Humanized mice are frequently utilized in bench to bedside therapeutic tests to combat human infectious, cancerous and degenerative diseases. For the fields of hematology-oncology, regenerative medicine, and infectious diseases, the immune deficient mice have been used commonly in basic research efforts. Obstacles in true translational efforts abound, as the relationship between mouse and human cells in disease pathogenesis and therapeutic studies requires lengthy investigations. The interplay between human immunity and mouse biology proves ever more complicated when aging, irradiation, and human immune reconstitution are considered. All can affect a range of biochemical and behavioral functions. To such ends, we show age-and irradiation-dependent influences for the development of macrocytic hyper chromic anemia, myelodysplasia, blood protein reductions and body composition changes. Humanization contributes to hematologic abnormalities. Home cage behavior revealed day and dark cycle locomotion also influenced by human cell reconstitutions. Significant age-related day-to-day variability in movement, feeding and drinking behaviors were observed. We posit that this data serves to enable researchers to better design translational studies in this rapidly emerging field of mouse humanization.

Background: Host-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rg(c)(null) mice transplanted with human CD34(+) hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4(+) T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus.Methods: Changes in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N-acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens.Results: Behavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum.Conclusions: The findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease.

Astrocytes, the most abundant cells of the CNS are believed to play vital roles in brain development and functioning, providing trophic support to neurons and eliciting CNS responses to pathogens/injury. During HIV infection of the CNS, glial activation and infection play major roles in generating the immune activation, a process which, in turn, leads to release of neurotoxic mediators (viral and cellular). Accompanying the activation and proliferation of astroglia is also recruitment of mononuclear phagocytes across the endothelium. Regulated signal transduction pathways finely control all these processes. While earlier believed to support only abortive HIV infection, astrocytes are now recognized to be active participants of productive viral replication. Following infection and/or exposure to viral proteins released from neighboring infected cells, astrocytes become activated and elicit release of inflammatory mediators, such as cytokines, chemokines and growth factors, that are toxic not only for neurons but also for neighboring cells around astrocytes within the CNS. This cascade of inflammation triggers the ensuing neuropathogenesis associated with HIV-1. The normally neuroprotective role of astrocytes thus transforms into a functionally deleterious function, with the ultimate result of disrupted CNS homeostasis. The current review is an attempt to summarize the cellular signal transduction pathways critical for astrocyte activation and inflammation involved in HIV-1 associated dementia.

: Monitoring the health of the GIG is one of the most critical aspects of operationalizing cyber missions. This report focuses on the health of the Global Information Grid (GIG), a globally interconnected Department of Defense (DoD) network (of systems) that collects, processes, and manages information for warfighters, policymakers, and support personnel. The three primary components of GIG health (as defined by the customer) include sustainability, reliability and survivability. Sustainability is the consistent performance of network tasks over time; whereas reliability is the accuracy, accessibility and obtainability of information for the user; and survivability being the availability of alternate data route despite internal/external issues. The focus of the project was to design a framework for metrics to assess the health of the GIG. Private sector metrics were extrapolated to measure the sustainability, reliability, and survivability of the GIG and were included as commercial best practices. Also investigated were internal and external threats, such as interference, intrusion, and malicious activity (e.g., cyber-terrorists) that could undermine the system's capability.