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Two-dimensional substructure of MT receptive fields.

Neurons at progressively higher levels of the visual system have progressively larger, more complicated receptive fields, presumably constructed from simpler antecedent receptive fields. To study this hierarchical organization, we used sparse white noise to map receptive-field substructure (second order Wiener-like kernels) in an extrastriate motion processing area (MT) of alert monkeys. The maps revealed a clear substructure, on a spatial scale comparable to the receptive fields of the V1 inputs. There were both facilitatory and suppressive interactions that differed in spatial organization and time course. Directional interactions were remarkably precise over a very small spatial range, and reversed when successive stimuli reversed contrast--a neural correlate of "reverse phi" motion perception. The maps of some cells had an unexpected, curved shape, which challenges existing models for direction selectivity.

Animals↗

Visualization of flow by vector analysis of multidirectional cine MR velocity mapping.

OBJECTIVE: We describe a noninvasive method for visualization of flow and demonstrate its application in a flow phantom and in the great vessels of healthy volunteers and patients with aortic and pulmonary arterial disease. The technique uses multidirectional MR velocity mapping acquired in selected planes. Maps of orthogonal velocity components were then processed into a graphic form immediately recognizable as flow. MATERIALS AND METHODS: Cine MR velocity maps of orthogonal velocity components in selected planes were acquired in a flow phantom, 10 healthy volunteers, and 13 patients with dilated great vessels. Velocities were presented by multiple computer-generated streaks whose orientation, length, and movement corresponded to velocity vectors in the chosen plane. RESULTS: The velocity vector maps allowed visualization of complex patterns of primary and secondary flow in the thoracic aorta and pulmonary arteries. The technique revealed coherent, helical forward blood movements in the normal thoracic aorta during midsystole and a reverse flow during early diastole. Abnormal flow patterns with secondary vortices were seen in patients with dilated arteries. CONCLUSION: The potential of MR velocity vector mapping for in vitro and in vivo visualization of flow patterns is demonstrated. Although this study was limited to two-directional flow in a single anatomical plane, the method provides information that might advance our understanding of the human vascular system in health and disease. Further developments to reduce the acquisition time and the handling and presenting of three-directional velocity data are required to enhance the capability of this method.

Adolescent↗

MAP kinases mediate phagocytosis and melanization via prophenoloxidase activation in medfly hemocytes.

E. coli phagocytosis by medfly hemocytes, in contrast to mammalian macrophages, associates with E. coli-challenged hemocyte secretion by mitogen activating protein (MAP) kinases. In the present work, we examined whether this system links with the proteolytic activation of prophenoloxidase (proPO). ProPO and prophenoloxidase-activating proteinases (PAPs) were initially identified within freshly isolated medfly hemocytes. Moreover, flow cytometry and immunocytochemical analysis revealed the constitutive expression of proPO and its stable association with hemocyte surface. The expression level of hemocyte surface proPO is not affected by E. coli infection. In addition, flow cytometry analysis in freshly isolated hemocytes showed that E. coli phagocytosis is markedly blocked by antibodies against proPO or PAPs, as well as by several serine protease inhibitors, strongly supporting the involvement of proPO cascade in the phagocytosis process. Similarly, it was shown that melanization process depends on proPO activation. MAP kinases appeared to control both phagocytosis and melanization, since they regulate PAPs secretion, a prerequisite for the conversion of proPO to active PO. From this and previous studies, hemocytes appear to be central to immune response in medfly.

Animals↗

Genome-wide expression dynamics during mouse embryonic development reveal similarities to Drosophila development.

Gene transcription mediates many vital aspects of mammalian embryonic development. A comprehensive characterization and analysis of the dynamics of gene transcription in the embryo is therefore likely to provide significant insights into the basic mechanisms of this process. We used microarrays to map transcription in the mouse embryo in the important period from embryonic day 8 (e8.0) to postnatal day 1 (p1) during which the bulk of the differentiation and development of organ systems takes place. Analysis of these expression profiles revealed distinct patterns of gene expression which correlate with the differentiation of organs including the nervous system, liver, skin, lungs, and digestive system, among others. Statistical analysis of the data based on Gene Ontology (GO) group annotation showed that specific temporal sequence patterns in gene class utilization across development are very similar to patterns seen during the embryonic development of Drosophila, suggesting conservation of the temporal progression of these processes across 550 million years of evolution. The temporal profiles of gene expression and activation of processes revealed here provide intriguing insights into the mechanisms of mammalian development, embryogenesis, and organogenesis, as well as into the evolution of developmental processes.

Animals↗

HC-gp39 contributes to chondrocyte differentiation by inducing SOX9 and type II collagen expressions.

