Interleukin-17A promotes parietal cell atrophy by inducing apoptosis

Background & Aims: Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin-17A (IL-17A) in causing parietal cell atrophy. Methods: A mouse model of autoimmune atrophic gastritis was used to examine IL-17A production during early and late stages of disease. Organoids derived from corpus glands were used to determine the direct effects of IL-17A on gastric epithelial cells. Immunofluorescent staining was used to examine IL-17A receptors and the direct effect of signaling on parietal cells. Mice were infected with an IL-17A-producing adenovirus to determine the effects of IL-17A on parietal cells in vivo. Finally, IL-17A neutralizing antibodies were administered to mice with active atrophic gastritis to evaluate the effects on parietal cell atrophy and metaplasia. Results: Increased IL-17A correlated with disease severity in mice with chronic atrophic gastritis. IL-17A caused caspase-dependent gastric organoid degeneration, which could not be rescued with a necroptosis inhibitor. Parietal cells expressed IL-17A receptors and IL-17A treatment induced apoptosis in parietal cells. Overexpressing IL-17A in vivo induced caspase-3 activation and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining in parietal cells. Finally, IL-17A neutralizing antibody decreased parietal cell atrophy and metaplasia in mice with chronic atrophic gastritis. Conclusions: These data identify IL-17A as a cytokine that promotes parietal cell apoptosis during atrophic gastritis, a precursor lesion for gastric cancer. Keywords: IL-17A, Atrophy, Metaplasia, Apoptosi

Software Development Process Modeling. Developers Perspective to Contemporary Modeling Techniques

Formal software development processes and well-defined development methodologies are nowadays seen as the definite way to produce high-quality software within time-limits and budgets. The variety of such high-level methodologies is huge ranging from rigorous process frameworks like CMMI and RUP to more lightweight agile methodologies. The need for managing this variety and the fact that practically every software development organization has its own unique set of development processes and methods have created a profession of software process engineers. Different kinds of informal and formal software process modeling languages are essential tools for process engineers. These are used to define processes in a way which allows easy management of processes, for example process dissemination, process tailoring and process enactment. The process modeling languages are usually used as a tool for process engineering where the main focus is on the processes themselves. This dissertation has a different emphasis. The dissertation analyses modern software development process modeling from the software developers’ point of view. The goal of the dissertation is to investigate whether the software process modeling and the software process models aid software developers in their day-to-day work and what are the main mechanisms for this. The focus of the work is on the Software Process Engineering Metamodel (SPEM) framework which is currently one of the most influential process modeling notations in software engineering. The research theme is elaborated through six scientific articles which represent the dissertation research done with process modeling during an approximately five year period. The research follows the classical engineering research discipline where the current situation is analyzed, a potentially better solution is developed and finally its implications are analyzed. The research applies a variety of different research techniques ranging from literature surveys to qualitative studies done amongst software practitioners. The key finding of the dissertation is that software process modeling notations and techniques are usually developed in process engineering terms. As a consequence the connection between the process models and actual development work is loose. In addition, the modeling standards like SPEM are partially incomplete when it comes to pragmatic process modeling needs, like light-weight modeling and combining pre-defined process components. This leads to a situation, where the full potential of process modeling techniques for aiding the daily development activities can not be achieved. Despite these difficulties the dissertation shows that it is possible to use modeling standards like SPEM to aid software developers in their work. The dissertation presents a light-weight modeling technique, which software development teams can use to quickly analyze their work practices in a more objective manner. The dissertation also shows how process modeling can be used to more easily compare different software development situations and to analyze their differences in a systematic way. Models also help to share this knowledge with others. A qualitative study done amongst Finnish software practitioners verifies the conclusions of other studies in the dissertation. Although processes and development methodologies are seen as an essential part of software development, the process modeling techniques are rarely used during the daily development work. However, the potential of these techniques intrigues the practitioners. As a conclusion the dissertation shows that process modeling techniques, most commonly used as tools for process engineers, can also be used as tools for organizing the daily software development work. This work presents theoretical solutions for bringing the process modeling closer to the ground-level software development activities. These theories are proven feasible by presenting several case studies where the modeling techniques are used e.g. to find differences in the work methods of the members of a software team and to share the process knowledge to a wider audience.Siirretty Doriast

