Development of a mouse model for the t(10:11)(p13;q14) chromosomal translocation associated with acute leukemia in humans

Acute leukemia is associated with a wide spectrum of gross chromosomal rearrangements. These acquired mutations include balanced and unbalanced chromosomal translocations. The analysis of chromosomal translocations has provided much insight into understanding the biology of hematologic malignancies, leading to improved diagnosis and classification, as well as identification of novel therapeutic targets. The rare but recurring chromosomal translocation [t(10;11)(p13;q21)] results in a CALM-AF10 fusion that occurs in patients with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). CALM-AF10 transgenic mice developed AML with lymphoid features and had Hoxa gene cluster upregulation. In this model, mice developed leukemia after a long latency period with incomplete penetrance. These findings suggest that additional genetic events are needed to complement CALM-AF10 mediated leukemic transformation. Retroviral insertional mutagenesis was used to identify complementary genetic events that might collaborate with CALM-AF10 during leukemic transformation. A cohort of CALM-AF10 mice was infected with the Mol4070LTR retrovirus; by 5.5 months of age, 50% of the transgenic mice developed AML, a clear acceleration of disease onset compared to either wild type littermates injected with the retrovirus or CALM-AF10 mice not injected with the retrovirus. The tumors assayed by Southern blotting for viral integration showed clonal to oligoclonal expansion. Ligation-mediated PCR and sequence analysis of DNA derived from leukemic cells was used to identify potential collaborating genes at the retroviral insertion sites including Evi1, Nf1, kRas, Zeb2, and Mnl. Identification of these genes as a potential collaborating gene with CALM-AF10 supports the emerging paradigm in leukemia biology that predicts that most, if not all leukemic cells must undergo at least two collaborative events to produce a fully transformed cell. One of these events typically leads to impaired differentiation and enhanced renewal of stem cells, whereas the second event leads to increased proliferation and/or decreased apoptosis. It has been shown here that retroviral infection accelerates the onset of acute leukemia, and identified genes that potentially collaborate with the CALM-AF10 fusion gene in the leukemic transformation process. This transgenic murine model serves as a model system for studying leukemogenesis similar to that observed in humans with leukemia

An Optoelectronic Adaptive Resonance Unit

The authors demonstrate a hardware implementation of the adaptive resonance theory ART 1 neural network architecture. The optoelectronic ART1 unit, is a novel application of an old device. This device-the 4-f or Van der Lugt correlator-has historically been used as a fast pattern classifier. Usually the correlation operation is employed as a matched filter, so that a maximum correlation peak corresponds to a well-matched pattern. The device described also uses the large peaks, but takes specific advantage of the fact that a zero-shift correlation is mathematically equivalent to a two-dimensional inner product. The authors describe a promising method for emulating an ART1 unit in optics. They review ART1 from an algorithmic point of view, which shows that inner products are a critical part of ART1. They then discuss its implementation, and show some experimental results. The device works by performing the most computationally intensive parts of the algorithm in optical hardware, and thus offers a suitable marriage of the strengths of electronics and optics

Quantification of HTLV-I proviral load in experimentally infected rabbits

BACKGROUND: Levels of proviral load in HTLV-1 infected patients correlate with clinical outcome and are reasonably prognostic. Adaptation of proviral load measurement techniques is examined here for use in an experimental rabbit model of HTLV-1 infection. Initial efforts sought to correlate proviral load with route and dose of inoculation and with clinical outcome in this model. These methods contribute to our continuing goal of using the model to test treatments that alleviate virus infection. RESULTS: A real-time PCR assay was used to measure proviral load in blood and tissue samples from a series of rabbits infected using HTLV-1 inocula prepared as either cell-free virus particles, infected cells or blood, or by naked DNA injection. Proviral loads from asymptomatically infected rabbits showed levels corresponding to those reported for human patients with clinically silent HTLV-1 infections. Proviral load was comparably increased in 50% of experimentally infected rabbits that developed either spontaneous benign or malignant tumors while infected. Similarly elevated provirus was found in organs of rabbits with experimentally induced acute leukemia/lymphoma-like disease. Levels of provirus in organs taken at necropsy varied widely suggesting that reservoirs of infections exist in non-lymphoid organs not traditionally thought to be targets for HTLV-1. CONCLUSION: Proviral load measurement is a valuable enhancement to the rabbit model for HTLV-1 infection providing a metric to monitor clinical status of the infected animals as well as a means for the testing of treatment to combat infection. In some cases proviral load in blood did not reflect organ proviral levels, revealing a limitation of this method for monitoring health status of HTLV-1 infected individuals

