The inactivation of the retinoblastoma (Rb) tumor suppressor gene in mice results in ectopic proliferation, apoptosis, and impaired differentiation in extraembryonic, neural, and erythroid lineages, culminating in fetal death by embryonic day 15.5 (E15.5). Here we show that the specific loss of Rb in trophoblast stem (TS) cells, but not in trophoblast derivatives, leads to an overexpansion of trophoblasts, a disruption of placental architecture, and fetal death by E15.5. Despite profound placental abnormalities, fetal tissues appeared remarkably normal, suggesting that the full manifestation of fetal phenotypes requires the loss of Rb in both extraembryonic and fetal tissues. Loss of Rb resulted in an increase of E2f3 expression, and the combined ablation of Rb and E2f3 significantly suppressed Rb mutant phenotypes. This rescue appears to be cell autonomous since the inactivation of Rb and E2f3 in TS cells restored placental development and extended the life of embryos to E17.5. Taken together, these results demonstrate that loss of Rb in TS cells is the defining event causing lethality of Rb(-/-) embryos and reveal the convergence of extraembryonic and fetal functions of Rb in neural and erythroid development. We conclude that the Rb pathway plays a critical role in the maintenance of a mammalian stem cell population.

In this paper, we propose a technique for detecting pockets on a surface-of-interest. A sequence of propagating fronts converging to the target surface is used as the basis for inspection. We compute a correspondence function between the initial and the target surface. This leads to a natural definition of the local feature size measured as the evolution distance between mapped points. Surface pockets are then extracted as salient clusters embedded in the feature space. The level-set initialization also determines the scale-space of the extracted pockets. Results are presented on a case-study in which the focus is to chronicle the phenotyping differences in genetically modified mouse placenta. Our results are validated based on manually verified ground-truth.

In this paper, we utilize the N-point correlation functions (N-pcfs) to construct an appropriate feature space for achieving tissue segmentation in histology-stained microscopic images. The N-pcfs estimate microstructural constituent packing densities and their spatial distribution in a tissue sample. We represent the multi-phase properties estimated by the N-pcfs in a tensor structure. Using a variant of higher-order singular value decomposition (HOSVD) algorithm, we realize a robust classifier that provides a multi-linear description of the tensor feature space. Validated results of the segmentation are presented in a case-study that focuses on understanding the genetic phenotyping differences in mouse placentae.

Early efforts in the visualization of microscopic biological structures have been impeded by the lack of a rigorous cellular segmentation approach, insufficient slicing resolution and slicing deformations associated with serial-section histology volumes. We develop algorithms that address these challenges. In this paper, geodesic active contours using shape priors is employed to obtain initial segmentations of salient cellular structures. Overlapping cells are resolved by imposing a Voronoi-like tessellation of the image space optimized by a Bayesian probability framework. Intermediate slices are introduced between images to account for the insufficient slicing resolution. Results of the cellular segmentation step are used in conjunction with a cell shape model to interpolate the 3D cellular locations and shapes onto the adjacent slices thereby enhancing the expressivity and utility of the resulting visualizations. Our methods are applied in a case-study involving the 3D visualization of the epithelial cell lining and lobules in mouse mammary ducts.

caGrid is a middleware system which combines the Grid computing, the service oriented architecture, and the model driven architecture paradigms to support development of interoperable data and analytical resources and federation of such resources in a Grid environment. The functionality provided by caGrid is an essential and integral component of the cancer Biomedical Informatics Grid (caBIG(TM)) program. This program is established by the National Cancer Institute as a nationwide effort to develop enabling informatics technologies for collaborative, multi-institutional biomedical research with the overarching goal of accelerating translational cancer research. Although the main application domain for caGrid is cancer research, the infrastructure provides a generic framework that can be employed in other biomedical research and healthcare domains. The development of caGrid is an ongoing effort, adding new functionality and improvements based on feedback and use cases from the community. This paper provides an overview of potential future architecture and tooling directions and areas of improvement for caGrid and caGrid-like systems. This summary is based on discussions at a roadmap workshop held in February with participants from biomedical research, Grid computing, and high performance computing communities.