OBJECTIVE: The transcription factor SOX9 has been shown to be linked to chondrocyte differentiation and induction of type II collagen synthesis. Since the chitinase-like protein, human cartilage glycoprotein 39 (HC-gp39), can be expressed by articular chondrocytes and has been shown to enhance chondrocyte mitogenesis through MAP kinase and PI3 kinase-mediated signalling, we hypothesized that it may also promote synthesis of cartilage matrix components through induction of SOX9, utilizing similar signalling pathways. METHODS: Primary chondrocytes from neonatal mouse rib cartilage were exposed to purified HC-gp39. The response of the cells was evaluated in terms of SOX9 induction and synthesis of type II collagen. Signalling pathways activated following HC-gp9 exposure were analyzed by Western blotting of cell lysates with phosphorylation-specific antibodies as well as by using selective inhibitors. RESULTS: HC-gp39 induced both SOX9 and type II collagen synthesis. Similar results were observed for IGF-1. This process required signalling through both MAP kinase and PI3 kinase pathways resulting in rapid phosphorylation of ERK1/2 and AKT, respectively. Neither HC-gp39 nor IGF-1 induced activation of SAPK/JNK. CONCLUSIONS: The effects of HC-gp39 on chondrocyte function suggest that this molecule may promote the maintenance or expression of a chondrocytic phenotype. Its expression in injured or degenerate cartilage could be related to the initial repair-response and increased matrix synthesis observed in osteoarthritic cartilage.

Adipokines↗

Computational models of MRI characteristics of focal cortical dysplasia improve lesion detection.

In many patients, focal cortical dysplasia (FCD) is characterized by minor structural changes that may go unrecognized by standard radiological analysis. We previously demonstrated that visual analysis of a composite map based on three simple models of MRI features of FCD increased the sensitivity of FCD lesion detection, compared to visual analysis of conventional MRI. Here we report on the use of improved methods for characterizing FCD which improve contrast in the composite maps: a Laplacian-based metric for measuring cortical thickness, a convolutional kernel to model blurring of the GM-WM interface, and an operator to measure hyperintense T1 signal. To validate these methods, we processed the MRIs of 14 FCD patients with our original set of image processing operators and an improved set of image processing operators. Comparison of the composite maps associated with the two sets of operators revealed that contrast between lesional tissue and nonlesional cortex was significantly increased in the composite maps associated with the set of improved operators. Increasing this contrast is an important step toward the goal of automated FCD lesion detection.

Brain Mapping↗

The scalp distribution of the fractal dimension of the EEG and its variation with mental tasks.

The insights gained by the concept of deterministic chaos for the EEG is that this seemingly disordered process may be governed by relatively few simple laws which could be determined. One of the quantitative measures of a complex dynamical system is that of its dimension. The term 'dimension' refers to the ability of a space to contain a set of points. We estimated the correlational dimension of the EEG and compared the outcome to traditional Fourier analyses. In addition, we tested the hypothesis that the EEG can be described as filtered noise. Data from 15 electrode sites and 31 subjects are reported in the present study. We have utilized a variety of tasks that cut across sensory modalities including touch, vision, and imagery which reflect neuropsychological processes that differentially engage areas of the cortex in the first part of the study. In the second part, the differences between the perception of an object and the imagination of the same object were evaluated. The outcome shows variations between scalp sites for all measures and also variations between tasks in terms of dimensionality of the EEG. The hypothesis of a higher dimensionality ("complexity") of imagery compared to actual perceptual processing was confirmed. A statistical comparison between the maps generated by means of the various measures shows that different informations are extracted when using the different measures. There is also statistical evidence that the EEG cannot completely be described by the model of filtered noise.

Adult↗

Visuo-spatial neural response interactions in early cortical processing during a simple reaction time task: a high-density electrical mapping study.

The timecourse and scalp topography of interactions between neural responses to stimuli in different visual quadrants, straddling either the vertical or horizontal meridian, were studied in 15 subjects. Visual evoked potentials (VEPs) were recorded from 64 electrodes during a simple reaction time (RT) task. VEPs to single stimuli displayed in different quadrants were summed ('sum') and compared to the VEP response from simultaneous stimulation of the same two quadrants ('pair'). These responses would be equivalent if the neural responses to the single stimuli were independent. Divergence between the 'pair' and 'sum' VEPs indicates a neural response interaction. In each visual field, interactions occurred within 72-86 ms post-stimulus over parieto-occipital brain regions. Independent of visual quadrant, RTs were faster for stimulus pairs than single stimuli. This replicates the redundant target effect (RTE) observed for bilateral stimulus pairs and generalizes the RTE to unilateral stimulus pairs. Using Miller's 'race' model inequality (Miller J. Divided attention: evidence for coactivation with redundant signals, Cognitive Psychology 1982;14:247-79), we found that probability summation could fully account for the RTE in each visual field. Although measurements from voltage waveforms replicated the observation of earlier peak P1 latencies for the 'pair' versus 'sum' comparison (Miniussi C, Girelli M, Marzi CA. Neural site of the redundant target effect: electrophysiological evidence. Journal of Cognitive Neuroscience 1998;10:216-30), this did not hold with measurements taken from second derivative (scalp current density) waveforms. Since interaction effects for bilateral stimulus pairs occurred within 86 ms and require interhemispheric transfer, transcallosal volleys must arrive within 86 ms, which is earlier than previously calculated. Interaction effects for bilateral conditions were delayed by approximately 10 ms versus unilateral conditions, consistent with current estimates of interhemispheric transmission time. Interaction effects place an upper limit on the time required for neuronal ensembles to combine inputs from different quadrants of visual space ( approximately 72 ms for unilateral and approximately 82 ms for bilateral conditions).

