bluuebunny/crossref_metadata_2025 huggingface dataset:
Social Networks: Their Impact on the Innovative Behaviour of Small Service Firms
Authors: Shaw Eleanor
Published: September 2003

This paper presents and discusses some findings of a research study that applied social network theory to small, professional business service firms. These findings demonstrate that social networks impact upon the innovative behaviour of small firms. They reveal that through the innovative use of social networks, small, professional business service firms are able to expand their customer and resource base while minimising the costs involved. The paper draws attention to the contents of the social networks in which a purposive sample of graphic design agencies are embedded. It demonstrates that multiplex relationships, particularly with individuals holding broker positions within these networks, are perceived to be important to innovative behaviour. The paper concludes by suggesting a number of recommendations for owner-managers, policymakers and researchers.
Mapping Innovation Networks
Authors: Conway Steve , Steward Fred
Published: September 2003

This paper outlines a detailed and systematic method for revealing and mapping out the network mobilised in the development of a discrete innovation. This is termed a focal action-set. Important to the utility of this approach has been the development of a set of conventions for the graphical expression of the network and its components: actors, links and flows. It is argued that the network graphic provides a powerful, though under-utilised, tool for the representation of relational data. It may be employed, for example, to reveal variations in network configuration and to highlight key networking or boundary-spanning actors. The network mapping approach is illustrated through three cases of small firm innovation drawn from a wider investigation of award-winning technological innovations. A comparison between the network maps show a variation in the key boundary-spanning interactions, which is related to the organisational background of the entrepreneurial actor.
The Management Ladder for Recent Engineering Graduates in Canada
Authors: Lavoie Marie , Finnie Ross
Published: September 2003

Engineers play a crucial role in the growing complexity of the innovation process and in an economy's national system of innovation. This paper focuses on the role of engineers as managers. It is based on the understanding that the rising technical complexily of the activities of most enterprises and the central role of technology to economic performance has made it increasingly important to bring engineers into all levels of management activities. We use longitudinal data on three recent cohorts of Canadian engineering graduates to document the extent and nature of the flows into engineering and non-engineering management positions, and to compare various outcomes (earnings levels, job satisfaction, skill use and overall evaluation of the educational programme) associated with these different career paths using both static and dynamic perspectives. We are thus able to assess the general attractiveness of the management ladder for engineering graduates and identify some implications of the outcomes for the accumulation of technology.
The Emerging Internet Retailing Market as a Nested Diffusion Process
Authors: Jimeniz Ed , Greenstein Shane
Published: September 2003

In this essay, we analyse the diffusion of the Internet and online retailing within the standard framework of diffusion to heterogeneous consumers. We show that many conditions favour the diffusion of Internet retailing in the short run, but not in the long run. We argue that the standard framework needs to account for the "nested" diffusion process. That is, the diffusion of online retailing depends on the diffusion of many other goods, whose underlying diffusion process is also changing. An understanding of these interrelated processes leads to a richer understanding of the prospects for the long-term diffusion of online retailing.
The Superweight Project Team and Manager
Authors: Karlsson Christer , Nellore Rajesh
Published: September 2003

This paper presents a model for managing product development projects in which new strategic platforms that are of paramount importance to a company are developed. The model incorporales a superweight manager who manages a "live or die" strategic programme across different projects. From this study, an additional model emerges besides the four generic types of product development, project organisations and leadership presented by Clark and Wheelwright (1993a). The analysis was conducted by screening data into five categories, namely, strategic control of the project, resource allocation, organisational structure, targets and leadership. The data were collected through interviews and validated by triangulation and internal seminars.
Corporate Technological Specialisation in the European Information and Communications Technology Industry
Authors: Santangelo Grazia D.
Published: September 2003

This paper aims to test whether the same technological characteristics specific to the European ICT industry emerged over time in terms of large firms' profiles of specialisation. Against the background of an ongoing European integration process, the analysis takes into account the role played by country-specific factors. The increasing overlap between the ICT technological specialisation profiles of European multi-nationals seems to be the major finding of this paper. European technology policy might be identified as one of the factors explaining this pattern without, however, disregarding the broad impact of European integration, which has increased the extent of market-based and technology-based interaction between firms.
Assessing Organisational Creativity: An Innovative Benchmarking Approach
Authors: Rickards Tudor
Published: September 2003

