IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV.

CD8(+) T-cell functions are critical for preventing chronic viral infections by eliminating infected cells. For healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. These processes are regulated by factors controlling CD8(+) T-cell function, which are still incompletely understood. Here, we show that the interferon regulatory factor 4 (IRF4) and its cooperating binding partner B-cell-activating transcription factor (BATF) are necessary for sustained CD8(+) T-cell effector function. Although Irf4(-/-) CD8(+) T cells were initially capable of proliferation, IRF4 deficiency resulted in limited CD8(+) T-cell responses after infection with the lymphocytic choriomeningitis virus. Consequently, Irf4(-/-) mice established chronic infections, but were protected from fatal immunopathology. Absence of BATF also resulted in reduced CD8(+) T-cell function, limited immunopathology, and promotion of viral persistence. These data identify the transcription factors IRF4 and BATF as major regulators of antiviral cytotoxic T-cell immunity.

Estimating vadose zone hydraulic properties using ground penetrating radar: The impact of prior information

A number of geophysical methods, such as ground-penetrating radar (GPR), have the potential to provide valuable information on hydrological properties in the unsaturated zone. In particular, the stochastic inversion of such data within a coupled geophysical-hydrological framework may allow for the effective estimation of vadose zone hydraulic parameters and their corresponding uncertainties. A critical issue in stochastic inversion is choosing prior parameter probability distributions from which potential model configurations are drawn and tested against observed data. A well chosen prior should reflect as honestly as possible the initial state of knowledge regarding the parameters and be neither overly specific nor too conservative. In a Bayesian context, combining the prior with available data yields a posterior state of knowledge about the parameters, which can then be used statistically for predictions and risk assessment. Here we investigate the influence of prior information regarding the van Genuchten-Mualem (VGM) parameters, which describe vadose zone hydraulic properties, on the stochastic inversion of crosshole GPR data collected under steady state, natural-loading conditions. We do this using a Bayesian Markov chain Monte Carlo (MCMC) inversion approach, considering first noninformative uniform prior distributions and then more informative priors derived from soil property databases. For the informative priors, we further explore the effect of including information regarding parameter correlation. Analysis of both synthetic and field data indicates that the geophysical data alone contain valuable information regarding the VGM parameters. However, significantly better results are obtained when we combine these data with a realistic, informative prior.

Thermoset Composite Concrete Reinforcement, HR-325, Part 1, 1992

The feasibility of substituting fibercomposite (FC) (thermoset) pavement dowels for steel pavement dowels was investigated in this research project. Load transfer capacity, flexural capacity, and material properties were examined. The objectives of Part 1 of this final report included the shear behavior and strength deformations of FC dowel bars without aging. Part 2 will contain the aging effects. This model included the effects of modulus of elasticity for the pavement dowel and concrete, dowel diameter, subgrade stiffness, and concrete compressive strength. An experimental investigation was carried out to establish the modulus of dowel support which is an important parameter for the analysis of dowels. The experimental investigation included measured deflections, observed behavioral characteristics, and failure mode observations. An extensive study was performed on various shear testing procedures. A modified Iosipescu shear method was selected for the test procedure. Also, a special test frame was designed and fabricated for this procedure. The experimental values of modulus of support for shear and FC dowels were used for arriving at the critical stresses and deflections for the theoretical model developed. Different theoretical methods based on analyses suggested by Timoshenko, Friberg, Bradbury, and Westergaard were studied and a comprehensive theoretical model was developed. The fibercomposite dowels were found to provide strengths and behavioral characteristics that appear promising as a potential substitute for steel dowels.

Implementing statistical learning methods through Bayesian networks. Part 1: a guide to Bayesian parameter estimation using forensic science data

As a thorough aggregation of probability and graph theory, Bayesian networks currently enjoy widespread interest as a means for studying factors that affect the coherent evaluation of scientific evidence in forensic science. Paper I of this series of papers intends to contribute to the discussion of Bayesian networks as a framework that is helpful for both illustrating and implementing statistical procedures that are commonly employed for the study of uncertainties (e.g. the estimation of unknown quantities). While the respective statistical procedures are widely described in literature, the primary aim of this paper is to offer an essentially non-technical introduction on how interested readers may use these analytical approaches - with the help of Bayesian networks - for processing their own forensic science data. Attention is mainly drawn to the structure and underlying rationale of a series of basic and context-independent network fragments that users may incorporate as building blocs while constructing larger inference models. As an example of how this may be done, the proposed concepts will be used in a second paper (Part II) for specifying graphical probability networks whose purpose is to assist forensic scientists in the evaluation of scientific evidence encountered in the context of forensic document examination (i.e. results of the analysis of black toners present on printed or copied documents).

