Retroanálise de parâmetros geomecânicos baseada em algoritmos de otimização

Dissertação de mestrado integrado em Engenharia Civil

Atrial infarction is a unique and often unrecognized clinical entity

A patient with heart failure and acute atrial fibrillation received the final diagnosis of atrial infarction associated with ventricular infarction based on clinical findings of ischemia in association with atrial fibrillation and heart failure (mechanisms probably involved: contractile dysfunction and loss of atrial contribution). Although a transesophageal echocardiography, which could refine the diagnosis of anatomic abnormalities, was not performed, all evidence led to the diagnosis of atrial involvement. Electrocardiographic findings were consistent with Liu's major criterion 3. Therapy with digitalis, quinidine and angiotensin-converting enzyme inhibitors was chosen, as the patient had acute pulmonary edema. The use of beta-blockers and verapamil was restricted. No other complications, such as thrombo-embolism or atrial rupture, were noted.

Structural analysis of Turtle mountain (Alberta) using digital elevation model: Toward a progressive failure

In 1903, the eastern slope of Turtle Mountain (Alberta) was affected by a 30 M m3-rockslide named Frank Slide that resulted in more than 70 casualties. Assuming that the main discontinuity sets, including bedding, control part of the slope morphology, the structural features of Turtle Mountain were investigated using a digital elevation model (DEM). Using new landscape analysis techniques, we have identified three main joint and fault sets. These results are in agreement with those sets identified through field observations. Landscape analysis techniques, using a DEM, confirm and refine the most recent geology model of the Frank Slide. The rockslide was initiated along bedding and a fault at the base of the slope and propagated up slope by a regressive process following a surface composed of pre-existing discontinuities. The DEM analysis also permits the identification of important geological structures along the 1903 slide scar. Based on the so called Sloping Local Base Level (SLBL) an estimation was made of the present unstable volumes in the main scar delimited by the cracks, and around the south area of the scar (South Peak). The SLBL is a method permitting a geometric interpretation of the failure surface based on a DEM. Finally we propose a failure mechanism permitting the progressive failure of the rock mass that considers gentle dipping wedges (30°). The prisms or wedges defined by two discontinuity sets permit the creation of a failure surface by progressive failure. Such structures are more commonly observed in recent rockslides. This method is efficient and is recommended as a preliminary analysis prior to field investigation.

Combined clonotyping and gene signatures of individual tumor-reactive CD8 T-cells define their functional relevance following peptide vaccination in melanoma patients

Novel cancer vaccines are capableto efficiently induce and boost humantumor antigen specific T-cells. However,the properties of these CD8T-cells are only partially characterized.For in depth investigation ofT-cells following Melan-A/MART-1peptide vaccination in melanoma patients,we conducted a detailed prospectivestudy at the single cell level.We first sorted individual human naiveand effector CD8 T-cells from peripheralblood by flow cytometry, andtested a modified RT-PCR protocolincluding a global amplification ofexpressed mRNAs to obtain sufficientcDNAfromsingle cells.We successfullydetected the expression ofseveral specific genes of interest evendown to 106-fold dilution (equivalentto 10-5 cell). We then analyzed tumor-specific effector memory (EM)CD8T-cell subpopulations ex vivo, assingle cells from vaccinated melanomapatients. To elucidate the hallmarksof effective immunity the genesignatures were defined by a panel ofgenes related to effector functions(e.g. IFN-, granzyme B, perforin),and individual clonotypes were identifiedaccording to the expression ofdistinct T-cell receptors (TCR). Usingthis novel single cell analysis approach,we observed that T-cell differentiationis clonotype dependent,with a progressive restriction in TCRBV clonotype diversity from EMCD28pos to EMCD28neg subsets. However,the effector function gene imprintingis clonotype-independent,but dependent on differentiation,since it correlates with the subset oforigin (EMCD28pos or EMCD28neg). We also conducted a detailedcomparative analysis after vaccinationwith natural vs. analog Melan-Apeptide. We found that the peptideused for vaccination determines thefunctional outcome of individualT-cell clonotypes, with native peptideinducing more potent effector functions.Yet, selective clonotypic expansionwith differentiation was preservedregardless of the peptide usedfor vaccination. In summary, the exvivo single cell RT-PCR approach ishighly sensitive and efficient, andrepresents a reliable and powerfultool to refine our current view of molecularprocesses taking place duringT-cell differentiation.

