A new Bayesian approach to the reconstruction of spectral functions

We present a novel approach for the reconstruction of spectra from Euclidean correlator data that makes close contact to modern Bayesian concepts. It is based upon an axiomatically justified dimensionless prior distribution, which in the case of constant prior function m(ω) only imprints smoothness on the reconstructed spectrum. In addition we are able to analytically integrate out the only relevant overall hyper-parameter α in the prior, removing the necessity for Gaussian approximations found e.g. in the Maximum Entropy Method. Using a quasi-Newton minimizer and high-precision arithmetic, we are then able to find the unique global extremum of P[ρ|D] in the full Nω » Nτ dimensional search space. The method actually yields gradually improving reconstruction results if the quality of the supplied input data increases, without introducing artificial peak structures, often encountered in the MEM. To support these statements we present mock data analyses for the case of zero width delta peaks and more realistic scenarios, based on the perturbative Euclidean Wilson Loop as well as the Wilson Line correlator in Coulomb gauge.

An fMRI-Study on context-specificity of inhibitory functions in alcohol-dependency: Preliminary results

Introduction: Alcohol-dependency is a common disease with many negative consequences in the daily life. A typical symptom of alcoholic-patients is the persistent and uncontrollable desire to consume alcohol. Inspite of different treatments, alcohol-dependency has a relapse rate of about 85%. This high rate is facilitated by a dysfunction of cognitive control-processes. In order to understand this disease sustaining factor, the present study investigated the neurophysiological correlates of inhibition of alcoholic-patients in a neutral as well as an alcohol-related context. Methods: A total of 18 participants, (9 alcohol-dependent-patients (age range: 27-62 years), 9 healthy controls (age range: 29-60 years)) have been measured with functional magnetic resonance imaging while they participated in an alcohol-specific Go/NoGo-Task. Neurophysiological correlates of inhibition in an alcohol-related as well as a neutral context were compared in both groups. Results: When comparing correct stop-trials in alcohol-related to neutral context, only alcohol-dependent patients showed significant hyperactivation in frontal regions (superior and medial gyrus frontalis, anterior gyrus cinguli, gyrus paracentralis and the gyrus praecentralis). No significant differences were found in any of the behavioral analyses. Discussion: These preliminary results thus indicate that successful inhibition in a drug-related context demands additional resources in patients. Especially the hyperactivation of the anterior gyrus cinguli might be important because of its involvement in decision-processes. In the absent of deficits in behavioral data, this suggests that alcohol-dependent patients need more neuronal activity to achieve the same performance-level like healthy controls.

Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice

Invariant natural killer T (iNKT) cells undergo canonical, Vα14-Jα18 rearrangement of the T-cell receptor (TCR) in mice; this form of the TCR recognizes glycolipids presented by CD1d. iNKT cells mediate many different immune reactions. Their constitutive activated and memory phenotype and rapid initiation of effector functions after stimulation indicate previous antigen-specific stimulation. However, little is known about this process. We investigated whether symbiotic microbes can determine the activated phenotype and function of iNKT cells.

Strengthening of laterality of verbal and visuospatial functions during childhood and adolescence

Cognitive functions in the child's brain develop in the context of complex adaptive processes, determined by genetic and environmental factors. Little is known about the cerebral representation of cognitive functions during development. In particular, knowledge about the development of right hemispheric (RH) functions is scarce. Considering the dynamics of brain development, localization and lateralization of cognitive functions must be expected to change with age. Twenty healthy subjects (8.6-20.5 years) were examined with fMRI and neuropsychological tests. All participants completed two fMRI tasks known to activate left hemispheric (LH) regions (language tasks) and two tasks known to involve predominantly RH areas (visual search tasks). A laterality index (LI) was computed to determine the asymmetry of activation. Group analysis revealed unilateral activation of the LH language circuitry during language tasks while visual search tasks induced a more widespread RH activation pattern in frontal, superior temporal, and occipital areas. Laterality of language increased between the ages of 8-20 in frontal (r = 0.392, P = 0.049) and temporal (r = 0.387, P = 0.051) areas. The asymmetry of visual search functions increased in frontal (r = -0.525, P = 0.009) and parietal (r = -0.439, P = 0.027) regions. A positive correlation was found between Verbal-IQ and the LI during a language task (r = 0.585, P = 0.028), while visuospatial skills correlated with LIs of visual search (r = -0.621, P = 0.018). To summarize, cognitive development is accompanied by changes in the functional representation of neuronal circuitries, with a strengthening of lateralization not only for LH but also for RH functions. Our data show that age and performance, independently, account for the increases of laterality with age.

