Functional MRI of stimulus interference on auditory processing in normal listeners and tinnitus patients

We are constantly immersed in stimuli. Upon reaching our senses, stimuli are processed within various brain systems along various pathways into the brain, and eventually turned into a percept. However, there are percepts that do not result from responses to external source stimuli. A particular case of this situation is the auditory percept known as tinnitus. Tinnitus can be seen as a task-irrelevant auditory percept, commonly reported to interfere with normal daily tasks. This is known from reports made by tinnitus sufferers that refer to their phantom percept as distracting, and that it diverts their focus from the task-relevant stimuli.(...)

Rely-guarantee protocols for safe interference over shared memory

Mutable state can be useful in certain algorithms, to structure programs, or for efficiency purposes. However, when shared mutable state is used in non-local or nonobvious ways, the interactions that can occur via aliases to that shared memory can be a source of program errors. Undisciplined uses of shared state may unsafely interfere with local reasoning as other aliases may interleave their changes to the shared state in unexpected ways. We propose a novel technique, rely-guarantee protocols, that structures the interactions between aliases and ensures that only safe interference is possible. We present a linear type system outfitted with our novel sharing mechanism that enables controlled interference over shared mutable resources. Each alias is assigned separate, local roles encoded in a protocol abstraction that constrains how an alias can legally use that shared state. By following the spirit of rely-guarantee reasoning, our rely-guarantee protocols ensure that only safe interference can occur but still allow many interesting uses of shared state, such as going beyond invariant and monotonic usages. This thesis describes the three core mechanisms that enable our type-based technique to work: 1) we show how a protocol models an alias’s perspective on how the shared state evolves and constrains that alias’s interactions with the shared state; 2) we show how protocols can be used while enforcing the agreed interference contract; and finally, 3) we show how to check that all local protocols to some shared state can be safely composed to ensure globally safe interference over that shared memory. The interference caused by shared state is rooted at how the uses of di↵erent aliases to that state may be interleaved (perhaps even in non-deterministic ways) at run-time. Therefore, our technique is mostly agnostic as to whether this interference was the result of alias interleaving caused by sequential or concurrent semantics. We show implementations of our technique in both settings, and highlight their di↵erences. Because sharing is “first-class” (and not tied to a module), we show a polymorphic procedure that enables abstract compositions of protocols. Thus, protocols can be specialized or extended without requiring specific knowledge of the interference produce by other protocols to that state. We show that protocol composition can ensure safety even when considering abstracted protocols. We show that this core composition mechanism is sound, decidable (without the need for manual intervention), and provide an algorithm implementation.

Human and murine clonal CD8+ T cell expansions arise during tuberculosis because of TCR selection

The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRß bias. Using a retro genic model of TB10.44-11-specific CD8+ Tcells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-? production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.

Quantifying, generating and mitigating radio interference in Low-Power Wireless Networks

Doctoral Programme in Telecommunication - MAP-tele

The interference of methods in the collection of teredinids (Mollusca, Bivalvia) in mangrove habitats

In the estuary of the Mamanguape River (Paraíba, Brazil), a new collection technique was developed and applied with virgin poles of mangrove trees Avicennia schaueriana (Verbenaceae), Rhizophora mangle (Rhizophoraceae), and Laguncularia racemosa (Combretaceae), taking into account wood preference, water salinity and depth influence during teredinid larval settlement. Sets of poles were vertically fixed in the riverbed at three sites along a decreasing salinity gradient, where they stayed for four months. The poles were collected and divided into upper, median, and lower segments, in agreement with different immersion regimes. An increase of 239% was obtained in the number of individuals when compared to a previous study in the same area using a different methodology. The species Teredo bartschi (Clapp, 1923), Nausitora fusticula (Jeffreys, 1860) and Bankia fimbriatula Moll & Roch, 1931 were registered in both studies, and the species Psiloteredo healdi (Bartsch, 1931) is here registered for the first time as occurring in that estuary. The species Neoteredo reynei (Bartsch, 1920), previously registered on tree branches of the mangrove habitat, was not found in the present work. Bankia fimbriatula, the most abundant species, did not show preference for any substratum but occurred significantly on the lower segment of the poles. N. fusticula, second in abundance, preferred to settle on poles of A. schaueriana and on any of the three segments. Aiming to assess the habitat variations, a more accurate study on teredinids diversity in mangrove ecosystems should be performed through a concomitant analysis from tree branches of the mangrove habitat, as well as from poles of mangrove trees or panels made of pine wood or mangrove trees wood. These collection devices should be maintained along a decreasing salinity gradient exposed to different tide levels.

