Multimodal (EEG-fMRI) functional connectivity study of levodopa effect in Parkinson’s disease

Aim: To assess if the intake of levodopa in patients with Parkinson’s Disease (PD) changes cerebral connectivity, as revealed by simultaneous recording of hemodynamic (functional MRI, or fMRI) and electric (electroencephalogram, EEG) signals. Particularly, we hypothesize that the strongest changes in FC will involve the motor network, which is the most impaired in PD. Methods: Eight patients with diagnosis of PD “probable”, therapy with levodopa exclusively, normal cognitive and affective status, were included. Exclusion criteria were: moderate-severe rest tremor, levodopa induced dyskinesia, evidence of gray or white matter abnormalities on structural MRI. Scalp EEG (64 channels) were acquired inside the scanner (1.5 Tesla) before and after the intake of levodopa. fMRI functional connectivity was computed from four regions of interest: right and left supplementary motor area (SMA) and right and left precentral gyrus (primary motor cortex). Weighted partial directed coherence (w-PDC) was computed in the inverse space after the removal of EEG gradient and cardioballistic artifacts. Results and discussion: fMRI group analysis shows that the intake of levodopa increases hemodynamic functional connectivity among the SMAs / primary motor cortex and: sensory-motor network itself, attention network and default mode network. w-PDC analysis shows that EEG connectivity among regions of the motor network has the tendency to decrease after the intake the levodopa; furthermore, regions belonging to the DMN have the tendency to increase their outflow toward the rest of the brain. These findings, even if in a small sample of patients, suggest that other resting state physiological functional networks, beyond the motor one, are affected in patients with PD. The behavioral and cognitive tasks corresponding to the affected networks could benefit from the intake of levodopa.

Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases

Meprin and , zinc metalloproteinases, play significant roles in inflammation, including inflammatory bowel disease (IBD), possibly by activating cytokines, like interleukin 1 , interleukin 18, or tumor growth factor . Although a number of potential activators for meprins are known, no endogenous inhibitors have been identified. In this work, we analyzed the inhibitory potential of human plasma and identified bovine fetuin-A as an endogenous meprin inhibitor with a K(i) (inhibition constant) of 4.2 × 10(-5) M for meprin and a K(i) of 1.1 × 10(-6) M meprin . This correlated with data obtained for a fetuin-A homologue from carp (nephrosin inhibitor) that revealed a potent meprin and inhibition (residual activities of 27 and 22%, respectively) at a carp fetuin concentration of 1.5 × 10(-6) M. Human fetuin-A is a negative acute phase protein involved in inflammatory diseases, thus being a potential physiological regulator of meprin activity. We report kinetic studies of fetuin-A with the proteolytic enzymes astacin, LAST, LAST_MAM, trypsin, and chymotrypsin, indeed demonstrating that fetuin-A is a broad-range protease inhibitor. Fetuin-A inhibition of meprin activity was 40 times weaker than that of meprin activity. Therefore, we tested cystatin C, a protein structurally closely related to fetuin-A. Indeed, cystatin C was an inhibitor for human meprin (K(i) = 8.5 × 10(-6) M) but, interestingly, not for meprin . Thus, the identification of fetuin-A and cystatin C as endogenous proteolytic regulators of meprin activity broadens our understanding of the proteolytic network in plasma.

The Design of XML-Based Model and Experiment Description Languages for Network Simulation

The Simulation Automation Framework for Experiments (SAFE) is a project created to raise the level of abstraction in network simulation tools and thereby address issues that undermine credibility. SAFE incorporates best practices in network simulationto automate the experimental process and to guide users in the development of sound scientific studies using the popular ns-3 network simulator. My contributions to the SAFE project: the design of two XML-based languages called NEDL (ns-3 Experiment Description Language) and NSTL (ns-3 Script Templating Language), which facilitate the description of experiments and network simulationmodels, respectively. The languages provide a foundation for the construction of better interfaces between the user and the ns-3 simulator. They also provide input to a mechanism which automates the execution of network simulation experiments. Additionally,this thesis demonstrates that one can develop tools to generate ns-3 scripts in Python or C++ automatically from NSTL model descriptions.

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis.

