bluuebunny/crossref_metadata_2025 huggingface dataset:
Strategies to Evaluate the Safety of Bioengineered Foods
Authors: Delaney Bryan
Published: October 2007

A number of genetically modified (GM) crops bioengineered to express agronomic traits including herbicide resistance and insect tolerance have been commercialized. Safety studies conducted for the whole grains and food and feed fractions obtained from GM crops (i.e., bioengineered foods) bear similarities to and distinctive differences from those applied to substances intentionally added to foods (e.g., food ingredients). Similarities are apparent in common animal models, route of exposure, duration, and response variables typically assessed in toxicology studies. However, because of differences in the nutritional and physical properties of food ingredients and bioengineered foods and in the fundamental goals of the overall safety assessment strategies for these different classes of substances, there are recognizable differences in the individual components of the safety assessment process. The fundamental strategic difference is that the process for food ingredients is structured toward quantitative risk assessment whereas that for bioengineered foods is structured for the purpose of qualitative risk assessment. The strategy for safety assessment of bioengineered foods focuses on evaluating the safety of the transgenic proteins used to impart the desired trait or traits and to demonstrate compositional similarity between the grains of GM and non-GM comparator crops using analytical chemistry and, in some cases, feeding studies. Despite these differences, the similarities in the design of safety studies conducted with bioengineered foods should be recognized by toxicologists. The current paper reviews the basic principles of safety assessment for bioengineered foods and compares them with the testing strategies applied to typical food ingredients. From this comparison it can be seen that the strategies used to assess the safety of bioengineered foods are at least as robust as that used to assess the safety of typical food ingredients.
Evaluation of the Wound‐Healing Activity of Ethanolic Extract of Morinda citrifolia L. Leaf
Authors: Nayak B. Shivananda , Sandiford Steve , Maxwell Anderson
Published: October 2007

Morinda citrifolia L. (noni) is one of the most important traditional Polynesian medicinal plants. The primary indigenous use of this plant appears to be of the leaves, as a topical treatment for wound healing. The ethanol extract of noni leaves (150 mg kg−1 day−1) was used to evaluate the wound‐healing activity on rats, using excision and dead space wound models. Animals were randomly divided into two groups of six for each model. Test group animals in each model were treated with the ethanol extract of noni orally by mixing in drinking water and the control group animals were maintained with plain drinking water. Healing was assessed by the rate of wound contraction, time until complete epithelialization, granulation tissue weight and hydoxyproline content. On day 11, the extract‐treated animals exhibited 71% reduction in the wound area when compared with controls which exhibited 57%. The granulation tissue weight and hydroxyproline content in the dead space wounds were also increased significantly in noni‐treated animals compared with controls (P < 0.002). Enhanced wound contraction, decreased epithelialization time, increased hydroxyproline content and histological characteristics suggest that noni leaf extract may have therapeutic benefits in wound healing.
Influence of Puroindolines A and B Individually and in Combination on Wheat Milling and Bread Traits
Authors: Wanjugi H. W. , Martin J. M. , Giroux M. J.
Published: October 2007

Endosperm texture in wheat (Triticum aestivum L.) is determined by the Pina and Pinb genes located within the Hardness (Ha) locus on chromosome 5D. We have previously shown that Pina and Pinb can act alone to produce intermediate‐textured grain or act together to produce soft grain. The objective here was to isolate the role of PINA and PINB individually and in combination on milling and bread traits by analyzing F3 recombinant lines created by crosses between PINA and PINB null cultivars with Pina‐D1a and Pinb‐D1a overexpressing transgenic lines. Homozygous lines that contained either the Pina‐D1b/Pinb‐D1a (Pina null) or Pina‐D1a/Pinb‐D1e (Pinb null) Ha locus with or lacking transgenically added Pina or Pinb were analyzed for milling and bread traits. Addition of Pina‐D1a to Pina‐D1b/Pinb‐D1a and addition of Pinb‐D1a to Pina‐D1a/Pinb‐D1e Ha locus genotypes gave soft grain with lower flour yield, flour ash, and a higher proportion of small flour particles. Addition of Pinb‐D1a produced greater negative effects on loaf volume than addition of Pina‐D1a. Grain hardness, flour protein, flour ash, and mixograph water absorption were positively correlated, which is indicative of the complex phenotype conditioned by PINs. The results demonstrate that PIN overexpression leads to a reduction in grain hardness and reduced flour yield, flour ash, and flour particle size. PIN expression also results in reduced loaf volume and flour water absorption.
Dynamic Water Adsorption Characteristics of Distillers Dried Grains with Solubles (DDGS)
Authors: Ganesan V. , Rosentrater K. A. , Muthukumarappan K.
Published: October 2007