Substrate Grain-Dependent Chemistry of Carburized Planar Anodic TiO2 on Polycrystalline Ti

open11Mixtures or composites of titania and carbon have gained considerable research interest as innovative catalyst supports for low-and intermediate-temperature proton-exchange membrane fuel cells. For applications in electro-catalysis, variations in the local physicochemical properties of the employed materials can have significant effects on their behavior as catalyst supports. To assess microscopic hetero-geneities in composition, structure, and morphology, a microscopic multitechnique approach is required. In this work, compact anodic TiO2 films on planar polycrystalline Ti substrates are converted into carbon/titania composites or multiphase titanium oxycarbides through carbothermal treatment in an acetylene/argon atmosphere in a flow reactor. The local chemical composition, structure, and morphology of the converted films are studied with scanning photoelectron microscopy, micro-Raman spectroscopy, and scanning electron microscopy and are related with the crystallographic orientations of the Ti substrate grains by means of electron backscatter diffraction. Different annealing temperatures, ranging from 550 to 850 degrees C, are found to yield different substrate grain-dependent chemical compositions, structures, and morphologies. The present study reveals individual time scales for the carbothermal conversion and subsequent surface re-oxidation on substrate grains of a given orientation. Furthermore, it demonstrates the power of a microscopic multitechnique approach for studying polycrystalline heterogeneous materials for electrocatalytic applications.openRüdiger, Celine; Favaro, Marco; Valero-Vidal, Carlos; Calvillo, Laura; Bozzolo, Nathalie; Jacomet, Suzanne; Hein, Jennifer; Gregoratti, Luca; Agnoli, Stefano; Granozzi, Gaetano; Kunze-Liebhäuser, JuliaRüdiger, Celine; Favaro, Marco; Valero Vidal, Carlos; CALVILLO LAMANA, Laura; Bozzolo, Nathalie; Jacomet, Suzanne; Hein, Jennifer; Gregoratti, Luca; Agnoli, Stefano; Granozzi, Gaetano; Kunze Liebhäuser, Juli

Practical Saccade Prediction for Head-Mounted Displays: Towards a Comprehensive Model

Eye-tracking technology is an integral component of new display devices suchas virtual and augmented reality headsets. Applications of gaze informationrange from new interaction techniques exploiting eye patterns togaze-contingent digital content creation. However, system latency is still asignificant issue in many of these applications because it breaks thesynchronization between the current and measured gaze positions. Consequently,it may lead to unwanted visual artifacts and degradation of user experience. Inthis work, we focus on foveated rendering applications where the quality of animage is reduced towards the periphery for computational savings. In foveatedrendering, the presence of latency leads to delayed updates to the renderedframe, making the quality degradation visible to the user. To address thisissue and to combat system latency, recent work proposes to use saccade landingposition prediction to extrapolate the gaze information from delayedeye-tracking samples. While the benefits of such a strategy have already beendemonstrated, the solutions range from simple and efficient ones, which makeseveral assumptions about the saccadic eye movements, to more complex andcostly ones, which use machine learning techniques. Yet, it is unclear to whatextent the prediction can benefit from accounting for additional factors. Thispaper presents a series of experiments investigating the importance ofdifferent factors for saccades prediction in common virtual and augmentedreality applications. In particular, we investigate the effects of saccadeorientation in 3D space and smooth pursuit eye-motion (SPEM) and how theirinfluence compares to the variability across users. We also present a simpleyet efficient correction method that adapts the existing saccade predictionmethods to handle these factors without performing extensive data collection.<br

A Model-Driven Approach for the Design, Implementation, and Execution of Software Development Methods

[EN] Software development projects are diverse in nature. For this reason, software companies are often forced to define their methods in-house. In order to define methods efficiently and effectively, software companies require systematic solutions that are built upon sound methodical foundations. Providing these solutions is the main goal of the Method Engineering discipline. Method Engineering is the discipline to design, construct, and adapt methods, techniques, and tools for the development of information systems. Over the last two decades, a lot of research work has been performed in this area. However, despite its potential benefits, Method Engineering is not widely used in industrial settings. Some of the causes of this reality are the high theoretical complexity of Method Engineering and the lack of adequate software support. In this thesis, we aim to mitigate some of the problems that affect Method Engineering by providing a novel methodological approach that is built upon Model-Driven Engineering (MDE) foundations. The use of MDE enables a rise in abstraction, automation, and reuse that allows us to alleviate the complexity of our Method Engineering approach. Furthermore, by leveraging MDE techniques (such as metamodeling, model transformations, and models at runtime), our approach supports three phases of the Method Engineering lifecycle: design, implementation, and execution. This is unlike traditional Method Engineering approaches, which, in general, only support one of these phases. In order to provide software support for our proposal, we developed a Computer-Aided Method Engineering (CAME) environment that is called MOSKitt4ME. To ensure that MOSKitt4ME offered the necessary functionality, we identified a set of functional requirements prior to developing the tool. Then, after these requirements were identified, we defined the architecture of our CAME environment, and, finally, we implemented the architecture in the context of Eclipse. The thesis work was evaluated by means of a study that involved the participation of end users. In this study, MOSKitt4ME was assessed by means of the Technology Acceptance Model (TAM) and the Think Aloud method. While the TAM allowed us to measure usefulness and ease of use in a subjective manner, the Think Aloud method allowed us to analyze these measures objectively. Overall, the results were favorable. MOSKitt4ME was highly rated in perceived usefulness and ease of use; we also obtained positive results with respect to the users' actual performance and the difficulty experienced.[ES] Los proyectos de desarrollo de software son diversos por naturaleza. Por este motivo, las compañías de software se ven forzadas frecuentemente a definir sus métodos de manera interna. Para poder definir métodos de forma efectiva y eficiente, las compañías necesitan soluciones sistemáticas que estén definidas sobre unos fundamentos metodológicos sólidos. Proporcionar estas soluciones es el principal objetivo de la Ingeniería de Métodos. La Ingeniería de Métodos es la disciplina que aborda el diseño, la construcción y la adaptación de métodos, técnicas y herramientas para el desarrollo de sistemas de información. Durante las dos últimas décadas, se ha llevado a cabo mucho trabajo de investigación en esta área. Sin embargo, pese a sus potenciales beneficios, la Ingeniería de Métodos no se aplica ampliamente en contextos industriales. Algunas de las principales causas de esta situación son la alta complejidad teórica de la Ingeniería de Métodos y la falta de un apropiado soporte software. En esta tesis, pretendemos mitigar algunos de los problemas que afectan a la Ingeniería de Métodos proporcionando una propuesta metodológica innovadora que está basada en la Ingeniería Dirigida por Modelos (MDE). El uso de MDE permite elevar el nivel de abstracción, automatización y reuso, lo que posibilita una reducción de la complejidad de nuestra propuesta. Además, aprovechando técnicas de MDE (como por ejemplo el metamodelado, las transformaciones de modelos y los modelos en tiempo de ejecución), nuestra aproximación da soporte a tres fases del ciclo de vida de la Ingeniería de Métodos: diseño, implementación y ejecución. Esto es a diferencia de las propuestas existentes, las cuales, por lo general, sólo dan soporte a una de estas fases. Con el objetivo de proporcionar soporte software para nuestra propuesta, implementamos una herramienta CAME (Computer-Aided Method Engineering) llamada MOSKitt4ME. Para garantizar que MOSKitt4ME proporcionaba la funcionalidad necesaria, definimos un conjunto de requisitos funcionales como paso previo al desarrollo de la herramienta. Tras la definción de estos requisitos, definimos la arquitectura de la herramienta CAME y, finalmente, implementamos la arquitectura en el contexto de Eclipse. El trabajo desarrollado en esta tesis se evaluó por medio de un estudio donde participaron usuarios finales. En este estudio, MOSKitt4ME se evaluó por medio del Technology Acceptance Model (TAM) y del método Think Aloud. Mientras que el TAM permitió medir utilidad y facilidad de uso de forma subjetiva, el método Think Aloud permitió analizar estas medidas objetivamente. En general, los resultados obtenidos fueron favorables. MOSKitt4ME fue valorado de forma positiva en cuanto a utilidad y facilidad de uso percibida; además, obtuvimos resultados positivos en cuanto al rendimiento objetivo de los usuarios y la dificultad experimentada.[CA] Els projectes de desenvolupament de programari són diversos per naturalesa. Per aquest motiu, les companyies es veuen forçades freqüenment a definir els seus mètodes de manera interna. Per poder definir mètodes de forma efectiva i eficient, les companyies necessiten solucions sistemàtiques que estiguin definides sobre uns fundaments metodològics sòlids. Proporcionar aquestes solucions és el principal objectiu de l'Enginyeria de Mètodes. L'Enginyeria de Mètodes és la disciplina que aborda el diseny, la construcció i l'adaptació de mètodes, tècniques i eines per al desenvolupament de sistemes d'informació. Durant les dues últimes dècades, s'ha dut a terme molt de treball de recerca en aquesta àrea. No obstant, malgrat els seus potencials beneficis, l'Enginyeria de Mètodes no s'aplica àmpliament en contextes industrials. Algunes de les principals causes d'aquesta situació són l'alta complexitat teòrica de l'Enginyeria de Mètodes i la falta d'un apropiat suport de programari. En aquesta tesi, pretenem mitigar alguns dels problemes que afecten a l'Enginyeria de Mètodes proporcionant una proposta metodològica innovadora que està basada en l'Enginyeria Dirigida per Models (MDE). L'ús de MDE ens permet elevar el nivell d'abstracció, automatització i reutilització, possibilitant una reducció de la complexitat de la nostra proposta. A més a més, aprofitant tècniques de MDE (com per exemple el metamodelat, les transformacions de models i els models en temps d'execució), la nostra aproximació suporta tres fases del cicle de vida de l'Enginyeria de Mètodes: diseny, implementació i execució. Açò és a diferència de les propostes existents, les quals, en general, només suporten una d'aquestes fases. Amb l'objectiu de proporcionar suport de programari per a la nostra proposta, implementàrem una eina CAME (Computer-Aided Method Engineering) anomenada MOSKitt4ME. Per garantir que MOSKitt4ME oferia la funcionalitat necessària, definírem un conjunt de requisits funcionals com a pas previ al desenvolupament de l'eina. Després de la definició d'aquests requisits, definírem la arquitectura de l'eina CAME i, finalment, implementàrem l'arquitectura en el contexte d'Eclipse. El treball desenvolupat en aquesta tesi es va avaluar per mitjà d'un estudi on van participar usuaris finals. En aquest estudi, MOSKitt4ME es va avaluar per mitjà del Technology Acceptance Model (TAM) i el mètode Think Aloud. Mentre que el TAM va permetre mesurar utilitat i facilitat d'ús de manera subjectiva, el mètode Think Aloud va permetre analitzar aquestes mesures objectivament. En general, els resultats obtinguts van ser favorables. MOSKitt4ME va ser valorat de forma positiva pel que fa a utilitat i facilitat d'ús percebuda; a més a més, vam obtenir resultats positius pel que fa al rendiment objectiu dels usuaris i a la dificultat experimentada.Cervera Úbeda, M. (2015). A Model-Driven Approach for the Design, Implementation, and Execution of Software Development Methods [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/53931TESI

Learners\u27 Motivational Response to the Science, PE, & Me! Curriculum: A Situational Interest Perspective

Background: The Science, PE, & Me! (SPEM) curriculum is a concept-based physical education curriculum that offers students coherent educational experiences for constructing health-related fitness knowledge through movement experiences. The purpose of this study was to evaluate students’ motivational response to the SPEM curriculum from the situational interest perspective. Methods: The study used a cluster randomized controlled design in which 30 elementary schools in one of the largest metropolitan areas in the eastern United States were randomly assigned to an experimental or comparison condition. Although all students in the 3rd, 4th, and 5th grades in the targeted schools were eligible to participate in the study, a random sample of students from the experimental (n = 1749; 15 schools) and comparison groups (n = 1985; 15 schools) provided data. Students’ motivational response to the SPEM curriculum or comparison curriculum was measured using the previously validated Situational Interest Scale Elementary. Data were analyzed using structural mean modeling. Results: The results demonstrated that the experimental group (as reference group) showed significantly higher enjoyment (z = 2.01), challenge (z = 6.54), exploration (z = 12.195), novelty (z = 8.80), and attention demand (z = 7.90) than the comparison group. Conclusion: The findings indicate that the SPEM curriculum created a more situationally interesting context for learning than the comparison physical education curriculum

SPEM 2.0 extension for pervasive information systems

Pervasive computing is a research field of computing technology that aims to achieve a new computing paradigm. In this paradigm, the physical environment has a high degree of pervasiveness and availability of computers and other information technology (IT) devices, usually with communication capabilities. Pervasive Information Systems (PIS), composed by these kinds of devices, bring issues that challenge software development for them. Model-Driven Development (MDD), strongly focusing and relying on models, has the potential to allow: the use of concepts closer to the domain and the reduction of semantic gaps; higher automation and lower dependency to technological changes; higher capture of expert knowledge and reuse; an overall increased productivity. Along with the focus and use of models, software development processes are fundamental to efficient development efforts of successful software systems. For the description of processes, Software & Systems Process Engineering Meta-Model Specification (SPEM) is the current standard specification published by the Object Management Group (OMG). This paper presents an extension to SPEM (version 2.0) Base Plug-In Profile that includes stereotypes needed to support a suitable structural process organization for MDD approaches aiming to develop software for PIS. A case study is provided to evaluate the applicability of the extension

Transcriptional Regulation of the Endoplasmic Reticulum in Dedicated Secretory Cells

Differentiating cells express subsets of genes to build the cellular machinery necessary to perform their specific function as they acquire their mature fate. These subsets of genes are regulated by networks of transcription factors as cells progress through their developmental program. In secretory tissue, highly-specialized cells establish a complex secretory apparatus and scale up their cellular architecture to facilitate the production and secretion of large amounts of protein. Here, we identify a network of transcription factors responsible for the development of this cellular machinery in these professional secretory cells, and develop new tools to better study the molecular networks that control the differentiation of secretory cell lineages. We present that the expression of Xbp1, a transcription factor responsible for establishing and maintaining the ER in gastric zymogenic (chief) cells (ZCs), is enhanced by HNF4α. HNF4α directly binds the Xbp1 promoter and is sufficient to enhance its expression in gastric epithelial cells. We observe that loss of HNF4α disrupts normal differentiation in the gastric epithelium, and causes morphological changes similar to the loss of XBP1, suggesting it acts through Xbp1 to maintain homeostasis in the mouse stomach. To facilitate the characterization of the molecular underpinnings of ZC differentiation, we sought to develop a technique to isolate pure ZC populations from the gastric mucosa. Using a microarray-based screen, we identified ANPEP as a surface marker of mature ZCs that enabled us to sort homogenous ZC populations using flow cytometry. We found that ANPEP is rapidly lost as ZCs dedifferentiate in response to damage or disease in both mouse and human models, and our improved method allowed us to use flow cytometry to quantify these molecular changes to the ZC surface. While we found that HNF4α is required for maintenance of the gastric epithelium, it has already been well-established that HNF4α plays a critical role in pancreatic beta-cell function. Mutations in HNF4α cause a prevalent subset of inheritable diabetes, MODYI. However, the mechanism through which mutated HNF4α causes beta-cell dysfunction has not yet been established. Our data shows that HNF4α is required for expression of both Xbp1, and downstream targets of Xbp1, and that loss of HNF4α leads to diminished ER morphology in mouse beta-cells. We show data suggesting that the loss of glucose-stimulated insulin secretion in MODYI may be due to impaired calcium signaling from the ER, and that restoring Xbp1 expression is sufficient to rescue insulin secretion in HNF4α-null beta-cells. Taken together, the data presented below characterizes an important new transcriptional relationship in both the stomach and endocrine pancreas, and establishes new tools for the study of secretory cells. These results illustrate how the study of a basic transcriptional relationship can have broad implications in the development and treatment of prevalent human diseases

