Analcime crystallization and compositional profiles - Comparing approaches to detect post-depositional alterations in archaeological pottery

The approaches of comparative studies and profile measurements, often used in order to detect post-depositional alterations of ceramics, have been applied simultaneously to two sets of Roman pottery, both of which include altered individuals. As analytical techniques, Neutron Activation Analysis and X-Ray Diffraction have been used. Both approaches lead to substantially different results. This shows that they detect different levels of alteration and should complement each other rather than being used exclusively. For the special process of a glassy phase decomposition followed by a crystallization of the Na-zeolite analcime, the results suggest that it changes high-fired calcareous pottery rapidly, and so fundamentally that the results of various archaeometric techniques can be severely disturbed.

De la perception à l'apprentissage [From perception to learning]

Dans le domaine de la perception, l'apprentissage est contraint par la présence d'une architecture fonctionnelle constituée d'aires corticales distribuées et très spécialisées. Dans le domaine des troubles visuels d'origine cérébrale, l'apprentissage d'un patient hémi-anopsique ou agnosique sera limité par ses capacités perceptives résiduelles, mais un déficit de reconnaissance visuelle de nature apparemment perceptive, peut également être associé à une altération des représentations en mémoire à long terme. Des réseaux neuronaux distincts pour la reconnaissance - cortex temporal - et pour la localisation des sons - cortex pariétal - ont été décrits chez l'homme. L'étude de patients cérébro-lésés confirme le rôle des indices spatiaux dans un traitement auditif explicite du « where » et dans la discrimination implicite du « what ». Cette organisation, similaire à ce qui a été décrit dans la modalité visuelle, faciliterait les apprentissages perceptifs. Plus généralement, l'apprentissage implicite fonde une grande partie de nos connaissances sur le monde en nous rendant sensible, à notre insu, aux règles et régularités de notre environnement. Il serait impliqué dans le développement cognitif, la formation des réactions émotionnelles ou encore l'apprentissage par le jeune enfant de sa langue maternelle. Le caractère inconscient de cet apprentissage est confirmé par l'étude des temps de réaction sériels de patients amnésiques dans l'acquisition d'une grammaire artificielle. Son évaluation pourrait être déterminante dans la prise en charge ré-adaptative. [In the field of perception, learning is formed by a distributed functional architecture of very specialized cortical areas. For example, capacities of learning in patients with visual deficits - hemianopia or visual agnosia - from cerebral lesions are limited by perceptual abilities. Moreover a visual deficit in link with abnormal perception may be associated with an alteration of representations in long term (semantic) memory. Furthermore, perception and memory traces rely on parallel processing. This has been recently demonstrated for human audition. Activation studies in normal subjects and psychophysical investigations in patients with focal hemispheric lesions have shown that auditory information relevant to sound recognition and that relevant to sound localisation are processed in parallel, anatomically distinct cortical networks, often referred to as the "What" and "Where" processing streams. Parallel processing may appear counterintuitive from the point of view of a unified perception of the auditory world, but there are advantages, such as rapidity of processing within a single stream, its adaptability in perceptual learning or facility of multisensory interactions. More generally, implicit learning mechanisms are responsible for the non-conscious acquisition of a great part of our knowledge about the world, using our sensitivity to the rules and regularities structuring our environment. Implicit learning is involved in cognitive development, in the generation of emotional processing and in the acquisition of natural language. Preserved implicit learning abilities have been shown in amnesic patients with paradigms like serial reaction time and artificial grammar learning tasks, confirming that implicit learning mechanisms are not sustained by the cognitive processes and the brain structures that are damaged in amnesia. In a clinical perspective, the assessment of implicit learning abilities in amnesic patients could be critical for building adapted neuropsychological rehabilitation programs.]

Approche preventive des pathologies démentietlles [Preventive approaches to dementia].

Prevalence and incidence of dementia increase with demographic aging. Benefits of current antidementia drugs are modest, both in cognitive and functional domains. Therefore, interest is growing to evaluate the effects of interventions aiming at preventing cognitive decline and, ideally, dementia onset. Cognitive training and physical activity seem promising. This paper describes recent studies that assessed the benefits of preventive strategies in the domain of dementia, especially in Alzheimer's disease.

