Functional MRI Mapping of the Human Auditory Cortex

Mapping the human auditory cortex with standard functional imaging techniques is difficult because of its small size and angular position along the Sylvian fissure. As a result, the exact number and location of auditory cortex areas in the human remains unknown. In a first experiment, we measured the two largest tonotopic areas of primary auditory cortex (PAC, Al and R) using high-resolution functional MRI at 7 Tesla relative to the underlying anatomy of Heschl's gyrus (HG). The data reveals a clear anatomical- functional relationship that indicates the location of PAC across the range of common morphological variants of HG (single gyri, partial duplication and complete duplication). Human PAC tonotopic areas are oriented along an oblique posterior-to-anterior axis with mirror-symmetric frequency gradients perpendicular to HG, as in the macaque. In a second experiment, we tested whether these primary frequency-tuned units were modulated by selective attention to preferred vs. non-preferred sound frequencies in the dynamic manner needed to account for human listening abilities in noisy environments, such as cocktail parties or busy streets. We used a dual-stream selective attention experiment where subjects attended to one of two competing tonal streams presented simultaneously to different ears. Attention to low-frequency tones (250 Hz) enhanced neural responses within low-frequency-tuned voxels relative to high (4000 Hz), and vice versa when at-tention switched from high to low. Human PAC is able to tune into attended frequency channels and can switch frequencies on demand, like a radio. In a third experiment, we investigated repetition suppression effects to environmental sounds within primary and non-primary early-stage auditory areas, identified with the tonotopic mapping design. Repeated presentations of sounds from the same sources, as compared to different sources, gave repetition suppression effects within posterior and medial non-primary areas of the right hemisphere, reflecting their potential involvement in semantic representations. These three studies were conducted at 7 Tesla with high-resolution imaging. However, 7 Tesla scanners are, for the moment, not yet used for clinical diagnosis and mostly reside in institutions external to hospitals. Thus, hospital-based clinical functional and structural studies are mainly performed using lower field systems (1.5 or 3 Tesla). In a fourth experiment, we acquired tonotopic maps at 3 and 7 Tesla and evaluated the consistency of a tonotopic mapping paradigm between scanners. Mirror-symmetric gradients within PAC were highly similar at 7 and 3 Tesla across renderings at different spatial resolutions. We concluded that the tonotopic mapping paradigm is robust and suitable for definition of primary tonotopic areas, also at 3 Tesla. Finally, in a fifth study, we considered whether focal brain lesions alter tonotopic representations in the intact ipsi- and contralesional primary auditory cortex in three patients with hemispheric or cerebellar lesions, without and with auditory complaints. We found evidence for tonotopic reorganisation at the level of the primary auditory cortex in cases of brain lesions independently of auditory complaints. Overall, these results reflect a certain degree of plasticity within primary auditory cortex in different populations of subjects, assessed at different field strengths. - La cartographie du cortex auditif chez l'humain est difficile à réaliser avec des techniques d'imagerie fonctionnelle standard, étant donné sa petite taille et position angulaire le long de la fissure sylvienne. En conséquence, le nombre et l'emplacement exacts des différentes aires du cortex auditif restent inconnus chez l'homme. Lors d'une première expérience, nous avons mesuré, avec de l'imagerie par résonance magnétique à haute intensité (IRMf à 7 Tesla) chez des sujets humains sains, deux larges aires au sein du cortex auditif primaire (PAC; Al et R) avec une représentation spécifique des fréquences pures préférées - ou tonotopie. Nos résultats ont démontré une relation anatomico- fonctionnelle qui définit clairement la position du PAC à travers toutes les variantes du gyrus d'Heschl's (HG). Les aires tonotopiques du PAC humain sont orientées le long d'un axe postéro-antérieur oblique avec des gradients de fréquences spécifiques perpendiculaires à HG, d'une manière similaire à celles mesurées chez le singe. Dans une deuxième expérience, nous avons testé si ces aires primaires pouvaient être modulées, de façon dynamique, par une attention sélective pour des fréquences préférées par rapport à celles non-préférées. Cette modulation est primordiale lors d'interactions sociales chez l'humain en présence de bruits distracteurs tels que d'autres discussions ou un environnement sonore nuisible (comme par exemple, dans la circulation routière). Dans cette étude, nous avons utilisé une expérience d'attention sélective où le sujet devait être attentif à une des deux voies sonores présentées simultanément à chaque oreille. Lorsque le sujet portait était attentif aux sons de basses fréquences (250 Hz), la réponse neuronale relative à ces fréquences augmentait par rapport à celle des hautes fréquences (4000 Hz), et vice versa lorsque l'attention passait des hautes aux basses fréquences. De ce fait, nous pouvons dire que PAC est capable de focaliser sur la fréquence attendue et de changer de canal selon la demande, comme une radio. Lors d'une troisième expérience, nous avons étudié les effets de suppression due à la répétition de sons environnementaux dans les aires auditives primaires et non-primaires, d'abord identifiées via le protocole de la première étude. La présentation répétée de sons provenant de la même source sonore, par rapport à de sons de différentes sources sonores, a induit un effet de suppression dans les aires postérieures et médiales auditives non-primaires de l'hémisphère droite, reflétant une implication de ces aires dans la représentation de la catégorie sémantique. Ces trois études ont été réalisées avec de l'imagerie à haute résolution à 7 Tesla. Cependant, les scanners 7 Tesla ne sont pour le moment utilisés que pour de la recherche fondamentale, principalement dans des institutions externes, parfois proches du patient mais pas directement à son chevet. L'imagerie fonctionnelle et structurelle clinique se fait actuellement principalement avec des infrastructures cliniques à 1.5 ou 3 Tesla. Dans le cadre dune quatrième expérience, nous avons avons évalués la cohérence du paradigme de cartographie tonotopique à travers différents scanners (3 et 7 Tesla) chez les mêmes sujets. Nos résultats démontrent des gradients de fréquences définissant PAC très similaires à 3 et 7 Tesla. De ce fait, notre paradigme de définition des aires primaires auditives est robuste et applicable cliniquement. Finalement, nous avons évalués l'impact de lésions focales sur les représentations tonotopiques des aires auditives primaires des hémisphères intactes contralésionales et ipsilésionales chez trois patients avec des lésions hémisphériques ou cérébélleuses avec ou sans plaintes auditives. Nous avons trouvé l'évidence d'une certaine réorganisation des représentations topographiques au niveau de PAC dans le cas de lésions cérébrales indépendamment des plaintes auditives. En conclusion, nos résultats démontrent une certaine plasticité du cortex auditif primaire avec différentes populations de sujets et différents champs magnétiques.