Organisational creativity remains an ill-defined concept. Studies have failed to arrive at a convincing general theory of creativity and, more recently, attention has turned to the possibilities of middle-range theories in which creativity is treated as a context-specific phenomenon. A new approach for exploring the nature of creativity of organisations is reported with preliminary empirical results. The method draws on signalling theory applied to a database of companies generated from citations and executive nominations. Companies such as 3M, IBM, Sony, Disney and Proctor & Gamble were found to yield strong and frequent signals over extended time periods. Strong signals have also been detected from younger firms such as Microsoft, Virgin and Nike. The approach offers the possibility of industry-specific benchmarking for corporate creativity, and for testing the relationship between an organisation's creativity, innovativeness and other change-related features.
Firm Innovation and Region: The Role of Space in Innovation Processes
Authors: Koschatzky Knut
Published: September 2003

Based on theoretical reflections about the importance of regions in firm innovation, it is the aim of this paper to assess the probability, as well as the degree, that structural (firm internal) and regional characteristics, such as the type of region, agglomeration economies, regional and inter-regional networking, account for the undertaking of product and process innovations. Guided by four core hypotheses incorporating different theoretical arguments, logistic regression models for urban, intermediate and peripheral regions are set up to test the explanatory contribution of firm-related and regional variables in the realisation of innovations in different regional environments. The data used in this paper originate from an industrial innovation survey carried out in several German regions and two French regions. It will be shown that for firms located in the regions under investigation, "space" clearly matters in innovation. However, this takes place more on a perceptive rather than on a politically defined territorial basis.
Developing Continuous Improvement Capability
Authors: Bessant John
Published: September 2003

Dealing with complex and uncertain environments requires a steady stream of innovation as well as occasional radical transition. Developing mechanisms to secure such continuous improvement (CI) is seen as a major strategic priority for many organisations. In particular, it raises the challenge of increasing employee involvement in the innovation process and of mobilising widespread problem-solving and learning behaviour. This paper reports on a major five-year research programme in the United Kingdom which explores the implementation of high involvement incremental innovation activities. It presents a reference model developed in this work for helping position and guide organisations in their implementation of CI.
Learning and Innovation Management in Project-Based, Service-Enhanced Firms
Authors: Gann David M. , Salter Ammon
Published: September 2003

This paper explores the management of innovation in project-based firms. Our research indicates that the traditional boundary between manufacturing and services is becoming obsolete as new forms of manufacturing emerge to supply physical products packaged together with intangible services. Many complex products are now designed, produced and operated as discrete or small batch projects, leading to a growth in firms specialising in project-based activities. These range from the provision of specialist services to co-ordination and systems integration. Not enough is known about how project-based firms manage technology. This paper attempts to develop a framework for understanding the dynamics of project-based firms. It offers a new approach to understanding how they improve performance by focusing on the development of technical capabilities in the context of the provision of enhanced services.
Brands, Innovation and Growth: A Pims Study of Brand Value
Authors: Clayton Tony , Turner Graham
Published: September 2003

New research on the behaviour and performance of over 200 fast-moving consumer businesses selling through multiple outlets show that: (i) the "economic case" for branding can be demonstrated — there is evidence that brands can help producers bring new products and services to market, and that they help consumers exercise effective choice of "value for money"; (ii) branded producers are more innovative than their non-branded counterparts; (iii) branded producers typically create significantly more value added from investment in innovation; and (iv) non-price competition is particularly strong in the branded sector, with the key drivers of growth for individual businesses being improving value position, innovation advantage and reputation. Branded product markets show these "rules" for business growth much more clearly than businesses in the economy as a whole. In branded businesses, we can identify the impact of investment in intangibles — communication and technology development — through the strengthening of capabilities, the building of intangible business assets in the form of reputation, innovative edge and value advantage. This comprises a model for innovation which is both statistically valid and endorsed by practising managers.
An Analysis of the Relationship Between Publishing Activity and Internal Knowledge Development
Authors: Mcmillan G. Steven
Published: September 2003

Previous research has explored the value of using patent citations, versus simple patent counts, as indicators of innovative value. However, little work has delved into whether a company's patent citations are to its own patents or to external ones. This study examines the relationship between publishing and patenting using patent citation analysis that is separated into internal and external cites, with self-citations as a measure of internal knowledge development. Its results are that publishing patterns and internal knowledge development are correlated, which may provide a different view of Cohen and Levinthal's absorptive capacity model. In addition, these findings' plausibility was confirmed through an interview with a practising research manager.
Laboratory X-Ray Astrophysics
Authors: Beiersdorfer Peter
Published: September 2003

▪ Abstract  Targeted laboratory astrophysics measurements are being conducted to address the needs of X-ray astronomy. The measurements are producing large sets of reliable atomic data, which include ionization and recombination cross sections for charge balance calculations, as well as line lists, excitation cross sections, and dielectronic recombination rates for interpreting X-ray line formation. Additional experiments focus on resolving specific puzzles posed by astrophysical observations, as well as on calibrating existing and developing new X-ray line diagnostics. We discuss the types of data produced and illustrate how the laboratory measurements support such missions as ASCA, EUVE, Chandra, XMM, and ASTRO-E2.
Quantitative Spectroscopy of Photoionized Clouds
Authors: Ferland Gary J.
Published: September 2003