Public-health and individual approaches to antiretroviral therapy: township South Africa and Switzerland compared.

BACKGROUND: The provision of highly active antiretroviral therapy (HAART) in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. We compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting HAART in South Africa and Switzerland. METHODS AND FINDINGS: We analysed data from the Swiss HIV Cohort Study and two HAART programmes in townships of Cape Town, South Africa. We included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded intravenous drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4+ T cell counts were 80 cells/mul in South Africa and 204 cells/mul in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%-97%) in South Africa and 96% (94%-97%) in Switzerland, and 26% (22%-29%) and 27% (24%-31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of HAART: adjusted hazard ratios were 5.90 (95% CI 1.81-19.2) during months 1-3 and 1.77 (0.90-3.50) during months 4-24. CONCLUSIONS: Compared to the highly individualised approach in Switzerland, programmatic HAART in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to HAART and improve the prognosis of patients who start HAART with advanced disease.

Different likelihood ratio approaches to evaluate the strength of evidence of MDMA tablet comparisons

Two likelihood ratio (LR) approaches are presented to evaluate the strength of evidence of MDMA tablet comparisons. The first one is based on a more 'traditional' comparison of MDMA tablets by using distance measures (e.g., Pearson correlation distance or a Euclidean distance). In this approach, LRs are calculated using the distribution of distances between tablets of the same-batch and that of different-batches. The second approach is based on methods used in some other fields of forensic comparison. Here LRs are calculated based on the distribution of values of MDMA tablet characteristics within a specific batch and from all batches. The data used in this paper must be seen as examples to illustrate both methods. In future research the methods can be applied to other and more complex data. In this paper, the methods and their results are discussed, considering their performance in evidence evaluation and several practical aspects. With respect to evidence in favor of the correct hypothesis, the second method proved to be better than the first one. It is shown that the LRs in same-batch comparisons are generally higher compared to the first method and the LRs in different-batch comparisons are generally lower. On the other hand, for operational purposes (where quick information is needed), the first method may be preferred, because it is less time consuming. With this method a model has to be estimated only once in a while, which means that only a few measurements have to be done, while with the second method more measurements are needed because each time a new model has to be estimated.

A comparison of Bayesian and frequentist approaches to incorporating external information for the prediction of prostate cancer risk.

We present the most comprehensive comparison to date of the predictive benefit of genetics in addition to currently used clinical variables, using genotype data for 33 single-nucleotide polymorphisms (SNPs) in 1,547 Caucasian men from the placebo arm of the REduction by DUtasteride of prostate Cancer Events (REDUCE®) trial. Moreover, we conducted a detailed comparison of three techniques for incorporating genetics into clinical risk prediction. The first method was a standard logistic regression model, which included separate terms for the clinical covariates and for each of the genetic markers. This approach ignores a substantial amount of external information concerning effect sizes for these Genome Wide Association Study (GWAS)-replicated SNPs. The second and third methods investigated two possible approaches to incorporating meta-analysed external SNP effect estimates - one via a weighted PCa 'risk' score based solely on the meta analysis estimates, and the other incorporating both the current and prior data via informative priors in a Bayesian logistic regression model. All methods demonstrated a slight improvement in predictive performance upon incorporation of genetics. The two methods that incorporated external information showed the greatest receiver-operating-characteristic AUCs increase from 0.61 to 0.64. The value of our methods comparison is likely to lie in observations of performance similarities, rather than difference, between three approaches of very different resource requirements. The two methods that included external information performed best, but only marginally despite substantial differences in complexity.

ML approaches to channel estimation for pilot-aided multi-rate DS/CDMA systems

This paper analyzes the asymptotic performance of maximum likelihood (ML) channel estimation algorithms in wideband code division multiple access (WCDMA) scenarios. We concentrate on systems with periodic spreading sequences (period larger than or equal to the symbol span) where the transmitted signal contains a code division multiplexed pilot for channel estimation purposes. First, the asymptotic covariances of the training-only, semi-blind conditional maximum likelihood (CML) and semi-blind Gaussian maximum likelihood (GML) channelestimators are derived. Then, these formulas are further simplified assuming randomized spreading and training sequences under the approximation of high spreading factors and high number of codes. The results provide a useful tool to describe the performance of the channel estimators as a function of basicsystem parameters such as number of codes, spreading factors, or traffic to training power ratio.

