Foxo-mediated Bim transcription is dispensable for the apoptosis of hematopoietic cells that is mediated by this BH3-only protein

The BH3-only protein Bim is a critical initiator of apoptosis in hematopoietic cells. Bim is upregulated in response to growth factor withdrawal and in vitro studies have implicated the transcription factor Foxo3a as a critical inducer. To test the importance of this regulation in vivo, we generated mice with mutated Foxo-binding sites within the Bim promoters (Bim(ΔFoxo/ΔFoxo)). Contrary to Bim-deficient mice, Bim(ΔFoxo/ΔFoxo) mice had a normal hematopoietic system. Moreover, cytokine-dependent haematopoietic cells from Bim(ΔFoxo/ΔFoxo) and wt mice died at similar rates. These results indicate that regulation of Bim by Foxo transcription factors is not critical for the killing of hematopoietic cells.

Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation

While many anticancer therapies aim to target the death of tumor cells, sophisticated resistance mechanisms in the tumor cells prevent cell death induction. In particular enzymes of the glutathion-S-transferase (GST) family represent a well-known detoxification mechanism, which limit the effect of chemotherapeutic drugs in tumor cells. Specifically, GST of the class P1 (GSTP1-1) is overexpressed in colorectal tumor cells and renders them resistant to various drugs. Thus, GSTP1-1 has become an important therapeutic target. We have recently shown that thiazolides, a novel class of anti-infectious drugs, induce apoptosis in colorectal tumor cells in a GSTP1-1-dependent manner, thereby bypassing this GSTP1-1-mediated drug resistance. In this study we investigated in detail the underlying mechanism of thiazolide-induced apoptosis induction in colorectal tumor cells. Thiazolides induce the activation of p38 and Jun kinase, which is required for thiazolide-induced cell death. Activation of these MAP kinases results in increased expression of the pro-apoptotic Bcl-2 homologs Bim and Puma, which inducibly bind and sequester Mcl-1 and Bcl-xL leading to the induction of the mitochondrial apoptosis pathway. Of interest, while an increase in intracellular glutathione levels resulted in increased resistance to cisplatin, it sensitized colorectal tumor cells to thiazolide-induced apoptosis by promoting increased Jun kinase activation and Bim induction. Thus, thiazolides may represent an interesting novel class of anti-tumor agents by specifically targeting tumor resistance mechanisms, such as GSTP1-1.

F. Bimḳo : der Dramaturg un Reʾalisṭ

Aharon Beḳerman

BIM MEDIATES IMATINIB-INDUCED APOPTOSIS OF GASTROINTESTINAL STROMAL TUMORS: TRANSLATIONAL IMPLICATIONS

Gastrointestinal stromal tumors (GISTs) are oncogene-addicted cancers driven by activating mutations in the genes encoding receptor tyrosine kinases KIT and PDGFR-α. Imatinib mesylate, a specific inhibitor of KIT and PDGFR-α signaling, delays progression of GIST, but is incapable of achieving cure. Thus, most patients who initially respond to imatinib therapy eventually experience tumor progression, and have limited therapeutic options thereafter. To address imatinib-resistance and tumor progression, these studies sought to understand the molecular mechanisms that regulate apoptosis in GIST, and evaluate combination therapies that kill GISTs cells via complementary, but independent, mechanisms. BIM (Bcl-2 interacting mediator of apoptosis), a pro-apoptotic member of the Bcl-2 family, effects apoptosis in oncogene-addicted malignancies treated with targeted therapies, and was recently shown to mediate imatinib-induced apoptosis in GIST. This dissertation examined the molecular mechanism of BIM upregulation and its cytotoxic effect in GIST cells harboring clinically-representative KIT mutations. Additionally, imatinib-induced alterations in BIM and pro-survival Bcl-2 proteins were studied in specimens from patients with GIST, and correlated to apoptosis, FDG-PET response, and survival. Further, the intrinsic pathway of apoptosis was targeted therapeutically in GIST cells with the Bcl-2 inhibitor ABT-737. These studies show that BIM is upregulated in GIST cells and patient tumors after imatinib exposure, and correlates with induction of apoptosis, response by FDG-PET, and disease-free survival. These studies contribute to the mechanistic understanding of imatinib-induced apoptosis in clinically-relevant models of GIST, and may facilitate prediction of resistance and disease progression in patients. Further, combining inhibition of KIT and Bcl-2 induces apoptosis synergistically and overcomes imatinib-resistance in GIST cells. Given that imatinib-resistance and GIST progression may reflect inadequate BIM-mediated inhibition of pro-survival Bcl-2 proteins, the preclinical evidence presented here suggests that direct engagement of apoptosis may be an effective approach to enhance the cytotoxicity of imatinib and overcome resistance.