Effect of immune pressure on hepatitis C virus evolution: insights from a single-source outbreak.

The host's immune response to hepatitis C virus (HCV) can result in the selection of characteristic mutations (adaptations) that enable the virus to escape this response. The ability of the virus to mutate at these sites is dependent on the incoming virus, the fitness cost incurred by the mutation, and the benefit to the virus in escaping the response. Studies examining viral adaptation in chronic HCV infection have shown that these characteristic immune escape mutations can be observed at the population level as human leukocyte antigen (HLA)-specific viral polymorphisms. We examined 63 individuals with chronic HCV infection who were infected from a single HCV genotype 1b source. Our aim was to determine the extent to which the host's immune pressure affects HCV diversity and the ways in which the sequence of the incoming virus, including preexisting escape mutations, can influence subsequent mutations in recipients and infection outcomes. Conclusion: HCV sequences from these individuals revealed 29 significant associations between specific HLA types within the new hosts and variations within their viruses, which likely represent new viral adaptations. These associations did not overlap with previously reported adaptations for genotypes 1a and 3a and possibly reflected a combination of constraint due to the incoming virus and genetic distance between the strains. However, these sites accounted for only a portion of the sites in which viral diversity was observed in the new hosts. Furthermore, preexisting viral adaptations in the incoming (source) virus likely influenced the outcomes in the new hosts.