The contact region between three domains of the extracellular loop of ASIC1a is critical for channel function.

Acid-sensing ion channels are members of the epithelial Na(+) channel/degenerin family. They are neuronal nonvoltage-gated Na(+) channels that are activated by extracellular acidification. In this study, we investigated the role of a highly conserved region of the extracellular part of ASIC1a that forms the contact between the finger domain, the adjacent beta-ball, and the upper palm domain in ASIC1a. The finger domain contributes to the pH-dependent gating and is linked via this contact zone to the rest of the protein. We found that mutation to Cys of residues in this region led to decreased channel expression and current amplitudes. Exposure of the engineered Cys residues to Cd(2+) or to charged methane thiosulfonate sulfhydryl reagents further reduced current amplitudes. This current inhibition was not due to changes in acid-sensing ion channel pH dependence or unitary conductance and was likely due to a decrease of the probability of channel opening. For some mutants, the effect of sulfhydryl reagents depended on the pH of exposure in the range 7.4 to 6.8, suggesting that this zone undergoes conformational changes during inactivation. Our study identifies a region in ASIC1a whose integrity is required for normal channel function.

Trypsin cleaves acid-sensing ion channel 1a in a domain that is critical for channel gating.

Acid-sensing ion channels (ASICs) are neuronal Na(+) channels that are members of the epithelial Na(+) channel/degenerin family and are transiently activated by extracellular acidification. ASICs in the central nervous system have a modulatory role in synaptic transmission and are involved in cell injury induced by acidosis. We have recently demonstrated that ASIC function is regulated by serine proteases. We provide here evidence that this regulation of ASIC function is tightly linked to channel cleavage. Trypsin cleaves ASIC1a with a similar time course as it changes ASIC1a function, whereas ASIC1b, whose function is not modified by trypsin, is not cleaved. Trypsin cleaves ASIC1a at Arg-145, in the N-terminal part of the extracellular loop, between a highly conserved sequence and a sequence that is critical for ASIC1a inhibition by the venom of the tarantula Psalmopoeus cambridgei. This channel domain controls the inactivation kinetics and co-determines the pH dependence of ASIC gating. It undergoes a conformational change during inactivation, which renders the cleavage site inaccessible to trypsin in inactivated channels.

Structural assessment of single amino acid mutations: application to TP53 function.

Single amino acid substitution is the type of protein alteration most related to human diseases. Current studies seek primarily to distinguish neutral mutations from harmful ones. Very few methods offer an explanation of the final prediction result in terms of the probable structural or functional effect on the protein. In this study, we describe the use of three novel parameters to identify experimentally-verified critical residues of the TP53 protein (p53). The first two parameters make use of a surface clustering method to calculate the protein surface area of highly conserved regions or regions with high nonlocal atomic interaction energy (ANOLEA) score. These parameters help identify important functional regions on the surface of a protein. The last parameter involves the use of a new method for pseudobinding free-energy estimation to specifically probe the importance of residue side-chains to the stability of protein fold. A decision tree was designed to optimally combine these three parameters. The result was compared to the functional data stored in the International Agency for Research on Cancer (IARC) TP53 mutation database. The final prediction achieved a prediction accuracy of 70% and a Matthews correlation coefficient of 0.45. It also showed a high specificity of 91.8%. Mutations in the 85 correctly identified important residues represented 81.7% of the total mutations recorded in the database. In addition, the method was able to correctly assign a probable functional or structural role to the residues. Such information could be critical for the interpretation and prediction of the effect of missense mutations, as it not only provided the fundamental explanation of the observed effect, but also helped design the most appropriate laboratory experiment to verify the prediction results.