Evidence for chemokine-mediated coalescence of preformed flotillin hetero-oligomers in human T-cells

We have shown previously that endogenous flotillin-1 and -2, closely related proteins implicated in scaffolding of membrane microdomains, are rapidly recruited to the uropods of chemoattractant-stimulated human neutrophils and T-cells and are involved in cell polarization. Coexpressed flotillin-1 and -2, but not singly expressed proteins, are also targeted to the uropod of T-cells and neutrophils. Biochemical studies suggest formation of flotillin homo- and hetero-oligomers in other cell types, but so far knowledge is lacking on in situ flotillin organization in leukocytes. We have now analyzed flotillin organization in human T-cells using fluorescence resonance energy transfer (FRET). Coexpressed C-terminally tagged flotillin-1-mCherry and flotillin-2-enhanced green fluorescent protein (EGFP) show significant FRET when analyzed in intact human T-cells in the absence and presence of chemokine. In contrast, little FRET was observed between coexpressed flotillin-1-mCherry and flotillin-1-EGFP before or after chemokine addition, indicating predominant formation of heterodimers and/or -oligomers. Interestingly coexpression of untagged flotillin-2 strongly enhanced FRET between differently tagged flotillin-1 molecules in resting and chemokine-stimulated cells, indicating that close contacts of flotillin-1 molecules only occur in flotillin-2-containing hetero-oligomers. Comparable results were obtained for tagged flotillin-2. We further show that disruption of the actin network, depletion of intracellular calcium, and inhibition of phospholipase C all result in suppression of chemokine-induced polarization and flotillin cap formation, but do not abolish FRET between tagged flotillin-1 and -2. Our results support predominant formation of flotillin-1 and -2 hetero-oligomers in resting and chemokine-stimulated human T-cells which may importantly contribute to structuring of the uropod.

Quantification of network perfusion in ASL cerebral blood flow data with seed based and ICA approaches

Independent component analysis (ICA) or seed based approaches (SBA) in functional magnetic resonance imaging blood oxygenation level dependent (BOLD) data became widely applied tools to identify functionally connected, large scale brain networks. Differences between task conditions as well as specific alterations of the networks in patients as compared to healthy controls were reported. However, BOLD lacks the possibility of quantifying absolute network metabolic activity, which is of particular interest in the case of pathological alterations. In contrast, arterial spin labeling (ASL) techniques allow quantifying absolute cerebral blood flow (CBF) in rest and in task-related conditions. In this study, we explored the ability of identifying networks in ASL data using ICA and to quantify network activity in terms of absolute CBF values. Moreover, we compared the results to SBA and performed a test-retest analysis. Twelve healthy young subjects performed a fingertapping block-design experiment. During the task pseudo-continuous ASL was measured. After CBF quantification the individual datasets were concatenated and subjected to the ICA algorithm. ICA proved capable to identify the somato-motor and the default mode network. Moreover, absolute network CBF within the separate networks during either condition could be quantified. We could demonstrate that using ICA and SBA functional connectivity analysis is feasible and robust in ASL-CBF data. CBF functional connectivity is a novel approach that opens a new strategy to evaluate differences of network activity in terms of absolute network CBF and thus allows quantifying inter-individual differences in the resting state and task-related activations and deactivations.

A Social Network Analysis Of Hamadryas Baboons

The study of animal sociality investigates the immediate and long-term consequences that a social structure has on its group members. Typically, social behavior is observed from interactions between two individuals at the dyadic level. However, a new framework for studying social behavior has emerged that allows the researcher to assess social complexity at multiple scales. Social Network Analysis has been recently applied in the field of ethology, and this novel tool enables an approach of focusing on social behavior in context of the global network rather than limited to dyadic interactions. This new technique was applied to a group of captive hamadryas baboons (Papio hamadryas hamadryas) in order to assess how overall network topology of the social group changes over time with the decline of an aging leader male. Observations on aggressive, grooming, and proximity spatial interactions were collected from three separate years in order to serve as `snapshots¿ of the current state of the group. Data on social behavior were collected from the group when the male was in prime health, when the male was at an old age, and after the male¿s death. A set of metrics was obtained from each time period for each type of social behavior and quantified a change in the patterns of interactions. The results suggest that baboon social behavior varies across context, and changes with the attributes of its individual members. Possible mechanisms for adapting to a changing social environment were also explored.

Speech perception benefits of internet versus conventional telephony for hearing-impaired individuals

Telephone communication is a challenge for many hearing-impaired individuals. One important technical reason for this difficulty is the restricted frequency range (0.3-3.4 kHz) of conventional landline telephones. Internet telephony (voice over Internet protocol [VoIP]) is transmitted with a larger frequency range (0.1-8 kHz) and therefore includes more frequencies relevant to speech perception. According to a recently published, laboratory-based study, the theoretical advantage of ideal VoIP conditions over conventional telephone quality has translated into improved speech perception by hearing-impaired individuals. However, the speech perception benefits of nonideal VoIP network conditions, which may occur in daily life, have not been explored. VoIP use cannot be recommended to hearing-impaired individuals before its potential under more realistic conditions has been examined.