Nouvelles approches therapeutiques de l'hypertension arterielle. [New therapeutic approaches to arterial hypertension]

Today two largely new approaches are available for the treatment of clinical hypertension. First, captopril, an orally active angiotensin converting enzyme inhibitor, makes possible chronic blockade of the renin-angiotensin system. This compound, given alone or in combination with a diuretic, normalizes the blood pressure of most hypertensive patients. Unfortunately, because captopril may induce serious adverse effects the use of this inhibitor must be restricted to patients with high blood pressure refractory to conventional antihypertensive drugs. Second, compounds such as verapamil and nifedipine are capable of producing a marked vasodilating effect by inhibiting the entry of calcium into the vascular smooth muscle cells. However, the role of calcium channel blockers in the treatment of hypertensive disease awaits more precise definition.

Exploring transparent approaches to the authentication of signatures on artwork

This thesis is composed of three main parts. The first consists of a state of the art of the different notions that are significant to understand the elements surrounding art authentication in general, and of signatures in particular, and that the author deemed them necessary to fully grasp the microcosm that makes up this particular market. Individuals with a solid knowledge of the art and expertise area, and that are particularly interested in the present study are advised to advance directly to the fourth Chapter. The expertise of the signature, it's reliability, and the factors impacting the expert's conclusions are brought forward. The final aim of the state of the art is to offer a general list of recommendations based on an exhaustive review of the current literature and given in light of all of the exposed issues. These guidelines are specifically formulated for the expertise of signatures on paintings, but can also be applied to wider themes in the area of signature examination. The second part of this thesis covers the experimental stages of the research. It consists of the method developed to authenticate painted signatures on works of art. This method is articulated around several main objectives: defining measurable features on painted signatures and defining their relevance in order to establish the separation capacities between groups of authentic and simulated signatures. For the first time, numerical analyses of painted signatures have been obtained and are used to attribute their authorship to given artists. An in-depth discussion of the developed method constitutes the third and final part of this study. It evaluates the opportunities and constraints when applied by signature and handwriting experts in forensic science. A brief summary covering each chapter allows a rapid overview of the study and summarizes the aims and main themes of each chapter. These outlines presented below summarize the aims and main themes addressed in each chapter. Part I - Theory Chapter 1 exposes legal aspects surrounding the authentication of works of art by art experts. The definition of what is legally authentic, the quality and types of the experts that can express an opinion concerning the authorship of a specific painting, and standard deontological rules are addressed. The practices applied in Switzerland will be specifically dealt with. Chapter 2 presents an overview of the different scientific analyses that can be carried out on paintings (from the canvas to the top coat). Scientific examinations of works of art have become more common, as more and more museums equip themselves with laboratories, thus an understanding of their role in the art authentication process is vital. The added value that a signature expertise can have in comparison to other scientific techniques is also addressed. Chapter 3 provides a historical overview of the signature on paintings throughout the ages, in order to offer the reader an understanding of the origin of the signature on works of art and its evolution through time. An explanation is given on the transitions that the signature went through from the 15th century on and how it progressively took on its widely known modern form. Both this chapter and chapter 2 are presented to show the reader the rich sources of information that can be provided to describe a painting, and how the signature is one of these sources. Chapter 4 focuses on the different hypotheses the FHE must keep in mind when examining a painted signature, since a number of scenarios can be encountered when dealing with signatures on works of art. The different forms of signatures, as well as the variables that may have an influence on the painted signatures, are also presented. Finally, the current state of knowledge of the examination procedure of signatures in forensic science in general, and in particular for painted signatures, is exposed. The