic bias. We predict that animals reared with complete but asynchronous stimulation of the optic nerves do not develop a dendritic bias. We suggest that the emergence of a dendritic bias might provide a partial account for the critical period for a response to monocular deprivation. In particular, we predict that animals reared with asynchronous optic nerve stimulation might exhibit an extended critical period. Our results also indicate that the number of synapses supported by cortical cells depends on the intra-ocular image correlations used in our simulations. This suggests that inter-ocular image correlations, and thus strabismic rearing of kittens, may also affect the innervation density.

Afferent Pathways↗

Surname distribution in France: a distance analysis by a distorted geographical map.

The distribution of surnames in 90 distinct regions in France during two successive periods, 1889-1915 and 1916-1940, is analysed from the civil birth registers of the 36,500 administrative units in France. A new approach, called 'Mobile Site Method' (MSM), is developed to allow representation of a surname distance matrix by a distorted geographical map. A surname distance matrix between the various regions in France is first calculated, then a distorted geographical map called the 'surname similarity map' is built up from the surname distances between regions. To interpret this map we draw (a) successive map contours obtained during the step-by-step distortion process, revealing zones of high surname dissimilarity, and (b) maps in grey levels representing the displacement magnitude, and allowing the segmentation of the geographical and surname maps into 'homogeneous surname zones'. By integrating geography and surname information in the same analysis, and by comparing results obtained for the two successive periods, the MSM approach produces convenient maps showing: (a) 'regionalism' of some peripheral populations such as Pays Basque, Alsace, Corsica and Brittany; (b) the presence of preferential axes of communications (Rhodanian corridor, Garonne valley); (c) barriers such as the Central Massif, Vosges; (d) the weak modifications of the distorted maps associated with the two periods studied suggest an extension (but limited) of the tendency of surname uniformity in France. These results are interpreted, in the nineteenth- and twentieth century context, as the consequences of a slow process of local migrations occurring over a long period of time.

France↗

Toso, a cell surface, specific regulator of Fas-induced apoptosis in T cells.

Fas is a surface receptor that can transmit signals for apoptosis. Using retroviral cDNA library-based functional cloning we identified a gene, toso, that blocks Fas-mediated apoptosis. Toso expression was confined to lymphoid cells and was enhanced after cell-specific activation processes in T cells. Toso appeared limited to inhibition of apoptosis mediated by members of the TNF receptor family and was capable of inhibiting T cell self-killing induced by TCR activation processes that up-regulate Fas ligand. We mapped the effect of Toso to inhibition of caspase-8 processing, the most upstream caspase activity in Fas-mediated signaling, potentially through activation of cFLIP. Toso therefore serves as a novel regulator of Fas-mediated apoptosis and may act as a regulator of cell fate in T cells and other hematopoietic lineages.

Adaptor Proteins, Signal Transducing↗

High throughput fingerprint analysis of large-insert clones.

As part of the Human Genome Project, the Washington University Genome Sequencing Center has commenced systematic sequencing of human chromsome 7. To organize and supply the effort, we have undertaken the construction of sequence-ready physical maps for defined chromosomal intervals. Map construction is a serial process composed of three main activities. First, candidate STS-positive large-insert PAC and BAC clones are identified. Next, these candidate clones are subjected to fingerprint analysis. Finally, the fingerprint data are used to assemble sequence-ready maps. The fingerprinting method we have devised is key to the success of the overall approach. We present here the details of the method and show that the fingerprints are of sufficient quality to permit the construction of megabase-size contigs in defined regions of the human genome. We anticipate that the high throughput and precision characteristic of our fingerprinting method will make it of general utility.

Base Sequence↗

A single mediaprocessor-based programmable ultrasound system.

We have developed a programmable ultrasound imaging system using a single commercially available mediaprocessor. We have efficiently mapped all of the necessary B-mode processing algorithms on the underlying processor architecture, including envelope detection, dynamic range compression, lateral and axial filtering, persistence processing, and scan conversion. Our system can handle varying specifications ranging from 128 vectors and 512 samples per vector to more than 256 vectors and 1024 samples per vector. For an image size of 330 vectors and 512 samples per vector, it can process 30 frames per second using a 300-MHz MAP-CA mediaprocessor from Hitachi/Equator Technologies. This programmable ultrasound machine will not only offer significant advantages in terms of low cost, portability, scalability, and reduced development time, but also provide a flexible platform for developing and deploying new clinical applications to aid the clinicians and improve the quality of healthcare to patients.