▪ Abstract  Photoionized clouds are ubiquitous. They define the endpoints of stellar evolution (H II regions and planetary nebulae), constitute the interstellar and intergalactic media, and are found in high redshift quasars and star-forming galaxies. The spectra of these objects are dominated by emission lines that are sensitive to details of the emitting gas. These details include the microscopic atomic processes that cause the gas to glow; the density, composition, and temperature of the gas; and the radiation field of the central continuum source. Large-scale numerical codes that incorporate all the needed physics and predict the observed spectrum have become essential tools in understanding these objects. This article reviews the current status of the numerical simulations of emitting gas, with particular emphasis on photoionized clouds and the underlying simplicity that governs these nebulae; the types of questions that can be addressed by today's codes; and the big questions that remain unanswered.
Interstellar Dust Grains
Authors: Draine B.T.
Published: September 2003

▪ Abstract  This review surveys the observed properties of interstellar dust grains: the wavelength-dependent extinction of starlight, including absorption features, from UV to infrared; optical luminescence; infrared emission; microwave emission; optical, UV, and X-ray scattering by dust; and polarization of starlight and of infrared emission. The relationship between presolar grains in meteorites and the interstellar grain population is discussed. Candidate grain materials and abundance constraints are considered. A dust model consisting of amorphous silicate grains, graphite grains, and polycyclic aromatic hydrocarbons is compared with observed emission and scattering. Some issues concerning evolution of interstellar dust are discussed.
Embedded Clusters in Molecular Clouds
Authors: Lada Charles J. , Lada Elizabeth A.
Published: September 2003

▪ Abstract  Stellar clusters are born embedded within giant molecular clouds (GMCs) and during their formation and early evolution are often only visible at infrared wavelengths, being heavily obscured by dust. Over the past 15 years advances in infrared detection capabilities have enabled the first systematic studies of embedded clusters in galactic molecular clouds. In this article we review the current state of empirical knowledge concerning these extremely young protocluster systems. From a survey of the literature we compile the first extensive catalog of galactic embedded clusters. We use the catalog to construct the mass function and estimate the birthrate for embedded clusters within ∼2 kpc of the sun. We find that the embedded cluster birthrate exceeds that of visible open clusters by an order of magnitude or more indicating a high infant mortality rate for protocluster systems. Less than 4–7% of embedded clusters survive emergence from molecular clouds to become bound clusters of Pleiades age. The vast majority (90%) of stars that form in embedded clusters form in rich clusters of 100 or more members with masses in excess of 50 M⊙. Moreover, observations of nearby cloud complexes indicate that embedded clusters account for a significant (70–90%) fraction of all stars formed in GMCs. We review the role of embedded clusters in investigating the nature of the initial mass function (IMF) that, in one nearby example, has been measured over the entire range of stellar and substellar mass, from OB stars to substellar objects near the deuterium burning limit. We also review the role embedded clusters play in the investigation of circumstellar disk evolution and the important constraints they provide for understanding the origin of planetary systems. Finally, we discuss current ideas concerning the origin and dynamical evolution of embedded clusters and the implications for the formation of bound open clusters.
The Internal Rotation of the Sun
Authors: Thompson Michael J. , Christensen-Dalsgaard Jørgen , Miesch Mark S. , Toomre Juri
Published: September 2003

▪ Abstract  Helioseismology has transformed our knowledge of the Sun's rotation. Earlier studies revealed the Sun's surface rotation, but now a detailed observational picture has been built up of the internal rotation of our nearest star. Unlike the predictions of stellar-evolution models, the radiative interior is found to rotate roughly uniformly. The rotation within the convection zone is also very different from prior expectations, which had been that the rotation rate would depend primarily on the distance from the rotation axis. Layers of rotational shear have been discovered at the base of the convection zone and in the subphotospheric layers. Studies of the time variation of rotation have uncovered zonal-flow bands, extending through a substantial fraction of the convection zone, which migrate over the course of the solar cycle, and there are hints of other temporal variations and of a jet-like structure. At the same time, building on earlier work with mean-field models, researchers have made great progress in supercomputer simulations of the intricate interplay between turbulent convection and rotation in the Sun's interior. Such studies are beginning to transform our understanding of how rotation organizes itself in a stellar interior.
My Life in Astrophysics
Authors: Bethe Hans A.
Published: September 2003

