Peter Windrem Oral History Interview

https://scholarlycommons.pacific.edu/raymond-college/1087/thumbnail.jp

System for Secure Integration of Aviation Data

The Aviation Data Integration System (ADIS) of Ames Research Center has been established to promote analysis of aviation data by airlines and other interested users for purposes of enhancing the quality (especially safety) of flight operations. The ADIS is a system of computer hardware and software for collecting, integrating, and disseminating aviation data pertaining to flights and specified flight events that involve one or more airline(s). The ADIS is secure in the sense that care is taken to ensure the integrity of sources of collected data and to verify the authorizations of requesters to receive data. Most importantly, the ADIS removes a disincentive to collection and exchange of useful data by providing for automatic removal of information that could be used to identify specific flights and crewmembers. Such information, denoted sensitive information, includes flight data (here signifying data collected by sensors aboard an aircraft during flight), weather data for a specified route on a specified date, date and time, and any other information traceable to a specific flight. The removal of information that could be used to perform such tracing is called "deidentification." Airlines are often reluctant to keep flight data in identifiable form because of concerns about loss of anonymity. Hence, one of the things needed to promote retention and analysis of aviation data is an automated means of de-identification of archived flight data to enable integration of flight data with non-flight aviation data while preserving anonymity. Preferably, such an automated means would enable end users of the data to continue to use pre-existing data-analysis software to identify anomalies in flight data without identifying a specific anomalous flight. It would then also be possible to perform statistical analyses of integrated data. These needs are satisfied by the ADIS, which enables an end user to request aviation data associated with de-identified flight data. The ADIS includes client software integrated with other software running on flight-operations quality-assurance (FOQA) computers for purposes of analyzing data to study specified types of events or exceedences (departures of flight parameters from normal ranges). In addition to ADIS client software, ADIS includes server hardware and software that provide services to the ADIS clients via the Internet (see figure). The ADIS server receives and integrates flight and non-flight data pertaining to flights from multiple sources. The server accepts data updates from authorized sources only and responds to requests from authorized users only. In order to satisfy security requirements established by the airlines, (1) an ADIS client must not be accessible from the Internet by an unauthorized user and (2) non-flight data as airport terminal information system (ATIS) and weather data must be displayed without any identifying flight information. ADIS hardware and software architecture as well as encryption and data display scheme are designed to meet these requirements. When a user requests one or more selected aviation data characteristics associated with an event (e.g., a collision, near miss, equipment malfunction, or exceedence), the ADIS client augments the request with date and time information from encrypted files and submits the augmented request to the server. Once the user s authorization has been verified, the server returns the requested information in de-identified form

Phyllis Morales Oral History Interview

https://scholarlycommons.pacific.edu/raymond-college/1082/thumbnail.jp

Statin therapy inhibits remyelination in the central nervous system

Remyelination of lesions in the central nervous system contributes to neural repair following clinical relapses in multiple sclerosis. Remyelination is initiated by recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes. Simvastatin, a blood-brain barrier-permeable statin in multiple sclerosis clinical trials, has been shown to impact the in vitro processes that have been implicated in remyelination. Animals were fed a cuprizone-supplemented diet for 6 weeks to induce localized demyelination in the corpus callosum; subsequent return to normal diet for 3 weeks stimulated remyelination. Simvastatin was injected intraperitoneally during the period of coincident demyelination and OPC maturation (weeks 4 to 6), throughout the entire period of OPC responses (weeks 4 to 9), or during the remyelination-only phase (weeks 7 to 9). Simvastatin treatment (weeks 4 to 6) caused a decrease in myelin load and both Olig2(strong) and Nkx2.2(strong) OPC numbers. Simvastatin treatment (weeks 4 to 9 and 7 to 9) caused a decrease in myelin load, which was correlated with a reduction in Nkx2.2(strong) OPCs and an increase in Olig2(strong) cells, suggesting that OPCs were maintained in an immature state (Olig2(strong)/Nkx2.2(weak)). NogoA+ oligodendrocyte numbers were decreased during all simvastatin treatment regimens. Our findings suggest that simvastatin inhibits central nervous system remyelination by blocking progenitor differentiation, indicating the need to monitor effects of systemic immunotherapies that can access the central nervous system on brain tissue-repair processes

Phenotype overlap in glial cell populations: astroglia, oligodendroglia and NG-2(+) cells.