Reseña del libro : Memorias del BIM : Biografías. Las víctimas de la Fuerza de Tareas 5 en La Plata, Berisso y Ensenada de Ana Julia Ramírez y Margarita Merbilhaá (editoras)

Fil: Codaro, Laura. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Reseña del libro : Memorias del BIM : Biografías. Las víctimas de la Fuerza de Tareas 5 en La Plata, Berisso y Ensenada de Ana Julia Ramírez y Margarita Merbilhaá (editoras)

Fil: Codaro, Laura. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Reseña del libro : Memorias del BIM : Biografías. Las víctimas de la Fuerza de Tareas 5 en La Plata, Berisso y Ensenada de Ana Julia Ramírez y Margarita Merbilhaá (editoras)

Fil: Codaro, Laura. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Técnicas BIM aplicadas a la reconstrucción virtual del yacimiento arqueológico Mleiha 5 (E.A.U.)

El objetivo del siguiente Proyecto Fin de Carrera consiste en definir y describir de forma ordenada, clara y precisa el procedimiento a seguir en el desarrollo de un trabajo mediante técnicas BIM (Building Information Modeling - Modelado de Información de Construcción)con la finalidad añadida de que pueda servir como un protocolo general para los profesionales relacionados con el ámbito de estas materias. Este proyecto se ocupará de las siguientes tareas: 1.-Terminología, normativa, ámbitos de aplicación, metodología y flujo de trabajo empleados en la utilización de técnicas denominadas BIM. 2.- Aplicación sobre el yacimiento arqueológico Mleiha zona 5 situado en Emiratos Árabes Unidos, incluyendo la elaboración de un modelo de reconstrucción virtual de este cementerio y sus antiguos panteones. Para ello contaremos con la topografía y cartografía de la zona, en una superficie aproximada de 1 Hectárea, procedente de un levantamiento a escala 1:200 realizado en Mayo de 2013.

Aprendizaje integrado en arquitectura con modelos virtuales : implementación de metodología BIM en la docencia universitaria