▪ Abstract  Astrophysics has been an important part of my personal and scientific life three times. The first was in 1938 when I did work on stellar energy production. The second was a joyful period nearly 30 years later when that work was rewarded with the Nobel Prize in physics. And the third has lasted over the time since my retirement in 1975 during which Gerry Brown and I have had a very satisfactory collaboration exploring various aspects of supernovae and, more recently, binary pairs.
High-Resolution X-Ray Spectroscopy withChandraandXMM-Newton
Authors: Paerels Frederik B.S. , Kahn Steven M.
Published: September 2003

▪ Abstract  The launches of the Chandra X-Ray Observatory in June 1999 and the XMM-Newton Observatory in December 1999 opened a new era in X-ray astronomy. Both of these missions incorporate novel diffraction grating spectrometers that are providing the first high-resolution X-ray spectra of most classes of astrophysical sources. The spectra obtained to date exhibit a wealth of discrete detail, yielding sensitive constraints on physical conditions in the emitting plasmas. We review the essential characteristics of these instruments, the basics of X-ray spectral formation in cosmic sources, and the exciting new results that have emerged from Chandra and XMM-Newton grating observations of a wide variety of astrophysical systems.
Post-AGB Stars
Authors: Van Winckel Hans
Published: September 2003

▪ Abstract  In this contribution, a review is presented on the ample data obtained on post-AGB stars, both on the central stars and their circumstellar material. The fast evolutionary phase is characterized by a rapid change in the properties of the objects, but the variety is so large that there is yet no clear consensus on how the detailed studies of individual objects are linked together by evolutionary channels. The absence of strong molecular veiling in the photospheres of the central stars, together with a spread in intrinsic metallicity make post-AGB stars very useful in constraining AGB chemical evolutionary models. We discuss the surprisingly wide variety of chemical signatures observed. The onset in the creation process of the panoply of structures and shapes observed in planetary nebulae occurs during the short post-AGB evolution, but the physical nature of the processes involved is still badly understood. In the rapidly growing field of circumstellar mineralogy, post-AGB stars have their story to tell and also the molecular envelope changes significantly due to dilution and hardening of the stellar radiation. The real-time evolution of some objects suffering a late thermal flash is reviewed and their possible link to other hydrogen-deficient objects is discussed. Any review on stellar evolution has a section on binaries and this contribution is no exception because binaries make up a significant fraction of the post-AGB stars known to date.
Massive Stars in the Local Group: Implications for Stellar Evolution and Star Formation
Authors: Massey Philip
Published: September 2003

▪ Abstract  The galaxies of the Local Group serve as important laboratories for understanding the physics of massive stars. Here I discuss what is involved in identifying various kinds of massive stars in nearby galaxies: the hydrogen-burning O-type stars and their evolved He-burning evolutionary descendants, the luminous blue variables, red supergiants, and Wolf-Rayet stars. Primarily I review what our knowledge of the massive star population in nearby galaxies has taught us about stellar evolution and star formation. I show that the current generation of stellar evolutionary models do well at matching some of the observed features and provide a look at the sort of new observational data that will provide a benchmark against which new models can be evaluated.
Evolution of a Habitable Planet
Authors: Kasting James F. , Catling David
Published: September 2003

▪ Abstract  Giant planets have now been discovered around other stars, and it is only a matter of time until Earth-sized planets are detected. Whether any of these planets are suitable for life depends on their volatile abundances, especially water, and on their climates. Only planets within the liquid-water habitable zone (HZ) can support life on their surfaces and, thus, can be analyzed remotely to determine whether they are inhabited. Fortunately, current models predict that HZs are relatively wide around main-sequence stars not too different from our sun. This conclusion is based on studies of how our own planet has evolved over time. Earth's climate has remained conducive to life for the past 3.5 billion years or more, despite a large increase in solar luminosity, probably because of previous higher concentrations of CO2and/or CH4. Both these gases are involved in negative feedback loops that help to stabilize the climate. In addition to these topics, we also briefly discuss the rise of atmospheric O2and O3, along with their possible significance as indicators of life on other planets.
Cool White Dwarfs
Authors: Hansen Brad M.S. , Liebert James
Published: September 2003

▪ Abstract  Old, cool white dwarfs convey valuable information about the early history of our Galaxy. They have been used to determine the age of the galactic disk, several open clusters, and a globular cluster. We review the current understanding of the physics of cool white dwarfs, including their mass distribution, chemical evolution, magnetism, and cooling. We also examine the role of white dwarfs as tracers of various stellar populations, both in terms of observational searches and theoretical models.
Enhanced Angular Momentum Transport in Accretion Disks
Authors: Balbus Steven A.
Published: September 2003