Algorithms↗

[The application of multilevel B-splines in 3D emulation of dynamic epicardium mapping].

This paper presents an algorithm for data interpolation and approximation used in the whole atria mapping. Multilevel B-splines are introduced to compute the whole atria surface through a set of irregularly spaced points and to draw the 3D isopotential map, which can reflect the conduction process of depolarization in complex arrhythmia such as atrial fibrillation.

Algorithms↗

Transcriptional mapping of a DNA replication gene cluster in bacteriophage T4. Sites for initiation, termination, and mRNA processing.

A phage T4 genetic cluster that encodes DNA polymerase, several other DNA replication proteins, transcriptional factors, and the translation repressor RegA has been shown to be controlled by overlapping modes of transcription which initiate at several promoters. The promoters were mapped by using a combination of assays including Northern blotting, S1-mapping, RNA sequencing, and analysis of products of radioactive labeling of 5' ends on T4-induced RNA in vitro via the reaction catalyzed by eukaryotic guanylyl transferase (RNA capping assay). The most proximal in the cluster are two promoters that do not require any phage-induced factors for activation, i.e. they are T4 early promoters. Initiation at these promoters yields several RNA species having overlapping 5'-terminal sequences, the largest of which is estimated to be about 15,000 nucleotides long and to include all the cistrons of the cluster. A third early promoter maps inside the protein encoding segment of one of the cistrons (T4 gene 47), while at least five additional promoters map in intercistronic regions and are T4 middle promoters, i.e. they require the T4-induced DNA-binding transcription factor MotA. Transcriptional readthrough at a termination site within the T4 gene 45-44 intercistronic region is required for synthesis of gp44 and gp62, two essential T4 DNA-polymerase (gp43) accessory proteins. In contrast, transcription of T4 gene 43 is serviced by readthrough across a termination site in the regA-43 intercistronic region as well as by a MotA-dependent promoter that maps downstream of the termination site, and the region contains a site for processing by a T4-induced enzyme that also cleaves elsewhere in the polycistronic mRNA from the cluster (i.e. in the Shine-Dalgarno sequence of the gene 45.2 mRNA). The termination events in the gene 45-44 and regA-43 intercistronic regions both occur downstream of RNA stem-loop structures containing the sequence 5'CUUCGG3' in the loop segments. Transcription termination in the 78-base-pair regA-43 intercistronic region occurs about 60 nucleotides away from the gp43 initiator AUG, transcription initiation occurs at 38-40 nucleotides upstream from the AUG, and T4-dependent RNA processing occurs at several sites (including a GGAG sequence) between the transcription termination and initiation sites. Thus, all gp43-encoding mRNAs contain the translational operator (residues -40 to -1 relative to the AUG) for autogenous repression by this DNA polymerase (Andrake et al., 1988).(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗

Protein kinase C decreases the hepatocyte growth factor-induced activation of Erk1/Erk2 MAP kinases.

HGF and phorbol ester induce the scattering of HepG2 cells. Recently, we have reported that the motility and morphological responses that accompany this process require the activation of Erk1/Erk2 MAP kinases, and phosphatidylinositol 3-kinase contributes to the activation of Erk1/Erk2 in HGF-induced cells. The cell scattering-associated appearance of a high-M(r) (>300 kDa) protein pair has also been observed, and has been proven to be a sensitive marker of the intensity of Erk1/Erk2 activation. Our present study demonstrates that in HGF-induced cells protein kinase C and phosphatidylinositol 3-kinase regulate oppositely the expression of these cell scattering-associated proteins. While in phorbol ester-treated cells the sustained activation of protein kinase C is essential for this expression, in HGF-induced cells the inhibition of protein kinase C with bisindolylmaleimide I stimulates the expression. Protein kinase C reduces the HGF-induced phosphorylation of Erk1/Erk2, and in this way it can limit the intensity of Erk1/Erk2-dependent gene-expression

Enzyme Activation↗

Correction for EPI distortions using multi-echo gradient-echo imaging.

A novel and effective technique is described for distortion correction in echo planar imaging (EPI) utilizing the field maps derived from multi-echo gradient-echo images. The distortions from different off-resonance related factors such as field inhomogeneity, eddy current effect, radiofrequency pulse frequency offset, and chemical shift effect can be simultaneously reduced to a great extent. With the proposed post-processing algorithm of multi-channel modulation, distortions may be corrected without unwrapping the phase discontinuities in the derived field map, a process that usually restricts the application of other field map-based correction methods. Results from phantom and animal experiments at 4.7 T demonstrate the efficiency of the method in reducing the geometrical distortions in gradient-echo EPI.