Dissecting TCR-MHC/peptide complex interactions with A2/peptide multimers incorporating tumor antigen peptide variants: crucial role of interaction kinetics on functional outcomes.

Soluble peptide/MHC-class-I (pMHC) multimers have recently emerged as unique reagents for the study of specific interactions between the pMHC complex and the TCR. Here, we assessed the relative binding efficiency of a panel of multimers incorporating single-alanine-substituted variants of the tumor-antigen-derived peptide MAGE-A10(254-262) to specific CTL clones displaying different functional avidity. For each individual clone, the efficiency of binding of multimers incorporating MAGE-A10 peptide variants was, in most cases, in good although not linear correlation with the avidity of recognition of the corresponding variant. In addition, we observed two types of discrepancies between efficiency of recognition and multimer binding. First, for some peptide variants, efficient multimer binding was detected in the absence of measurable effector functions. Some of these peptide variants displayed antagonist activity. Second, when comparing different clones we found clear discrepancies between the dose of peptide required to obtain half-maximal lysis in CTL assays and the binding efficiency of the corresponding multimers. These discrepancies, however, were resolved when the differential stability of the TCR/pMHC complexes was determined. For individual clones, decreased recognition correlated with increased TCR/pMHC off-rate. TCR/pMHC complexes formed by antagonist ligands displayed off-rates faster than those of TCR/pMHC complexes formed with weak agonists. In addition, when comparing different clones, the efficiency of multimer staining correlated better with relative multimer off-rates than with half-maximal lysis values. Altogether, the data presented here reconcile and extend our previous results on the impact of the kinetics of interaction of TCR with pMHC complexes on multimer binding and underline the crucial role of TCR/pMHC off-rates for the functional outcome of such interactions.

Antifungal activity of extracts from Atacama Desert fungi againstParacoccidioides brasiliensis and identification ofAspergillus felis as a promising source of natural bioactive compounds

Fungi of the genus Paracoccidioides are responsible for paracoccidioidomycosis. The occurrence of drug toxicity and relapse in this disease justify the development of new antifungal agents. Compounds extracted from fungal extract have showing antifungal activity. Extracts of 78 fungi isolated from rocks of the Atacama Desert were tested in a microdilution assay against Paracoccidioides brasiliensis Pb18. Approximately 18% (5) of the extracts showed minimum inhibitory concentration (MIC) values≤ 125.0 µg/mL. Among these, extract from the fungus UFMGCB 8030 demonstrated the best results, with an MIC of 15.6 µg/mL. This isolate was identified as Aspergillus felis (by macro and micromorphologies, and internal transcribed spacer, β-tubulin, and ribosomal polymerase II gene analyses) and was grown in five different culture media and extracted with various solvents to optimise its antifungal activity. Potato dextrose agar culture and dichloromethane extraction resulted in an MIC of 1.9 µg/mL against P. brasiliensis and did not show cytotoxicity at the concentrations tested in normal mammalian cell (Vero). This extract was subjected to bioassay-guided fractionation using analytical C18RP-high-performance liquid chromatography (HPLC) and an antifungal assay using P. brasiliensis. Analysis of the active fractions by HPLC-high resolution mass spectrometry allowed us to identify the antifungal agents present in the A. felis extracts cytochalasins. These results reveal the potential of A. felis as a producer of bioactive compounds with antifungal activity.