ANOVA kernels and RKHS of zero mean functions for model-based sensitivity analysis

Given a reproducing kernel Hilbert space (H,〈.,.〉)(H,〈.,.〉) of real-valued functions and a suitable measure μμ over the source space D⊂RD⊂R, we decompose HH as the sum of a subspace of centered functions for μμ and its orthogonal in HH. This decomposition leads to a special case of ANOVA kernels, for which the functional ANOVA representation of the best predictor can be elegantly derived, either in an interpolation or regularization framework. The proposed kernels appear to be particularly convenient for analyzing the effect of each (group of) variable(s) and computing sensitivity indices without recursivity.

Improving executive functions in 5- and 6-year-olds: Evaluation of a small group intervention in prekindergarten and kindergarten children

Research suggests a central role of executive functions for children's cognitive and social development during preschool years, especially in promoting school readiness. Interventions aiming to improve executive functions are therefore being called for. The present study examined the effect of a small group intervention implemented in kindergarten settings focusing on basic components of executive functions, i.e., working memory, interference control and cognitive flexibility. A total of 135 children enrolled in Swiss prekindergarten (5-year-olds) and kindergarten (6-year-olds) were involved. Results revealed that the small group intervention promoted gains in all three included components of executive functions: prekindergarten children substantially improved their working memory and cognitive flexibility processes, whereas significant training effects were found for the kindergarten children in interference control. Implications of these findings for early intervention programs and for tailoring preschool curricula are discussed, particularly with respect to children's school readiness. Copyright © 2011 John Wiley & Sons, Ltd.

The effects of qualitatively different acute physical activity interventions in real-world settings on executive functions in preadolescent children

There is growing evidence indicating a positive effect of acute physical activity on cognitive performance in children. Most of the evidence originates, however, from studies in highly controlled laboratory settings. The aim of the present study was to investigate whether the same effects can be found in more real-world settings. We examined the effects of qualitatively different acute physical activity interventions on the three core dimensions of executive functions (updating, inhibition, shifting). In an experimental between-subject design, 219 ten to twelve year-olds were assigned to one of four conditions which varied systematically in physical activation and cognitive engagement. Executive functions were measured before and immediately after the intervention. Contrary to the hypothesis, no effects of acute physical activity with and without cognitive engagement were found on executive functions in the overall sample. Only children with higher fitness and/or higher academic achievement benefitted from the interventions in terms of their updating performance. Thus, the results indicate that it may be more difficult to attain positive effects through acute physical activity in real-world settings than in laboratory settings and that physiological and cognitive requirements may have to be adjusted to individual capacity to make an intervention effective.

Radiation dose optimized lateral expansion of the field of view in synchrotron radiation X-ray tomographic microscopy

Volumetric data at micrometer level resolution can be acquired within a few minutes using synchrotron-radiation-based tomographic microscopy. The field of view along the rotation axis of the sample can easily be increased by stacking several tomograms, allowing the investigation of long and thin objects at high resolution. On the contrary, an extension of the field of view in the perpendicular direction is non-trivial. This paper presents an acquisition protocol which increases the field of view of the tomographic dataset perpendicular to its rotation axis. The acquisition protocol can be tuned as a function of the reconstruction quality and scanning time. Since the scanning time is proportional to the radiation dose imparted to the sample, this method can be used to increase the field of view of tomographic microscopy instruments while optimizing the radiation dose for radiation-sensitive samples and keeping the quality of the tomographic dataset on the required level. This approach, dubbed wide-field synchrotron radiation tomographic microscopy, can increase the lateral field of view up to five times. The method has been successfully applied for the three-dimensional imaging of entire rat lung acini with a diameter of 4.1 mm at a voxel size of 1.48 microm.