Comparison of time-lapse GPR data collected under natural and forced infiltration conditions to estimate vadose zone hydraulic parameters

Time-lapse crosshole ground-penetrating radar (GPR) data, collected while infiltration occurs, can provide valuable information regarding the hydraulic properties of the unsaturated zone. In particular, the stochastic inversion of such data provides estimates of parameter uncertainties, which are necessary for hydrological prediction and decision making. Here, we investigate the effect of different infiltration conditions on the stochastic inversion of time-lapse, zero-offset-profile, GPR data. Inversions are performed using a Bayesian Markov-chain-Monte-Carlo methodology. Our results clearly indicate that considering data collected during a forced infiltration test helps to better refine soil hydraulic properties compared to data collected under natural infiltration conditions

Modularity of the Consani-Scholten quintic

We prove that the Consani-Scholten quintic, a Calabi-Yau threefold over Q, is Hilbert modular. For this, we refine several techniques known from the context of modular forms. Most notably, we extend the Faltings-Serre-Livn´e method to induced four-dimensional Galois representations over Q. We also need a Sturm bound for Hilbert modular forms; this is developed in an appendix by José Burgos Gil and the second author.

Geodynamic reconstructions of the South America-Antarctica plate system

The South America-Antarctica plate system shows many oceanic accretionary systems and subduction zones that initiated and then stopped. To better apprehend the evolution of the system, geodynamic reconstructions (global) have been created from Jurassic (165 Ma) to present, following the techniques used at the University of Lausanne. However, additional synthetic magnetic anomalies were used to refine the geodynamics between 33 Ma and present. The reconstructions show the break up of Gondwana with oceanisation between South America (SAM) and Antarctica (ANT), together with the break off of `Andean' geodynamical units (GDUs). We propose that oceanisation occurs also east and south of the Scotian GDUs. Andean GDUs collide with other GDUs crossing the Pacific. The west coast of SAM and ANT undergo a subsequent collision with all those GDUs between 103 Ma and 84 Ma, and the Antarctic Peninsula also collides with Tierra del Fuego. The SAM-ANT plate boundary experienced a series of extension and shortening with large strike-slip component, culminating with intra-oceanic subduction leading to the presence of the `V-' and anomalies in the Weddell Sea. From 84 Ma, a transpressive collision takes place in the Scotia region, with active margin to the east. As subduction propagates northwards into an old and dense oceanic crust, slab roll-back initiates, giving rise to the western Scotia Sea and the Powell Basin opening. The Drake Passage opens. As the Scotian GDUs migrate eastwards, there is enough space for them to spread and allow a north-south divergence with a spreading axis acting simultaneously with the western Scotia ridge. Discovery Bank stops the migration of South Orkney and `collides with' the SAM-ANT spreading axis, while the northern Scotian GDUs are blocked against the Falkland Plateau and the North-East Georgia Rise. The western and central Scotia and the Powell Basin spreading axes must cease, and the ridge jumps to create the South Sandwich Islands Sea. The Tierra del Fuego-Patagonia region has always experienced mid-oceanic ridge subduction since 84 Ma. Slab window location is also presented (57-0 Ma), because of its important implication for heat flux and magmatism. (C) 2011 Elsevier Ltd. All rights reserved.

Three-dimensional models of 14α-sterol demethylase (Cyp51A) from Aspergillus lentulus and Aspergillus fumigatus: an insight into differences in voriconazole interaction.

Aspergillus lentulus, an Aspergillus fumigatus sibling species, is increasingly reported in corticosteroid-treated patients. Its clinical significance is unknown, but the fact that A. lentulus shows reduced antifungal susceptibility, mainly to voriconazole, is of serious concern. Heterologous expression of cyp51A from A. fumigatus and A. lentulus was performed in Saccharomyces cerevisiae to assess differences in the interaction of Cyp51A with the azole drugs. The absence of endogenous ERG11 was efficiently complemented in S. cerevisiae by the expression of either Aspergillus cyp51A allele. There was a marked difference between azole minimum inhibitory concentration (MIC) values of the clones expressing each Aspergillus spp. cyp51A. Saccharomyces cerevisiae clones expressing A. lentulus alleles showed higher MICs to all of the azoles tested, supporting the hypothesis that the intrinsic azole resistance of A. lentulus could be associated with Cyp51A. Homology models of A. fumigatus and A. lentulus Cyp51A protein based on the crystal structure of Cyp51p from Mycobacterium tuberculosis in complex with fluconazole were almost identical owing to their mutual high sequence identity. Molecular dynamics (MD) was applied to both three-dimensional protein models to refine the homology modelling and to explore possible differences in the Cyp51A-voriconazole interaction. After 20ns of MD modelling, some critical differences were observed in the putative closed form adopted by the protein upon voriconazole binding. A closer study of the A. fumigatus and A. lentulus voriconazole putative binding site in Cyp51A suggested that some major differences in the protein's BC loop could differentially affect the lock-up of voriconazole, which in turn could correlate with their different azole susceptibility profiles.