▪ Abstract  The status of our current understanding of angular momentum transport in accretion disks is reviewed. The last decade has seen a dramatic increase both in the recognition of key physical processes and in our ability to carry through direct numerical simulations of turbulent flow. Magnetic fields have at once powerful and subtle influences on the behavior of (sufficiently) ionized gas, rendering them directly unstable to free energy gradients. Outwardly descreasing angular velocity profiles are unstable. The breakdown of Keplerian rotation into MHD turbulence may be studied in some numerical detail, and key transport coefficients may be evaluated. Chandra observations of the Galactic Center support the existence of low luminosity accretion, which may ultimately prove amenable to global three-dimensional numerical simulation.
Mass Loss from the Nuclei of Active Galaxies
Authors: Crenshaw D. Michael , Kraemer Steven B. , George Ian M.
Published: September 2003

▪ Abstract  Blueshifted absorption lines in the UV and X-ray spectra of active galaxies reveal the presence of massive outflows of ionized gas from their nuclei. The “intrinsic” UV and X-ray absorbers show large global covering factors of the central continuum source, and the inferred mass loss rates are comparable to the mass accretion rates. Many absorbers show variable ionic column densities, which are attributed to a combination of variable ionizing flux and motion of gas into and out of the line of sight. Detailed studies of the intrinsic absorbers, with the assistance of monitoring observations and photoionization models, provide constraints on their kinematics, physical conditions, and locations relative to the central continuum source, which range from the inner nucleus (∼0.01 pc) to the galactic disk or halo (∼10 kpc). Dynamical models that make use of thermal winds, radiation pressure, and/or hydromagnetic flows have reached a level of sophistication that permits comparisons with the observational constraints.
Hot Gas in and Around Elliptical Galaxies
Authors: Mathews William G. , Brighenti Fabrizio
Published: September 2003

▪ Abstract  We review the origin, evolution, and physical nature of hot gas in elliptical galaxies and associated galaxy groups. Unanticipated recent X-ray observations with Chandra and XMM indicate much less cooling than previously expected. Consequently, many long-held assumptions must be reexamined or discarded and new approaches must be explored. Chief among these are the role of heating by active galactic nuclei, the influence of radio lobes on the hot gas, details of the cooling process, possible relation between the hot and colder gas in elliptical galaxies, and the complexities of stellar enrichment of the hot gas.
Weak Gravitational Lensing by Large-Scale Structure
Authors: Refregier Alexandre
Published: September 2003

▪ Abstract  Weak gravitational lensing provides a unique method to map directly the distribution of dark matter in the universe and to measure cosmological parameters. This cosmic-shear technique is based on the measurement of the weak distortions that lensing induces in the shape of background galaxies as photons travel through large-scale structures. This technique is now widely used to measure the mass distribution of galaxy clusters and has recently been detected in random regions of the sky. In this review, we present the theory and observational status of cosmic shear. We describe the principles of weak lensing and the predictions for the shear statistics in favored cosmological models. Next, we review the current measurements of cosmic shear and show how they constrain cosmological parameters. We then describe the prospects offered by upcoming and future cosmic-shear surveys as well as the technical challenges that have to be met for the promises of cosmic shear to be fully realized.
Action at a Distance and Cosmology: A Historical Perspective
Authors: Narlikar J.V.
Published: September 2003

▪ Abstract  The first law of theoretical physics, the Newtonian law of gravitation, relies on the concept of action at a distance. The success of this law led to the concept being applied to electricity and magnetism, which were next to be explored in depth. Here the action at a distance had a limited success and ultimately had to be abandoned in favor of the increasingly more popular field theory. Nevertheless, in the 1940s, an attempt was made to revive the concept of action at a distance in a relativistically invariant way by Wheeler & Feynman (1945 , 1949) . It inspired a series of investigations in both electrodynamics and gravity in which the field concept was not used but the interaction was described as taking place directly between particles. As it impinged very intimately on cosmology, Hoyle was keenly interested in it. This review discusses the work by Hoyle, the author, and others on the development of electrodynamics and gravitation as direct particle theories. In this review, the author discusses how the work was started and went through stages of increasing sophistication, e.g., extending the Wheeler-Feynman electrodynamics to curved spacetime, its consequences in different cosmologies, and the issues arising from its quantization. The resolution of ultraviolet divergences in quantum electrodynamics is also briefly discussed. The parallel development of a Machian theory of gravitation followed the lead from electrodynamics. In both theories one sees a strong link between the large-scale structure of the universe and local physics, as might be expected from an action-at-a-distance framework.
Blood Vessel Constitutive Models—1995–2002
Authors: Vito Raymond P. , Dixon Stacey A.
Published: September 2003