A hybrid method for sag source location in power network

The work presented in this paper belongs to the power quality knowledge area and deals with the voltage sags in power transmission and distribution systems. Propagating throughout the power network, voltage sags can cause plenty of problems for domestic and industrial loads that can financially cost a lot. To impose penalties to responsible party and to improve monitoring and mitigation strategies, sags must be located in the power network. With such a worthwhile objective, this paper comes up with a new method for associating a sag waveform with its origin in transmission and distribution networks. It solves this problem through developing hybrid methods which hire multiway principal component analysis (MPCA) as a dimension reduction tool. MPCA reexpresses sag waveforms in a new subspace just in a few scores. We train some well-known classifiers with these scores and exploit them for classification of future sags. The capabilities of the proposed method for dimension reduction and classification are examined using the real data gathered from three substations in Catalonia, Spain. The obtained classification rates certify the goodness and powerfulness of the developed hybrid methods as brand-new tools for sag classification

Effects of the encapsulation of usnic acid into liposomes and interactions with antituberculous agents against multidrug-resistant tuberculosis clinical isolates

Mycobacterium tuberculosis (Mtb) has acquired resistance and consequently the antibiotic therapeutic options available against this microorganism are limited. In this scenario, the use of usnic acid (UA), a natural compound, encapsulated into liposomes is proposed as a new approach in multidrug-resistant tuberculosis (MDR-TB) therapy. Thus the aim of this study was to evaluate the effect of the encapsulation of UA into liposomes, as well as its combination with antituberculous agents such as rifampicin (RIF) and isoniazid (INH) against MDR-TB clinical isolates. The in vitro antimycobacterial activity of UA-loaded liposomes (UA-Lipo) against MDR-TB was assessed by the microdilution method. The in vitro interaction of UA with antituberculous agents was carried out using checkerboard method. Minimal inhibitory concentration values were 31.25 and 0.98 µg/mL for UA and UA-Lipo, respectively. The results exhibited a synergistic interaction between RIF and UA [fractional inhibitory concentration index (FICI) = 0.31] or UA-Lipo (FICI = 0.28). Regarding INH, the combination of UA or UA-Lipo revealed no marked effect (FICI = 1.30-2.50). The UA-Lipo may be used as a dosage form to improve the antimycobacterial activity of RIF, a first-line drug for the treatment of infections caused by Mtb.

Protein-protein interactions at the adrenergic receptors.

The adrenergic receptors are among the best characterized G protein-coupled receptors (GPCRs) and knowledge on this receptor family has provided several important paradigms about GPCR function and regulation. One of the most recent paradigms initially supported by studies on adrenergic receptors is that both βarrestins and G proteincoupled receptors themselves can act as scaffolds binding a variety of proteins and this can result in growing complexity of the receptor-mediated cellular effects. In this review we will briefly summarize the main features of βarrestin binding to the adrenergic receptor subtypes and we will review more in detail the main proteins found to selectively interact with distinct AR subtype. At the end, we will review the main findings on oligomerization of the AR subtypes.

The chemical variability at the surface of Mars: implications for exogenic processes

The chemical composition of sediments and rocks, as well as their distribution at theMartian surface, represent a long term archive of processes, which have formed theplanetary surface. A survey of chemical compositions by means of Compositional DataAnalysis represents a valuable tool to extract direct evidence for weathering processesand allows to quantify weathering and sedimentation rates. clr-biplot techniques areapplied for visualization of chemical relationships across the surface (“chemical maps”).The variability among individual suites of data is further analyzed by means of clr-PCA,in order to extract chemical alteration vectors between fresh rocks and their crusts andfor an assessment of different source reservoirs accessible to soil formation. Bothtechniques are applied to elucidate the influence of remote weathering by combinedanalysis of several soil forming branches. Vector analysis in the Simplex provides theopportunity to study atmosphere surface interactions, including the role andcomposition of volcanic gases

Horizontal, but not vertical, biotic interactions affect fine-scale plant distribution patterns in a low-energy system