state of the art of the assessment of the authorship of signatures on paintings is established and discussed in light of the theoretical facets mentioned previously. Chapter 5 considers key elements that can have an impact on the FHE during his or her2 examinations. This includes a discussion on elements such as the skill, confidence and competence of an expert, as well as the potential bias effects he might encounter. A better understanding of elements surrounding handwriting examinations, to, in turn, better communicate results and conclusions to an audience, is also undertaken. Chapter 6 reviews the judicial acceptance of signature analysis in Courts and closes the state of the art section of this thesis. This chapter brings forward the current issues pertaining to the appreciation of this expertise by the non- forensic community, and will discuss the increasing number of claims of the unscientific nature of signature authentication. The necessity to aim for more scientific, comprehensive and transparent authentication methods will be discussed. The theoretical part of this thesis is concluded by a series of general recommendations for forensic handwriting examiners in forensic science, specifically for the expertise of signatures on paintings. These recommendations stem from the exhaustive review of the literature and the issues exposed from this review and can also be applied to the traditional examination of signatures (on paper). Part II - Experimental part Chapter 7 describes and defines the sampling, extraction and analysis phases of the research. The sampling stage of artists' signatures and their respective simulations are presented, followed by the steps that were undertaken to extract and determine sets of characteristics, specific to each artist, that describe their signatures. The method is based on a study of five artists and a group of individuals acting as forgers for the sake of this study. Finally, the analysis procedure of these characteristics to assess of the strength of evidence, and based on a Bayesian reasoning process, is presented. Chapter 8 outlines the results concerning both the artist and simulation corpuses after their optical observation, followed by the results of the analysis phase of the research. The feature selection process and the likelihood ratio evaluation are the main themes that are addressed. The discrimination power between both corpuses is illustrated through multivariate analysis. Part III - Discussion Chapter 9 discusses the materials, the methods, and the obtained results of the research. The opportunities, but also constraints and limits, of the developed method are exposed. Future works that can be carried out subsequent to the results of the study are also presented. Chapter 10, the last chapter of this thesis, proposes a strategy to incorporate the model developed in the last chapters into the traditional signature expertise procedures. Thus, the strength of this expertise is discussed in conjunction with the traditional conclusions reached by forensic handwriting examiners in forensic science. Finally, this chapter summarizes and advocates a list of formal recommendations for good practices for handwriting examiners. In conclusion, the research highlights the interdisciplinary aspect of signature examination of signatures on paintings. The current state of knowledge of the judicial quality of art experts, along with the scientific and historical analysis of paintings and signatures, are overviewed to give the reader a feel of the different factors that have an impact on this particular subject. The temperamental acceptance of forensic signature analysis in court, also presented in the state of the art, explicitly demonstrates the necessity of a better recognition of signature expertise by courts of law. This general acceptance, however, can only be achieved by producing high quality results through a well-defined examination process. This research offers an original approach to attribute a painted signature to a certain artist: for the first time, a probabilistic model used to measure the discriminative potential between authentic and simulated painted signatures is studied. The opportunities and limits that lie within this method of scientifically establishing the authorship of signatures on works of art are thus presented. In addition, the second key contribution of this work proposes a procedure to combine the developed method into that used traditionally signature experts in forensic science. Such an implementation into the holistic traditional signature examination casework is a large step providing the forensic, judicial and art communities with a solid-based reasoning framework for the examination of signatures on paintings. The framework and preliminary results associated with this research have been published (Montani, 2009a) and presented at international forensic science conferences (Montani, 2009b; Montani, 2012).