Distillers dried grains with solubles (DDGS) is one of the coproducts obtained from dry‐grind ethanol manufacturing. As the ethanol industry is growing exponentially, the production of DDGS has been significantly increasing as well. To optimize the use of DDGS, it has to be economically transported from one part of the country to other parts, and stored efficiently. But DDGS has some flow issues, which often makes storage and transportation very problematic. So the objective of this study was to investigate the dynamic water adsorption characteristics of DDGS with four soluble levels at four temperatures and four relative humidities. Three mathematical models were then used to fit the adsorption data (Peleg, Pilosof, and Singh‐Kulshrestha). As there was no model available for describing the water adsorption characteristics of DDGS with varying soluble levels at various temperature and relative humidity conditions, a new comprehensive model was developed. The new model, Ganesan‐Rosentrater‐Muthu (GRM) model, encompassed soluble level, temperature, and relative humidity effects, along with time and moisture content. The GRM model (R2 = 0.94; F =16503.90) provided a good description of DDGS water adsorption behavior and can be used to predict the dynamic adsorption of water in DDGS for a broad range of storage conditions.
Modeling the Flow Properties of DDGS
Authors: Ganesan V. , Rosentrater K. A. , Muthukumarappan K.
Published: October 2007

Distillers dried grains with solubles (DDGS) are an excellent source of energy, minerals, and bypass protein for ruminants. With the remarkable growth of the U.S. fuel ethanol industry in the past decade, large quantities of distillers grains are now being produced. DDGS flow is often restricted by caking and bridging during its storage and transportation. In our previous works, increased soluble and moisture levels significantly affected the flow properties of DDGS. Currently, however, there is no model available to predict the flowability of DDGS. So the objectives of this study were to thoroughly investigate the data obtained from our previous work using exploratory data analysis techniques and to develop a comprehensive model to predict the flowability of DDGS. A simple and robust model (R2 = 0.93, SE = 0.12) was developed by combining the important flow properties obtained from conventional Carr and Jenike tests using dimensional analysis and response surface modeling. However, the model developed was exclusively based on the DDGS from one ethanol plant and, as DDGS flow properties will differ with each plant, it is suggested to use this methodology to develop similar models to predict the flowability of DDGS for other plants as well.
Protein reconstitution and three‐dimensional domain swapping: Benefits and constraints of covalency
Authors: Carey Jannette , Lindman Stina , Bauer Mikael , Linse Sara
Published: October 2007

The phenomena of protein reconstitution and three‐dimensional domain swapping reveal that highly similar structures can be obtained whether a protein is comprised of one or more polypeptide chains. In this review, we use protein reconstitution as a lens through which to examine the range of protein tolerance to chain interruptions and the roles of the primary structure in related features of protein structure and folding, including circular permutation, natively unfolded proteins, allostery, and amyloid fibril formation. The results imply that noncovalent interactions in a protein are sufficient to specify its structure under the constraints imposed by the covalent backbone.
Crystal structure of an apo form of Shigella flexneri ArsH protein with an NADPH‐dependent FMN reductase activity
Authors: Vorontsov Ivan I. , Minasov George , Brunzelle Joseph S. , Shuvalova Ludmilla , Kiryukhina Olga , Collart Frank R. , Anderson Wayne F.
Published: October 2007