Studies of species range determinants have traditionally focused on abiotic variables (typically climatic conditions), and therefore the recent explicit consideration of biotic interactions represents an important advance in the field. While these studies clearly support the role of biotic interactions in shaping species distributions, most examine only the influence of a single species and/or a single interaction, failing to account for species being subject to multiple concurrent interactions. By fitting species distribution models (SDMs), we examine the influence of multiple vertical (i.e., grazing, trampling, and manuring by mammalian herbivores) and horizontal (i.e., competition and facilitation; estimated from the cover of dominant plant species) interspecific interactions on the occurrence and cover of 41 alpine tundra plant species. Adding plant-plant interactions to baseline SDMs (using five field-quantified abiotic variables) significantly improved models' predictive power for independent data, while herbivore-related variables had only a weak influence. Overall, abiotic variables had the strongest individual contributions to the distribution of alpine tundra plants, with the importance of horizontal interaction variables exceeding that of vertical interaction variables. These results were consistent across three modeling techniques, for both species occurrence and cover, demonstrating the pattern to be robust. Thus, the explicit consideration of multiple biotic interactions reveals that plant-plant interactions exert control over the fine-scale distribution of vascular species that is comparable to abiotic drivers and considerably stronger than herbivores in this low-energy system.

Species distributions and interactions in a changing world : from understanding to forecasting

Les écosystèmes fournissent de nombreuses ressources et services écologiques qui sont utiles à la population humaine. La biodiversité est une composante essentielle des écosystèmes et maintient de nombreux services. Afin d'assurer la permanence des services écosystémiques, des mesures doivent être prises pour conserver la biodiversité. Dans ce but, l'acquisition d'informations détaillées sur la distribution de la biodiversité dans l'espace est essentielle. Les modèles de distribution d'espèces (SDMs) sont des modèles empiriques qui mettent en lien des observations de terrain (présences ou absences d'une espèce) avec des descripteurs de l'environnement, selon des courbes de réponses statistiques qui décrive la niche réalisée des espèces. Ces modèles fournissent des projections spatiales indiquant les lieux les plus favorables pour les espèces considérées. Le principal objectif de cette thèse est de fournir des projections plus réalistes de la distribution des espèces et des communautés en montagne pour le climat présent et futur en considérant non-seulement des variables abiotiques mais aussi biotiques. Les régions de montagne et l'écosystème alpin sont très sensibles aux changements globaux et en même temps assurent de nombreux services écosystémiques. Cette thèse est séparée en trois parties : (i) fournir une meilleure compréhension du rôle des interactions biotiques dans la distribution des espèces et l'assemblage des communautés en montagne (ouest des Alpes Suisses), (ii) permettre le développement d'une nouvelle approche pour modéliser la distribution spatiale de la biodiversité, (iii) fournir des projections plus réalistes de la distribution future des espèces ainsi que de la composition des communautés. En me focalisant sur les papillons, bourdons et plantes vasculaires, j'ai détecté des interactions biotiques importantes qui lient les espèces entre elles. J'ai également identifié la signature du filtre de l'environnement sur les communautés en haute altitude confirmant l'utilité des SDMs pour reproduire ce type de processus. A partir de ces études, j'ai contribué à l'amélioration méthodologique des SDMs dans le but de prédire les communautés en incluant les interactions biotiques et également les processus non-déterministes par une approche probabiliste. Cette approche permet de prédire non-seulement la distribution d'espèces individuelles, mais également celle de communautés dans leur entier en empilant les projections (S-SDMs). Finalement, j'ai utilisé cet outil pour prédire la distribution d'espèces et de communautés dans le passé et le futur. En particulier, j'ai modélisé la migration post-glaciaire de Trollius europaeus qui est à l'origine de la structure génétique intra-spécifique chez cette espèce et évalué les risques de perte face au changement climatique. Finalement, j'ai simulé la distribution des communautés de bourdons pour le 21e siècle afin d'évaluer les changements probables dans ce groupe important de pollinisateurs. La diversité fonctionnelle des bourdons va être altérée par la perte d'espèces spécialistes de haute altitude et ceci va influencer la pollinisation des plantes en haute altitude. - Ecosystems provide a multitude of resources and ecological services, which are useful to human. Biodiversity is an essential component of those ecosystems and guarantee many services. To assure the permanence of ecosystem services for future generation, measure should be applied to conserve biodiversity. For this purpose, the acquisition of detailed information on how biodiversity implicated in ecosystem function is distributed in space is essential. Species distribution models (SDMs) are empirical models relating field observations to environmental predictors based on statistically-derived response surfaces that fit the realized niche. These models result in spatial predictions indicating locations of the most suitable environment for the species and may potentially be applied to predict composition of communities and their functional properties. The main objective of this thesis was to provide more accurate projections of species and communities distribution under current and future climate in mountains by considering not solely abiotic but also biotic drivers of species distribution. Mountain areas and alpine ecosystems are considered as particularly sensitive to global changes and are also sources of essential ecosystem services. This thesis had three main goals: (i) a better ecological understanding of biotic interactions and how they shape the distribution of species and communities, (ii) the development of a novel approach to the spatial modeling of biodiversity, that can account for biotic interactions, and (iii) ecologically more realistic projections of future species distributions, of future composition and structure of communities. Focusing on butterfly and bumblebees in interaction with the vegetation, I detected important biotic interactions for species distribution and community composition of both plant and insects along environmental gradients. I identified the signature of environmental filtering processes at high elevation confirming the suitability of SDMs for reproducing patterns of filtering. Using those case-studies, I improved SDMs by incorporating biotic interaction and accounting for non-deterministic processes and uncertainty using a probabilistic based approach. I used improved modeling to forecast the distribution of species through the past and future climate changes. SDMs hindcasting allowed a better understanding of the spatial range dynamic of Trollius europaeus in Europe at the origin of the species intra-specific genetic diversity and identified the risk of loss of this genetic diversity caused by climate change. By simulating the future distribution of all bumblebee species in the western Swiss Alps under nine climate change scenarios for the 21st century, I found that the functional diversity of this pollinator guild will be largely affected by climate change through the loss of high elevation specialists. In turn, this will have important consequences on alpine plant pollination.