Algorithms↗

Wavelets and functional magnetic resonance imaging of the human brain.

The discrete wavelet transform (DWT) is widely used for multiresolution analysis and decorrelation or "whitening" of nonstationary time series and spatial processes. Wavelets are naturally appropriate for analysis of biological data, such as functional magnetic resonance images of the human brain, which often demonstrate scale invariant or fractal properties. We provide a brief formal introduction to key properties of the DWT and review the growing literature on its application to fMRI. We focus on three applications in particular: (i) wavelet coefficient resampling or "wavestrapping" of 1-D time series, 2- to 3-D spatial maps and 4-D spatiotemporal processes; (ii) wavelet-based estimators for signal and noise parameters of time series regression models assuming the errors are fractional Gaussian noise (fGn); and (iii) wavelet shrinkage in frequentist and Bayesian frameworks to support multiresolution hypothesis testing on spatially extended statistic maps. We conclude that the wavelet domain is a rich source of new concepts and techniques to enhance the power of statistical analysis of human fMRI data.

Algorithms↗

A model of ion channel kinetics using deterministic chaotic rather than stochastic processes.

Models of ion channel kinetics have previously assumed that the switching between the open and closed states is an intrinsically random process. Here, we present an alternative model based on a deterministic process. This model is a piecewise linear iterated map. We calculate the dwell time distributions, autocorrelation function, and power spectrum of this map. We also explore non-linear generalizations of this map. The chaotic nature of our model implies that its long-term behavior mimics the stochastic properties of a random process. In particular, the linear map produces an exponential probability distribution of dwell times in the open and closed states, the same as that produced by the two-state, closed in equilibrium open, Markov model. We show how deterministic and random models can be distinguished by their different phase space portraits. A test of some experimental data seems to favor the deterministic model, but further experimental evidence is needed for an unequivocal decision.

Animals↗

Cloning, mapping, and characterization of the Escherichia coli prc gene, which is involved in C-terminal processing of penicillin-binding protein 3.

The prc gene, which is involved in cleavage of the C-terminal peptide from the precursor form of penicillin-binding protein 3 (PBP 3) of Escherichia coli, was cloned and mapped at 40.4 min on the chromosome. The gene product was identified as a protein of about 80 kDa in maxicell and in vitro systems. Fractionation of the maxicells producing the product suggested that the product was associated with the periplasmic side of the cytoplasmic membrane. This was consistent with the notion that the C-terminal processing of PBP 3 probably occurs outside the cytoplasmic membrane: the processing was found to be dependent on the secY and secA functions, indicating that the prc product or PBP 3 or both share the translocation machinery with other extracytoplasmic proteins. DNA sequencing analysis of the prc gene region identified an open reading frame, with two possible translational starts 6 bp apart from each other, that could code for a product with a calculated molecular weight of 76,667 or 76,432. The prc mutant was sensitive to thermal and osmotic stresses. Southern analysis of the chromosomal DNA of the mutant unexpectedly revealed that the mutation was a deletion of the entire prc gene and thus that the prc gene is conditionally dispensable. The mutation resulted in greatly reduced heat shock response at low osmolarity and in leakage of periplasmic proteins.

Amino Acid Sequence↗

Male-associated polypeptide (MAP) expression in different compartments of the reproductive system of the mussel Mytilus galloprovincialis: immunocytochemical and western blot study.

Mytilus mussels are characterized by annually repeated reproduction which is associated with subsequent growth, morphogenesis, breakdown and redevelopment of the gonad and reproductive tract into mantle mesenchyme. We present a description of the expression of the male-associated polypeptide (MAP; see Mikhailov et al. 1995) in different compartments of the male reproductive system as well as in mantle gonad-supporting tissue. MAP is expressed in both gonad and mantle structures in dynamic patterns that show a substantial overlap in terms of dependence on the stage of gonad development/involution. In general, the total MAP concentration directly correlates with the volume of gonad tubule/duct structures but inversely correlates with mantle connective tissue cell fraction. A maximum of MAP expression is reached in the fully ripe male gonad. MAP is localized around gonad tubules/ducts, in the gonoduct epithelium, membranes of follicle-like structures as well as in the extracellular fiber-like structures of the mantle. However, we also demonstrate unique sites of MAP accumulation in the lumen of gonad follicle-like tubules and in ductal fluid. The latter is characterized by a very high MAP concentration. MAP is also detected in sperm-containing cell suspension obtained by gonad biopsy which we interpret as a result of the adsorption of MAP on mature spermatozoa. The results obtained should be taken into consideration in the interpretation of possible MAP functions since they seem to point to MAP as a major component of ductal (seminal) fluid of the male reproductive tract. It is likely that MAP is able to complement the processes of sperm terminal differentiation and maturation. In addition, we demonstrate that the male-predominant character of MAP expression is restricted by gonad-containing tissues (i.e., mantle and visceral mass) only, although the polypeptide is also detected in other somatic organs in both males and females.