An Optoelectronic Implementation of the Adaptive Resonance Neural Network

A solution to the problem of implementation of the adaptive resonance theory (ART) of neural networks that uses an optical correlator which allows the large body of correlator research to be leveraged in the implementation of ART is presented. The implementation takes advantage of the fact that one ART-based architecture, known as ART1, can be broken into several parts, some of which are better to implement in parallel. The control structure of ART, often regarded as its most complex part, is actually not very time consuming and can be done in electronics. The bottom-up and top-down gated pathways, however, are very time consuming to simulate and are difficult to implement directly in electronics due to the high number of interconnections. In addition to the design, the authors present experiments with a laboratory prototype to illustrate its feasibility and to discuss implementation details that arise in practice. This device can potentially outperform alternative implementations of ART1 by as much as two to three orders of magnitude in problems requiring especially large input field

A Neural Architecture for Unsupervised Learning with Shift, Scale and Rotation Invariance, Efficient Software Simulation Heuristics, and Optoelectronic Implementation

A simple modification of the adaptive resonance theory (ART) neural network allows shift, scale and rotation invariant learning. The authors point out that this can be accomplished as a neural architecture by modifying the standard ART with hardwired interconnects that perform a Fourier-Mellin transform, and show how to modify the heuristics for efficient simulation of ART architectures to accomplish the additional innovation. Finally, they discuss the implementation of this in optoelectronic hardware, using a modification of the Van der Lugt optical correlato

Control of T lymphocyte morphology by the GTPase Rho

BACKGROUND: Rho family GTPase regulation of the actin cytoskeleton governs a variety of cell responses. In this report, we have analyzed the role of the GTPase Rho in maintenance of the T lymphocyte actin cytoskeleton. RESULTS: Inactivation of the GTPase Rho in the human T lymphocytic cell line HPB-ALL does not inhibit constitutively high adhesion to the integrin β1 substrate fibronectin. It did however result in the aberrant extension of finger-like dendritic processes on the substrates VCAM-1, Fn, and mAb specific to β1 integrins. Time-lapse video microscopy demonstrated that C3 induced extensions were primarily the result of an altered pseudopod elongation rather than retraction. Once the stellate pseudopodia extended, none retracted, and cells became completely immobile. Filipodial structures were absent and the dendritic-like processes in C3 treated cells were rich in filamentous actin. Immunolocalization of RhoA in untreated HPB-ALL cells spreading on fibronectin demonstrated a diffuse staining pattern within the pseudopodia. In C3 treated cells, clusters of RhoA were pronounced and localized within the altered extensions. CONCLUSIONS: GTPase Rho is actively involved in the regulation of T lymphocyte morphology and motility

Deletion of PPAR-γ in immune cells enhances susceptibility to antiglomerular basement membrane disease

Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) has been shown to be immunoregulatory in autoimmune diseases by inhibiting production of a number of inflammatory mediators. We investigated whether PPAR-γ gene deletion in hematopoietic cells would alter disease pathogenesis in the antiglomerular basement membrane (anti-GBM) mouse model. PPAR-γ+/+ and PPAR-γ−/− mice were immunized with rabbit antimouse GBM antibodies and lipopolysaccharide and evaluated for two weeks. Although both the PPAR-γ+/+ and PPAR-γ−/− mice had IgG deposition in the glomerulus and showed proteinuria two weeks after injection, glomerular and tubulointerstitial disease in PPAR-γ−/− mice were significantly more severe compared with the PPAR-γ+/+ animals. We observed that the PPAR-γ−/− mice had decreased CD4+CD25+ regulatory T cells and an increased CD8+:CD4+ ratio as compared with the PPAR-γ+/+ mice, suggesting that PPAR-γ has a role in the regulation of T cells. Furthermore, plasma interleukin-6 levels were significantly increased in the PPAR-γ−/− mice at two weeks as compared with the PPAR-γ+/+ animals. Taken together, these studies show that the lack of PPAR-γ expression enhances inflammatory renal disease in the anti-GBM antibody-induced glomerulonephritis mouse model and suggests targeting PPAR-γ may have therapeutic efficacy

A surety engineering framework to reduce cognitive systems risks.

Cognitive science research investigates the advancement of human cognition and neuroscience capabilities. Addressing risks associated with these advancements can counter potential program failures, legal and ethical issues, constraints to scientific research, and product vulnerabilities. Survey results, focus group discussions, cognitive science experts, and surety researchers concur technical risks exist that could impact cognitive science research in areas such as medicine, privacy, human enhancement, law and policy, military applications, and national security (SAND2006-6895). This SAND report documents a surety engineering framework and a process for identifying cognitive system technical, ethical, legal and societal risks and applying appropriate surety methods to reduce such risks. The framework consists of several models: Specification, Design, Evaluation, Risk, and Maturity. Two detailed case studies are included to illustrate the use of the process and framework. Several Appendices provide detailed information on existing cognitive system architectures; ethical, legal, and societal risk research; surety methods and technologies; and educing information research with a case study vignette. The process and framework provide a model for how cognitive systems research and full-scale product development can apply surety engineering to reduce perceived and actual risks