Event-related potentials (P300) in primary headache in childhood and adolescence

There is strong evidence for a loss of habituation during cognitive processing in migraine as measured by P300 and contingent negative variation in adults. Event-related potentials evoked by an oddball paradigm have not yet been studied in children and adolescents suffering from different primary headache types. We recorded visually evoked event-related potentials (two consecutive trials, 200 stimuli each) in 48 children and adolescents suffering from migraine without or with aura, from episodic tension-type headache, and from ergotamine-induced headache and analyzed the latencies, amplitudes, and reaction times. No statistically significant differences were noted between all headache types and healthy controls analyzing the averaged parameters for the whole measurement. However, a highly significant loss of cortical habituation as measured by P300 amplitude and latency could be observed in migraine without and with aura by analyzing the first and the second trial of measurement separately. This phenomenon increased with age and could not be seen in healthy controls, or patients with tension-type headache or ergotamine-induced headache. Our data suggest a specific cognitive processing in migraine even in children and adolescents. Measurement of the habituation effect in P300 latency and amplitude provides a specific method to differentiate between primary headache types in childhood and adolescence.     

Restoration of peroxisome formation in two conditional peroxisome-deficient mutants of Hansenula polymorpha during growth of cells on specific organic nitrogen sources

Expression of the peroxisome-deficient (Per^?) phenotype by per mutants of Hansenula polymorpha is shown to be dependent on specific environmental conditions. Analysis of our collection of constitutive and conditional per mutants showed that, irrespective of the carbon source used, the mutants invariably lacked functional peroxisomes when ammonium sulphate was used as a nitrogen source. However, in two temperature-sensitive (ts) mutants, per13-6^ts and per14-11^ts, peroxisomes were present at the restrictive temperature when cells were grown on organic nitrogen sources which are known to induce peroxisomes in wild-type cells, namely D -alanine (for both mutants) or methylamine (for per14-11^ts). These organelles displayed normal wild-type properties with respect to morphology, mode of development and protein composition. However, under these conditions not all the peroxisomal matrix proteins synthesized were correctly located inside peroxisomes. Detailed biochemical and (immuno) cytochemical analyses indicated that during growth of cells on methanol in the presence of either D -alanine or methylamine, a minor portion of these proteins (predominantly alcohol oxidase, dihydroxyacetone synthase and catalase) still resided in the cytosol. This residual cytosolic activity may explain the observation that the functional restoration of the two ts mutants is not complete under these conditions, as is reflected by the retarded growth of the cells in batch cultures on methanol.     

One billion transistors, one uniprocessor, one chip

Billion-transistor processors will be much as they are today, just bigger, faster and wider (issuing more instructions at once). The authors describe the key problems (instruction supply, data memory supply and an implementable execution core) that prevent current superscalar computers from scaling up to 16- or 32-instructions per issue. They propose using out-of-order fetching, multi-hybrid branch predictors and trace caches to improve the instruction supply. They predict that replicated first-level caches, huge on-chip caches and data value speculation will enhance the data supply. To provide a high-speed, implementable execution core that is capable of sustaining the necessary instruction throughput, they advocate a large, out-of-order-issue instruction window (2,000 instructions), clustered (separated) banks of functional units and hierarchical scheduling of ready instructions. They contend that the current uniprocessor model can provide sufficient performance and use a billion transistors effectively without changing the programming model or discarding software compatibility     

An audio enhancement system to improve intelligibility for social-awareness in HRI

Multimedia Tools and Applications - Improving the ability to interact through voice with a robot is still a challenge especially in real environments where multiple speakers coexist. This work has...     

GPCR antitarget modeling: pharmacophore models for biogenic amine binding GPCRs to avoid GPCR-mediated side effects

G protein-coupled receptors (GPCRs) form a large protein family that plays an important role in many physiological and pathophysiological processes. However, the central role that the biogenic amine binding GPCRs and their ligands play in cell signaling poses a risk in new drug candidates that reveal side affinities towards these receptor sites. These candidates have the potential to interfere with the physiological signaling processes and to cause undesired effects in preclinical or clinical studies. Here, we present 3D cross-chemotype pharmacophore models for three biogenic amine antitargets: the alpha(1A) adrenergic, the 5-HT(2A) serotonin, and the D2 dopamine receptors. These pharmacophores describe the key chemical features present within these biogenic amine antagonists and rationalize the biogenic amine side affinities found for numerous new drug candidates. First applications of the alpha(1A) adrenergic receptor model reveal that these in silico tools can be used to guide the chemical optimization towards development candidates with fewer alpha(1A)-mediated side effects (for example, orthostatic hypotension) and, thus, with an improved clinical safety profile.     

Flavin adenine dinucleotide binding is the crucial step in alcohol oxidase assembly in the yeast Hansenula polymorpha

We have studied the role of flavin adenine dinucleotide (FAD) in the in vivo assembly of peroxisomal alcohol oxidase (AO) in the yeast Hansenula polymorpha. In previous studies, using a riboflavin (Rf) autotrophic mutant, an unequivocal judgement could not be made, since Rf-limitation led to a partial block of AO import in this mutant. This resulted in the accumulation of AO precursors in the cytosol where they remained separated from the putative peroxisomal AO assembly factors. In order to circumvent the peroxisomal membrane barrier, we have now studied AO assembly in a peroxisome-deficient/Rf-autotrophic double mutant (Δper1.rif1) of H. polymorpha. By sucrose density centrifugation and native gel electrophoresis, three conformations of AO were detected in crude extracts of Δper1.rif1 cells grown under Rf-limitation, namely active octameric AO and two inactive, monomeric forms. One of the latter forms lacked FAD; this form was barely detectable in extracts wild-type and Δper1 cells, but had accumulated in the cytosol of rif1 cells. The second form of monomeric AO contained FAD; this form was also present in Δper1 cells but absent/very low in wild-type and rif1 cells. In vivo only these FAD-containing monomers associate into the active, octameric protein. We conclude that in H. polymorpha FAD binding to the AO monomer is mediated by a yet unknown peroxisomal factor and represents the crucial and essential step to enable AO oligomerization; the actual octamerization and the eventual crystallization in peroxisomes most probably occurs spontaneously.