Immune Memory and Exhaustion: Clinically Relevant Lessons from the LCMV Model.

The development of dysfunctional or exhausted T cells is characteristic of immune responses to chronic viral infections and cancer. Exhausted T cells are defined by reduced effector function, sustained upregulation of multiple inhibitory receptors, an altered transcriptional program and perturbations of normal memory development and homeostasis. This review focuses on (a) illustrating milestone discoveries that led to our present understanding of T cell exhaustion, (b) summarizing recent developments in the field, and (c) identifying new challenges for translational research. Exhausted T cells are now recognized as key therapeutic targets in human infections and cancer. Much of our knowledge of the clinically relevant process of exhaustion derives from studies in the mouse model of Lymphocytic choriomeningitis virus (LCMV) infection. Studies using this model have formed the foundation for our understanding of human T cell memory and exhaustion. We will use this example to discuss recent advances in our understanding of T cell exhaustion and illustrate the value of integrated mouse and human studies and will emphasize the benefits of bi-directional mouse-to-human and human-to-mouse research approaches.

Development process and initial validation of the ethical conflict in nursing questionnaire-critical care version

Background: Ethical conflicts are arising as a result of the growing complexity of clinical care, coupled with technological advances. Most studies that have developed instruments for measuring ethical conflict base their measures on the variables"frequency" and"degree of conflict". In our view, however, these variables are insufficient for explaining the root of ethical conflicts. Consequently, the present study formulates a conceptual model that also includes the variable"exposure to conflict", as well as considering six"types of ethical conflict". An instrument was then designed to measure the ethical conflicts experienced by nurses who work with critical care patients. The paper describes the development process and validation of this instrument, the Ethical Conflict in Nursing Questionnaire Critical Care Version (ECNQ-CCV). Methods: The sample comprised 205 nursing professionals from the critical care units of two hospitals in Barcelona (Spain). The ECNQ-CCV presents 19 nursing scenarios with the potential to produce ethical conflict in the critical care setting. Exposure to ethical conflict was assessed by means of the Index of Exposure to Ethical Conflict (IEEC), a specific index developed to provide a reference value for each respondent by combining the intensity and frequency of occurrence of each scenario featured in the ECNQ-CCV. Following content validity, construct validity was assessed by means of Exploratory Factor Analysis (EFA), while Cronbach"s alpha was used to evaluate the instrument"s reliability. All analyses were performed using the statistical software PASW v19. Results: Cronbach"s alpha for the ECNQ-CCV as a whole was 0.882, which is higher than the values reported for certain other related instruments. The EFA suggested a unidimensional structure, with one component accounting for 33.41% of the explained variance. Conclusions: The ECNQ-CCV is shown to a valid and reliable instrument for use in critical care units. Its structure is such that the four variables on which our model of ethical conflict is based may be studied separately or in combination. The critical care nurses in this sample present moderate levels of exposure to ethical conflict. This study represents the first evaluation of the ECNQ-CCV.

A Model for Product Transfer Project

In this thesis a model for managing the product data in a product transfer project was created for ABB Machines. This model was then applied for the ongoing product transfer project during its planning phase. Detailed information about the demands and challenges in product transfer projects was acquired by analyzing previous product transfer projects in participating organizations. This analysis and the ABB Gate Model were then used as a base for the creation of the model for managing the product data in a product transfer project. The created model shows the main tasks during each phase in the project, their sub-tasks and relatedness on general level. Furthermore the model emphasizes need for detailed analysis of the situation during the project planning phase. The created model for managing the product data in a product transfer project was applied into ongoing project two main areas; manufacturing instructions and production item data. The results showed that the greatest challenge considering the product transfer project in previously mentioned areas is the current state of the product data. Based on the findings, process and resource proposals for both the ongoing product transfer project and the BU Machines were given. For manufacturing instructions it is necessary to create detailed process instructions in receiving organizations own language for each department so that the manufacturing instructions can be used as a training material during the training in sending organization. For production item data the English version of the bill of materials needs to be fully in English. In addition it needs to be ensured that bill of materials is updated and these changes implemented before the training in sending organization begins.

