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At least 991 records · Page 55Linked to original sources
PubMed2005

The wound repair response controls outcome to cutaneous leishmaniasis.

Chronic microbial infections are associated with fibrotic and inflammatory reactions known as granulomas showing similarities to wound-healing and tissue repair processes. We have previously mapped three leishmaniasis susceptibility loci, designated lmr1, -2, and -3, which exert their effect independently of T cell immune responses. Here, we show that the wound repair response is critically important for the rapid cure in murine cutaneous leishmaniasis caused by Leishmania major. Mice congenic for leishmaniasis resistance loci, which cured their lesions more rapidly than their susceptible parents, also expressed differentially genes involved in tissue repair, laid down more ordered collagen fibers, and healed punch biopsy wounds more rapidly. Fibroblast monolayers from these mice repaired in vitro wounds faster, and this process was accelerated by supernatants from infected macrophages. Because these effects are independent of T cell-mediated immunity, we conclude that the rate of wound healing is likely to be an important component of innate immunity involved in resistance to cutaneous leishmaniasis.

Animals↗
PubMed2005

Protein interfaces in signaling regulated by arginine methylation.

Posttranslational modifications are well-known effectors of signal transduction. Arginine methylation is a covalent modification that results in the addition of methyl groups to the nitrogen atoms of the arginine side chains. A probable role of arginine methylation in signal transduction is emerging with the identification of new arginine-methylated proteins. However, the functional consequences of arginine methylation and its mode of regulation remain unknown. The identification of the protein arginine methyltransferase family and the development of methylarginine-specific antibodies have raised renewed interest in this modification during the last decade. Arginine methylation was mainly observed on abundant proteins such as RNA-binding proteins and histones, but recent advances have revealed a plethora of arginine-methylated proteins implicated in a variety of cellular processes, including signaling by interferon and cytokines, and in T cell signaling. We discuss these recent advances and the role of arginine methylation in signal transduction.

Animals↗
PubMed1992

Genetic mapping of the murine gene and 14 related sequences encoding chromosomal protein HMG-14.

The high-mobility-group chromosomal protein HMG-14 preferentially binds to nucleosomal core particles of mammalian chromatin and may modulate the chromatin configuration of transcriptionally active genes. The human gene for HMG-14 has been localized to the Down syndrome region of Chromosome (Chr) 21 and may be involved in the etiology of this syndrome. Here we show, by means of genetic linkage analysis of interspecific and intersubspecific backcross mice, that the murine functional gene, Hmg14, is located on the distal end of mouse Chr 16, a region known to have conserved synteny with human Chr 21. In addition to the functional gene for HMG-14, both human and mouse genomes contain many related sequences that are probably processed pseudogenes. Here we map the locations of 14 Hmg14-related sequences in two mouse genomes. The 14 mapped loci are widely dispersed on ten chromosomes (Chrs 3, 5, 7, 9, 11, 12, 16, 17, 19, and X) and can be detected efficiently with a single cDNA probe. Thus, the Hmg14 multigene family is well suited to serve as genetic markers for other linkage studies in mice.

Animals↗
PubMed2004

Biological abnormality of impaired reading is constrained by culture.

Developmental dyslexia is characterized by a severe reading problem in people who have normal intelligence and schooling. Impaired reading of alphabetic scripts is associated with dysfunction of left temporoparietal brain regions. These regions perform phonemic analysis and conversion of written symbols to phonological units of speech (grapheme-to-phoneme conversion); two central cognitive processes that mediate reading acquisition. Furthermore, it has been assumed that, in contrast to cultural diversities, dyslexia in different languages has a universal biological origin. Here we show using functional magnetic resonance imaging with reading-impaired Chinese children and associated controls, that functional disruption of the left middle frontal gyrus is associated with impaired reading of the Chinese language (a logographic rather than alphabetic writing system). Reading impairment in Chinese is manifested by two deficits: one relating to the conversion of graphic form (orthography) to syllable, and the other concerning orthography-to-semantics mapping. Both of these processes are critically mediated by the left middle frontal gyrus, which functions as a centre for fluent Chinese reading that coordinates and integrates various information about written characters in verbal and spatial working memory. This finding provides an insight into the fundamental pathophysiology of dyslexia by suggesting that rather than having a universal origin, the biological abnormality of impaired reading is dependent on culture.

Asian People↗
PubMed1999

Morphological and physiological characteristics of discontinuous linear atrial ablations during atrial pacing and atrial fibrillation.

INTRODUCTION: Linear atrial ablations are thought to be necessary to accomplish successful catheter ablation of atrial fibrillation. In order to investigate the conduction characteristics of atrial myocardium in regions of linear lesion discontinuity (gaps), we performed activation sequence mapping in gap regions during atrial pacing and atrial fibrillation. METHODS AND RESULTS: In seven dogs, a linear epicardial ablation was created on the right atrial free wall with a discontinuous segment (gap) in the mid-portion of the lesion. A plaque electrode was used to measure conduction across the gap. Conduction was assessed during (1) atrial pacing from the edge of the plaque electrode during sinus rhythm, and (2) during atrial fibrillation. After each series of measurements, the lesion gap was decreased by creating additional radiofrequency ablations and repeat conduction maps were obtained. The process was repeated until conduction block was observed during atrial pacing. Gap lengths ranged from 0 to 25 mm. During atrial pacing, gaps as narrow as 2 mm demonstrated normal conduction and gaps as large as 5 mm demonstrated block during pacing. Although conduction block was never present across gaps greater than 5 mm, the ability to predict conduction block as a function of gap width was difficult for lesions < or = 5 mm due to a significant degree of overlap between normal conduction and conduction block in this gap range. During atrial fibrillation, 1/175 (0.6%) mapped wavelets conducted across gaps that demonstrated block during pacing; whereas, 411/600 (68.5%; P < 0.0001) wavelets conducted across gaps that did not demonstrate block during pacing (P = NS compared to preablation measurements). Histologically normal atrial myocytes were observed within gaps exhibiting conduction block. CONCLUSIONS: Visible gaps > 5 mm rarely demonstrate conduction block during atrial pacing and atrial fibrillation; whereas, gaps < or = 5 mm in length may demonstrate block. Lesion gaps that do not demonstrate conduction block during atrial pacing have no higher rate of functional conduction block during atrial fibrillation than fibrillating atria without ablation lesions.

Animals↗
PubMed2000

Regional distribution of NPC1 protein in monkey brain.

NPC1 is a member of a family of polytopic membrane-bound proteins with sterol-sensing domains. Inactivating mutations of NPC1 are responsible for most cases of Niemann-Pick type C disease, whose hallmark is progressive neurodegeneration. The precise molecular mechanisms whereby defective NPC1 function leads to neurodegeneration are unknown. In the brain, we have previously found NPC1 to localize predominantly within perisynaptic astrocytic processes. Here we have mapped the regional distribution of NPC1 in the monkey brain. Dense NPC1 immunoreactivity was observed in telencephalic structures, including the cerebral neocortex, hippocampus, caudate nucleus and putamen, whilst light immunostaining was observed in diencephalic structures, including the globus pallidus, thalamus and hypothalamus. Light staining was also generally observed in the midbrain, pons, medulla oblongata and cerebellum, except the inferior olive, which was densely stained. By light microscopy, only a few indistinctly labeled cell bodies were observed even within densely labeled regions, where most of the immunoreactivity appeared to be due to the large numbers of labeled cellular processes. On electron microscopy, these processes were identified as glial, and not neuronal. The astrocytic localization of NPC1 was further confirmed by double labeling for NPC1 and GFAP. The regional pattern of NPC1 expression suggests that areas normally expressing low levels of the NPC1 protein are more susceptible to neuronal degeneration in Niemann-Pick type C disease.

Animals↗
PubMed1997

Structural and functional analyses of human cerebral cortex using a surface-based atlas.

We have analyzed the geometry, geography, and functional organization of human cerebral cortex using surface reconstructions and cortical flat maps of the left and right hemispheres generated from a digital atlas (the Visible Man). The total surface area of the reconstructed Visible Man neocortex is 1570 cm2 (both hemispheres), approximately 70% of which is buried in sulci. By linking the Visible Man cerebrum to the Talairach stereotaxic coordinate space, the locations of activation foci reported in neuroimaging studies can be readily visualized in relation to the cortical surface. The associated spatial uncertainty was empirically shown to have a radius in three dimensions of approximately 10 mm. Application of this approach to studies of visual cortex reveals the overall patterns of activation associated with different aspects of visual function and the relationship of these patterns to topographically organized visual areas. Our analysis supports a distinction between an anterior region in ventral occipito-temporal cortex that is selectively involved in form processing and a more posterior region (in or near areas VP and V4v) involved in both form and color processing. Foci associated with motion processing are mainly concentrated in a region along the occipito-temporal junction, the ventral portion of which overlaps with foci also implicated in form processing. Comparisons between flat maps of human and macaque monkey cerebral cortex indicate significant differences as well as many similarities in the relative sizes and positions of cortical regions known or suspected to be homologous in the two species.

Anatomy, Cross-Sectional↗
PubMed1978

A second gene affecting the sialylation of lysosomal alpha-mannosidase in mouse liver.

We have previously reported on a mouse liver-specific genetic polymorphism associated with altered sialylation of lysosomal alpha-mannosidase. A second electrophoretic polymorphism for liver lysosomal alpha-mannosidase has now been found and characterized. This variation, between SWR/J and SM/JCv inbred mice, is determined by a single genetic locus (Map-2) on chromosome 17 and appears to be the result of further differences in sialylation of the lysosomal enzyme. The Map-2 gene appears to affect the processing of liver, spleen, and lung lysosomal alpha-mannosidase, whereas the Map-1 gene appears to be specific to the processing of liver lysosomal alpha-mannosidase (Dizik and Elliott, 1977). The more negatively charged electrophoretic liver phenotype (MA-A) characteristic of the SM/JCv strain is recessive to the phenotype (MA-B) characteristic of the SWR/J strain. In contrast, at the Map-1 locus, the more negatively charged phenotype is dominant. The electrophoretic pattern of development of the liver enzyme from SM/JCv mice is described.

Animals↗
PubMed1992

Lymphoproliferative activity of Pseudomonas exotoxin A is dependent on intracellular processing and is associated with the carboxyl-terminal portion.

Pseudomonas aeruginosa exotoxin A (PE) represents a microbial superantigen that requires processing by accessory cells in order to induce the proliferation of V beta 8-bearing murine T lymphocytes. In this study, we have observed that PE requires intracellular processing by a protease in order to induce lymphoproliferation. Pepstatin A, an inhibitor of acid proteases, inhibited PE-induced lymphoproliferation, whereas leupeptin, an inhibitor of serine and thiol proteases, had no effect on PE-induced lymphoproliferation. A number of mutant forms of PE were examined for their ability to induce lymphoproliferation. The mutant form which lacks amino acids 5 to 224 of the receptor-binding domain, PE43, was capable of inducing murine thymocytes to proliferate in the presence of accessory cells. However, neither PEgly276, a mutant toxin which undergoes a different intracellular processing pattern than wild-type PE, nor PE589, a mutant toxin which lacks amino acids 590 to 613 at the carboxyl terminus, was able to induce thymocyte proliferation. In addition, the lymphoproliferation induced by the PE43 mutant form of PE could also be inhibited by pepstatin A. Therefore, our data indicate that intracellular processing by a proteolytic enzyme which is inhibited by pepstatin A is critical for PE-induced lymphoproliferation. Furthermore, the lymphoproliferative activity of PE is associated with the carboxyl-terminal portion of PE.

