Modeling technology innovation: How science, engineering, and industry methods can combine to generate beneficial socioeconomic impacts

ABSTRACT: BACKGROUND: Government-sponsored science, technology, and innovation (STI) programs support the socioeconomic aspects of public policies, in addition to expanding the knowledge base. For example, beneficial healthcare services and devices are expected to result from investments in research and development (R&D) programs, which assume a causal link to commercial innovation. Such programs are increasingly held accountable for evidence of impact--that is, innovative goods and services resulting from R&D activity. However, the absence of comprehensive models and metrics skews evidence gathering toward bibliometrics about research outputs (published discoveries), with less focus on transfer metrics about development outputs (patented prototypes) and almost none on econometrics related to production outputs (commercial innovations). This disparity is particularly problematic for the expressed intent of such programs, as most measurable socioeconomic benefits result from the last category of outputs. METHODS: This paper proposes a conceptual framework integrating all three knowledge-generating methods into a logic model, useful for planning, obtaining, and measuring the intended beneficial impacts through the implementation of knowledge in practice. Additionally, the integration of the Context-Input-Process-Product (CIPP) model of evaluation proactively builds relevance into STI policies and programs while sustaining rigor. RESULTS: The resulting logic model framework explicitly traces the progress of knowledge from inputs, following it through the three knowledge-generating processes and their respective knowledge outputs (discovery, invention, innovation), as it generates the intended sociobeneficial impacts. It is a hybrid model for generating technology-based innovations, where best practices in new product development merge with a widely accepted knowledgetranslation approach. Given the emphasis on evidence-based practice in the medical and health fields and "bench to bedside" expectations for knowledge transfer, sponsors and grantees alike should find the model useful for planning, implementing, and evaluating innovation processes. CONCLUSIONS: High-cost/high-risk industries like healthcare require the market deployment of technologybased innovations to improve domestic society in a global economy. An appropriate balance of relevance and rigor in research, development, and production is crucial to optimize the return on public investment in such programs. The technology-innovation process needs a comprehensive operational model to effectively allocate public funds and thereby deliberately and systematically accomplish socioeconomic benefits.     

Studies on perineural junctional complexes and the sites of uptake of microperoxidase and lanthanum in the cockroach central nervous system

The perineurial junctional complexes in the nerve cord of Periplaneta americana have been shown to consist of septate desmosomes, extensive gap junctions and relatively limited regions of tight junctions. Microperoxidase (M.W. 1,900) undergoes limited intercellular penetration into the septate desmosomes. Lanthanum penetrates both the septate desmosomes and gap junctions. It is concluded that the restricted access of these substances to the underlying extracellular spaces results from the presence of the perineurial tight junctions. These results contrast with those for small peripheral nerves, which lack equivalent junctional complexes, and in which the extracellular spaces are found to be accessible to externally applied lanthanum. The results are discussed in relation to current concepts of the insect blood-brain barrier.     

Antibody fragments from a ''single pot'' phage display library as immunochemical reagents.

The display of repertoires of antibody fragments on the surface of filamentous bacteriophage offers a new way of making antibodies with predefined binding specificities. Here we explored the use of this technology to make immunochemical reagents to a range of antigens by selection from a repertoire of > 10(8) clones made in vitro from human V gene segments. From the same 'single pot' repertoire, phage were isolated with binding activities to each of 18 antigens, including the intracellular proteins p53, elongation factor EF-1 alpha, immunoglobulin binding protein, rhombotin-2 oncogene protein and sex determining region Y protein. Both phage and scFv fragments secreted from infected bacteria were used as monoclonal and polyclonal reagents in Western blots. Furthermore the monoclonal reagents were used for epitope mapping (a new epitope of p53 was identified) and for staining of cells. This shows that antibody reagents for research can be readily derived from 'single pot' phage display libraries.     

Scotin: A new p63 target gene expressed during epidermal differentiation

Accumulating evidence indicates that bacteria and bacterial products promote hepatic fibrogenesis. The activation of hepatic stellate cells (HSC) plays a central role in hepatic fibrosis. Here, we demonstrate that HSC express toll-like receptor 9 (TLR9), a pattern recognition receptor that is activated by CpG motifs present specifically in bacterial DNA. Upon CpG stimulation human as well as murine HSC isolated from wild-type (TLR9+/+) mice express increased levels of the profibrogenic chemokine monocyte chemotactic protein 1 (MCP-1). In contrast, HSC isolated from TLR9 deficient (TLR9−/−) mice lacked CpG motif induced MCP-1 expression indicating the functionality of TLR9 in HSC. Bile duct ligation revealed significantly lower hepatic MCP-1 and collagen expression and less hepatic fibrosis in TLR9−/− compared to TLR9+/+ mice. In addition, the expression of hepatic α-smooth-muscle actin, a known marker for HSC activation, was reduced in TLR9−/− mice indicating that bacterial DNA induces the activation of HSC and therefore promotes hepatic fibrosis.     

Observation of correlated X-ray scattering at atomic resolution

Tools to study disordered systems with local structural order, such as proteins in solution, remain limited. Such understanding is essential for e.g. rational drug design. Correlated X-ray scattering (CXS) has recently attracted new interest as a way to leverage next-generation light sources to study such disordered matter. The CXS experiment measures angular correlations of the intensity caused by the scattering of X-rays from an ensemble of identical particles, with disordered orientation and position. Averaging over 15 496 snapshot images obtained by exposing a sample of silver nanoparticles in solution to a micro-focused synchrotron radiation beam, we report on experimental efforts to obtain CXS signal from an ensemble in three dimensions. A correlation function was measured at wide angles corresponding to atomic resolution that matches theoretical predictions. These preliminary results suggest that other CXS experiments on disordered ensembles—such as proteins in solution—may be feasible in the future.     

Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase

Diminished nitric oxide (NO) bioactivity and enhanced peroxynitrite formation have been implicated as major contributors to atherosclerotic vascular dysfunctions. Hallmark reactions of peroxynitrite include the accumulation of 3-nitrotyrosine (3-NT) in proteins and oxidation of the NO synthase (NOS) cofactor, tetrahydrobiopterin (BH(4)). The present study sought to 1) quantify the extent to which 3-NT accumulates and BH(4) becomes oxidized in organs of apolipoprotein E-deficient (ApoE(-/-)) atherosclerotic mice and 2) determine the specific contribution of inducible NOS (iNOS) to these processes. Whereas protein 3-NT and oxidized BH(4) were undetected or near the detection limit in heart, lung, and kidney of 3-wk-old ApoE(-/-) mice or ApoE(-/-) mice fed a regular chow diet for 24 wk, robust accumulation was evident after 24 wk on a Western (atherogenic) diet. Since 3-NT accumulation was diminished 3- to 20-fold in heart, lung, and liver in ApoE(-/-) mice missing iNOS, iNOS-derived species are involved in this reaction. In contrast, iNOS-derived species did not contribute to elevated protein 3-NT formation in kidney or brain. iNOS deletion also afforded marked protection against BH(4) oxidation in heart, lung, and kidney of atherogenic ApoE(-/-) mice but not in brain or liver. These findings demonstrate that iNOS-derived species are increased during atherogenesis in ApoE(-/-) mice and that these species differentially contribute to protein 3-NT accumulation and BH(4) oxidation in a tissue-selective manner. Since BH(4) oxidation can switch the predominant NOS product from NO to superoxide, we predict that progressive NOS uncoupling is likely to drive atherogenic vascular dysfunctions.     

Synthetic polyploid production of Miscanthus sacchariflorus,Miscanthus sinensis,and Miscanthus x giganteus

Plants from the genus Miscanthus are potential renewable sources of lignocellulosic biomass for energy production. A potential strategy for Miscanthus crop improvement involves interspecific manipulation of ploidy levels to generate superior germplasm and to circumvent reproductive barriers for the introduction of new genetic variation into core germplasm. Synthetic autotetraploid lines of Miscanthus sacchariflorus and Miscanthus sinensis, and autoallohexaploid Miscanthus x giganteus were produced in tissue culture from oryzalin treatments to seed‐ and immature inflorescence‐derived callus lines. This is the first report of the genome doubling of diploid M. sacchariflorus. Genome doubling of diploid M. sinensis, M. sacchariflorus, and triploid M. x giganteus to generate tetraploid and hexaploid lines was confirmed by stomata size, nuclear DNA content, and chromosome counts. A putative pentaploid line was also identified among the M. x giganteus synthetic polyploid lines by nuclear DNA content and chromosome counts. Comparisons of phenotypic performance of synthetic polyploid lines with their diploid and triploid progenitors in the greenhouse found species‐specific differences in plant tiller number, height, and flowering time among the doubled lines. Stem diameter tended to increase after polyploidization but there were no significant improvements in biomass traits. Under field conditions, M. x giganteus synthetic hexaploid lines showed greater phenotypic variation, in terms of plant height, stem diameter, and tiller number, than their progenitor lines. Production of synthetic autopolyploid lines displaying significant phenotypic variation suggests that ploidy manipulation can introduce useful genetic diversity in the limited Miscanthus germplasm currently available in the United States. The role of polyploidization in the evolution and breeding of the genus Miscanthus is discussed.