Los procesos de diseño y construcción en Arquitectura han mostrado un desarrollo de optimización históricamente muy deficiente cuando se compara con las restantes actividades típicamente industriales. La aspiración constante a una industrialización efectiva, tanto en aras de alcanzar mayores cotas de calidad así como de ahorro de recursos, recibe hoy una oportunidad inmejorable desde el ámbito informático: el Building Information Modelling o BIM. Lo que en un inicio puede parecer meramente un determinado tipo de programa informático, en realidad supone un concepto de “proceso” que subvierte muchas rutinas hoy habituales en el desarrollo de proyectos y construcciones arquitectónicas. La inclusión y desarrollo de datos ligados al proyecto, desde su inicio hasta el fin de su ciclo de vida, conlleva la oportunidad de crear una realidad virtual dinámica y actualizable, que por añadidura posibilita su ensayo y optimización en todos sus aspectos: antes y durante su ejecución, así como vida útil. A ello se suma la oportunidad de transmitir eficientemente los datos completos de proyecto, sin apenas pérdidas o reelaboración, a la cadena de fabricación, lo que facilita el paso a una industrialización verdaderamente significativa en edificación. Ante una llamada mundial a la optimización de recursos y el interés indudable de aumentar beneficios económicos por medio de la reducción del factor de incertidumbre de los procesos, BIM supone un opción de mejora indudable, y así ha sido reconocido a través de la inminente implantación obligatoria por parte de los gobiernos (p. ej. Gran Bretaña en 2016 y España en 2018). La modificación de procesos y roles profesionales que conlleva la incorporación de BIM resulta muy significativa y marcará el ejercicio profesional de los futuros graduados en las disciplinas de Arquitectura, Ingeniería y Construcción (AEC por sus siglas en inglés). La universidad debe responder ágilmente a estas nuevas necesidades incorporando esta metodología en la enseñanza reglada y aportando una visión sinérgica que permita extraer los beneficios formativos subyacentes en el propio marco BIM. En este sentido BIM, al aglutinar el conjunto de datos sobre un único modelo virtual, ofrece un potencial singularmente interesante. La realidad tridimensional del modelo, desarrollada y actualizada continuamente, ofrece al estudiante una gestión radicalmente distinta de la representación gráfica, en la que las vistas parciales de secciones y plantas, tan complejas de asimilar en los inicios de la formación universitaria, resultan en una mera petición a posteriori, para ser extraída según necesidad del modelo virtual. El diseño se realiza siempre sobre el propio modelo único, independientemente de la vista de trabajo elegida en cada momento, permaneciendo los datos y sus relaciones constructivas siempre actualizados y plenamente coherentes. Esta descripción condensada de características de BIM preconfiguran gran parte de las beneficios formativos que ofrecen los procesos BIM, en especial, en referencia al desarrollo del diseño integrado y la gestión de la información (incluyendo TIC). Destacan a su vez las facilidades en comprensión visual de elementos arquitectónicos, sistemas técnicos, sus relaciones intrínsecas así como procesos constructivos. A ello se une el desarrollo experimental que la plataforma BIM ofrece a través de sus software colaborativos: la simulación del comportamiento estructural, energético, económico, entre otros muchos, del modelo virtual en base a los datos inherentes del proyecto. En la presente tesis se describe un estudio de conjunto para explicitar tanto las cualidades como posibles reservas en el uso de procesos BIM, en el marco de una disciplina concreta: la docencia de la Arquitectura. Para ello se ha realizado una revisión bibliográfica general sobre BIM y específica sobre docencia en Arquitectura, así como analizado las experiencias de distintos grupos de interés en el marco concreto de la enseñanza de la en Arquitectura en la Universidad Europea de Madrid. El análisis de beneficios o reservas respecto al uso de BIM se ha enfocado a través de la encuesta a estudiantes y la entrevista a profesionales AEC relacionados o no con BIM. Las conclusiones del estudio permiten sintetizar una implantación de metodología BIM que para mayor claridad y facilidad de comunicación y manejo, se ha volcado en un Marco de Implantación eminentemente gráfico. En él se orienta sobre las acciones docentes para el desarrollo de competencias concretas, valiéndose de la flexibilidad conceptual de los Planes de Estudio en el contexto del Espacio Europeo de Educación Superior (Declaración de Bolonia) para incorporar con naturalidad la nueva herramienta docente al servicio de los objetivos formativo legalmente establecidos. El enfoque global del Marco de Implementación propuesto facilita la planificación de acciones formativas con perspectiva de conjunto: combinar los formatos puntuales o vehiculares BIM, establecer sinergias transversales y armonizar recursos, de modo que la metodología pueda beneficiar tanto la asimilación de conocimientos y habilidades establecidas para el título, como el propio flujo de aprendizaje o learn flow BIM. Del mismo modo reserva, incluso visualmente, aquellas áreas de conocimiento en las que, al menos en la planificación actual, la inclusión de procesos BIM no se considera ventajosa respecto a otras metodologías, o incluso inadecuadas para los objetivos docentes establecidos. Y es esta última categorización la que caracteriza el conjunto de conclusiones de esta investigación, centrada en: 1. la incuestionable necesidad de formar en conceptos y procesos BIM desde etapas muy iniciales de la formación universitaria en Arquitectura, 2. los beneficios formativos adicionales que aporta BIM en el desarrollo de competencias muy diversas contempladas en el currículum académico y 3. la especificidad del rol profesional del arquitecto que exigirá una implantación cuidadosa y ponderada de BIM que respete las metodologías de desarrollo creativo tradicionalmente efectivas, y aporte valor en una reorientación simbiótica con el diseño paramétrico y fabricación digital que permita un diseño finalmente generativo. ABSTRACT The traditional architectural design and construction procedures