Animals↗

H2O2 accumulation by catalase reduction changes MAP kinase signaling in aged human skin in vivo.

To understand the molecular alterations occurring during the aging process, we compared mitogen-activated protein (MAP) kinase activities in the intrinsically aged and photoaged skins in the same individuals. Furthermore, we investigated the molecular events related to MAP kinase changes in intrinsically aged and photoaged skins. We found that extracellular-signal-regulated kinase (ERK) activity in photoaged skin was reduced, and that the activities of c-Jun N-terminal kinase (JNK) and p38 kinase were increased compared with intrinsically aged skin in the same individuals. Phospho-c-Jun levels and activator protein 1 activities in photoaged skin were also higher than in intrinsically aged skin. Moreover, catalase activity was found to be much reduced in primary dermal fibroblasts from photoaged skin, and as a result, H2O2 accumulated more in primary dermal fibroblasts in photoaged skin. In addition, treating primary dermal fibroblasts from photoaged skin with catalase reduced H2O2 levels, reversed aging-dependent MAP kinase changes, and inhibited matrix metalloproteinase (MMP)-1 expression. Our results indicate that the accumulation of reactive oxygen species due to catalase attenuation may be a critical aspect of the MAP kinase signaling changes that may lead to skin aging and photoaging in human skin in vivo. Thus, the induction and regulation of endogenous antioxidant enzymes including catalase may offer a strategy for preventing and treating skin aging.

Adult↗

A post-processing/region of interest (ROI) method for discriminating patterns of activity in statistical maps of fMRI data.

To combine functional neuroimaging studies across subjects, anatomical and functional data are typically either transformed to a common space or averaged across regions of interest (ROIs). However, if there are (1) anatomical variations within the subject pool (as in clinical or aging populations), (2) non-Gaussian distributions of task-related activity within a typical ROI or, (3) more ROIs than subjects, neither spatial transformation of the data to a common space nor averaging across all subjects' ROIs is suitable for standard discriminant analysis. To solve these problems, we describe a post-processing method that uses voxel-based statistics representing task-related activity (pooled within ROIs) to establish combinations of ROIs that maximally differentiate tasks across all subjects. The method involves randomized resampling from multiple ROIs within each subject, multivariate linear discriminant analysis across all subjects and validation with bootstrapping techniques. When applied to experimental data from healthy subjects performing two motor tasks, the method detected some brain regions, including the supplementary motor area (SMA), that participated in a distributed network differentially active between tasks. However there was not a significant difference in SMA activity when this region was examined in isolation. We suggest this method is a practical means to combine voxel-based statistics within anatomically defined ROIs across subjects.

Brain↗

New approaches to the understanding of tamoxifen action and resistance.