The effect of learning on the evolution of new courtship behavior: a simulation model

The fact that individuals learn can change the relationship between genotype and phenotype in the population, and thus affect the evolutionary response to selection. Here we ask how male ability to learn from female response affects the evolution of a novel male behavioral courtship trait under pre-existing female preference (sensory drive). We assume a courtship trait which has both a genetic and a learned component, and a two-level female response to males. With individual-based simulations we show that, under this scenario, learning generally increases the strength of selection on the genetic component of the courtship trait, at least when the population genetic mean is still low. As a consequence, learning not only accelerates the evolution of the courtship trait, but also enables it when the trait is costly, which in the absence of learning results in an adaptive valley. Furthermore, learning can enable the evolution of the novel trait in the face of gene flow mediated by immigration of males that show superior attractiveness to females based on another, non-heritable trait. However, rather than increasing monotonically with the speed of learning, the effect of learning on evolution is maximized at intermediate learning rates. This model shows that, at least under some scenarios, the ability to learn can drive the evolution of mating behaviors through a process equivalent to Waddington's genetic assimilation.

On the dynamics of exports and FDI: The Spanish Internationalization Process

This paper provides further insights into the dynamics of exports and outward foreign direct investment (FDI) flows in Spain from a time-series approach. The contribution of the paper is twofold: 1) the existence of either substitution or a complementary relationship between Spanish outward investments and exports is empirically tested using a multivariate cointegrated model (VECM). The evolution in exchange flows (1993-2008) and country-specific variables (such as world demand - including Spain’s main recently growing foreign markets - for trade flows and the relative price of exports in order to proxy new global competitors) are taken into account for the first time. And 2) the growth in the trade of services in recent decades leads us to test a specific causality relationship by disaggregating between goods and services flows. Our results provide evidence of a positive (Granger) causality relationship running from FDI to exports of goods (stronger) and to exports of services (weaker) in the long run, the complementarity relation of which is consistent with vertical FDI strategies. In the short run, however, only exports of goods are affected (positively) by FDIs.

A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia.

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

How to Model Heterogeneity in Costly Punishment: Insights from Responders' Response Times

We investigate what processes may underlie heterogeneity in social preferences. We address this question by examining participants' decisions and associated response times across 12 mini-ultimatum games. Using a finite mixture model and cross-validating its classification with a response time analysis, we identified four groups of responders: one group takes little to no account of the proposed split or the foregone allocation and swiftly accepts any positive offer; two groups process primarily the objective properties of the allocations (fairness and kindness) and need more time the more properties need to be examined; and a fourth group, which takes more time than the others, appears to take into account what they would have proposed had they been put in the role of the proposer. We discuss implications of this joint decision-response time analysis.

The forced adoption of a fast-track appraisal process for a breast cancer treatment in UK

Trastuzumab (Herceptin ®, Roche) is approved in UK for the treatment of the metastatic breast cancer since 2001. As of 2005, concomitantly with the publication of 3 studies that showed it produces a 50% reduction of the recurrence rates of breast cancer, trastuzumab started to be prescribed in the earlt adjuvant treatrnent of this disease. Und June 2006, trastuzumab did not have both: 1) regulatory approval and 2) NICE [National Institute for Health and Clinical Excellence] recommendation for the use in early stages of breast cancer. During the period until June 2006, the trastuzumab use in those patients was not reimbursed and because the cost of trastuzumab is equal with the yearly UK average income, most of patients could not self fund their treatrnent. Before the publication of the final NICE guidance, the new data of trastuzumab in early breast cancer raised enormous patient and professional interest and expectations. A great volume of public and professional pressure was generated to transcend a system by which Primary Care Trusts can reimburse a treatment only after a formal guidance was issued. This paper draw on a case study depicting and analyzing the process by which regulatory approval and NICE recommendations were achieved in a record time and how trastuzumab became a standard treatment on early adjuvant breast cancer. According to the data we gathered in this work we were witnessing one of the fastest processes of adoption of a health care technology since the creation of NICE, in 1999. This study addresses the following research question: How and why does the adoption pattern of trastuzumab differ from the rational decision-making model of the reimbursement process in UK? [Author, p. 4]

Fostering Collaborative Knowledge Building by the Effective Provision of Knowledge about the Discussion Process

Peer-reviewed

Model-based objects recognition in industrial environments for autonomous vehicles control

Behavior-based navigation of autonomous vehicles requires the recognition of the navigable areas and the potential obstacles. In this paper we describe a model-based objects recognition system which is part of an image interpretation system intended to assist the navigation of autonomous vehicles that operate in industrial environments. The recognition system integrates color, shape and texture information together with the location of the vanishing point. The recognition process starts from some prior scene knowledge, that is, a generic model of the expected scene and the potential objects. The recognition system constitutes an approach where different low-level vision techniques extract a multitude of image descriptors which are then analyzed using a rule-based reasoning system to interpret the image content. This system has been implemented using a rule-based cooperative expert system