have proven to be deficient where process optimization is concerned, particularly when compared to other common industrial activities. The ever‐growing strife to achieve effective industrialization, both in favor of reaching greater quality levels as well as sustainable management of resources, has a better chance today than ever through a mean out of the realm of information technology, the Building Information Modelling o BIM. What may initially seem to be merely another computer program, in reality turns out to be a “process” concept that subverts many of today’s routines in architectural design and construction. Including and working with project data from the very beginning to the end of its full life cycle allows for creating a dynamic and updatable virtual reality, enabling data testing and optimizing throughout: before and during execution, all the way to the end of its lifespan. In addition, there is an opportunity to transmit complete project data efficiently, with hardly any loss or redeveloping of the manufacture chain required, which facilitates attaining a truly significant industrialization within the construction industry. In the presence of a world‐wide call for optimizing resources, along with an undeniable interest in increasing economic benefits through reducing uncertainty factors in its processes, BIM undoubtedly offers a chance for improvement as acknowledged by its imminent and mandatory implementation on the part of governments (for example United Kingdom in 2016 and Spain in 2018). The changes involved in professional roles and procedures upon incorporating BIM are highly significant and will set the course for future graduates of Architecture, Engineering and Construction disciplines (AEC) within their professions. Higher Education must respond to such needs with swiftness by incorporating this methodology into their educational standards and providing a synergetic vision that focuses on the underlying educational benefits inherent in the BIM framework. In this respect, BIM, in gathering data set under one single virtual model, offers a uniquely interesting potential. The three‐dimensional reality of the model, under continuous development and updating, provides students with a radically different graphic environment, in which partial views of elevation, section or plan that tend characteristically to be difficult to assimilate at the beginning of their studies, become mere post hoc requests to be ordered when needed directly out the virtual model. The design is always carried out on the sole model itself, independently of the working view chosen at any particular moment, with all data and data relations within construction permanently updated and fully coherent. This condensed description of the features of BIM begin to shape an important part of the educational benefits posed by BIM processes, particularly in reference to integrated design development and information management (including ITC). At the same time, it highlights the ease with which visual understanding is achieved regarding architectural elements, technology systems, their intrinsic relationships, and construction processes. In addition to this, there is the experimental development the BIM platform grants through its collaborative software: simulation of structural, energetic, and economic behavior, among others, of the virtual model according to the data inherent to the project. This doctoral dissertation presents a broad study including a wide array of research methods and issues in order to specify both the virtues and possible reservations in the use of BIM processes within the framework of a specific discipline: teaching Architecture. To do so, a literature review on BIM has been carried out, specifically concerning teaching in the discipline of Architecture, as well as an analysis of the experience of different groups of interest delimited to Universidad Europea de Madrid. The analysis of the benefits and/or limitations of using BIM has been approached through student surveys and interviews with professionals from the AEC sector, associated or not, with BIM. Various diverse educational experiences are described and academic management for experimental implementation has been analyzed. The conclusions of this study offer a synthesis for a Framework of Implementation of BIM methodology, which in order to reach greater clarity, communication ease and user‐friendliness, have been posed in an eminently graphic manner. The proposed framework proffers guidance on teaching methods conducive to the development of specific skills, taking advantage of the conceptual flexibility of the European Higher Education Area guidelines based on competencies, which naturally facilitate for the incorporation of this new teaching tool to achieve the educational objectives established by law. The global approach of the Implementation Framework put forth in this study facilitates the planning of educational actions within a common perspective: combining exceptional or vehicular BIM formats, establishing cross‐disciplinary synergies, and sharing resources, so as to purport a methodology that contributes to the assimilation of knowledge and pre‐defined competencies within the degree program, and to the flow of learning itself. At the same time, it reserves, even visually, those areas of knowledge in which the use of BIM processes is not considered necessarily an advantage over other methodologies, or even inadequate for the learning outcomes established, at least where current planning is concerned. It is this last category which characterizes the research conclusions as a whole, centering on: 1. The unquestionable need for teaching BIM concepts and processes in Architecture very early on, in the initial stages of higher education; 2. The additional educational benefits that BIM offers in a varied array of competency development within the academic curriculum; and 3. The specific nature of the professional role of the Architect, which demands a careful and balanced implementation of BIM that respects the traditional teaching methodologies that have proven effective and creative, and adds value by a symbiotic reorientation merged with parametric design and digital manufacturing so to enable for a finally generative design.