OBJECTIVE To develop a security infrastructure to support controlled and secure access to data and analytical resources in a biomedical research Grid environment, while facilitating resource sharing among collaborators. DESIGN A Grid security infrastructure, called Grid Authentication and Authorization with Reliably Distributed Services (GAARDS), is developed as a key architecture component of the NCI-funded cancer Biomedical Informatics Grid (caBIG(TM)). The GAARDS is designed to support in a distributed environment 1) efficient provisioning and federation of user identities and credentials; 2) group-based access control support with which resource providers can enforce policies based on community accepted groups and local groups; and 3) management of a trust fabric so that policies can be enforced based on required levels of assurance. MEASUREMENTS GAARDS is implemented as a suite of Grid services and administrative tools. It provides three core services: Dorian for management and federation of user identities, Grid Trust Service for maintaining and provisioning a federated trust fabric within the Grid environment, and Grid Grouper for enforcing authorization policies based on both local and Grid-level groups. RESULTS The GAARDS infrastructure is available as a stand-alone system and as a component of the caGrid infrastructure. More information about GAARDS can be accessed at http://www.cagrid.org. CONCLUSIONS GAARDS provides a comprehensive system to address the security challenges associated with environments in which resources may be located at different sites, requests to access the resources may cross institutional boundaries, and user credentials are created, managed, revoked dynamically in a de-centralized manner.

Collaborations in biomedical research and clinical studies require that data, software, and computational resources be shared between geographically distant institutions. In radiology, there is a related issue of sharing remote DICOM data over the Internet. This paper focuses on the problem of federating multiple image data resources such that clients can interact with them as if they are stored in a centralized PACS. We present a toolkit, called VirtualPACS, to support this functionality. Using the toolkit, users can perform standard DICOM operations (query, retrieve, and submit) across distributed image databases. The key features of the toolkit are:(1) VirtualPACS makes it easy to use existing DICOM client applications for data access;(2) it can easily be incorporated into an imaging workflow as a DICOM source;(3) using VirtualPACS, heterogeneous collections of DICOM sources are exposed to clients through a uniform interface and common data model; and (4) DICOM image databases without DICOM messaging can be accessed.

This paper describes a Grid-aware image reviewing system (GridIMAGE) that allows practitioners to (a) select images from multiple geographically distributed digital imaging and communication in medicine (DICOM) servers,(b) send those images to a specified group of human readers and computer-assisted detection (CAD) algorithms, and (c) obtain and compare interpretations from human readers and CAD algorithms. The currently implemented system was developed using the National Cancer Institute caGrid infrastructure and is designed to support the identification of lung nodules on thoracic computed tomography. However, the infrastructure is general and can support any type of distributed review. caGrid data and analytical services are used to link DICOM image databases and CAD systems and to interact with human readers. Moreover, the service-oriented and distributed structure of the GridIMAGE framework enables a flexible system, which can be deployed in an institution (linking multiple DICOM servers and CAD algorithms) and in a Grid environment (linking the resources of collaborating research groups). GridIMAGE provides a framework that allows practitioners to obtain interpretations from one or more human readers or CAD algorithms. It also provides a mechanism to allow cooperative imaging groups to systematically perform image interpretation tasks associated with research protocols.

In neurobiology, the 3D reconstruction of neurons followed by the identification of dendritic spines is essential for studying neuronal morphology, function and biophysical properties. Most existing methods suffer from problems of low reliability, poor accuracy and require much user interaction. In this paper, we present a method to reconstruct dendrites using a surface representation of the neuron. The skeleton of the dendrite is extracted by a procedure based on the medial geodesic function that is robust and topology preserving, and it is used to accurately identify spines. The sensitivity of the algorithm on the various parameters is explored in detail and the method is shown to be robust.

Motion during the acquisition of dynamic contrast enhanced MRI can cause model-fitting errors requiring co-registration. Clinical implementations use a pharmacokinetic model to determine lesion parameters from the contrast passage. The input to the model is the time-intensity plot from a region of interest (ROI) covering the lesion extent. Motion correction meanwhile involves interpolation and smoothing operations thereby affecting the time-intensity plots. This paper explores the trade-offs in applying an elastic matching procedure on the lesion detection and proposes enhancements. The method of choice is the 3D realization of the Demon's elastic matching procedure. We validate our enhancements using synthesized deformation of stationary datasets that also serve as ground-truth. The framework is tested on 42 human eye datasets. Hence, we show that motion correction is beneficial in improving the model-fit and yet needs enhancements to correct for the intensity reductions during parameter estimation.