Model-based objects recognition in man-made environments

We describe a model-based objects recognition system which is part of an image interpretation system intended to assist autonomous vehicles navigation. The system is intended to operate in man-made environments. Behavior-based navigation of autonomous vehicles involves the recognition of navigable areas and the potential obstacles. The recognition system integrates color, shape and texture information together with the location of the vanishing point. The recognition process starts from some prior scene knowledge, that is, a generic model of the expected scene and the potential objects. The recognition system constitutes an approach where different low-level vision techniques extract a multitude of image descriptors which are then analyzed using a rule-based reasoning system to interpret the image content. This system has been implemented using CEES, the C++ embedded expert system shell developed in the Systems Engineering and Automatic Control Laboratory (University of Girona) as a specific rule-based problem solving tool. It has been especially conceived for supporting cooperative expert systems, and uses the object oriented programming paradigm

Non-Linear Journal Bearing Model for Analysis of Superharmonic Vibrations of Rotor Systems

A rotating machine usually consists of a rotor and bearings that supports it. The nonidealities in these components may excite vibration of the rotating system. The uncontrolled vibrations may lead to excessive wearing of the components of the rotating machine or reduce the process quality. Vibrations may be harmful even when amplitudes are seemingly low, as is usually the case in superharmonic vibration that takes place below the first critical speed of the rotating machine. Superharmonic vibration is excited when the rotational velocity of the machine is a fraction of the natural frequency of the system. In such a situation, a part of the machine’s rotational energy is transformed into vibration energy. The amount of vibration energy should be minimised in the design of rotating machines. The superharmonic vibration phenomena can be studied by analysing the coupled rotor-bearing system employing a multibody simulation approach. This research is focused on the modelling of hydrodynamic journal bearings and rotorbearing systems supported by journal bearings. In particular, the non-idealities affecting the rotor-bearing system and their effect on the superharmonic vibration of the rotating system are analysed. A comparison of computationally efficient journal bearing models is carried out in order to validate one model for further development. The selected bearing model is improved in order to take the waviness of the shaft journal into account. The improved model is implemented and analyzed in a multibody simulation code. A rotor-bearing system that consists of a flexible tube roll, two journal bearings and a supporting structure is analysed employing the multibody simulation technique. The modelled non-idealities are the shell thickness variation in the tube roll and the waviness of the shaft journal in the bearing assembly. Both modelled non-idealities may cause subharmonic resonance in the system. In multibody simulation, the coupled effect of the non-idealities can be captured in the analysis. Additionally one non-ideality is presented that does not excite the vibrations itself but affects the response of the rotorbearing system, namely the waviness of the bearing bushing which is the non-rotating part of the bearing system. The modelled system is verified with measurements performed on a test rig. In the measurements the waviness of bearing bushing was not measured and therefore it’s affect on the response was not verified. In conclusion, the selected modelling approach is an appropriate method when analysing the response of the rotor-bearing system. When comparing the simulated results to the measured ones, the overall agreement between the results is concluded to be good.

Transgenic mice overexpressing neuropeptide Y: An experimental model of metabolic and cardiovascular diseases

Neuropeptide Y (NPY) is an abundant neurotransmitter in the brain and sympathetic nervous system (SNS). Hypothalamic NPY is known to be a key player in food intake and energy expenditure. NPY’s role in cardiovascular regulation has also been shown. In humans, a Leucine 7 to Proline 7 single nucleotide polymorphism (p.L7P) in the signal peptide of the NPY gene has been associated with traits of metabolic syndrome. The p.L7P subjects also show increased stress-related release of NPY, which suggests that more NPY is produced and released from SNS. The main objective of this study was to create a novel mouse model with noradrenergic cell-targeted overexpression of NPY, and to characterize the metabolic and vascular phenotype of this model. The mouse model was named OE-NPY^DBH mouse. Overexpression of NPY in SNS and brain noradrenergic neurons led to increased adiposity without significant weight gain or increased food intake. The mice showed lipid accumulation in the liver at young age, which together with adiposity led to impaired glucose tolerance and hyperinsulinemia with age. The mice displayed stress-related increased mean arterial blood pressure, increased plasma levels of catecholamines and enhanced SNS activity measured by GDP binding activity to brown adipose tissue mitochondria. Sexual dimorphism in NPY secretion pattern in response to stress was also seen. In an experimental model of vascular injury, the OE-NPY^DBH mice developed more pronounced neointima formation compared with wildtype controls. These results together with the clinical data indicate that NPY in noradrenergic cells plays an important role in the pathogenesis of metabolic syndrome and related diseases. Furthermore, new insights on the role of the extrahypothalamic NPY in the process have been obtained. The OE-NPY^DBH model provides an important tool for further stress and metabolic syndrome-related studies.