The extent to which NG-2(+) cells form a distinct population separate from astrocytes is central to understanding whether this important cell class is wholly an oligodendrocyte precursor cell (OPC) or has additional functions akin to those classically ascribed to astrocytes. Early immuno-staining studies indicate that NG-2(+) cells do not express the astrocyte marker GFAP, but orthogonal reconstructions of double-labeled confocal image stacks here reveal a significant degree of co-expression in individual cells within post-natal day 10 (P10) and adult rat optic nerve (RON) and rat cortex. Extensive scanning of various antibody/fixation/embedding approaches identified a protocol for selective post-embedded immuno-gold labeling. This first ultrastructural characterization of identified NG-2(+) cells revealed populations of both OPCs and astrocytes in P10 RON. NG-2(+) astrocytes had classic features including the presence of glial filaments but low levels of glial filament expression were also found in OPCs and myelinating oligodendrocytes. P0 RONs contained few OPCs but positively identified astrocytes were observed to ensheath pre-myelinated axons in a fashion previously described as a definitive marker of the oligodendrocyte lineage. Astrocyte ensheathment was also apparent in P10 RONs, was absent from developing nodes of Ranvier and was never associated with compact myelin. Astrocyte processes were also shown to encapsulate some oligodendrocyte somata. The data indicate that common criteria for delineating astrocytes and oligodendroglia are insufficiently robust and that astrocyte features ascribed to OPCs may arise from misidentification

Experimental and Therapeutic Opportunities for Stem Cells in Multiple Sclerosis

Multiple Sclerosis (MS) is an inflammatory demyelinating neurodegenerative disorder of the brain and spinal cord that causes significant disability in young adults. Although the precise aetiopathogenesis of MS remains unresolved, its pathological hallmarks include inflammation, demyelination, axonal injury (acute and chronic), astrogliosis and variable remyelination. Despite major recent advances in therapeutics for the early stage of the disease there are currently no disease modifying treatments for the progressive stage of disease, whose pathological substrate is axonal degeneration. This represents the great and unmet clinical need in MS. Against this background, human stem cells offer promise both to improve understanding of disease mechanism(s) through in-vitro modeling as well as potentially direct use to supplement and promote remyelination, an endogenous reparative process where entire myelin sheaths are restored to demyelinated axons. Conceptually, stem cells can act directly to myelinate axons or indirectly through different mechanisms to promote endogenous repair; importantly these two mechanisms of action are not mutually exclusive. We propose that discovery of novel methods to invoke or enhance remyelination in MS may be the most effective therapeutic strategy to limit axonal damage and instigate restoration of structure and function in this debilitating condition. Human stem cell derived neurons and glia, including patient specific cells derived through reprogramming, provide an unprecedented experimental system to model MS “in a dish” as well as enable high-throughput drug discovery. Finally, we speculate upon the potential role for stem cell based therapies in MS

Human Glial Progenitor Cells Effectively Remyelinate the Demyelinated Adult Brain

Neonatally transplanted human glial progenitor cells (hGPCs) can myelinate the brains of myelin-deficient shiverer mice, rescuing their phenotype and survival. Yet, it has been unclear whether implanted hGPCs are similarly able to remyelinate the diffusely demyelinated adult CNS. We, therefore, ask if hGPCs could remyelinate both congenitally hypomyelinated adult shiverers and normal adult mice after cuprizone demyelination. In adult shiverers, hGPCs broadly disperse and differentiate as myelinating oligodendrocytes after subcortical injection, improving both host callosal conduction and ambulation. Implanted hGPCs similarly remyelinate denuded axons after cuprizone demyelination, whether delivered before or after demyelination. RNA sequencing (RNA-seq) of hGPCs back from cuprizone-demyelinated brains reveals their transcriptional activation of oligodendrocyte differentiation programs, while distinguishing them from hGPCs not previously exposed to demyelination. These data indicate the ability of transplanted hGPCs to disperse throughout the adult CNS, to broadly myelinate regions of dysmyelination, and also to be recruited as myelinogenic oligodendrocytes later in life, upon demyelination-associated demand

Human Glia Can Both Induce and Rescue Aspects of Disease Phenotype in Huntington Disease

The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder