Institutional entrepreneurship in constructing alternative paths: A comparison of biotech hybrids

This paper investigates how firms adapt their innovation strategies to cope with constraints in national institutional environments. It is a comparative case study of Dutch and British dedicated biotechnology firms focusing on a particular type of strategy, the hybrid model. Patterns of skill accumulation and learning present in the Dutch hybrids are indications of how they use institutional advantages to focus on low-risk innovation and build deeper competences while also pursuing high-risk innovation strategies. The Dutch hybrid offers insight into how firms comply with the dominant logic of the biotechnology field even when their institutional frameworks encourage the pursuit of low-risk innovation strategies

Software Certification for Temporal Properties With Affordable Tool Qualification

It has been recognized that a framework based on proof-carrying code (also called semantic-based software certification in its community) could be used as a candidate software certification process for the avionics industry. To meet this goal, tools in the "trust base" of a proof-carrying code system must be qualified by regulatory authorities. A family of semantic-based software certification approaches is described, each different in expressive power, level of automation and trust base. Of particular interest is the so-called abstraction-carrying code, which can certify temporal properties. When a pure abstraction-carrying code method is used in the context of industrial software certification, the fact that the trust base includes a model checker would incur a high qualification cost. This position paper proposes a hybrid of abstraction-based and proof-based certification methods so that the model checker used by a client can be significantly simplified, thereby leading to lower cost in tool qualification

Cysteine transport through excitatory amino acid transporter 3 (EAAT3)

Excitatory amino acid transporters (EAATs) limit glutamatergic signaling and maintain extracellular glutamate concentrations below neurotoxic levels. Of the five known EAAT isoforms (EAATs 1-5), only the neuronal isoform, EAAT3 (EAAC1), can efficiently transport the uncharged amino acid L-cysteine. EAAT3-mediated cysteine transport has been proposed to be a primary mechanism used by neurons to obtain cysteine for the synthesis of glutathione, a key molecule in preventing oxidative stress and neuronal toxicity. The molecular mechanisms underlying the selective transport of cysteine by EAAT3 have not been elucidated. Here we propose that the transport of cysteine through EAAT3 requires formation of the thiolate form of cysteine in the binding site. Using Xenopus oocytes and HEK293 cells expressing EAAT2 and EAAT3, we assessed the transport kinetics of different substrates and measured transporter-associated currents electrophysiologically. Our results show that L-selenocysteine, a cysteine analog that forms a negatively-charged selenolate ion at physiological pH, is efficiently transported by EAATs 1-3 and has a much higher apparent affinity for transport when compared to cysteine. Using a membrane tethered GFP variant to monitor intracellular pH changes associated with transport activity, we observed that transport of either L-glutamate or L-selenocysteine by EAAT3 decreased intracellular pH, whereas transport of cysteine resulted in cytoplasmic alkalinization. No change in pH was observed when cysteine was applied to cells expressing EAAT2, which displays negligible transport of cysteine. Under conditions that favor release of intracellular substrates through EAAT3 we observed release of labeled intracellular glutamate but did not detect cysteine release. Our results support a model whereby cysteine transport through EAAT3 is facilitated through cysteine de-protonation and that once inside, the thiolate is rapidly re-protonated. Moreover, these findings suggest that cysteine transport is predominantly unidirectional and that reverse transport does not contribute to depletion of intracellular cysteine pools

Automated segmentation of tissue images for computerized IHC analysis

This paper presents two automated methods for the segmentation ofimmunohistochemical tissue images that overcome the limitations of themanual approach aswell as of the existing computerized techniques. The first independent method, based on unsupervised color clustering, recognizes automatically the target cancerous areas in the specimen and disregards the stroma; the second method, based on colors separation and morphological processing, exploits automated segmentation of the nuclear membranes of the cancerous cells. Extensive experimental results on real tissue images demonstrate the accuracy of our techniques compared to manual segmentations; additional experiments show that our techniques are more effective in immunohistochemical images than popular approaches based on supervised learning or active contours. The proposed procedure can be exploited for any applications that require tissues and cells exploration and to perform reliable and standardized measures of the activity of specific proteins involved in multi-factorial genetic pathologie

Baseline Assessment and Prioritization Framework for IVHM Integrity Assurance Enabling Capabilities

Fundamental to vehicle health management is the deployment of systems incorporating advanced technologies for predicting and detecting anomalous conditions in highly complex and integrated environments. Integrated structural integrity health monitoring, statistical algorithms for detection, estimation, prediction, and fusion, and diagnosis supporting adaptive control are examples of advanced technologies that present considerable verification and validation challenges. These systems necessitate interactions between physical and software-based systems that are highly networked with sensing and actuation subsystems, and incorporate technologies that are, in many respects, different from those employed in civil aviation today. A formidable barrier to deploying these advanced technologies in civil aviation is the lack of enabling verification and validation tools, methods, and technologies. The development of new verification and validation capabilities will not only enable the fielding of advanced vehicle health management systems, but will also provide new assurance capabilities for verification and validation of current generation aviation software which has been implicated in anomalous in-flight behavior. This paper describes the research focused on enabling capabilities for verification and validation underway within NASA s Integrated Vehicle Health Management project, discusses the state of the art of these capabilities, and includes a framework for prioritizing activities

Analysis Strategies for Bioactive, Polar Fatty Amides in Complex Samples

Bioactive lipids are known to exert physiological effects and interact with neuroreceptors. Little is known about the bioregulation of primary fatty acid amides, though N-acyl glycines are thought to be their anabolic precursors. Chapter 1 details the current metabolic, physiological, and receptor interactions of primary fatty acid amides and their related congeners and reviews current strategies for isolation and detection. Chapter 2 outlines mass spectrometry collision induced fragmentation assignments pertaining to method development of multiple reaction monitoring detection of these species. Chromatographic separation methods of fatty acyls, with a focus on primary fatty acid amides and N-acyl glycines, are outlined in chapter 3 and these results are used to develop a two dimensional liquid chromatography tandem mass spectrometry analysis method. Multiple reaction monitoring was utilized as the detection mode due to the enhanced limit of detection obtained from mass filtering background and matrix components. The implementation of our developed analytical separation and detection approach for quantitation of these bioactive lipids in vertebrate samples and future implications of primary fatty acid amide and N-acyl glycine analysis are reviewed in chapter 4. In addition, the appendix summarizes a method for selective, sensitive multiple reaction monitoring detection of palmitoylethanolamine, an N-acylethanolamine with analgesic and anti-inflammatory properties

The development of a data acquisition system for a vacuum-ultraviolet spectroradiometer

An improved vacuum-ultraviolet spectroradiometer has been developed for use in the characterization of rocket plume radiant emission and the study of combustion processes in liquid rocket engines. The system acquires and processes the data so as to display the spectrum in units of volts per pixel. With proper calibration, it will display the spectrum in spectral radiance units of power per unit solid angle per unit source area per unit wavelength. The spectrometer displays the plume\u27s radiant emission in terms of its electromagnetic spectrum. Two light image intensifier (LII) tubes and two charge- coupled device (CCD) arrays convert the spectrum to an electrical signal and pass the signal on to the electronic hardware. The hardware digitizes the signal and stores the data in a buffer until a computer can transfer it to disk. The computer\u27s software controls the entire operation. Off-line, code reduces the acquired data to engineering units and displays the spectrum on the computer\u27s monitor. This thesis describes the development of the data acquisition system (CCDs, electronic hardware, computer, and software) of the improved spectroradiometer. The device can monitor a continuous spectral range of 44 nm or two ranges of 22 nm each anywhere in the ultraviolet (UV) spectrum extending from 120 nm to 320 nm. The device can also provide simultaneous spatial-spectral measurements. That is, the charges in each CCD pixel column can be summed as one vertical group with a minimum integration period of 50 ms or the pixel column can be divided and summed in 2, 10, or 20 vertical groups with minimum integration periods of 120 ms, 600 ms, or 1200 ms, respectively