La pertinence en science forensique. Une (en)quête épistémologique et empirique

A criminal investigation requires to search and to interpret vestiges of a criminal act that happened in a past time. The forensic investigator arises in this context as a critical reader of the investigation scene, in search of physical traces that should enable her to tell a story of the offence/crime which allegedly occurred. The challenge of any investigator is to detect and recognise relevant physical traces in order to provide forensic clues for investigation and intelligence purposes. Inspired by this obser- vation, the current research focuses on the following questions : What is a relevant physical trace? And, how does the forensic investigator know she is facing one ? The interest of such questions is to provide a definition of a dimension often used in forensic science but never studied in its implications and operations. This doctoral research investigates scientific paths that are not often explored in forensic science, by using semiotic and sociological tools combined with statistical data analysis. The results are shown following a semiotic path, strongly influenced by Peir- ce's studies, and a second track, called empirical, where investigations data were analysed and forensic investigators interviewed about their work practices in the field. By the semiotic track, a macroscopic view is given of a signification process running from the discove- red physical trace at the scene to what is evaluated as being relevant for the investigator. The physical trace is perceived in the form of several signs, whose meaning is culturally codified. The reasoning should consist of three main steps : 1- What kind of source does the discovered physical trace refer to ? 2- What cause/activity is at the origin of this source in the specific context of the case ? 3- What story can be told from these observations ? The stage 3 requires to reason in creating hypotheses that should explain the presence of the discovered trace coming from an activity ; the specific activity that is related to the investigated case. To validate this assumption, it would depend on their ability to respond to a rule of relevancy. The last step is the symbolisation of the relevancy. The rule would consist of two points : the recognition of the factual/circumstantial relevancy (Is the link between the trace and the case recognised with the formulated hypothesis ? ) and appropriate relevancy (What investment is required to collect and analyse the discovered trace considering the expected outcome at the investigation/intelligence level?). This process of meaning is based on observations and a conjectural reasoning subject to many influences. In this study, relevancy in forensic science is presented as a conventional dimension that is symbolised and conditioned by the context, the forensic investigator's practice and her workplace environment (culture of the place). In short, the current research states relevancy results of the interactions between parameters from situational, structural (or organisational) and individual orders. The detection, collection and analysis of relevant physical traces at scenes depends on the knowledge and culture mastered by the forensic investigator. In the study of the relation relevant trace-forensic investigator, this research introduces the KEE model as a conceptual map that illustrates three major areas of forensic knowledge and culture acquisition, involved in the research and evaluation of the relevant physical trace. Through the analysis of the investigation data and interviews, the relationship between those three parameters and the relevancy was highlighted. K, for knowing, embodies a rela- tionship to the immediate knowledge allowing to give an overview of the reality at a specific moment ; an important point since relevancy is signified in a context. E, for education, is considered through its relationship with relevancy via a culture that tends to become institutionalised ; it represents the theoretical knowledge. As for the parameter E, for experience, it exists in its relation to relevancy in the adjustments of the strategies of intervention (i.e a practical knowledge) of each practitioner having modulated her work in the light of success and setbacks case after case. The two E parameters constitute the library resources for the semiotic recognition process and the K parameter ensures the contextualisation required to set up the reasoning and to formulate explanatory hypotheses for the discovered physical traces, questioned in their relevancy. This research demonstrates that the relevancy is not absolute. It is temporal and contextual; it is a conventional and relative dimension that must be discussed. This is where the whole issue of the meaning of what is relevant to each stakeholder of the investigation process rests. By proposing a step by step approach to the meaning process from the physical trace to the forensic clue, this study aims to provide a more advanced understanding of the reasoning and its operation, in order to streng- then forensic investigators' training. This doctoral research presents a set of tools critical to both pedagogical and practical aspects for crime scene management while identifying key-influences with individual, structural and situational dimensions. - Une enquête criminelle consiste à rechercher et à faire parler les vestiges d'un acte incriminé passé. L'investigateur forensique se pose dans ce cadre comme un lecteur critique des lieux à la recherche de traces devant lui permettre de former son récit, soit l'histoire du délit/crime censé s'être produit. Le challenge de tout investigateur est de pouvoir détecter et reconnaître les traces dites pertinentes pour fournir des indices forensiques à buts d'enquête et de renseignement. Inspirée par un tel constat, la présente recherche pose au coeur de ses réflexions les questions suivantes : Qu'est-ce qu'une trace pertinente ? Et, comment fait le forensicien pour déterminer qu'il y fait face ? L'intérêt de tels questionnements se comprend dans la volonté de définir une dimension souvent utili- sée en science forensique, mais encore jamais étudiée dans ses implications et fonctionnements. Cette recherche se lance dans des voies d'étude encore peu explorées en usant d'outils sémiotiques et des pratiques d'enquêtes sociologiques combinés à des traitements statistiques de données. Les résultats sont représentés en suivant une piste sémiotique fortement influencée par les écrits de Peirce et une seconde piste dite empirique où des données d'interventions ont été analysées et des investigateurs forensiques interviewés sur leurs pratiques de travail sur le terrain. Par la piste sémiotique, une vision macroscopique du processus de signification de la trace en élément pertinent est représentée. La trace est perçue sous la forme de plusieurs signes dont la signification est codifiée culturellement. Le raisonnement se formaliserait en trois principales étapes : 1- Quel type de source évoque la trace détectée? 2- Quelle cause/activité est à l'origine de cette source dans le contexte précis du cas ? 3- Quelle histoire peut être racontée à partir de ces observations ? Cette dernière étape consiste à raisonner en créant des hypothèses devant expliquer la présence de la trace détectée suite à une activité posée comme étant en lien avec le cas investigué. Pour valider ces hypothèses, cela dépendrait de leur capacité à répondre à une règle, celle de la pertinence. Cette dernière étape consiste en la symbolisation de la pertinence. La règle se composerait de deux points : la reconnaissance de la pertinence factuelle (le lien entre la trace et le cas est-il reconnu dans l'hypothèse fournie?) et la pertinence appropriée (quel est l'investissement à fournir dans la collecte et l'exploitation de la trace pour le bénéfice attendu au niveau de l'investigation/renseignement?). Tout ce processus de signification se base sur des observations et un raisonnement conjectural soumis à de nombreuses influences. Dans cette étude, la pertinence en science forensique se formalise sous les traits d'une dimension conventionnelle, symbolisée, conditionnée par le contexte, la pratique de l'investigateur forensique et la culture du milieu ; en somme cette recherche avance que la pertinence est le fruit d'une interaction entre des paramètres d'ordre situationnel, structurel (ou organisationnel) et individuel. Garantir la détection, la collecte et l'exploitation des traces pertinentes sur les lieux dépend de la connaissance et d'une culture maîtrisées par le forensicien. Dans l'étude du rapport trace pertinente-investigateur forensique, la présente recherche pose le modèle SFE comme une carte conceptuelle illustrant trois grands axes d'acquisition de la connaissance et de la culture forensiques intervenant dans la recherche et l'évaluation de la trace pertinente. Par l'analyse des données d'in- terventions et des entretiens, le rapport entre ces trois paramètres et la pertinence a été mis en évidence. S, pour savoir, incarne un rapport à la connaissance immédiate pour se faire une représentation d'une réalité à un instant donné, un point important pour une pertinence qui se comprend dans un contexte. F, pour formation, se conçoit dans son rapport à la pertinence via cette culture qui tend à s'institutionnaliser (soit une connaissance théorique). Quant au paramètre E, pour expérience, il se comprend dans son rapport à la pertinence dans cet ajustement des stratégies d'intervention (soit une connaissance pratique) de chaque praticien ayant modulé leur travail au regard des succès et échecs enregistrés cas après cas. F et E formeraient la bibliothèque de ressources permettant le processus de reconnaissance sémiotique et S assurerait la contextualisation nécessaire pour poser le raisonnement et formuler les hypothèses explicatives pour les traces détectées et questionnées dans leur pertinence. Ce travail démontre que la pertinence n'est pas absolue. Elle est temporelle et contextuelle, c'est une dimension conventionnelle relative et interprétée qui se doit d'être discutée. C'est là que repose toute la problématique de la signification de ce qui est pertinent pour chaque participant du processus d'investigation. En proposant une lecture par étapes du processus de signification depuis la trace à l'indice, l'étude vise à offrir une compréhension plus poussée du raisonnement et de son fonctionnement pour renforcer la formation des intervenants forensiques. Cette recherche présente ainsi un ensemble d'outils critiques à portée tant pédagogiques que pratiques pour la gestion des lieux tout en identifiant des influences-clé jouées par des dimensions individuelles, structurelles et situationnelles.