Identification of problems in functioning of people with sleep disorders in a clinical setting using the International Classification of Functioning Disability and Health (ICF) Checklist

We conducted an explorative, cross-sectional, multi-centre study in order to identify the most common problems of people with any kind of (primary) sleep disorder in a clinical setting using the International Classification of Functioning, Disability and Health (ICF) as a frame of reference. Data were collected from patients using a structured face-to-face interview of 45-60 min duration. A case record form for health professionals containing the extended ICF Checklist, sociodemographic variables and disease-specific variables was used. The study centres collected data of 99 individuals with sleep disorders. The identified categories include 48 (32%) for body functions, 13 (9%) body structures, 55 (37%) activities and participation and 32 (22%) for environmental factors. 'Sleep functions' (100%) and 'energy and drive functions', respectively, (85%) were the most severely impaired second-level categories of body functions followed by 'attention functions' (78%) and 'temperament and personality functions' (77%). With regard to the component activities and participation, patients felt most restricted in the categories of 'watching' (e.g. TV) (82%), 'recreation and leisure' (75%) and 'carrying out daily routine' (74%). Within the component environmental factors the categories 'support of immediate family', 'health services, systems and policies' and 'products or substances for personal consumption [medication]' were the most important facilitators; 'time-related changes', 'light' and 'climate' were the most important barriers. The study identified a large variety of functional problems reflecting the complexity of sleep disorders. The ICF has the potential to provide a comprehensive framework for the description of functional health in individuals with sleep disorders in a clinical setting.

Molecular mechanisms of muscle plasticity with exercise

The skeletal muscle phenotype is subject to considerable malleability depending on use. Low-intensity endurance type exercise leads to qualitative changes of muscle tissue characterized mainly by an increase in structures supporting oxygen delivery and consumption. High-load strength-type exercise leads to growth of muscle fibers dominated by an increase in contractile proteins. In low-intensity exercise, stress-induced signaling leads to transcriptional upregulation of a multitude of genes with Ca2+ signaling and the energy status of the muscle cells sensed through AMPK being major input determinants. Several parallel signaling pathways converge on the transcriptional co-activator PGC-1α, perceived as being the coordinator of much of the transcriptional and posttranscriptional processes. High-load training is dominated by a translational upregulation controlled by mTOR mainly influenced by an insulin/growth factor-dependent signaling cascade as well as mechanical and nutritional cues. Exercise-induced muscle growth is further supported by DNA recruitment through activation and incorporation of satellite cells. Crucial nodes of strength and endurance exercise signaling networks are shared making these training modes interdependent. Robustness of exercise-related signaling is the consequence of signaling being multiple parallel with feed-back and feed-forward control over single and multiple signaling levels. We currently have a good descriptive understanding of the molecular mechanisms controlling muscle phenotypic plasticity. We lack understanding of the precise interactions among partners of signaling networks and accordingly models to predict signaling outcome of entire networks. A major current challenge is to verify and apply available knowledge gained in model systems to predict human phenotypic plasticity.

Identification of a highly conserved valine-glycine-phenylalanine amino acid triplet required for HIV-1 Nef function

Background The Nef protein of HIV facilitates virus replication and disease progression in infected patients. This role as pathogenesis factor depends on several genetically separable Nef functions that are mediated by interactions of highly conserved protein-protein interaction motifs with different host cell proteins. By studying the functionality of a series of nef alleles from clinical isolates, we identified a dysfunctional HIV group O Nef in which a highly conserved valine-glycine-phenylalanine (VGF) region, which links a preceding acidic cluster with the following proline-rich motif into an amphipathic surface was deleted. In this study, we aimed to study the functional importance of this VGF region. Results The dysfunctional HIV group O8 nef allele was restored to the consensus sequence, and mutants of canonical (NL4.3, NA-7, SF2) and non-canonical (B2 and C1422) HIV-1 group M nef alleles were generated in which the amino acids of the VGF region were changed into alanines (VGF→AAA) and tested for their capacity to interfere with surface receptor trafficking, signal transduction and enhancement of viral replication and infectivity. We found the VGF motif, and each individual amino acid of this motif, to be critical for downregulation of MHC-I and CXCR4. Moreover, Nef’s association with the cellular p21-activated kinase 2 (PAK2), the resulting deregulation of cofilin and inhibition of host cell actin remodeling, and targeting of Lck kinase to the trans-golgi-network (TGN) were affected as well. Of particular interest, VGF integrity was essential for Nef-mediated enhancement of HIV virion infectivity and HIV replication in peripheral blood lymphocytes. For targeting of Lck kinase to the TGN and viral infectivity, especially the phenylalanine of the triplet was essential. At the molecular level, the VGF motif was required for the physical interaction of the adjacent proline-rich motif with Hck. Conclusion Based on these findings, we propose that this highly conserved three amino acid VGF motif together with the acidic cluster and the proline-rich motif form a previously unrecognized amphipathic surface on Nef. This surface appears to be essential for the majority of Nef functions and thus represents a prime target for the pharmacological inhibition of Nef.