Tamoxifen (TAM) provides an effective agent for treatment of hormone-dependent breast cancer but resistance uniformly ensues upon continued use. Additional studies are required to define more precisely the mechanisms involved in development of resistance. We conducted systematic experimental and clinical studies based on the hypothesis that tumors exposed to TAM long-term may develop resistance by becoming hypersensitive to its estrogenic effects. These investigations uncovered new features of the TAM resistance (TR) phenomenon and identified possible means for its prevention and/or elimination. Initially we confirmed that TR may be divided into two subtypes, primary and acquired resistance, and that these differ by certain important characteristics including the level of the possible involvement of adaptive and genetic components. Then we distinguished at least three consequent stages of this phenomenon: stage I when TAM behaves as an antiestrogen, stage II with development of increased sensitivity to the agonistic (pro-estrogenic) properties of TAM and stage III with an adaptive increase in sensitivity to estradiol (E(2)). During this evolutionary process, as shown in vitro, MAP kinase (MAPK) and aromatase activities increase. The time frame of the increase in MAPK activity as a rule outpaces the increase in aromatase activity during the course of the development of TR. This may occur as a response to estrogen deprivation or interruption of the process of estrogen signaling and can be one of the promoting factors of increased aromatase activation. On the other hand, the chronology of these events indicates that changes in the MAPK cascade can be more important for the early steps of the development and maintenance of the TR state. Changes in local estrogen production/sensitivity to E(2) are perhaps essential for the later steps of this phenomenon. We have explored the use of a growth factor-blocking agent to abrogate the adaptive changes in sensitivity. Farnesylthiosalicylic acid (FTS), an inhibitor of GTP-Ras binding to its membrane acceptor site, reduces the increase in the number of MCF-7 cells induced by long-term TAM treatment. It also decreases MAPK activity in TAM-treated MCF-7 cells and in established TR cell lines. Alone or in combination with letrozole (presumably, through the influence on MAPK pathway) FTS exerts moderate inhibitory effects on aromatase activity in estrogen-deprived or estrogen-exposed MCF-7 cells. Taken together, our observations suggest that FTS is a 'candidate drug' for the treatment of TR. Both the adaptive and genetic types of resistance may be amenable to this approach. Our studies underline the possible importance of starting the treatment/prevention of TR early on. From our clinical studies using immunohistochemistry, there is a rather strong rationale to include as a predisposing factor in the development of TR the increase in MAPK and aromatase activities in human primary breast tumors. In summary, data obtained during the course of this project may be considered as evidence supporting the principle that processes resulting in responses to TAM as an agonist and the development of estrogen hypersensitivity of breast cancer cells could potentially be mechanistically linked.

Animals↗

Automated detection of focal cortical dysplasia lesions using computational models of their MRI characteristics and texture analysis.

Focal cortical dysplasia (FCD), a malformation of cortical development, is a frequent cause of pharmacologically intractable epilepsy. FCD is characterized on Tl-weighted MRI by cortical thickening, blurring of the gray-matter/white-matter interface, and gray-level hyperintensity. We have previously used computational models of these characteristics to enhance visual lesion detection. In the present study we seek to improve our methods by combining these models with features derived from texture analysis of MRI, which allows measurement of image properties not readily accessible by visual analysis. These computational models and texture features were used to develop a two-stage Bayesian classifier to perform automated FCD lesion detection. Eighteen patients with histologically confirmed FCD and 14 normal controls were studied. On the MRI volumes of the 18 patients, 20 FCD lesions were manually labeled by an expert observer. Three-dimensional maps of the computational models and texture features were constructed for all subjects. A Bayesian classifier was trained on the computational models to classify voxels as cerebrospinal fluid, gray-matter, white-matter, transitional, or lesional. Voxels classified as lesional were subsequently reclassified based on the texture features. This process produced a 3D lesion map, which was compared to the manual lesion labels. The automated classifier identified 17/20 manually labeled lesions. No lesions were identified in controls. Thus, combining models of the T1-weighted MRI characteristics of FCD with texture analysis enabled successful construction of a classifier. This computer-based, automated method may be useful in the presurgical evaluation of patients with severe epilepsy related to FCD.

Adult↗

Glial neoplasms: dynamic contrast-enhanced T2*-weighted MR imaging.

PURPOSE: To evaluate the role of T2*-weighted echo-planar perfusion imaging by using a first-pass gadopentetate dimeglumine technique to determine the association of magnetic resonance (MR) imaging-derived cerebral blood volume (CBV) maps with histopathologic grading of astrocytomas and to improve the accuracy of targeting of stereotactic biopsy. MATERIALS AND METHODS: MR imaging was performed in 29 patients by using a first-pass gadopentetate dimeglumine T2*-weighted echo-planar perfusion sequence followed by conventional imaging. The perfusion data were processed to obtain a color map of relative regional CBV. This information formed the basis for targeting the stereotactic biopsy. Relative CBV values were computed with a nondiffusible tracer model. The relative CBV of lesions was expressed as a percentage of the relative CBV of normal white matter. The maximum relative CBV of each lesion was correlated with the histopathologic grading of astrocytomas obtained from samples from stereotactic biopsy or volumetric resection. RESULTS: The maximum relative CBV in high-grade astrocytomas (n = 26) varied from 1.73 to 13.7, with a mean of 5.07 +/- 2.79 (+/- SD), and in the low-grade cohort (n = 3) varied from 0.92 to 2.19, with a mean of 1.44 +/- 0.68. This difference in relative CBV was statistically significant (P < .001; Student t test). CONCLUSION: Echo-planar perfusion imaging is useful in the preoperative assessment of tumor grade and in providing diagnostic information not available with conventional MR imaging. The areas of perfusion abnormality are invaluable in the precise targeting of the stereotactic biopsy.

Adolescent↗