Critical Mobilities

The field of mobility studies examines social phenomena through the lens of movement. In this perspective, societies are regarded as being constantly reconfigured as they are shaped by a series of mobile entities (capital, people, information). This book engages critically with many of the claims and challenges of mobility studies by providing empirically rich reports of mobilities and their limitations. Instead of assuming a seamless world of flows, the volume foregrounds questions of power, inequality, and moorings as integral to the movement of capital, goods, images, practices, or people. It brings together the work of several internationally renowned scholars, who engage with these movements at critical sites. This is the first book to provide a critical and interdisciplinary view of mobilities covering a broad range of issues rather than a single domain. The chapters deal with current and important issues, such as organ transplants, illegal migrations, urban globalization, international policies of higher education institutions, and scientific diasporas. As a whole, the book provides new insights into how power relations shape mobilities and societies.

Critical single proximal left arterial descending coronary artery stenosis to mimic chronic myocardial ischemia: a new model induced by minimal invasive technology.

BACKGROUND/AIMS: The present report examines a new pig model for progressive induction of high-grade stenosis, for the study of chronic myocardial ischemia and the dynamics of collateral vessel growth. METHODS: Thirty-nine Landrace pigs were instrumented with a novel experimental stent (GVD stent) in the left anterior descending coronary artery. Eight animals underwent transthoracic echocardiography at rest and under low-dose dobutamine. Seven animals were examined by nuclear PET and SPECT analysis. Epi-, mid- and endocardial fibrosis and the numbers of arterial vessels were examined by histology. RESULTS: Functional analysis showed a significant decrease in global left ventricular ejection fraction (24.5 +/- 1.6%) 3 weeks after implantation. There was a trend to increased left ventricular ejection fraction after low-dose dobutamine stress (36.0 +/- 6.6%) and a significant improvement of the impaired regional anterior wall motion. PET and SPECT imaging documented chronic hibernation. Myocardial fibrosis increased significantly in the ischemic area with a gradient from epi- to endocardial. The number of arterial vessels in the ischemic area increased and coronary angiography showed abundant collateral vessels of Rentrop class 1. CONCLUSION: The presented experimental model mimics the clinical situation of chronic myocardial ischemia secondary to 1-vessel coronary disease.

Role of glutamate in neuron-glia metabolic coupling.

The coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiologic principle of brain function that has provided the basis for 2-deoxyglucose-based functional imaging with positron emission tomography. Approximately 10 y ago we provided experimental evidence that indicated a central role of glutamate signaling on astrocytes in neurometabolic coupling. The basic mechanism in neurometabolic coupling is the glutamate-stimulated aerobic glycolysis in astrocytes, such that the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na(+)-K(+) ATPase triggers glucose uptake and its glycolytic processing, which results in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fueling of the neuronal energy demands associated with synaptic transmission. Analyses of this coupling have been extended in vivo and have defined the methods of coupling for inhibitory neurotransmission as well as its spatial extent in relation to the propagation of metabolic signals within the astrocytic syncytium. On the basis of a large body of experimental evidence, we proposed an operational model, "the astrocyte-neuron lactate shuttle." A series of results obtained by independent laboratories have provided further support for this model. This body of evidence provides a molecular and cellular basis for interpreting data that are obtained with functional brain imaging studies.

A critical analysis of three psychological research programs of doping behaviour

Objectives To consider the various specific substances-taking activities in sport an examination of three psychological models of doping behaviour utilised by researchers is presented in order to evaluate their real and potential impact, and to improve the relevance and efficiency of anti-doping campaigns. Design Adopting the notion of a "research program" (Lakatos, 1978) from the philosophy of science, a range of studies into the psychology of doping behaviour are classified and critically analysed. Method Theoretical and practical parameters of three research programs are critically evaluated (i) cognitive; (ii) drive; and (iii) situated-dynamic. Results The analysis reveals the diversity of theoretical commitments of the research programs and their practical consequences. The «cognitive program» assumes that athletes are accountable for their acts that reflect the endeavour to attain sporting and non-sporting goals. Attitudes, knowledge and rational decisions are understood to be the basis of doping behaviour. The «drive program» characterises the variety of traces and consequences on psychological and somatic states coming from athlete's experience with sport. Doping behaviour here is conceived of as a solution to reduce unconscious psychological and somatic distress. The «situated-dynamic program» considers a broader context of athletes' doping activity and its evolution during a sport career. Doping is considered as emergent and self-organized behaviour, grounded on temporally critical couplings between athletes' actions and situations and the specific dynamics of their development during the sporting life course. Conclusions These hypothetical, theoretical and methodological considerations offer a more nuanced understanding of doping behaviours, making an effective contribution to anti-doping education and research by enabling researchers and policy personnel to become more critically reflective about their explicit and implicit assumptions regarding models of explanations for doping behaviour.

Chronic Diseases A Critical Issue for Iowa, June 1, 2005

The prevalence of chronic disease is shaping the health care future of Iowa and its citizens. This paper profiles chronic disease in Iowa, examines responsible yet limited initiatives to mitigate chronic disease progression and provides a series of recommended key actions to address this quiet yet dramatic public health issue.

1st Conference on Arts-Based and Artistic Research. Critical reflections on the intersection between art and research

[eng] Proceedings for the 1st Conference on Arts-Based and Artistic Research: Critical Reflections on the Intersection of Art and Research. University of Barcelona, January 31st - February 1st, 2013.