A simple method for assessing the binding of concanavalin A to mononuclear cell surfaces: no interference of visceral leishmaniasis serum on this binding

We report a simple method for evaluating the binding of concanavalin A (ConA) to human peripheral blood mononuclear cells (PBMC). The binding is evidenced by an immunoenzymic assay using peroxidase-conjugated immunoglobulins of a rabbit anti-ConA serum. Using the method we show that sera from patients with American leishmaniasis do not interfere with binding of ConA to PBMC.

Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways.

The t(15;17) chromosomal translocation, specific for acute promyelocytic leukemia (APL), fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene, resulting in expression of a PML-RAR alpha hybrid protein. In this report, we analyzed the nature of PML-RAR alpha-containing complexes in nuclear protein extracts of t(15;17)-positive cells. We show that endogenous PML-RAR alpha can bind to DNA as a homodimer, in contrast to RAR alpha that requires the retinoid X receptor (RXR) dimerization partner. In addition, these cells contain oligomeric complexes of PML-RAR alpha and endogenous RXR. Treatment with retinoic acid results in a decrease of PML-RAR alpha protein levels and, as a consequence, of DNA binding by the different complexes. Using responsive elements from various hormone signaling pathways, we show that PML-RAR alpha homodimers have altered DNA-binding characteristics when compared to RAR alpha-RXR alpha heterodimers. In transfected Drosophila SL-3 cells that are devoid of endogenous retinoid receptors PML-RAR alpha inhibits transactivation by RAR alpha-RXR alpha heterodimers in a dominant fashion. In addition, we show that both normal retinoid receptors and the PML-RAR alpha hybrid bind and activate the peroxisome proliferator-activated receptor responsive element from the Acyl-CoA oxidase gene, indicating that retinoids and peroxisome proliferator receptors may share common target genes. These properties of PML-RAR alpha may contribute to the transformed phenotype of APL cells.

The Liberal Ethics of Non-Interference and the Pareto Principle

We analyse the liberal ethics of non-interference applied to social choice. A liberal principle capturing noninterfering views of society and inspired by John Stuart Mill s conception of liberty, is examined. The principle captures the idea that society should not penalise agents after changes in their situation that do not a¤ect others. An impossibility for liberal approaches is highlighted: every social decision rule that satis es unanimity and a general principle of noninterference must be dictatorial. This raises some important issues for liberal approaches in social choice and political philosophy.

Methicillin-susceptible Staphylococcus aureus clonal complex 398: high prevalence and geographical heterogeneity in bone and joint infection and nasal carriage.

The prevalence of clonal complex (CC) 398 methicillin-susceptible Staphylococcus aureus (MSSA) was unexpectedly high among bone and joint infections (BJIs) and nasal-colonizing isolates in France, with surprising geographical heterogeneity. With none of the major, most-known staphylococcal virulence genes, MSSA CC398 BJI was associated with lower biological inflammatory syndrome and lower treatment failure rates.

Manipulating keratinocyte stem cell proliferation and differentiation using RNA interference