Adult↗

Evidence that intramolecular interactions are involved in masking the activation domain of transcriptional activator Leu3p.

The Leu3 protein of Saccharomyces cerevisiae regulates the expression of genes involved in branched chain amino acid biosynthesis and in ammonia assimilation. It is modulated by alpha-isopropylmalate, an intermediate in leucine biosynthesis. In the presence of alpha-isopropylmalate, Leu3p is a transcriptional activator. In the absence of the signal molecule, the activation domain is masked, and Leu3p acts as a repressor. The recent discovery that Leu3p retains its regulatory properties when expressed in mammalian cells (Guo, H., and Kohlhaw, G. B. (1996) FEBS Lett. 390, 191-195) suggests that masking and unmasking of the activation domain occur without the participation of auxiliary proteins. Here we present experimental support for this notion and address the mechanism of masking. We show that modulation of Leu3p is exceedingly sensitive to mutations in the activation domain. An activation domain double mutant (D872N/D874N; designated Leu3-dd) was constructed that has the characteristics of a permanently masked activator. Using separately expressed segments containing either the DNA binding domain-middle region or the activation domain of wild type Leu3p (or Leu3-dd) in a modified yeast two-hybrid system, we provide direct evidence for alpha-isopropylmalate-dependent interaction between these segments. Finally, we use the phenotype of Leu3-dd-containing cells (slow growth in the absence of added leucine) to select for suppressor mutations that map to the middle region of Leu3-dd. The properties of nine such suppressors further support the idea that masking is an intramolecular process and suggest a means for mapping the surface involved in masking.

Amino Acid Sequence↗

The RUMBA software: tools for neuroimaging data analysis.

The enormous scale and complexity of data sets in functional neuroimaging makes it crucial to have well-designed and flexible software for image processing, modeling, and statistical analysis. At present, researchers must choose between general purpose scientific computing environments (e.g., Splus and Matlab), and specialized human brain mapping packages that implement particular analysis strategies (e.g., AFNI, SPM, VoxBo, FSL or FIASCO). For the vast majority of users in Human Brain Mapping and Cognitive Neuroscience, general purpose computing environments provide an insufficient framework for a complex data-analysis regime. On the other hand, the operational particulars of more specialized neuroimaging analysis packages are difficult or impossible to modify and provide little transparency or flexibility to the user for approaches other than massively multiple comparisons based on inferential statistics derived from linear models. In order to address these problems, we have developed open-source software that allows a wide array of data analysis procedures. The RUMBA software includes programming tools that simplify the development of novel methods, and accommodates data in several standard image formats. A scripting interface, along with programming libraries, defines a number of useful analytic procedures, and provides an interface to data analysis procedures. The software also supports a graphical functional programming environment for implementing data analysis streams based on modular functional components. With these features, the RUMBA software provides researchers programmability, reusability, modular analysis tools, novel data analysis streams, and an analysis environment in which multiple approaches can be contrasted and compared. The RUMBA software retains the flexibility of general scientific computing environments while adding a framework in which both experts and novices can develop and adapt neuroimaging-specific analyses.

Algorithms↗

Mapping of the "intervention channels" as a part of the community diagnosis process of the Stockholm Cancer Prevention Program (SCPP).

The Stockholm Cancer Prevention Program is to our knowledge the first community intervention program in the world aiming of a reduction in the incidence of cancer. A community diagnosis model has been used in the planning. A thorough description of different organizations in the local communities of Stockholm has been made. A model for describing the organizations or collaborators has been worked out, including description of the organizations and its environment, objectives of activities, possible activities to reach the objectives, resources needed, incentives for collaborative partners, formative evaluation criteria and anticipated problems and solutions. The main method of description has been by use of keyperson interviews. This was found to be a good method to reach commitment to the program.

Community Health Services↗

Molecular basis of insulin action.