The arsH gene or its homologs are a frequent part of the arsenic resistance system in bacteria and eukaryotes. Although a specific biological function of the gene product is unknown, the ArsH protein was annotated as a member of the NADPH‐dependent FMN reductase family based on a conserved (T/S)XRXXSX(T/S) fingerprint motif common for FMN binding proteins. Presented here are the first crystal structure of an ArsH protein from Shigella flexneri refined at 1.7 Å resolution and results of enzymatic activity assays that revealed a strong NADPH‐dependent FMN reductase and low azoreductase activities. The ArsH apo protein has an α/β/α−fold typical for FMN binding proteins. The asymmetric unit consists of four monomers, which form a tetramer. Buried surface analysis suggests that this tetramer is likely to be the relevant biological assembly. Dynamic light scattering experiments are consistent with this hypothesis and show that ArsH in solution at room temperature does exist predominantly in the tetrameric form.
The challenge of protein structure determination—lessons from structural genomics
Authors: Slabinski Lukasz , Jaroszewski Lukasz , Rodrigues Ana P.C. , Rychlewski Leszek , Wilson Ian A. , Lesley Scott A. , Godzik Adam
Published: October 2007

The process of experimental determination of protein structure is marred with a high ratio of failures at many stages. With availability of large quantities of data from high‐throughput structure determination in structural genomics centers, we can now learn to recognize protein features correlated with failures; thus, we can recognize proteins more likely to succeed and eventually learn how to modify those that are less likely to succeed. Here, we identify several protein features that correlate strongly with successful protein production and crystallization and combine them into a single score that assesses “crystallization feasibility.” The formula derived here was tested with a jackknife procedure and validated on independent benchmark sets. The “crystallization feasibility” score described here is being applied to target selection in the Joint Center for Structural Genomics, and is now contributing to increasing the success rate, lowering the costs, and shortening the time for protein structure determination. Analyses of PDB depositions suggest that very similar features also play a role in non‐high‐throughput structure determination, suggesting that this crystallization feasibility score would also be of significant interest to structural biology, as well as to molecular and biochemistry laboratories.
Mutagenesis of the phosphate‐binding pocket of KDPG aldolase enhances selectivity for hydrophobic substrates
Authors: Cheriyan Manoj , Toone Eric J. , Fierke Carol A.
Published: October 2007

Narrow substrate specificities often limit the use of enzymes in biocatalysis. To further the development of Escherichia coli 2‐keto‐3‐deoxy‐6‐phosphogluconate (KDPG) aldolase as a biocatalyst, the molecular determinants of substrate specificity were probed by mutagenesis. Our data demonstrate that S184 is located in the substrate‐binding pocket and interacts with the phosphate moiety of KDPG, providing biochemical support for the binding model proposed on the basis of crystallographic data. An analysis of the substrate selectivity of the mutant enzymes indicates that alterations to the phosphate‐binding site of KDPG aldolase changes the substrate selectivity. We report mutations that enhance catalysis of aldol cleavage of substrates lacking a phosphate moiety and demonstrate that electrophile reactivity correlates with the hydrophobicity of the substituted side chain. These mutations improve the selectivity for unnatural substrates as compared to KDPG by up to 2000‐fold. Furthermore, the S184L KDPG aldolase mutant improves the catalytic efficiency for the synthesis of a precursor for nikkomycin by 40‐fold, making it a useful biocatalyst for the preparation of fine chemicals.
Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3
Authors: Runyon Steven T. , Zhang Yingnan , Appleton Brent A. , Sazinsky Stephen L. , Wu Ping , Pan Borlan , Wiesmann Christian , Skelton Nicholas J. , Sidhu Sachdev S.
Published: October 2007