▪ Abstract  Knowledge of blood vessel mechanical properties is fundamental to the understanding of vascular function in health and disease. Analytic results can help physicians in the clinic, both in designing and in choosing appropriate therapies. Understanding the mechanical response of blood vessels to physiologic loads is necessary before ideal therapeutic solutions can be realized. For this reason, blood vessel constitutive models are needed. This article provides a critical review of recent blood vessel constitutive models, starting with a brief overview of the structure and function of arteries and veins, followed by a discussion of experimental techniques used in the characterization of material properties. Current models are classified by type, including pseudoelastic, randomly elastic, poroelastic, and viscoelastic. Comparisons are presented between the various models and existing experimental data. Applications of blood vessel constitutive models are also briefly presented, followed by the identification of future directions in research.
Engineered Nanomaterials for Biophotonics Applications: Improving Sensing, Imaging, and Therapeutics
Authors: West Jennifer L. , Halas Naomi J.
Published: September 2003

▪ Abstract  Advances in chemistry and physics are providing an expanding array of nanostructured materials with unique and powerful optical properties. These nanomaterials provide a new set of tools that are available to biomedical engineers, biologists, and medical scientists who seek new tools as biosensors and probes of biological fluids, cells, and tissue chemistry and function. Nanomaterials are also being used to develop optically controlled devices for applications such as modulated drug delivery as well as optical therapeutics. This review discusses applications that have been successfully demonstrated using nanomaterials including semiconductor nanocrystals, gold nanoparticles, gold nanoshells, and silver plasmon resonant particles.
Neural Tissue Engineering: Strategies for Repair and Regeneration
Authors: Schmidt Christine E. , Leach Jennie Baier
Published: September 2003

▪ Abstract  Nerve regeneration is a complex biological phenomenon. In the peripheral nervous system, nerves can regenerate on their own if injuries are small. Larger injuries must be surgically treated, typically with nerve grafts harvested from elsewhere in the body. Spinal cord injury is more complicated, as there are factors in the body that inhibit repair. Unfortunately, a solution to completely repair spinal cord injury has not been found. Thus, bioengineering strategies for the peripheral nervous system are focused on alternatives to the nerve graft, whereas efforts for spinal cord injury are focused on creating a permissive environment for regeneration. Fortunately, recent advances in neuroscience, cell culture, genetic techniques, and biomaterials provide optimism for new treatments for nerve injuries. This article reviews the nervous system physiology, the factors that are critical for nerve repair, and the current approaches that are being explored to aid peripheral nerve regeneration and spinal cord repair.
Metabolic Engineering: Advances in Modeling and Intervention in Health and Disease
Authors: Yarmush Martin L. , Banta Scott
Published: September 2003

▪ Abstract  The field of metabolic engineering encompasses a powerful set of tools that can be divided into (a) methods to model complex metabolic pathways and (b) techniques to manipulate these pathways for a desired metabolic outcome. These tools have recently seen increased utility in the medical arena, and this paper aims to review significant accomplishments made using these approaches. The modeling of metabolic pathways has been applied to better understand disease-state physiology in a variety of cellar, subcellular, and organ systems, including the liver, heart, mitochondria, and cancerous cells. Metabolic pathway engineering has been used to generate cells with novel biochemical functions for therapeutic use, and specific examples are provided in the areas of glycosylation engineering and dopamine-replacement therapy. In order to document the potential of applying both metabolic modeling and pathway manipulation, we describe pertinent advances in the field of diabetes research. Undoubtedly, as the field of metabolic engineering matures and is applied to a wider array of problems, new advances and therapeutic strategies will follow.
Mass Transport in Arteries and the Localization of Atherosclerosis
Authors: Tarbell John M.
Published: September 2003

▪ Abstract  Atherosclerosis is a disease of the large arteries that involves a characteristic accumulation of high-molecular-weight lipoprotein in the arterial wall. This review focuses on the mass transport processes that mediate the focal accumulation of lipid in arteries and places particular emphasis on the role of fluid mechanical forces in modulating mass transport phenomena. In the final analysis, four mass transport mechanisms emerge that may be important in the localization of atherosclerosis: blood phase controlled hypoxia, leaky endothelial junctions, transient intercellular junction remodeling, and convective clearance of the subendothelial intima and media. Further study of these mechanisms may contribute to the development of therapeutic strategies for atherosclerotic diseases.
Modeling Total Heart Function
Authors: Hunter Peter J. , Pullan Andrew J. , Smaill Bruce H.
Published: September 2003

▪ Abstract  Computational models of the electrical and mechanical function of the heart are reviewed. These models attempt to explain the integrated function of the heart in terms of ventricular anatomy, the structure and material properties of myocardial tissue, the membrane ion channels, and calcium handling and myofilament mechanics of cardiac myocytes. The models have established the computational framework for linking the structure and function of cardiac cells and tissue to the integrated behavior of the intact heart, but many more aspects of physiological function, including metabolic and signal transduction pathways, need to be included before significant progress can be made in understanding many disease processes.
The Engineering of Gene Regulatory Networks
Authors: Kærn Mads , Blake William J. , Collins J.J.
Published: September 2003