Enseñanza de sistemas BIM en el ámbito universitario

Una de las exigencias técnicas más demandadas hoy en día dentro del ámbito edificatorio es el manejo de programas de diseño arquitectónico integrado, al convertirse en una formación indispensable frente al diseño tradicional. De este modo, la utilización de tecnologías BIM (Building Information Modeling) en el ámbito proyectual está suponiendo un impulso profesional cualitativo muy importante mediante la utilización de bases de datos específicas asociadas a dibujos convencionales desde distintas perspectivas y a todos los niveles. El objeto del presente estudio es la aplicación constructiva de esta herramienta en el ámbito docente de la Universidad de Alicante, suponiendo una oportunidad para implementar el estudio de nuevas tecnologías y conocer una interesante herramienta de trabajo implantada actualmente en muchas empresas de arquitectura y construcción. La metodología y los contenidos impartidos en el curso consideran una aplicación práctica de forma que los conocimientos adquiridos sean graduales y de aplicación sucesiva. En conclusión, el curso planteado responde a las crecientes necesidades profesionales en el ámbito constructivo con herramientas BIM y enriquece las habilidades de los estudiantes, mejorando su pericia en el ámbito del diseño y ampliando su capacidad de visión espacial; ambas cualidades indispensables en la práctica profesional arquitectónica.

The Virtual Interactive Relationship Between BIM Project Teams: Effective Communication to aid Collaboration in the Design Process

Building Information Modelling (BIM) provides a shared source of information about a built asset, which creates a collaborative virtual environment for project teams. Literature suggests that to collaborate efficiently, the relationship between the project team is based on sympathy, obligation, trust and rapport. Communication increases in importance when working collaboratively but effective communication can only be achieved when the stakeholders are willing to act, react, listen and share information. Case study research and interviews with Architecture, Engineering and Construction (AEC) industry experts suggest that synchronous face-to-face communication is project teams’ preferred method, allowing teams to socialise and build rapport, accelerating the creation of trust between the stakeholders. However, virtual unified communication platforms are a close second-preferred option for communication between the teams. Effective methods for virtual communication in professional practice, such as virtual collaboration environments (CVE), that build trust and achieve similar spontaneous responses as face-to-face communication, are necessary to face the global challenges and can be achieved with the right people, processes and technology. This research paper investigates current industry methods for virtual communication within BIM projects and explores the suitability of avatar interaction in a collaborative virtual environment as an alternative to face-to-face communication to enhance collaboration between design teams’ professional practice on a project. Hence, this paper presents comparisons between the effectiveness of these communication methods within construction design teams with results of further experiments conducted to test recommendations for more efficient methods for virtual communication to add value in the workplace between design teams.

The Big BIM battle: BIM adoption in the UK for large and small companies

As BIM adoption continues, the goal of a totally collaborative model with multiple contributors is attainable. Many initiatives such as the 2016 UK government level 2 BIM deadline are putting pressure on the construction industry to speed up the changeover. Clients and collaborators have higher expectations of using digital 3D models to communicate design ideas and solve practical problems. Contractors and clients are benefitting from cost saving scheduling and clash detection offered by BIM. Effective collaboration on the project will also give speed and efficiency gains. Despite this, many businesses of varying sizes are still having problems. The cost of the software and the training provides an obvious barrier for micro-enterprises and could explain a delay in adoption. Many studies have looked at these problems faced by SME and micro-enterprises. Larger companies have different problems. The efforts made by government to encourage them are quite comprehensive, but is anything being done to help smaller sectors and keep the industry cohesive? This limited study examines several companies of varying size and varying project type: architectural design businesses, main contractor, structural engineer and building consultancy. The study examines the barriers to a truly collaborative BIM workflow facing different specialities on a larger project and a contrasting small/medium project. The findings will establish that different barriers for each sector are actually pushing further apart, thus potentially creating a BIM-only construction elite, leaving the small companies remaining on 2D based drawing.