Dormant and self-renewing hematopoietic stem cells and their niches.

In the mouse, over the last 20 years, a set of cell-surface markers and activities have been identified, enabling the isolation of bone marrow (BM) populations highly enriched in hematopoietic stem cells (HSCs). These HSCs have the ability to generate multiple lineages and are capable of long-term self-renewal activity such that they are able to reconstitute and maintain a functional hematopoietic system after transplantation into lethally irradiated recipients. Using single-cell reconstitution assays, various marker combinations can be used to achieve a functional HSC purity of almost 50%. Here we have used the differential expression of six of these markers (Sca1, c-Kit, CD135, CD48, CD150, and CD34) on lineage-depleted BM to refine cell hierarchies within the HSC population. At the top of the hierarchy, we propose a dormant HSC population (Lin(-)Sca1(+)c-Kit(+) CD48(-)CD150(+)CD34(-)) that gives rise to an active self-renewing CD34(+) HSC population. HSC dormancy, as well as the balance between self-renewal and differentiation activity, is at least, in part, controlled by the stem cell niches individual HSCs are attached to. Here we review the current knowledge about HSC niches and propose that dormant HSCs are located in niches at the endosteum, whereas activated HSCs are in close contact to sinusoids of the BM microvasculature.

Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation.

BACKGROUND: Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling. METHODS: The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score <or=123 on the MDRS. RESULTS: Both logistic and survival models confirmed that in addition to age and education level, premutation size plays a significant (p<0.01 and p<0.03 for logistic and survival model, respectively) role in cognitive impairment. The estimated penetrance of marked cognitive impairment in our sample (adjusted for the mean age 63.4 years and mean education level 9.7 years) for midsize/large (70-200 CGG) and small (55-69 CGG) premutation alleles was 33.3% (relative risk (RR) 6.5; p = 0.01) and 5.9% (RR 1.15; p = 0.9) respectively. Penetrance in the control group was 5.1%. CONCLUSIONS: Male carriers of midsize to large premutation alleles had a sixfold increased risk of developing cognitive decline and the risk increases with allele size. In addition, it was observed that cognitive impairment may precede motor symptoms. These data provide guidance for genetic counselling although larger samples are required to refine these estimates.

A methodology to event reconstruction from trace images

The widespread use of digital imaging devices for surveillance (CCTV) and entertainment (e.g., mobile phones, compact cameras) has increased the number of images recorded and opportunities to consider the images as traces or documentation of criminal activity. The forensic science literature focuses almost exclusively on technical issues and evidence assessment [1]. Earlier steps in the investigation phase have been neglected and must be considered. This article is the first comprehensive description of a methodology to event reconstruction using images. This formal methodology was conceptualised from practical experiences and applied to different contexts and case studies to test and refine it. Based on this practical analysis, we propose a systematic approach that includes a preliminary analysis followed by four main steps. These steps form a sequence for which the results from each step rely on the previous step. However, the methodology is not linear, but it is a cyclic, iterative progression for obtaining knowledge about an event. The preliminary analysis is a pre-evaluation phase, wherein potential relevance of images is assessed. In the first step, images are detected and collected as pertinent trace material; the second step involves organising and assessing their quality and informative potential. The third step includes reconstruction using clues about space, time and actions. Finally, in the fourth step, the images are evaluated and selected as evidence. These steps are described and illustrated using practical examples. The paper outlines how images elicit information about persons, objects, space, time and actions throughout the investigation process to reconstruct an event step by step. We emphasise the hypothetico-deductive reasoning framework, which demonstrates the contribution of images to generating, refining or eliminating propositions or hypotheses. This methodology provides a sound basis for extending image use as evidence and, more generally, as clues in investigation and crime reconstruction processes.

Nineteen additional unpredicted transcripts from human chromosome 21.

The identification of all human chromosome 21 (HC21) genes is a necessary step in understanding the molecular pathogenesis of trisomy 21 (Down syndrome). The first analysis of the sequence of 21q included 127 previously characterized genes and predicted an additional 98 novel anonymous genes. Recently we evaluated the quality of this annotation by characterizing a set of HC21 open reading frames (C21orfs) identified by mapping spliced expressed sequence tags (ESTs) and predicted genes (PREDs), identified only in silico. This study underscored the limitations of in silico-only gene prediction, as many PREDs were incorrectly predicted. To refine the HC21 annotation, we have developed a reliable algorithm to extract and stringently map sequences that contain bona fide 3' transcript ends to the genome. We then created a specific 21q graphical display allowing an integrated view of the data that incorporates new ESTs as well as features such as CpG islands, repeats, and gene predictions. Using these tools we identified 27 new putative genes. To validate these, we sequenced previously cloned cDNAs and carried out RT-PCR, 5'- and 3'-RACE procedures, and comparative mapping. These approaches substantiated 19 new transcripts, thus increasing the HC21 gene count by 9.5%. These transcripts were likely not previously identified because they are small and encode small proteins. We also identified four transcriptional units that are spliced but contain no obvious open reading frame. The HC21 data presented here further emphasize that current gene prediction algorithms miss a substantial number of transcripts that nevertheless can be identified using a combination of experimental approaches and multiple refined algorithms.