Revisió del model inclusiu en l’àmbit de l’educació no formal del futbol base a partir del criteri d’agrupació

Recerca centrada en l’anàlisi de característiques concretes de l’educació inclusiva en un entorn d’educació no formal, com és el futbol base. El criteri que s’ha utilitzat per realitzar l’anàlisi són els agrupaments. Des de l’educació inclusiva es promouen els agrupaments heterogenis, una forma d’agrupar a l’alumnat tenint en compte les seves diferències, per tal d’enriquir-se entre tot l’alumnat i treure profit d’elles. A la vegada aquest agrupament es caracteritza per fomentar la igualtat d’oportunitats en l’aprenentatge dels alumnes. En canvi, al futbol base predominen els agrupaments homogenis, distribuint als jugadors segons el seu nivell en diferents equips. A la recerca es fa una comparació entre l’opinió de diferents membres involucrats en el món del futbol base de dues entitats esportives, un club de futbol, on es fan els grups de forma homogènia, i una escola de futbol, on es fan els agrupaments de forma heterogènia. Els resultats mostren que realitzant agrupaments homogenis no s’assegura que tots els jugadors tinguin les mateixes oportunitats d’aprenentatge i que el nivell competencial dels jugadors en edat de formació pot ser un element que fomenti desigualtats en el seu procés d’aprenentatge esportiu.

Integration of a Bioethanol Process to a Pulp Mill

Tässä diplomityössä tutkittiin puuhakkeen esihydrolyysi- ja hakkuujätteen hydrolyysiprosessien integroimista sellutehtaaseen bioetanolin tuottamiseksi. Tällaisesta ns. biojalostamosta luotiin WinGEMS-simulointiohjelmalla simulointimalli, jonka avulla tutkittiin bioetanoliprosessin vaikutusta sellutehtaan massa- ja energiataseisiin sekä alustavaa biojalostamon kannattavuutta. Simuloinnissa tarkasteltiin kolmea eri tapausta, joissa mäntysellun tuotannon ajateltiin olevan 1000 tonnia päivässä ja hakkuujätettä käytettävän 10 % tarvittavan kuitupuun määrästä: 1) Puuhakkeen esihydrolyysi ja hakkuujätteen hydrolyysi etanolin tuottamiseksi 2) Puuhakkeen esihydrolyysi, hakkuujäte kuorikattilaan poltettavaksi 3) Ei esihydrolyysiä, hakkuujäte kuorikattilaan poltettavaksi Verrattuna tapaukseen 3, puun kulutus kasvaa 16 % esihydrolysoitaessa puuhake ennen keittoa tapauksissa 1 ja 2. Kasvaneella puun kulutuksella tuotetaan tapauksessa 1 149 tonnia etanolia ja 240 MWh enemmän ylimääräsähköä päivässä. Tapauksessa 2 tuotetaan 68 tonnia etanolia ja 460 MWh enemmän ylimääräsähköä päivässä. Tämä tuottaisi vuotuista lisäkassavirtaa 18,8 miljoonaa euroa tapauksessa 1 ja 9,4 miljoonaa euroa tapauksessa 2. Hydrolyysin tuoteliuoksen, hydrolysaatin, haihduttaminen sekä hydrolyysiprosessien orgaanisten jäännöstuotteiden haihduttaminen ja polttaminen kasvattavat haihduttamon ja soodakattilan kuormitusta. Verrattuna tapaukseen 3, tapauksissa 1 ja 2 haihduttamon vaiheiden määrä on kasvatettava viidestä seitsemään ja tarvittavat lämmönsiirtopinta-alat lähes kaksinkertaistettava. Soodakattilan kuormitus kasvaa 39 % tapauksessa 1 ja 26 % tapauksessa 2.