Computational Modeling of Macrophage Iron Sequestration during Host Defense against Aspergillus.

Iron is essential to the virulence of Aspergillus species, and restricting iron availability is a critical mechanism of antimicrobial host defense. Macrophages recruited to the site of infection are at the crux of this process, employing multiple intersecting mechanisms to orchestrate iron sequestration from pathogens. To gain an integrated understanding of how this is achieved in aspergillosis, we generated a transcriptomic time series of the response of human monocyte-derived macrophages to Aspergillus and used this and the available literature to construct a mechanistic computational model of iron handling of macrophages during this infection. We found an overwhelming macrophage response beginning 2 to 4 h after exposure to the fungus, which included upregulated transcription of iron import proteins transferrin receptor-1, divalent metal transporter-1, and ZIP family transporters, and downregulated transcription of the iron exporter ferroportin. The computational model, based on a discrete dynamical systems framework, consisted of 21 3-state nodes, and was validated with additional experimental data that were not used in model generation. The model accurately captures the steady state and the trajectories of most of the quantitatively measured nodes. In the experimental data, we surprisingly found that transferrin receptor-1 upregulation preceded the induction of inflammatory cytokines, a feature that deviated from model predictions. Model simulations suggested that direct induction of transferrin receptor-1 (TfR1) after fungal recognition, independent of the iron regulatory protein-labile iron pool (IRP-LIP) system, explains this finding. We anticipate that this model will contribute to a quantitative understanding of iron regulation as a fundamental host defense mechanism during aspergillosis. IMPORTANCE Invasive pulmonary aspergillosis is a major cause of death among immunosuppressed individuals despite the best available therapy. Depriving the pathogen of iron is an essential component of host defense in this infection, but the mechanisms by which the host achieves this are complex. To understand how recruited macrophages mediate iron deprivation during the infection, we developed and validated a mechanistic computational model that integrates the available information in the field. The insights provided by this approach can help in designing iron modulation therapies as anti-fungal treatments.

Cross-Platform Ubiquitous Volume Rendering Using Programmable Shaders in VTK for Scientific and Medical Visualization.

The visualization toolkit (VTK) is a popular cross-platform, open source toolkit for scientific and medical data visualization, processing, and analysis. It supports a wide variety of data formats, algorithms, and rendering techniques for both polygonal and volumetric data. In particular, VTK's volume rendering module has long provided a comprehensive set of features such as plane clipping, color and opacity transfer functions, lighting, and other controls needed for visualization. However, due to VTK's legacy OpenGL backend and its reliance on a deprecated API, the system did not take advantage of the latest improvements in graphics hardware or the flexibility of a programmable pipeline. Additionally, this dependence on an antiquated pipeline posed restrictions when running on emerging computing platforms, thereby limiting its overall applicability. In response to these shortcomings, the VTK community developed a new and improved volume rendering module, which not only provides a modern graphics processing unit-based implementation, but also augments its capabilities with new features such as fast volume clipping, gradient-magnitude-based opacity modulation, render to texture, and hardware-based volume picking.

Increasing the impact of medical image computing using community-based open-access hackathons: The NA-MIC and 3D Slicer experience.

The National Alliance for Medical Image Computing (NA-MIC) was launched in 2004 with the goal of investigating and developing an open source software infrastructure for the extraction of information and knowledge from medical images using computational methods. Several leading research and engineering groups participated in this effort that was funded by the US National Institutes of Health through a variety of infrastructure grants. This effort transformed 3D Slicer from an internal, Boston-based, academic research software application into a professionally maintained, robust, open source platform with an international leadership and developer and user communities. Critical improvements to the widely used underlying open source libraries and tools-VTK, ITK, CMake, CDash, DCMTK-were an additional consequence of this effort. This project has contributed to close to a thousand peer-reviewed publications and a growing portfolio of US and international funded efforts expanding the use of these tools in new medical computing applications every year. In this editorial, we discuss what we believe are gaps in the way medical image computing is pursued today; how a well-executed research platform can enable discovery, innovation and reproducible science ("Open Science"); and how our quest to build such a software platform has evolved into a productive and rewarding social engineering exercise in building an open-access community with a shared vision.

Engineering and algorithm design for an image processing Api: a technical report on ITK--the Insight Toolkit.

We present the detailed planning and execution of the Insight Toolkit (ITK), an application programmers interface (API) for the segmentation and registration of medical image data. This public resource has been developed through the NLM Visible Human Project, and is in beta test as an open-source software offering under cost-free licensing. The toolkit concentrates on 3D medical data segmentation and registration algorithms, multimodal and multiresolution capabilities, and portable platform independent support for Windows, Linux/Unix systems. This toolkit was built using current practices in software engineering. Specifically, we embraced the concept of generic programming during the development of these tools, working extensively with C++ templates and the freedom and flexibility they allow. Software development tools for distributed consortium-based code development have been created and are also publicly available. We discuss our assumptions, design decisions, and some lessons learned.

The National Alliance for Medical Image Computing, a roadmap initiative to build a free and open source software infrastructure for translational research in medical image analysis.

The National Alliance for Medical Image Computing (NA-MIC), is a multi-institutional, interdisciplinary community of researchers, who share the recognition that modern health care demands improved technologies to ease suffering and prolong productive life. Organized under the National Centers for Biomedical Computing 7 years ago, the mission of NA-MIC is to implement a robust and flexible open-source infrastructure for developing and applying advanced imaging technologies across a range of important biomedical research disciplines. A measure of its success, NA-MIC is now applying this technology to diseases that have immense impact on the duration and quality of life: cancer, heart disease, trauma, and degenerative genetic diseases. The targets of this technology range from group comparisons to subject-specific analysis.