ABSTRACT : The epidermis, the outermost compartment of the skin, is a stratified and squamous epithelium that constantly self-renews. Keratinocytes, which represent the main epidermal population, are responsible for its cohesion and barrier function. Epidermal renewal necessitates a fine equilibrium between keratinocyte proliferation and differentiation. The keratinocyte stem cell, located in the basal cell layer, is responsible for epidermal homeostasis and regeneration during the wound healing process. The transcription factor p63 structurally belongs to the p53 superfamily. It is expressed in the basal and supra-basal cell layers of stratified epithelia and is thought to be important for the renewal or the differentiation of keratinocyte stem cells (Yang et al., 1999; Mills et al., 1999). In order to better understand its function, we established an in vitro model of p63 deficient human keratinocyte stem cells using a shp63 mediated RNA interference. Knockdown of endogenous p63 induces downregulation of cell-adhesion genes as previously described (Carroll et al., 2006). Interestingly, the replating of attached p63-knockdown keratinocytes on a feeder layer results in a loss of attachment and proliferation. They are no longer clonogenic. However, if the same population are replated in a fibrin matrix, extended fibrinolysis is reported, a common process in wound healing, suggesting that p63 regulates the fibrinolytic pathway. This result was confirmed by Q-PCR and shows that the urokinase pathway, which mediates fibrinolysis, is upregulated. Altogether, these findings suggest a mechanism in which the fine tuning of p63 expression promotes attachment or release of the keratinocyte stem cell from the basement membrane by inducing genes of adhesion and/or of fibrinolysis. This mechanism may be important for epidermal self-renewal, differentiation as well as wound healing. Its misregulation may be partly responsible for the p63 knockout phenotype. The downregulation of p63 also induces a decrease in LEKTI expression. LEKTI (lymphoepithelial Kazal-type serine protease inhibitor) is a serine protease inhibitor encoded by the Spink5 gene. It is expressed and secreted in the uppermost differentiated layers of stratified epithelia and plays a role in the desquamation process. When this gene is disrupted, humans develop the Netherton syndrome (Chavanas et al., 2000b). It is a dermatosis characterized by hair dysplasias, ichtyosiform erythroderma and impairment in epidermal barrier function promoting inflammation similarly as in psoriasis with inflammatory infiltrate in excess. TNFα (tumor necrosis factor alpha) and EDA1 (ectodysplasin A1) are two transmembraneprecursors that belong to the TNF superfamily, which is involved in immune and inflammation regulation (Smahi et al., 2002). We suggest that the secreted serine protease inhibitor LEKTI plays a role in the regulation of TNFα and EDA1 precursor cleavage and absence of LEKTI induces excess of inflammation. To investigate this hypothesis, we induced downregulation of Spink5 expression in rat keratinocyte stem cells by using a shSpink5 mediated RNA interference approach. Interestingly, expression of TNFα and EDA1 is modified after knockdown of Spink5 by Q-PCR. Moreover, downregulation of Spink5 induces loss of cohesiveness between keratinocytes and colonies adopt a scattered phenotype. Altogether, these preliminary data suggest that downregulation of LEKTI may play a role in the inflammatory response in Netherton syndrome patients, by regulating TNFα expression.

Monophyletic origin of multiple clonal lineages in an asexual fish (Poecilia formosa).

Despite the advantage of avoiding the costs of sexual reproduction, asexual vertebrates are very rare and often considered evolutionarily disadvantaged when compared to sexual species. Asexual species, however, may have advantages when colonizing (new) habitats or competing with sexual counterparts. They are also evolutionary older than expected, leaving the question whether asexual vertebrates are not only rare because of their 'inferior' mode of reproduction but also because of other reasons. A paradigmatic model system is the unisexual Amazon molly, Poecilia formosa, that arose by hybridization of the Atlantic molly, Poecilia mexicana, as the maternal ancestor, and the sailfin molly, Poecilia latipinna, as the paternal ancestor. Our extensive crossing experiments failed to resynthesize asexually reproducing (gynogenetic) hybrids confirming results of previous studies. However, by producing diploid eggs, female F(1) -hybrids showed apparent preadaptation to gynogenesis. In a range-wide analysis of mitochondrial sequences, we examined the origin of P. formosa. Our analyses point to very few or even a single origin(s) of its lineage, which is estimated to be approximately 120,000 years old. A monophyletic origin was supported from nuclear microsatellite data. Furthermore, a considerable degree of genetic variation, apparent by high levels of clonal microsatellite diversity, was found. Our molecular phylogenetic evidence and the failure to resynthesize the gynogenetic P. formosa together with the old age of the species indicate that some unisexual vertebrates might be rare not because they suffer the long-term consequences of clonal reproduction but because they are only very rarely formed as a result of complex genetic preconditions necessary to produce viable and fertile clonal genomes and phenotypes ('rare formation hypothesis').

Analysis of the clonal diversity of Staphylococcus aureus methicillin-resistant strains isolated at João Pessoa, state of Paraíba, Brazil

To investigate the clonal diversity of Staphylococcus aureus strains isolated at João Pessoa, State of Paraíba, Brazil, digested genomic DNA were studied by pulsed-field gel electrophoresis (PFGE) in nine methicillin-resistant strains (MRSA) and three methicillin-sensitive strains (MSSA), selected among 67 isolates based on their antimicrobial susceptibility and epidemiology. The isolates were obtained between April and November 1992 from the Hospital of the Federal University of Paraíba, located in João Pessoa. Two MRSA isolates from the Oswaldo Cruz Hospital, São Paulo, Brazil, including an epidemic strain previously detected from different hospitals at the country were used as control. Five different patterns, were demonstrated by MRSA isolated in João Pessoa and these patterns were described in several epidemiologically unrelated hospitals in São Paulo. Our results suggest the interstate dissemination of a MRSA clone in João Pessoa which is similar to that described in other cities of Brazil.