Function of liver activation-regulated chemokine/CC chemokine ligand 20 is differently affected by cathepsin B and cathepsin D processing

Chemokine processing by proteases is emerging as an important regulatory mechanism of leukocyte functions and possibly also of cancer progression. We screened a large panel of chemokines for degradation by cathepsins B and D, two proteases involved in tumor progression. Among the few substrates processed by both proteases, we focused on CCL20, the unique chemokine ligand of CCR6 that is expressed on immature dendritic cells and subtypes of memory lymphocytes. Analysis of the cleavage sites demonstrate that cathepsin B specifically cleaves off four C-terminally located amino acids and generates a CCL20(1-66) isoform with full functional activity. By contrast, cathepsin D totally inactivates the chemotactic potency of CCL20 by generating CCL20(1-55), CCL20(1-52), and a 12-aa C-terminal peptide CCL20(59-70). Proteolytic cleavage of CCL20 occurs also with chemokine bound to glycosaminoglycans. In addition, we characterized human melanoma cells as a novel CCL20 source and as cathepsin producers. CCL20 production was up-regulated by IL-1alpha and TNF-alpha in all cell lines tested, and in human metastatic melanoma cells. Whereas cathepsin D is secreted in the extracellular milieu, cathepsin B activity is confined to cytosol and cellular membranes. Our studies suggest that CCL20 processing in the extracellular environment of melanoma cells is exclusively mediated by cathepsin D. Thus, we propose a model where cathepsin D inactivates CCL20 and possibly prevents the establishment of an effective antitumoral immune response in melanomas.

Creatine and neurotrophin-4/5 promote survival of nitric oxide synthase-expressing interneurons in striatal cultures

Nitric oxide (NO) mediates a variety of physiological functions in the central nervous system and acts as an important developmental regulator. Striatal interneurons expressing neuronal nitric oxide synthase (nNOS) have been described to be relatively spared from the progressive cell loss in Huntington's disease (HD). We have recently shown that creatine, which supports the phosphagen energy system, induces the differentiation of GABAergic cells in cultured striatal tissue. Moreover, neurotrophin-4/5 (NT-4/5) has been found to promote the survival and differentiation of cultured striatal neurons. In the present study, we assessed the effects of creatine and NT-4/5 on nNOS-immunoreactive (-ir) neurons of E14 rat ganglionic eminences grown for 1 week in culture. Chronic administration of creatine [5mM], NT-4/5 [10ng/ml], or a combination of both factors significantly increased numbers of nNOS-ir neurons. NT-4/5 exposure also robustly increased levels of nNOS protein. Interestingly, only NT-4/5 and combined treatment significantly increased general viability but no effects were seen for creatine supplementation alone. In addition, NT-4/5 and combined treatment resulted in a significant larger soma size and number of primary neurites of nNOS-ir neurons while creatine administration alone exerted no effects. Double-immunolabeling studies revealed that all nNOS-ir cells co-localized with GABA. In summary, our findings suggest that creatine and NT-4/5 affect differentiation and/or survival of striatal nNOS-ir GABAergic interneurons. These findings provide novel insights into the biology of developing striatal neurons and highlight the potential of both creatine and NT-4/5 as therapeutics for HD.