Development of Socio-Economic Behaviour and Attitudes of Baltic Nationalities: Perspectives for Integration with Europe

This project is the third stage of a comparative research project, The New Baltic Barometer, which was carried out simultaneously with the "New Democracies Barometer" of the Paul Lazerfeld Society (Vienna) and The Russian Barometer. It studied the opinion and behaviour of the largest Baltic ethnic groups (Estonians, Latvians, Lithuanians). The main focus was on the attitudes of Baltic residents towards the changes in the economic and political system, attitudes towards political values, political trust, and attitudes to the Baltic countries joining the European Union. An analysis of macroeconomic indicators of the Baltic states made it possible to deduce the link between the country's economic development, and satisfaction with the political regime and attitudes towards democratic values. The study analysed the conditions for the democratisation of society, i.e. the development of culture and public opinion in the Baltic states. Attention was also paid to the development of a social network of individuals, showing the transition from informal networks to impersonal institutions. The group concluded that the participation of residents in formal organisations, NGOs in particular, considerably fosters political trust and also increases political efficacy. Participation in formal organisations also reduces the importance of esteem for an authoritarian leader.

Impaired pericyte recruitment and abnormal retinal angiogenesis as a result of angiopoietin-2 overexpression

Angiopoietin-2 (Ang2) is among the relevant growth factors induced by hypoxia and plays an important role in the initiation of retinal neovascularizations. Ang2 is also involved in incipient diabetic retinopathy, as it may cause pericyte loss. To investigate the impact of Ang2 on developmental and hypoxia-induced angiogenesis, we used a transgenic mouse line overexpressing human Ang2 in the mouse retina. Transgenic mice displayed a reduced coverage of capillaries with pericytes (-14%; p < 0.01) and a 46% increase of vascular density of the capillary network at postnatal day 10 compared to wild type mice. In the model of oxygen-induced retinopathy (OIR), Ang2 overexpression resulted in enhanced preretinal (+103%) and intraretinal neovascularization (+29%). Newly formed intraretinal vessels in OIR were also pericyte-deficient (-26%; p < 0.01). The total expression of Ang2 in transgenic mice was seven-fold, compared with wild type controls. Ang2 modulated expression of genes encoding VEGF (+65%) and Ang1 (+79%) in transgenic animals. These data suggest that Ang2 is involved in pericyte recruitment, and modulates intraretinal, and preretinal vessel formation in the eye under physiological and pathological conditions.

Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis

Eph receptor tyrosine kinases and their cell-surface-bound ligands, the ephrins, regulate axon guidance and bundling in the developing brain, control cell migration and adhesion, and help patterning the embryo. Here we report that two ephrinB ligands and three EphB receptors are expressed in and regulate the formation of the vascular network. Mice lacking ephrinB2 and a proportion of double mutants deficient in EphB2 and EphB3 receptor signaling die in utero before embryonic day 11.5 (E11.5) because of defects in the remodeling of the embryonic vascular system. Our phenotypic analysis suggests complex interactions and multiple functions of Eph receptors and ephrins in the embryonic vasculature. Interaction between ephrinB2 on arteries and its EphB receptors on veins suggests a role in defining boundaries between arterial and venous domains. Expression of ephrinB1 by arterial and venous endothelial cells and EphB3 by veins and some arteries indicates that endothelial cell-to-cell interactions between ephrins and Eph receptors are not restricted to the border between arteries and veins. Furthermore, expression of ephrinB2 and EphB2 in mesenchyme adjacent to vessels and vascular defects in ephB2/ephB3 double mutants indicate a requirement for ephrin-Eph signaling between endothelial cells and surrounding mesenchymal cells. Finally, ephrinB ligands induce capillary sprouting in vitro with a similar efficiency as angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF), demonstrating a stimulatory role of ephrins in the remodeling of the developing vascular system.

Enumerating constrained elementary flux vectors of metabolic networks

The concept of elementary vector is generalised to the case where the steady-state space of the metabolic network is not a flux cone but is a general polyhedron due to further inhomogeneous constraints on the flows through some of the reactions. On one hand, this allows to selectively enumerate elementary modes which satisfy certain optimality criteria and this can yield a large computational gain compared with full enumeration. On the other hand, in contrast to the single optimum found by executing a linear program, this enables a comprehensive description of the set of alternate optima often encountered in flux balance analysis. The concepts are illustrated on a metabolic network model of human cardiac mitochondria.