High‐temperature requirement A (HtrA) and its homologs contain a serine protease domain followed by one or two PDZ domains. Bacterial HtrA proteins and the mitochondrial protein HtrA2/Omi maintain cell function by acting as both molecular chaperones and proteases to manage misfolded proteins. The biological roles of the mammalian family members HtrA1 and HtrA3 are less clear. We report a detailed structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3 using peptide libraries and affinity assays to define specificity, structural studies to view the molecular details of ligand recognition, and alanine scanning mutagenesis to investigate the energetic contributions of individual residues to ligand binding. In common with HtrA2/Omi, we show that the PDZ domains of HtrA1 and HtrA3 recognize hydrophobic polypeptides, and while C‐terminal sequences are preferred, internal sequences are also recognized. However, the details of the interactions differ, as different domains rely on interactions with different residues within the ligand to achieve high affinity binding. The results suggest that mammalian HtrA PDZ domains interact with a broad range of hydrophobic binding partners. This promiscuous specificity resembles that of bacterial HtrA family members and suggests a similar function for recognizing misfolded polypeptides with exposed hydrophobic sequences. Our results support a common activation mechanism for the HtrA family, whereby hydrophobic peptides bind to the PDZ domain and induce conformational changes that activate the protease. Such a mechanism is well suited to proteases evolved for the recognition and degradation of misfolded proteins.
Polymer‐driven crystallization
Authors: Nauli Sehat , Farr Saman , Lee Yueh‐Jung , Kim Hye‐Yeon , Faham Salem , Bowie James U.
Published: October 2007

Obtaining well‐diffracting crystals of macromolecules remains a significant barrier to structure determination. Here we propose and test a new approach to crystallization, in which the crystallization target is fused to a polymerizing protein module, so that polymer formation drives crystallization of the target. We test the approach using a polymerization module called 2TEL, which consists of two tandem sterile alpha motif (SAM) domains from the protein translocation Ets leukemia (TEL). The 2TEL module is engineered to polymerize as the pH is lowered, which allows the subtle modulation of polymerization needed for crystal formation. We show that the 2TEL module can drive the crystallization of 11 soluble proteins, including three that resisted prior crystallization attempts. In addition, the 2TEL module crystallizes in the presence of various detergents, suggesting that it might facilitate membrane protein crystallization. The crystal structures of two fusion proteins show that the TELSAM polymer is responsible for the majority of contacts in the crystal lattice. The results suggest that biological polymers could be designed as crystallization modules.
Short‐lived protease–serpin complexes: Partial disruption of the rat trypsin active site
Authors: Liu Lu , Mushero Nicole , Hedstrom Lizbeth , Gershenson Anne
Published: October 2007

Serpins inhibit serine proteases by mechanically disrupting the protease active site. The protease first reacts with the serpin's reactive center loop (RCL) to form an acylenzyme. Then the RCL inserts into a β‐sheet in the body of the serpin, translocating the attached protease ∼70 Å and deforming the protease active site, thereby trapping the acylenzyme. Loop insertion (∼1 s−1) is an order of magnitude slower than hydrolysis of a typical substrate acylenzyme (∼50 s−1), indicating that the protease is inhibited during translocation. We have previously trapped a partially translocated covalent complex of rat trypsin and α1‐proteinase inhibitor (EpartI*) resulting from attractive interactions between cationic dyes and anionic rat trypsin. Here, using single pair Förster resonance energy transfer, we demonstrate that EpartI* is a metastable complex that can dissociate to free protease and cleaved serpin (I*) as well as convert to the canonical fully translocated complex EfullI*. The partitioning between these two pathways is pH dependent, with conversion favored at low pH and dissociation favored at high pH. The short lifetime of EpartI* (∼3 h at pH 7.4) and the pH dependence of EpartI* dissociation suggest that, unlike in EfullI*, the catalytic triad is intact in EpartI*. These results also demonstrate that interactions between target proteases and the body of the serpin can hinder protease translocation leading to short‐lived covalent complexes.
On the role of structural class of a protein with two‐state folding kinetics in determining correlations between its size, topology, and folding rate
Authors: Istomin Andrei Y. , Jacobs Donald J. , Livesay Dennis R.
Published: October 2007

The time it takes for proteins to fold into their native states varies over several orders of magnitude depending on their native‐state topology, size, and amino acid composition. In a number of previous studies, it was found that there is strong correlation between logarithmic folding rates and contact order for proteins that fold with two‐state kinetics, while such correlation is absent for three‐state proteins. Conversely, strong correlations between folding rates and chain length occur within three‐state proteins, but not in two‐state proteins. Here, we demonstrate that chain lengths and folding rates of two‐state proteins are not correlated with each other only when all‐α, all‐β, and mixed‐class proteins are considered together, which is typically the case. However, when considering all‐α and all‐β two‐state proteins separately, there is significant linear correlation between folding rate and size. Moreover, the sets of data points for the all‐α and all‐β classes define asymptotes of lower and upper limits on folding rates of mixed‐class proteins. By analyzing correlation of other topological parameters with folding rates of two‐state proteins, we find that only the long‐range order exhibits correlation with folding rates that is uniform over all three classes. It is also the only descriptor to provide statistically significant correlations for each of the three structural classes. We give an interpretation of this observation in terms of Makarov and Plaxco's diffusion‐based topomer‐search model.
Protein aggregation processes: In search of the mechanism
Authors: Frieden Carl
Published: October 2007