Cutting artefacts and cutting process in vitreous sections for cryo-electron microscopy.

Cryo-electron microscopy of vitreous sections (CEMOVIS) has recently been shown to provide images of biological specimens with unprecedented quality and resolution. Cutting the sections remains however the major difficulty. Here, we examine the parameters influencing the quality of the sections and analyse the resulting artefacts. They are in particular: knife marks, compression, crevasses, and chatter. We propose a model taking into account the interplay between viscous flow and fracture. We confirm that crevasses are formed on only one side of the section, and define conditions by which they can be avoided. Chatter is an effect of irregular compression due to friction of the section of the knife edge and conditions to prevent this are also explored. In absence of crevasses and chatter, the bulk of the section is compressed approximately homogeneously. Within this approximation, it is possible to correct for compression by a simple linear transformation for the bulk of the section. A research program is proposed to test and refine our understanding of the sectioning process.

Hospital Universitari Vall d'Hebron. Institut de Recerca

En los transplantes de progenitores hematopoyéticos, la sangre de cordón umbilical es una fuente establecida de células madre hematopoyéticas que presenta como mayor ventaja una menor incidencia de enfermedades de injerto contra el huésped. Sin embargo, el bajo número de células madre obtenidas de una sola unidad limita su utilización a un número reducido de pacientes. Las células madre hematopoyéticas se definen por su capacidad de automantenimiento y reconstitución de todo el sistema hematopoyético de un huésped trasplantado. En ratón, la combinación de los marcadores de superficie Lin- LSK junto con los marcadores de la familia SLAM, ha permitido establecer una jerarquía en las poblaciones de células madre y progenitores hematopoyéticos. Sin embargo, la población de células madre hematopoyéticas humanas CD34+CD38- es heterogénea y las subpoblaciones de progenitores y células madre no están bien establecidas. Uno de los objetivos de este trabajo es determinar si los marcadores de la familia SLAM podrían redefinir la población de células madre hematopoyéticas humanas CD34+CD38- de forma similar a lo sucedido en ratón. En este trabajo se describe una nueva población de progenitores hematopoyéticos en sangre de cordón umbilical caracterizada por el fenotipo CD34+CD38-CD150+CD135-. Lon ensayos realizados tanto in vitro como in vivo han demostrado que esta población esta formada por células con capacidad de autorrenovación, de diferenciación a todos los linajes hematopoyéticos, y de reconstitución a corto y largo plazo de un modelo murino inmunodeficiente irradiado. Por otro lado, con la finalidad de obtener un número suficiente de progenitores hematopoyéticos para ser trasplantados, se han estudiado diferentes sistemas de expansión in vitro. Se ha observado que el ácido valproico (un inhibidor de las histona deacetilasas) y la activación de la vía de Notch, promueven el mantenimiento y expansión de los progenitores hematopoyéticos reduciendo los procesos de diferenciación.

Perspectives for Forensic Intelligence in anti-doping: thinking outside the box

Today's approach to anti-doping is mostly centered on the judicial process, despite pursuing a further goal in the detection, reduction, solving and/or prevention of doping. Similarly to decision-making in the area of law enforcement feeding on Forensic Intelligence, anti-doping might significantly benefit from a more extensive gathering of knowledge. Forensic Intelligence might bring a broader logical dimension to the interpretation of data on doping activities for a more future-oriented and comprehensive approach instead of the traditional case-based and reactive process. Information coming from a variety of sources related to doping, whether directly or potentially, would feed an organized memory to provide real time intelligence on the size, seriousness and evolution of the phenomenon. Due to the complexity of doping, integrating analytical chemical results and longitudinal monitoring of biomarkers with physiological, epidemiological, sociological or circumstantial information might provide a logical framework enabling fit for purpose decision-making. Therefore, Anti-Doping Intelligence might prove efficient at providing a more proactive response to any potential or emerging doping phenomenon or to address existing problems with innovative actions or/and policies. This approach might prove useful to detect, neutralize, disrupt and/or prevent organized doping or the trafficking of doping agents, as well as helping to refine the targeting of athletes or teams. In addition, such an intelligence-led methodology would serve to address doping offenses in the absence of adverse analytical chemical evidence.