▪ Abstract  The rapid accumulation of genetic information and advancement of experimental techniques have opened a new frontier in biomedical engineering. With the availability of well-characterized components from natural gene networks, the stage has been set for the engineering of artificial gene regulatory networks with sophisticated computational and functional capabilities. In these efforts, the ability to construct, analyze, and interpret qualitative and quantitative models is becoming increasingly important. In this review, we consider the current state of gene network engineering from a combined experimental and modeling perspective. We discuss how networks with increased complexity are being constructed from simple modular components and how quantitative deterministic and stochastic modeling of these modules may provide the foundation for accurate in silico representations of gene regulatory network function in vivo.
Structural, Functional, and Molecular MR Imaging of the Microvasculature
Authors: Neeman Michal , Dafni Hagit
Published: September 2003

▪ Abstract  Magnetic resonance imaging (MRI) is widely applied for functional imaging of the microcirculation and for functional and structural studies of the microvasculature. The interest in the capabilities of MRI in noninvasively monitoring changes in vascular structure and function expanded over the past years, with specific efforts directed toward the development of novel imaging methods for quantification of angiogenesis. Molecular imaging approaches hold promise for further expansion of the ability to characterize the microvasculature. Exciting applications for MRI are emerging in the study of the biology of microvessels and in the evaluation of potential pharmaceutical modulators of vascular function and development, and preclinical MRI tools can serve for the design of mechanism-of-action-based noninvasive clinical methods for monitoring response to therapy. The aim of this review is to provide a current snapshot of recent developments in this rapidly evolving field.
Temporal Dynamics of Brain Anatomy
Authors: Toga Arthur W. , Thompson Paul M.
Published: September 2003

▪ Abstract  The brain changes profoundly in structure and function during development and as a result of diseases such as the dementias, schizophrenia, multiple sclerosis, and tumor growth. Strategies to measure, map, and visualize these brain changes are of immense value in basic and clinical neuroscience. Algorithms that map brain change with sufficient spatial and temporal sensitivity can also assess drugs that aim to decelerate or arrest these changes. In neuroscience studies, these tools can reveal subtle brain changes in adolescence and old age and link these changes with measurable differences in brain function and cognition. Early detection of brain change in patients at risk for dementia; tumor recurrence; or relapsing-remitting conditions, such as multiple sclerosis, is also vital for optimizing therapy. We review a variety of mathematical and computational approaches to detect structural brain change with unprecedented sensitivity, both spatially and temporally. The resulting four-dimensional (4-D) maps of brain anatomy are warehoused in population-based brain atlases. Here, statistical tools compare brain changes across subjects and across populations, adjusting for complex differences in brain structure. Brain changes in an individual can be compared with a normative database comprised of subjects matched for age, gender, and other demographic factors. These dynamic brain maps offer key biological markers for understanding disease progression and testing therapeutic response. The early detection of disease-related brain changes is also critical for possible pre-emptive intervention before the ravages of disease have set in.
The Tissue Engineering Puzzle: A Molecular Perspective
Authors: Vogel Viola , Baneyx Gretchen
Published: September 2003

▪ Abstract  The inability of biomaterial scaffolds to functionally integrate into surrounding tissue is one of the major roadblocks to developing new biomaterials and tissue-engineering scaffolds. Despite considerable advances, current approaches to engineering cell-surface interactions fall short in mimicking the complexity of signals through which surrounding tissue regulates cell behavior. Cells adhere and interact with their extracellular environment via integrins, and their ability to activate associated downstream signaling pathways depends on the character of adhesion complexes formed between cells and their extracellular matrix. In particular, α5β1 and αvβ3 integrins are central to regulating downstream events, including cell survival and cell-cycle progression. In contrast to previous findings that αvβ3 integrins promote angiogenesis, recent evidence argues that αvβ3 integrins may act as negative regulators of proangiogenic integrins such as α5β1. This suggests that fibronectin is critical for scaffold vascularization because it is the only mammalian adhesion protein that binds and activates α5β1 integrins. Cells are furthermore capable of stretching fibronectin matrices such that the protein partially unfolds, and recent computational simulations provide structural models of how mechanical stretching affects fibronectin function. We propose a model whereby excessive tension generated by cells in contact to biomaterials may in fact render fibronectin fibrils nonangiogenic and potentially inhibit vascularization. The model could explain why current biomaterials independent of their surface chemistries and textures fail to vascularize.
Time-Reversal Acoustics in Biomedical Engineering
Authors: Fink Mathias , Montaldo Gabriel , Tanter Mickael
Published: September 2003