Anion Conducting States of Excitatory Amino Acid Transporters

Excitatory amino acid transporters (EAATs) are secondary active, electrogenic transporters which translocate L-glutamate (glu) against its concentration gradient using the co-transport of 3 Na+, 1 H+, and the counter-transport of 1 K+ ion. In addition, these carriers possess a thermodynamically uncoupled anion channel that fluxes Cl- but is promiscuous with several permeant anionic species. The roles of EAATs are to shape the spatio-temporal profile of released glu in both the synaptic cleft and extra-synaptic regions as well as maintaining a low ambient extracellular concentration of glu. This transport activity regulates activation of glu receptors and thus regulates excitatory neurotransmission. Using a combination of techniques, we were successful in identifying inward oriented transporter conformations which allow transitions to open channels states. This observation was enabled by our development of a novel method to isolate EAAT1 in the inward facing conformation. While constrained to these conformations, currents with the same macroscopic amplitudes as conducting states mediated by the outward facing, Na+ bound states were observed. The persistence of currents is indicative of a channel gating mechanism that is insensitive to transporter orientation and that the anion channel is open during the majority of the transport cycle. Additional conducting states allows for a larger contribution of the anion channel function of EAATs to shape cellular function then previously assumed. Next we investigated the gating mechanism of the anion channel. We assayed for the ability of Na+ to gate the anion channel in both glial (EAAT1 and EAAT2) and neuronal (EAAT3 and EAAT4) isoforms. We discovered that the glial isoforms are not gated by Na+ but are leak channels with an open probability and single channel conductance that is insensitive to Na+ concentrations. In contrast, neuronal EAAT isoforms EAAT3 and EAAT4 both display Na+ dependent channel activity. This is the first example of a significant functional difference between glial and neuronal transporter isoforms of the solute carrier 1 (SLC1) family. The research presented here allows for a greater understanding of low open probability channel states and the possible contributions of the EAAT anion channel to the functioning of the nervous system

Learning from the 21st century fight: insights from operations and training

Advanced militaries, optimised for conventional conflicts, are experiencing significant change as they attempt to adapt to the demands of a new defence and security paradigm. The effectiveness of that transformation will depend largely on their ability to fully absorb the lessons of history and of recent operations. The paper begins by juxtaposing the four key factors for ensuring that these lessons are identified and absorbed ('the environment', 'the culture', 'the leaders, and 'the process') within today's Australian Army. The paper then goes on to outline some of the insights (lessons) gained from operations and training activities, with an emphasis on force protection and urban operations. This is followed by an analysis of the way ahead for the Australian Army and why the Army must institutionalise a learning process and, perhaps more importantly, a true learning culture where all have an openness to new ideas and a thirst for constant improvement

A Formal Model of Partitioning for Integrated Modular Avionics

The aviation industry is gradually moving toward the use of integrated modular avionics (IMA) for civilian transport aircraft. An important concern for IMA is ensuring that applications are safely partitioned so they cannot interfere with one another. We have investigated the problem of ensuring safe partitioning and logical non-interference among separate applications running on a shared Avionics Computer Resource (ACR). This research was performed in the context of ongoing standardization efforts, in particular, the work of RTCA committee SC-182, and the recently completed ARINC 653 application executive (APEX) interface standard. We have developed a formal model of partitioning suitable for evaluating the design of an ACR. The model draws from the mathematical modeling techniques developed by the computer security community. This report presents a formulation of partitioning requirements expressed first using conventional mathematical notation, then formalized using the language of SRI'S Prototype Verification System (PVS). The approach is demonstrated on three candidate designs, each an abstraction of features found in real systems