ADP Ribose Transferases↗
PubMedDate not supplied

Investigations into the organization of information in sensory cortex.

One might take the exploration of sensory cortex in the first decades of the last century as the opening chapter of modern neuroscience. The combined approaches of (i) measuring effects of restricted ablation on functional capacities, both in the clinic and the laboratory, together with (ii) anatomical investigations of cortical lamination, arealization, and connectivity, and (iii) the early physiological probing of sensory representations, led to a fundamental body of knowledge that remains relevant to this day. In our time, there can be little doubt that its organization as a mosaic of columnar modules is the pervasive functional property of mammalian sensory cortex [Brain 120 (1997) 701]. If one accepts the assertion that columns and maps must improve the functioning of the brain (why else would they be the very hallmark of neocortex?), then the inevitable question is: exactly what advantages do they permit? In this review of our recent presentation at the workshop on Homeostasis, plasticity and learning at the Institut Henri Poincaré, we will outline a systematic approach to investigating the role of modular, map-like cortical organization in the processing of sensory information. We survey current evidence concerning the functional significance of cortical maps and modules, arguing that sensory cortex is involved not solely in the online processing of afferent data, but also in the storage and retrieval of information. We also show that the topographic framework of primary sensory cortex renders the encoding of sensory information efficient, fast and reliable.

Animals↗
PubMed2005

The Giardia duodenalis 14-3-3 protein is post-translationally modified by phosphorylation and polyglycylation of the C-terminal tail.

The flagellated protozoan Giardia duodenalis (syn. lamblia or intestinalis) has been chosen as a model parasite to further investigate the multifunctional 14-3-3s, a family of highly conserved eukaryotic proteins involved in many cellular processes, such as cell cycle, differentiation, apoptosis, and signal transduction pathways. We confirmed the presence of a single 14-3-3 homolog gene (g14-3-3) by an in silico screening of the complete genome of Giardia, and we demonstrated its constitutive transcription throughout the life stages of the parasite. We cloned and expressed the g14-3-3 in bacteria, and by protein-protein interaction assays we demonstrated that it is a functional 14-3-3. Using an anti-peptide antibody raised against a unique 18-amino acid sequence at the N terminus, we observed variations both in the intracellular localization and in the molecular size of the native g14-3-3 during the conversion of Giardia from trophozoites to the cyst stage. An affinity chromatography, based on the 14-3-3 binding to the polypeptide difopein, was set to purify the native g14-3-3. By matrix-assisted laser desorption ionization mass spectroscopy analysis, we showed that polyglycylation, an unusual post-translational modification described only for tubulin, occurred at the extreme C terminus of the native g14-3-3 on Glu246, Glu247, or both and that the Thr214, located in the loop between helices 8 and 9, is phosphorylated. We propose that the addition of the polyglycine chain can promote the binding of g14-3-3 to alternative ligands and that the differential rate of polyglycylation/deglycylation during the encystation process can act as a novel mechanism to regulate the intracellular localization of g14-3-3.

14-3-3 Proteins↗
PubMed2002

Formation of an hER alpha-COUP-TFI complex enhances hER alpha AF-1 through Ser118 phosphorylation by MAPK.

The enhancement of the human estrogen receptor alpha (hER alpha, NR3A1) activity by the orphan nuclear receptor COUP-TFI is found to depend on the establishment of a tight hER alpha-COUP-TFI complex. Formation of this complex seems to involve dynamic mechanisms different from those allowing hER alpha homodimerization. Although the hER alpha-COUP-TFI complex is present in all cells tested, the transcriptional cooperation between the two nuclear receptors is restricted to cell lines permissive to hER alpha activation function 1 (AF-1). In these cells, the physical interaction between COUP-TFI and hER alpha increases the affinity of hER alpha for ERK2/p42(MAPK), resulting in an enhanced phosphorylation state of the hER alpha Ser118. hER alpha thus acquires a strengthened AF-1 activity due to its hyperphosphorylation. These data indicate an alternative interaction process between nuclear receptors and demonstrate a novel protein intercommunication pathway that modulates hER alpha AF-1.