Amyloid formation typically follows a time course in which there is a long lag period followed by a rapid formation of fibrils. In this review, I show that the standard mechanisms of polymerization need to be expanded to consider that the monomeric proteins/peptides involved in amyloid formation are intrinsically disordered and exist as an ensemble of disordered‐collapsed states. The review focuses primarily on events which occur in the long lag period defining these as protein folding issues, coupled with formation of oligomers. Experimental methods to explore folding and oligomerization issues over a wide range of protein concentrations using primarily fluorescence and 19F‐NMR methods are discussed.
The imprint of Quaternary glaciers on the present‐day distribution of the obligate groundwater amphipodNiphargus virei(Niphargidae)
Authors: Foulquier Arnaud , Malard Florian , Lefébure Tristan , Douady Christophe J. , Gibert Janine
Published: October 2007

Aim A plausible yet untested biogeographical scenario suggests that Quaternary glaciers shaped the present‐day distribution of the groundwater amphipodNiphargus virei. This study was designed to test two hypotheses pertaining to this scenario: (1) the probability of occurrence ofN. vireiin ice‐free areas decreases in the vicinity of the Würm glacier; and (2) dispersal is sufficiently low for the historical record of glacial effects to persist over time.

Location The study area was located in the southern Jura Mountains, France.

Methods A total of 497 sites were sampled to ascertain the distribution ofN. vireiin the southern Jura. Amplified fragment length polymorphism was analysed from a subset of 24 sites. The relationships between the probability of occurrence ofN. vireiand distance to the Würm glacier or elevation were investigated using a logistic regression. Spatial autocorrelation analyses were performed on both the residuals of the logistic regression and genetic distance to test the significance of dispersal and barriers to post‐glacial recolonization. The influence of catchment boundaries as barriers to dispersal was examined using different neighbouring relationships between sites. We tested the statistical significance of the reduction in deviance and gain in precision of an autologistic regression that took into consideration the influence of dispersal constraints on the distribution ofN. virei.

Results Niphargus vireirarely occurred in formerly glaciated areas, and its probability of occurrence in ice‐free areas decreased in the vicinity of the Würm glacier. Combined autocorrelation analyses of spatial distribution and spatial genetic structure showed that: (1) the distance at which spatial autocorrelation was no longer significantly positive did not exceed 16 km; (2) genetic differentiation fitted a model of isolation by distance; and (3) catchment boundaries acted as barriers to dispersal. The autologistic regression with dispersal constraints significantly increased our capacity to predict the distribution ofN. virei. Maps of probabilities of occurrence suggested that post‐glacial recolonization was impeded by the extension of glacial outwash.

Main conclusions The present distribution ofN. vireiin southern Jura is probably the result of a historical range reduction driven by glaciation coupled with restricted dispersal and isolation by distance.
The barriers to oceanic island radiation in bryophytes: insights from the phylogeography of the moss Grimmia montana
Authors: Vanderpoorten Alain , Devos Nicolas , Goffinet Bernard , Hardy Olivier J. , Shaw A. Jonathan
Published: October 2007

Aim  In contrast to angiosperms, bryophytes do not appear to have radiated in Macaronesia and the western Mediterranean. We evaluate if: (1) the apparent lack of radiation in bryophytes reflects our failure to recognize cryptic endemic species; (2) bryophytes are characterized by extremely low evolutionary rates; or (3) bryophytes have a high dispersal ability, which prevents genetic isolation.

Location  Worldwide, with a special emphasis on Macaronesia and the western Mediterranean.