An EEG approach to the neurodevelopmental hypothesis of schizophrenia studying schizophrenics, normal controls and adolescents

Based on an integrative brain model which focuses on memory-driven and EEG state-dependent information processing for the organisation of behaviour, we used the developmental changes of the awake EEG to further investigate the hypothesis that neurodevelopmental abnormalities (deviations in organisation and reorganisation of cortico-cortical connectivity during development) are involved in the pathogenesis of schizophrenia. First-episode, neuroleptic-naive schizophrenics and their matched controls and three age groups of normal adolescents were studied (total: 70 subjects). 19-channel EEG delta-theta, alpha and beta spectral band centroid frequencies during resting (baseline) and after verbal stimuli were used as measure of the level of attained complexity and momentary excitability of the neuronal network (working memory). Schizophrenics compared with all control groups showed lower delta-theta activity centroids and higher alpha and beta activity centroids. Reactivity centroids (centroid after stimulus minus centroid during resting) were used as measure of update of working memory. Schizophrenics showed partial similarities in delta-theta and beta reactivity centroids with the 11-year olds and in alpha reactivity centroids with the 13-year olds. Within the framework of our model, the results suggest multifactorially elicited imbalances in the level of excitability of neuronal networks in schizophrenia, resulting in network activation at dissociated complexity levels, partially regressed and partially prematurely developed. It is hypothesised that activation of age- and/or state-inadequate representations for coping with realities becomes manifest as productive schizophrenic symptoms. Thus, the results support some aspects of the neurodevelopmental hypothesis.

Comparing satellite and ground-based observations of paroxysmal degassing events at Etna volcano, Italy

Mount Etna, Italy, is one of the most active volcanoes in the world, and is also regarded as one of the strongest volcanic sources of sulfur dioxide (SO2) emissions to the atmosphere. Since October 2004, an automated ultraviolet (UV) spectrometer network (FLAME) has provided ground-based SO2 measurements with high temporal resolution, providing an opportunity to validate satellite SO2 measurements at Etna. The Ozone Monitoring Instrument (OMI) on the NASA Aura satellite, which makes global daily measurements of trace gases in the atmosphere, was used to compare SO2 amount released by the volcano during paroxysmal lava-fountaining events from 2004 to present. We present the first comparison between SO2 emission rates and SO2 burdens obtained by the OMI transect technique and OMI Normalized Cloud-Mass (NCM) technique and the ground-based FLAME Mini-DOAS measurements. In spite of a good data set from the FLAME network, finding coincident OMI and FLAME measurements proved challenging and only one paroxysmal event provided a good validation for OMI. Another goal of this work was to assess the efficacy of the FLAME network in capturing paroxysmal SO2 emissions from Etna, given that the FLAME network is only operational during daylight hours and some paroxysms occur at night. OMI measurements are advantageous since SO2 emissions from nighttime paroxysms can often be quantified on the following day, providing improved constraints on Etna’s SO2 budget.

Implementation of a phenomenological evaporation model into a porous network simulation for water management in low temperature fuel cells

A phenomenological transition film evaporation model was introduced to a pore network model with the consideration of pore radius, contact angle, non-isothermal interface temperature, microscale fluid flows and heat and mass transfers. This was achieved by modeling the transition film region of the menisci in each pore throughout the porous transport layer of a half-cell polymer electrolyte membrane (PEM) fuel cell. The model presented in this research is compared with the standard diffusive fuel cell modeling approach to evaporation and shown to surpass the conventional modeling approach in terms of predicting the evaporation rates in porous media. The current diffusive evaporation models used in many fuel cell transport models assumes a constant evaporation rate across the entire liquid-air interface. The transition film model was implemented into the pore network model to address this issue and create a pore size dependency on the evaporation rates. This is accomplished by evaluating the transition film evaporation rates determined by the kinetic model for every pore containing liquid water in the porous transport layer (PTL). The comparison of a transition film and diffusive evaporation model shows an increase in predicted evaporation rates for smaller pore sizes with the transition film model. This is an important parameter when considering the micro-scaled pore sizes seen in the PTL and becomes even more substantial when considering transport in fuel cells containing an MPL, or a large variance in pore size. Experimentation was performed to validate the transition film model by monitoring evaporation rates from a non-zero contact angle water droplet on a heated substrate. The substrate was a glass plate with a hydrophobic coating to reduce wettability. The tests were performed at a constant substrate temperature and relative humidity. The transition film model was able to accurately predict the drop volume as time elapsed. By implementing the transition film model to a pore network model the evaporation rates present in the PTL can be more accurately modeled. This improves the ability of a pore network model to predict the distribution of liquid water and ultimately the level of flooding exhibited in a PTL for various operating conditions.