Adenocarcinoma↗
PubMed1998

Neural network classifications and correlation analysis of EEG and MEG activity accompanying spontaneous reversals of the Necker cube.

It has recently been suggested that reentrant connections are essential in systems that process complex information [A. Damasio, H. Damasio, Cortical systems for the retrieval of concrete knowledge: the convergence zone framework, in: C. Koch, J.L. Davis (Eds.), Large Scale Neuronal Theories of the Brain, The MIT Press, Cambridge, 1995, pp. 61-74; G. Edelman, The Remembered Present, Basic Books, New York, 1989; M.I. Posner, M. Rothbart, Constructing neuronal theories of mind, in: C. Koch, J.L. Davis (Eds.), Large Scale Neuronal Theories of the Brain, The MIT Press, Cambridge, 1995, pp. 183-199; C. von der Malsburg, W. Schneider, A neuronal cocktail party processor, Biol. Cybem., 54 (1986) 29-40]. Reentry is not feedback, but parallel signalling in the time domain between spatially distributed maps, similar to a process of correlation between distributed systems. Accordingly, it was expected that during spontaneous reversals of the Necker cube, complex patterns of correlations between distributed systems would be present in the cortex. The present study included EEG (n=4) and MEG recordings (n=5). Two experimental questions were posed: (1) Can distributed cortical patterns present during perceptual reversals be classified differently using a generalised regression neural network (GRNN) compared to processing of a two-dimensional figure? (2) Does correlated cortical activity increase significantly during perception of a Necker cube reversal? One-second duration single trials of EEG and MEG data were analysed using the GRNN. Electrode/sensor pairings based on cortico-cortical connections were selected to assess correlated activity in each condition. The GRNN significantly classified single trials recorded during Necker cube reversals as different from single trials recorded during perception of a two-dimensional figure for both EEG and MEG. In addition, correlated cortical activity increased significantly in the Necker cube reversal condition for EEG and MEG compared to the perception of a non-reversing stimulus. Coherent MEG activity observed over occipital, parietal and temporal regions is believed to represent neural systems related to the perception of Necker cube reversals.

Adolescent↗
PubMed2000

Nitric oxide down-regulates MKP-3 mRNA levels: involvement in endothelial cell protection from apoptosis.

MAP kinase-dependent phosphorylation processes have been shown to interfere with the degradation of the antiapoptotic protein Bcl-2. The cytosolic MAP kinase phosphatase MAP kinase phosphatase-3 (MKP-3) induces apoptosis of endothelial cells in response to tumor necrosis factor alpha (TNFalpha) via dephosphorylation of the MAP kinase ERK1/2, leading to Bcl-2 proteolysis. Here we report that the endothelial cell survival factor nitric oxide (NO) down-regulated MKP-3 by destabilization of MKP-3 mRNA. This effect of NO was paralleled by a decrease in MKP-3 protein levels. Moreover, ERK1/2 was found to be protected against TNFalpha-induced dephosphorylation by coincubation of endothelial cells with the NO donor. Subsequently, both the decrease in Bcl-2 protein levels and the mitochondrial release of cytochrome c in response to TNFalpha were largely prevented by exogenous NO. In cells overexpressing MKP-3, no differences in phosphatase activity in the presence or absence of NO were found, excluding potential posttranslational modifications of MKP-3 protein by NO. These data demonstrate that upstream of the S-nitrosylation of caspase-3, NO exerts additional antiapoptotic effects in endothelial cells, which rely on the down-regulation of MKP-3 mRNA.

Animals↗
PubMed1997

Development of orientation preference maps in area 18 of kitten visual cortex.