▪ Abstract  Time reversal is a very powerful method for focusing through complex and heterogeneous media and shows very promising results in biomedical applications. In this paper, we review some of the main applications investigated during the past decade. An iterative implementation of the time-reversal process allows tracking gallstones in real time during lithotripsy treatments. In this application domain, a smart exploitation of the reverberations in solid waveguides permits the focusing of high-amplitude ultrasonic shock waves with a small number of transducers. Finally, because time reversal is able to correct the strong distortions induced by the skull bone on ultrasonic propagation, this adaptive focusing technique is very promising for ultrasonic hyperthermia brain therapy.
Cochlear Implants: Some Likely Next Steps
Authors: Wilson Blake S. , Lawson Dewey T. , Müller Joachim M. , Tyler Richard S. , Kiefer Jan
Published: September 2003

▪ Abstract  The history of cochlear implants is marked by large improvements in performance, especially over the past two decades and especially due to the development of ever-better processing strategies. Although the progress to date has been substantial, present devices still do not restore normal speech reception, even for top performers and particularly for listening to speech in competition with noise or other talkers. In addition, a wide range of outcomes persists, with some patients receiving little benefit using the same devices that support high levels of speech reception for others. The purpose of this review is to describe some likely possibilities for further improvement, including (a) combined electric and acoustic stimulation of the auditory system for patients with significant residual hearing, (b) use of bilateral implants, (c) a closer replication with implants of the processing steps in the normal cochlea, and (d) applications of knowledge about factors that are correlated with outcomes to help patients presently at the low end of the performance scale.
Biomonitoring with Wireless Communications
Authors: Budinger Thomas F.
Published: September 2003

▪ Abstract  Wireless biomonitoring, first used in human beings for fetal heart-rate monitoring more than 30 years ago, has now become a technology for remote sensing of patients' activity, blood pulse pressure, oxygen saturation, internal pressures, orthopedic device loading, and gastrointestinal endoscopy. Technical advances in miniaturization and wireless communications have enabled development of monitoring devices that can be made available for general use by individuals/patients and caregivers. New methods for short-range wireless communications not encumbered by radio spectrum restrictions (e.g., ultra-wideband) will enable applications of wireless monitoring without interference in ambulatory subjects, in home care, and in hospitals.
Sequence Divergence, Functional Constraint, and Selection in Protein Evolution
Authors: Fay Justin C. , Wu Chung-I
Published: September 2003

The genome sequences of multiple species has enabled functional inferences from comparative genomics. A primary objective is to infer biological functions from the conservation of homologous DNA sequences between species. A second, more difficult, objective is to understand what functional DNA sequences have changed over time and are responsible for species' phenotypic differences. The neutral theory of molecular evolution provides a theoretical framework in which both objectives can be explicitly tested. Development of statistical tests within this framework has provided insight into the evolutionary forces that constrain and in some cases change DNA sequences and the resulting patterns that emerge. In this article, we review recent work on how functional constraint and changes in protein function are inferred from protein polymorphism and divergence data. We relate these studies to our understanding of the neutral theory and adaptive evolution.
Patterns of Human Genetic Diversity: Implications for Human Evolutionary History and Disease
Authors: Tishkoff Sarah A. , Verrelli Brian C.
Published: September 2003

Since the completion of the human genome sequencing project, the discovery and characterization of human genetic variation is a principal focus for future research. Comparative studies across ethnically diverse human populations and across human and nonhuman primate species is important for reconstructing human evolutionary history and for understanding the genetic basis of human disease. In this review, we summarize data on patterns of human genetic diversity and the evolutionary forces (mutation, genetic drift, migration, and selection) that have shaped these patterns of variation across both human populations and the genome. African population samples typically have higher levels of genetic diversity, a complex population substructure, and low levels of linkage disequilibrium (LD) relative to non-African populations. We discuss these differences and their implications for mapping disease genes and for understanding how population and genomic diversity have been important in the evolution, differentiation, and adaptation of humans.
Gene Annotation: Prediction and Testing
Authors: Ashurst Jennifer L. , Collins John E.
Published: September 2003

Fifty years after the publication of DNA structure, the whole human genome sequence will be officially finished. This achievement marks the beginning of the task to catalogue every human gene and identify each of their function expression patterns. Currently, researchers estimate that there are about 30,000 human genes and approximately 70% of these can be automatically predicted using a combination of ab initio and similarity-based programs. However, to experimentally investigate every gene's function, the research community requires a high-quality annotation of alternative splicing, pseudogenes, and promoter regions that can only be provided by manual intervention. Manual curation of the human genome will be a long-term project as experimental data are continually produced to confirm or refine the predictions, and new features such as noncoding RNAs and enhancers have not been fully identified. Such a highly curated human gene-set made publicly available will be a great asset for the experimental community and for future comparative genome projects.