Optimising approaches to active immunotherapy of cancer

The design of therapeutic cancer vaccines is aimed at inducing high numbers and potent T cells that are able to target and eradicate malignant cells. This calls for close collaboration between cells of the innate immune system, in particular dendritic cells (DCs), and cells of the adaptive immune system, notably CD4+ helper T cells and CD8+ cytotoxic T cells. Therapeutic vaccines are aided by adjuvants, which can be, for example, Toll¬like Receptor agonists or agents promoting the cytosolic delivery of antigens, among others. Vaccination with long synthetic peptides (LSPs) is a promising strategy, as the requirement for their intracellular processing will mainly target LSPs to professional antigen presenting cells (APCs), hence avoiding the immune tolerance elicited by the presentation of antigens by non-professional APCs. The unique property of antigen cross-processing and cross-presentation activity by DCs plays an important role in eliciting antitumour immunity given that antigens from engulfed dead tumour cells require this distinct biological process to be processed and presented to CD8+T cells in the context of MHC class I molecules. DCs expressing the XCR1 chemokine receptor are characterised by their superior capability of antigen cross- presentation and priming of highly cytotoxic T lymphocyte (CTL) responses. Recently, XCR1 was found to be also expressed in tissue-residents DCs in humans, with a simitar transcriptional profile to that of cross- presenting murine DCs. This shed light into the value of harnessing this subtype of XCR1+ cross-presenting DCs for therapeutic vaccination of cancer. In this study, we explored ways of adjuvanting and optimising LSP therapeutic vaccinations by the use, in Part I, of the XCLl chemokine that selectively binds to the XCR1 receptor, as a mean to target antigen to the cross-presenting XCR1+ DCs; and in Part II, by the inclusion of Q.S21 in the LSP vaccine formulation, a saponin with adjuvant activity, as well as the ability to promote cytosolic delivery of LSP antigens due to its intrinsic cell membrane insertion activity. In Part I, we designed and produced XCLl-(OVA LSP)-Fc fusion proteins, and showed that their binding to XCR1+ DCs mediate their chemoattraction. In addition, therapeutic vaccinations adjuvanted with XCLl-(OVA LSP)-Fc fusion proteins significantly enhanced the OVA-specific CD8+ T cell response, and led to complete tumour regression in the EL4-OVA model, and significant control of tumour growth in the B16.0VA tumour model. With the aim to optimise the co-delivery of LSP antigen and XCLl to skin-draining lymph nodes we also tested immunisations using nanoparticle (NP)-conjugated OVA LSP in the presence or absence of XCLl chemokine. The NP-mediated delivery of LSP potentiated the CTL response seen in the blood of vaccinated mice, and NP-OVA LSP vaccine in the presence of XCLl led to higher blood frequencies of OVA-specific memory-precursor effector cells. Nevertheless, in these settings, the addition XCLl to NP-OVA LSP vaccine formulation did not increase its antitumour therapeutic effect. In the Part II, we assessed in HLA-A2/DR1 mice the immunogenicity of the Melan-AA27L LSP or the Melan-A26. 35 AA27l short synthetic peptide (SSP) used in conjunction with the saponin adjuvant QS21, aiming to identify a potent adjuvant formulation that elicits a quantitatively and qualitatively strong immune response to tumour antigens. We showed a high CTL immune response elicited by the use of Melan-A LSP or SSP with QS21, which both exerted similar killing capacity upon in vivo transfer of target cells expressing the Melan-A peptide in the context of HLA-A2 molecules. However, the response generated by the LSP immunisation comprised higher percentages of CD8+T cells of the central memory phenotype (CD44hl CD62L+ and CCR7+ CD62L+) than those of SSP immunisation, and most importantly, the strong LSP+QS21 response was strictly CD4+T cell-dependent, as shown upon CD4 T cell depletion. Altogether, these results suggest that both XCLl and QS21 may enhance the ability of LSP to prime CD8 specific T cell responses, and promote a long-term memory response. Therefore, these observations may have important implications for the design of protein or LSP-based cancer vaccines for specific immunotherapy of cancer -- Les vacans thérapeutiques contre le cancer visent à induire une forte et durable réponse immunitaire contre des cellules cancéreuses résiduelles. Cette réponse requiert la collaboration