We investigated the development of orientation preference maps in the visual cortex of kittens by repeated optical imaging from the same animal. Orientation maps became detectable for the first time around postnatal day (P) 17 and improved continuously in strength unitl P30, the time at which their appearance became adultlike. During this developmental period the overall geometry of the maps remained unchanged, suggesting that the layout of the orientation map is specified prior to P17. Hence, before the visual cortex becomes susceptible to experience-dependent modifications its functional architecture is largely specified. This suggests that the initial development and layout of orientation preference maps are determined by intrinsic processes that are independent of visual experience. This conclusion is further supported by the result that orientation maps were well expressed at P24 in binocularly deprived kittens. Because the appearance of the first orientation-selective neurons and the subsequent development of orientation preference maps correlated well with the time course of the expression and refinement of clustered horizontal connections, we propose that these connections might contribute to the specification of orientation preference maps.

Animals↗
PubMed2000

Growth patterns in the developing brain detected by using continuum mechanical tensor maps.

The dynamic nature of growth and degenerative disease processes requires the design of sensitive strategies to detect, track and quantify structural change in the brain in its full spatial and temporal complexity. Although volumes of brain substructures are known to change during development, detailed maps of these dynamic growth processes have been unavailable. Here we report the creation of spatially complex, four-dimensional quantitative maps of growth patterns in the developing human brain, detected using a tensor mapping strategy with greater spatial detail and sensitivity than previously obtainable. By repeatedly scanning children (aged 3-15 years) across time spans of up to four years, a rostro-caudal wave of growth was detected at the corpus callosum, a fibre system that relays information between brain hemispheres. Peak growth rates, in fibres innervating association and language cortices, were attenuated after puberty, and contrasted sharply with a severe, spatially localized loss of subcortical grey matter. Conversely, at ages 3-6 years, the fastest growth rates occurred in frontal networks that regulate the planning of new actions. Local rates, profiles, and principal directions of growth were visualized in each individual child.

Adolescent↗
PubMed2003

The time-organized map algorithm: extending the self-organizing map to spatiotemporal signals.

The new time-organized map (TOM) is presented for a better understanding of the self-organization and geometric structure of cortical signal representations. The algorithm extends the common self-organizing map (SOM) from the processing of purely spatial signals to the processing of spatiotemporal signals. The main additional idea of the TOM compared with the SOM is the functionally reasonable transfer of temporal signal distances into spatial signal distances in topographic neural representations. This is achieved by neural dynamics of propagating waves, allowing current and former signals to interact spatiotemporally in the neural network. Within a biologically plausible framework, the TOM algorithm (1) reveals how dynamic neural networks can self-organize to embed spatial signals in temporal context in order to realize functional meaningful invariances, (2) predicts time-organized representational structures in cortical areas representing signals with systematic temporal relation, and (3) suggests that the strength with which signals interact in the cortex determines the type of signal topology realized in topographic maps (e.g., spatially or temporally defined signal topology). Moreover, the TOM algorithm supports the explanation of topographic reorganizations based on time-to-space transformations (Wiemer, Spengler, Joublin, Stagge, & Wacquant, 2000).

Algorithms↗
PubMed1996

Functional MRI applications in clinical epilepsy.

Functional MRI holds great promise as a diagnostic tool in presurgical evaluation of patients with epilepsy. Recent research has used fMRI for localization of the seizure focus by tracking interictal spikes and by observing blood flow changes during seizure onset. Localization of the language-dominant hemisphere with fMRI has been well-validated in normal volunteers and left-hemisphere-dominant epilepsy patients, but is less developed for patients with mixed- or right-hemisphere language dominance. Intrahemispheric mapping of sensory and motor functions with fMRI is fairly well established, and progress is being made in mapping higher-level cognitive functions, particularly language. Little research has convincingly demonstrated hippocampal function in the normal brain during memory processing, and applications of memory mapping in epilepsy are still lacking. While the clinical use of fMRI in epilepsy needs substantially more study, this is nonetheless a very promising technique that may dramatically change the presurgical diagnostic regimen for these patients.

Brain Mapping↗