Methods  Three chloroplast regions were sequenced from samples of the moss Grimmia montana from its entire distribution range. Network analyses, Fst and Nst statistics were used to describe and interpret the phylogeographical signal in the data.

Results  Despite significant phylogeographical signal in the chloroplast genome, which demonstrates limits to gene flow at the continental scale, repeated sister group relationships observed among accessions from different geographical areas suggest recurrent colonization patterns. These observations are consistent with mounting evidence that intercontinental distributions exhibited by many bryophyte species result from long‐distance dispersal rather than continental drift. Madeiran and western Mediterranean island haplotypes are either shared by, or closely related to, European and North American ones. Fst values between Madeira, western Mediterranean islands, North America and Europe are not significantly different from zero, and suggest that Madeira and the south‐western Mediterranean are subject to strong transatlantic gene flow. By contrast, haplotypes found in the Canary Islands are shared or closely related to those of populations from south‐western Europe or southern Africa.

Main conclusions  Multiple origins and colonization events are not consistent with the hypothesis of a relictual origin of the Macaronesian moss flora. One possible reason for the failure of taxa that experienced multiple colonization events to radiate is niche pre‐emption. We suggest that strong gene flow, coupled with the occupancy of all suitable niches, either by earlier conspecific colonizers or by other species, could be the mechanism preventing island radiation in G. montana and other cryptogams with high long‐distance dispersal abilities.
Growth‐ring variations of dwarf shrubs reflect regional climate signals in alpine environments rather than topoclimatic differences
Authors: Bär Annette , Pape Roland , Bräuning Achim , Löffler Jörg
Published: October 2007

Aim  Our main aim is to determine if ring‐width variations in Empetrum hermaphroditum reflect regional or local topoclimate signals in an alpine environment. In the case that topoclimate provides the dominant signal, a secondary aim is to link these to spatial distribution patterns of different vegetation types.

Location  The study area is situated in the middle alpine belt in the Vågåmo region, Central Norwegian Scandes. Sampling sites cover different topoclimates: ridges, north‐facing slopes and south‐facing slopes.

Methods  We constructed ring‐width chronologies of E. hermaphroditum for each type of microsite for the common period 1951–2004. Climate data were prepared on an hourly, daily and growing‐season time scale. Climate–growth relationships were evaluated using bivariate correlations and regression tree methods for continuous time‐series analyses. In addition, extreme growth anomalies (pointer years) were compared with the climate conditions in those years. The impact of water supply on wood anatomy was determined by correlating the conductive area (percentage of vessel per growth ring) with a running mean (sum) of 10‐day intervals for temperature and precipitation.

Results  This study indicates that mean summer (June–August) temperatures determine the width of the growth rings of E. hermaphroditum irrespective of topoclimate. The length of the growing season, which is the most differentiating climatic factor between microsites, does not substantially alter the anatomical ring structure. Microsite differences in mean growth rates are attributed to the higher frequency of warm days. Extremely warm days limit ring‐width development at south‐facing slopes, while plants at ridges and north‐facing slopes still benefit from higher temperatures. As a consequence, pointer years are not developed synchronously at all microsites. Vessel formation is affected by available moisture, especially in the later part of the growing season.

Main conclusions  Topoclimate induces slight modifications of annual growth‐ring increments of E. hermaphroditum at different microsites. In contrast to the distribution patterns of vegetation types that are determined by snow cover, growth‐ring variations are related to summer temperature conditions, and the prominent regional climate signal is still reflected at all microsites. This offers the opportunity to reconstruct climatic change in alpine regions from dwarf shrub ring‐width chronologies.
Fostering knowledge management deployment in R&D workspaces: a five‐stage approach
Authors: Chang Won‐Chen , Li Sheng‐Tun
Published: October 2007