Eye velocity gain fields for visuo- motor coordinate transformations

’Gain-field-like’ tuning behavior is characterized by a modulation of the neuronal response depending on a certain variable, without changing the actual receptive field characteristics in relation to another variable. Eye position gain fields were first observed in area 7a of the posterior parietal cortex (PPC), where visually responsive neurons are modulated by ocular position. Analysis of artificial neural networks has shown that this type of tuning function might comprise the neuronal substrate for coordinate transformations. In this work, neuronal activity in the dorsal medial superior temporal area (MSTd) has been analyzed with an focus on it’s involvement in oculomotor control. MSTd is part of the extrastriate visual cortex and located in the PPC. Lesion studies suggested a participation of this cortical area in the control of eye movements. Inactivation of MSTd severely impairs the optokinetic response (OKR), which is an reflex-like kind of eye movement that compensates for motion of the whole visual scene. Using a novel, information-theory based approach for neuronal data analysis, we were able to identify those visual and eye movement related signals which were most correlated to the mean rate of spiking activity in MSTd neurons during optokinetic stimulation. In a majority of neurons firing rate was non-linearly related to a combination of retinal image velocity and eye velocity. The observed neuronal latency relative to these signals is in line with a system-level model of OKR, where an efference copy of the motor command signal is used to generate an internal estimate of the head-centered stimulus velocity signal. Tuning functions were obtained by using a probabilistic approach. In most MSTd neurons these functions exhibited gain-field-like shapes, with eye velocity modulating the visual response in a multiplicative manner. Population analysis revealed a large diversity of tuning forms including asymmetric and non-separable functions. The distribution of gain fields was almost identical to the predictions from a neural network model trained to perform the summation of image and eye velocity. These findings therefore strongly support the hypothesis of MSTd’s participation in the OKR control system by implementing the transformation from retinal image velocity to an estimate of stimulus velocity. In this sense, eye velocity gain fields constitute an intermediate step in transforming the eye-centered to a head-centered visual motion signal.Another aspect that was addressed in this work was the comparison of the irregularity of MSTd spiking activity during optokinetic response with the behavior during pure visual stimulation. The goal of this study was an evaluation of potential neuronal mechanisms underlying the observed gain field behavior. We found that both inter- and intra-trial variability were decreased with increasing retinal image velocity, but increased with eye velocity. This observation argues against a symmetrical integration of driving and modulating inputs. Instead, we propose an architecture where multiplicative gain modulation is achieved by simultaneous increase of excitatory and inhibitory background synaptic input. A conductance-based single-compartment model neuron was able to reproduce realistic gain modulation and the observed stimulus-dependence of neural variability, at the same time. In summary, this work leads to improved knowledge about MSTd’s role in visuomotor transformation by analyzing various functional and mechanistic aspects of eye velocity gain fields on a systems-, network-, and neuronal level