Architectural Technology and the BIM Acronym 3: Getting to Grips with BIM

Among Small and Medium Sized Enterprises (SMEs) in particular, the UK Government’s ambitions regarding BIM uptake and diffusion across the construction sector may be tempered by a realpolitik shaped in part by interactions between the industry, Higher Education (HE) and professional practice. That premise also has a global perspective. Building on the previous 2 papers, Architectural technology and the BIM Acronym 1 and 2, this third iteration is a synthesis of research and investigations carried out over a number of years directly related to the practical implementation of BIM and its impact upon BE SMEs. First challenges, risks and potential benefits for SMEs and micros in facing up to the necessity to engage with digital tools in a competitive and volatile marketplace are discussed including tailoring BIM to suit business models, and filtering out achievable BIM outcomes from generic and bespoke aspects of practice. Second the focus is on setting up and managing teams engaging with BIM scenarios, including the role of clients; addresses a range of paradigms including lonely BIM and collaborative working. The significance of taking a whole life view with BIM is investigated including embedding soft landings principles into project planning and realisation. Thirdly procedures for setting up and managing common data environments are identified and the value of achieving smooth information flow is addressed. The overall objective of this paper is to provide SMEs with a practical strategy to develop a toolkit to BIM implementation.

SMEs and Level 2 BIM, the Way Forward

The UK construction industry comprises a very high proportion of SMEs that is companies employing up to 250. A Department for Business, Innovation and Skills research paper, found that SMEs had a 71.2% share of work in the construction industry. Micro and small firms (i.e. those employing up to 50) had a share of 46.7% of work (Ive and Murray 2013). The Government has high ambitions for UK construction. Having been found by successive government commissioned studies to be inefficient and highly fragmented, ambitious targets have been set for the industry to achieve 33% reduction in costs and 50% faster delivery by 2025. As a significant construction client, the Government has mandated the use of Level 2 BIM from 2016 on publicly funded projects over £5 million. The adoption of BIM plays a key role in the 2025 vision but a lack of clarity persists in the industry over BIM and significant barriers are perceived to its implementation, particularly amongst SMEs. However, industry wide transformation will be challenging without serious consideration of the capabilities of this large majority. Many larger firms, having implemented Level 2 BIM are now working towards Level 3 BIM while many of the smaller firms in the industry have not even heard of BIM. It would seem that fears of a ‘two tier’ industry are perhaps being realised. This paper builds on an earlier one (Mellon & Kouider 2014) and investigates, through field work, the level of Level 2 BIM implementation amongst SMEs compared to a large organisation. Challenges and innovative solutions identified through collected data are fully discussed and compared. It is suggested that where the SME perceives barriers towards adoption of the technologies which underpin BIM, they may consider collaborative methods of working as an interim step in order to work towards realising the efficiencies and benefits that these methods can yield. While the barriers to adoption of BIM are significant, it is suggested that they are not insurmountable for the SME and some recommendations for possible solutions are made.

The Impact of BIM on the Distribution of Cost and Return on Investment in UK Construction Projects

It has been widely documented that when Building Information Modelling (BIM) is used, there is a shift in effort to the design phase. Little investigation into the impact of this shift in effort has been done and how it impacts on costs. It can be difficult to justify the increased expenditure on BIM in a market that is heavily driven by costs. There are currently studies attempting to quantify the return on investment (ROI) for BIM for which these returns can be seen to balance out the shift in efforts and costs to the design phase. The studies however quantify the ROI based on the individual stakeholder’s investment without consideration for the impact that the use of BIM from their project partners may have on their own profitability. In this study, a questionnaire investigated opinions and experience of construction professionals, representing clients, consultants, designers and contractors, to determine fluctuations in costs by their magnitude and when they occur. These factors were examined more closely by interviewing senior members representing each of the stakeholder categories and comparing their experience in using BIM within environments where their project partners were also using BIM and when they were not. This determined the differences in how the use and the investment in BIM impacts on others and how costs are redistributed. This redistribution is not just through time but also between stakeholders and categories of costs. Some of these cost fluctuations and how the cost of BIM is currently financed are also highlighted in several case studies. The results show that the current distribution of costs set for traditional 2D delivery is hindering the potential success of BIM. There is also evidence that stakeholders who don’t use BIM may benefit financially from the BIM use of others and that collaborative BIM is significantly different to the use of ‘lonely’ BIM in terms of benefits and profitability.