Considerable progress has been made in our understanding of the molecular mechanisms of insulin action. The insulin receptor is a membrane receptor possessing tyrosine kinase activity. The binding of insulin to its receptor induces autophosphorylation of the receptor on tyrosine residues and thereby stimulates its tyrosine kinase activity towards intracellular substrates such as Shc or IRS1. This tyrosine kinase activity, which plays a crucial role in the transmission of the signal, is decreased in several insulin-resistance situations. This decrease was initially attributed to the phosphorylation of the receptor on serine or threonine residues, but this mechanism is now seriously questioned. Tyrosine phosphorylation of IRSs and Shc by the insulin receptor permits the activation of two major signalling pathways, the MAP kinase pathway and the Pl 3-kinase pathway. MAP kinases are involved in proliferation and differentiation processes, in particular by regulating the transcriptional activity of the nucleus. The MAP kinase pathway does not appear to play a significant role in the transmission of the metabolic effects of insulin. In contrast, the Pl 3-kinase pathway is involved in several of the metabolic effects of the hormone, such as glucose transport, glycolysis and glycogen synthesis. The Pl 3-kinase pathway also plays a crucial role in the regulation of protein synthesis by insulin. Moreover, this pathway is involved in cell growth and transmits a strong anti-apoptotic signal.

Calcium-Calmodulin-Dependent Protein Kinases↗

Motor cortex maps articulatory features of speech sounds.

The processing of spoken language has been attributed to areas in the superior temporal lobe, where speech stimuli elicit the greatest activation. However, neurobiological and psycholinguistic models have long postulated that knowledge about the articulatory features of individual phonemes has an important role in their perception and in speech comprehension. To probe the possible involvement of specific motor circuits in the speech-perception process, we used event-related functional MRI and presented experimental subjects with spoken syllables, including [p] and [t] sounds, which are produced by movements of the lips or tongue, respectively. Physically similar nonlinguistic signal-correlated noise patterns were used as control stimuli. In localizer experiments, subjects had to silently articulate the same syllables and, in a second task, move their lips or tongue. Speech perception most strongly activated superior temporal cortex. Crucially, however, distinct motor regions in the precentral gyrus sparked by articulatory movements of the lips and tongue were also differentially activated in a somatotopic manner when subjects listened to the lip- or tongue-related phonemes. This sound-related somatotopic activation in precentral gyrus shows that, during speech perception, specific motor circuits are recruited that reflect phonetic distinctive features of the speech sounds encountered, thus providing direct neuroimaging support for specific links between the phonological mechanisms for speech perception and production.

Adult↗

[The participation of cortical brain areas in the processes of perceiving and reproducing human emotional states].

New method of mapping intracortical interactions was used to study the participation of cortical brain areas in the processes of perception and of mental reproduction of emotional states in humans. When an emotion was identified, the activity focus was observed in the left temporal cortex. If emotion was not identified, the temporal focus did not appear, but activity foci were seen in frontal regions of both hemispheres. When emotional states were mentally reproduced, activity foci were encountered mostly in the frontal cortical areas.

Adolescent↗

Isolation, genetic mapping and some characterization of a mutation in Escherichia coli that affects the processing of ribonuleic acid.

Temperature-sensitive mutants were isolated from an rnc (RNase III-) strain of Escherichia coli, and their rRNA metabolism was analyzed on 3% polyacrylamide gels. One of these mutants was unable to produce 23S and 5S rRNAs at the nonpermissive temperature. When an rnc+ allele was introduced to this strain, it remained temperature sensitive. At the nonpermissive temperature, this strain could then produce 23S rRNA but was unable to make normal levels of 5S rRNA. In matings and transduction experiments, the defect in rRNA metabolism and temperature sensitivity behaved as a syndrome caused by a single point mutation, which was mapped at min 23.5 on the E. coli chromosome. This mutation probably affects an enzyme, ribonuclease E (RNase E), which introduces a cut in the nascent rRNA transcript between the 23S and the 5S rRNA cistrons. The mutation rne is recessive with respect to temperature sensitivity and the pattern of rRNA. Revertants able to grow at 43 degrees and with normal metabolism of rRNA were isolated; genetic analysis showed that they do not contain the original rne mutation, suggesting that they were true revertants. By combining the rne mutation with an rnc mutation, double rnc rne strains were synthesized, which behaved very similarly to the original rnc strain from which the rne mutation was isolated. Such strains have RNA metabolism that is similar to that of rnc strains at permissive temperatures, but at the nonpermissive temperature they fail to synthesize p23, m23, and 5S rRNAs. Thus, the experiments reported here, together with previous studies, suggest the existence of a new processing ribonuclease activity in Escherichia coli, which is called ribonuclease E.

Electrophoresis, Polyacrylamide Gel↗