entre le système immunitaire inné, en particulier les cellules dendrites (DCs), et le système immunitaire adaptatif, en l'occurrence les lymphocytes TCD4 hdper et CD8 cytotoxiques. La mise au point d'adjuvants et de molécules mimant un agent pathogène tels les ligands TLRs ou d'autres agents facilitant l'internalisation d'antigènes, est essentielle pour casser la tolérance du système immunitaire contre les cellules cancéreuses afin de générer une réponse effectrice et mémoire contre la tumeur. L'utilisation de longs peptides synthétiques (LSPs) est une approche prometteuse du fait que leur présentation en tant qu'antigénes requiert leur internalisation et leur transformation par les cellules dendrites (DCs, qui sont les mieux à même d'éviter la tolérance immunitaire. Récemment une sous-population de DCs exprimant le récepteur XCR1 a été décrite comme ayant une capacité supérieure dans la cross-présentation d'antigènes, d'où un intérêt à développer des vaccins ciblant les DCs exprimant le XCR1. Durant ma thèse de doctorat, j'ai exploré différentes approches pour optimiser les vaccins avec LSPs. La première partie visait à cibler les XCR1-DCs à l'aide de la chemokine XCL1 spécifique du récepteur XCR1, soit sou s la forme de protéine de fusion XCL1-OVA LSP-Fc, soit associée à des nanoparticules. La deuxième partie a consisté à tester l'association des LSPs avec I adjuvant QS21 dérivant d'une saponine dans le but d'optimiser l'internalisation cytosolique des longs peptides. Les protéines de fusion XCLl-OVA-Fc développées dans la première partie de mon travail, ont démontré leur capacité de liaison spécifique sur les XCRl-DCs associée à leur capacité de chemo-attractio. Lorsque inclues dans une mmunisation de souris porteuse de tumeurs établies, ces protéines de fusion XCL1-0VA LSP-Fc et XCLl-Fc plus OVA LSP ont induites une forte réponse CDS OVA spécifique permettant la complète régression des tumeurs de modèle EL4- 0VA et un retard de croissance significatif de tumeurs de type B16-0VA. Dans le but d'optimiser le drainage des LSPs vers es noyaux lymphatiques, nous avons également testé les LSPs fixés de manière covalente à des nanoparticules co- injectees ou non avec la chemokine XCL1. Cette formulation a également permis une forte réponse CD8 accompagnée d'un effet thérapeutique significatif, mais l'addition de la chemokine XCL1 n'a pas ajouté d'effet anti-tumeur supplémentaire. Dans la deuxième partie de ma thèse, j'ai comparé l'immunogénicité de l'antigène humain Melan A soit sous la forme d un LSP incluant un épitope CD4 et CD8 ou sous la forme d'un peptide ne contenant que l'épitope CD8 (SSP) Les peptides ont été formulés avec l'adjuvant QS21 et testés dans un modèle de souris transgéniques pour les MHC let II humains, respectivement le HLA-A2 et DR1. Les deux peptides LSP et SSP ont généré une forte réponse CD8 similaire assoc.ee a une capacité cytotoxique équivalente lors du transfert in vivo de cellules cibles présentant le peptide SSP' Cependant les souris immunisées avec le Melan A LSP présentaient un pourcentage plus élevé de CD8 ayant un Phénotype «centra, memory» (CD44h' CD62L+ and CCR7+ CD62L+) que les souris immunisées avec le SSP, même dix mois après I'immunisation. Par ailleurs, la réponse CD8 au Melan A LSP était strictement dépendante des lymphocytes CD4, contrairement à l'immunisation par le Melan A SSP qui n'était pas affectée. Dans l'ensemble ces résultats suggèrent que la chemokine XCL1 et l'adjuvant QS21 améliorent la réponse CD8 à un long peptide synthétique, favorisant ainsi le développement d'une réponse anti-tumeur mémoire durable. Ces observations pourraient être utiles au développement de nouveau vaccins thérapeutiques contre les tumeurs.

Approaches to the study of individual–landscape interaction as an evocation of intrapersonal communication Aproximaciones al estudio de la interacción individuo-paisaje a modo de evocación comunicativa intrapersonal

Analysis of the interaction between landscape and the individual opens up many research avenues linked to the generation and interpretation of symbolisms and imaginaries. The capacity of landscape for significant and/or communicative evocation finds in intrapersonal communication a relevant argument for the construction of a theoretical framework to study the process of appropriation and experience of the landscape in terms of communicative expression. The principal aim of this paper is to set up the theoretical framework that enables us to interpret the language of landscape and to decode its intangible discourse.