SwissTargetPrediction: a web server for target prediction of bioactive small molecules.

Bioactive small molecules, such as drugs or metabolites, bind to proteins or other macro-molecular targets to modulate their activity, which in turn results in the observed phenotypic effects. For this reason, mapping the targets of bioactive small molecules is a key step toward unraveling the molecular mechanisms underlying their bioactivity and predicting potential side effects or cross-reactivity. Recently, large datasets of protein-small molecule interactions have become available, providing a unique source of information for the development of knowledge-based approaches to computationally identify new targets for uncharacterized molecules or secondary targets for known molecules. Here, we introduce SwissTargetPrediction, a web server to accurately predict the targets of bioactive molecules based on a combination of 2D and 3D similarity measures with known ligands. Predictions can be carried out in five different organisms, and mapping predictions by homology within and between different species is enabled for close paralogs and orthologs. SwissTargetPrediction is accessible free of charge and without login requirement at http://www.swisstargetprediction.ch.

Cleaning wrasse species vary with respect to dependency on the mutualism and behavioural adaptations in interactions

Interspecific mutualisms are an essential feature of life on earth, yet we know little about their evolution and stability. In many mutualisms several species are available as partners, raising questions about the similarity in function and behavioural repertoire depending on the partner species. Furthermore, variation between species in the quantity and quality of interactions resulting in variation in payoffs may allow us to infer the potential evolutionary origin of a multispecies mutualism complex. We addressed these issues in the marine cleaning mutualism, in which so-called 'cleaners' remove ectoparasites from so-called 'client' reef fish. We measured several parameters concerning the quantity and quality of cleaning interactions in six sympatric cleaner wrasse species. We found significant variation between cleaner species with respect to client diversity, the number of interactions with predatory clients, the duration of interactions, the frequency of client jolts as a correlate of 'cheating' by cleaners, and behaviours used for manipulation of client decisions. Exploratory correlations between cleaner species' dependency and our variables of interest suggest that cleaning originated as a conflict-free by-product mutualism and evolved towards more sophisticated behaviours, including strategic behaviours for interactions with predators, cheating and manipulation specifically adapted to the client type.