In recent years, R&D institutes have encountered various intensified challenges. New instruments are needed to manage knowledge‐related activities more effectively and efficiently. This paper presents and discusses the lessons learned from a case study in fostering knowledge management (KM) initiatives and systems in a research‐oriented institute serving the metal industry, specifically the Metal Industries Research and Development Centre (MIRDC) in Taiwan. We perform a comparative review of the experience of embarking on KM among Taiwanese R&D institutes, a very rarely performed job. Following this, we investigate, by conducting the primary and secondary researches, how MIRDC has adopted a five‐stage approach to develop a deliberate framework of KM deployment in order to manipulate the KM operations in the context of a Chinese R&D institute. The MIRDC case demonstrates a sophisticated KM process that provides an activity‐based perspective of the plan, control, coordination and evaluation framework in an R&D workspace. This paper argues that well‐defined deployment frameworks embody qualities of goal pursuing that are important to KM activities and compel managers to examine more closely how to realize the KM initiatives. This paper also reveals that a rigid hierarchical R&D structure inhibits the dynamics of the knowledge cycle due to technology segmentation. A parallel R&D structure supported by mission offices and a ‘pioneer and innovation program’ that is cross‐departmental and industry‐focused can positively motivate horizontal ‘coopertition’ networking so as to better exploit and leverage knowledge assets. The practices applied in these elemental KM activities are useful to other R&D organizations by suggesting how each of the KM activities can be configured and implemented.
External technology commercialization in large firms: results of a quantitative benchmarking study
Authors: Lichtenthaler Ulrich , Ernst Holger
Published: October 2007

External technology commercialization (ETC), i.e., the commercialization of technological knowledge exclusively or in addition to its application inside the firm, has recently become a broader trend. However, this increase in outward technology transfer, e.g., by means of technology licensing, has been insufficiently reflected by academic research. Thus, we lack a detailed understanding of the evolution and the current scope of ETC, which represents an important component of technology portfolio management. Moreover, our insights into the functions of ETC and into firms' strategies, processes, and structures for managing ETC are limited. To address these research deficits, we present the results of a questionnaire‐based benchmarking study in 154 medium‐sized and large European firms spanning multiple industries. Thus, this article is among the first studies that provide quantitative empirical evidence for the current scope and management of ETC. After an introduction and theoretical considerations, the research design is described. Subsequently, the results of the survey are presented. In the final section, theoretical and managerial implications are discussed, and opportunities for further research are pointed out.
The Architecture Improvement Method: cost management and systemic learning about strategic product architectures
Authors: De Weerd‐Nederhof Petra C. , Wouters Marc J. F. , Teuns Steven J. A. , Hissel Paul H.
Published: October 2007

The architecture improvement method (AIM) is a method for multidisciplinary product architecture improvement, addressing uncertainty and complexity and incorporating feedback loops, facilitating trade‐off decision making during the architecture creation process. The research reported in this paper demonstrates the ability of the AIM to contribute to cost management and systemic learning in the creation of strategic product architectures, throughout the entire product life cycle. Application of the method in five case studies within two divisions of Royal Philips Electronics shows that in cases of medium uncertainty, substantial cost management benefits can be achieved and that the AIM facilitates systemic learning through the accumulation of architectural competence, thus facilitating organizational memory.
On the Magnet Effect of Price Limits
Authors: Abad David , Pascual Roberto
Published: October 2007

The ‘magnet’ or ‘gravitational’ effect hypothesis asserts that, when trading halts are rule‐based, investors concerned with a likely impediment to trade advance trades in time. This behaviour actually pushes prices further towards the limit. Empirical studies about the magnet effect are scarce, most likely because of the unavailability of data on rule‐based halts. In this paper, we use a large database from the Spanish Stock Exchange (SSE), which combines intraday stock specific price limits and short‐lived rule‐based call auctions to stabilise prices, to test this hypothesis. The SSE is particularly well suited to test the magnet effect hypothesis since trading halts are price‐triggered and, therefore, predictable to some extent. Still, the SSE microstructure presents two particularities: (i) a limit‐hit triggers an automatic switch to an alternative trading mechanism, a call auction, rather than a pure halt; (ii) the trading halt only lasts 5 minutes. We find that, even when prices are within a very short distance to the price limits, the probability of observing a limit‐hit is unexpectedly low. Additionally, prices either initiate reversion (non limit‐hit days) or slow down gradually (limit‐hit days) as they come near the intraday limits. Finally, the most aggressive traders progressively become more patient as prices approach the limits. Therefore, both the price patterns and the trading behaviour reported near the limits do not agree with the price limits acting as magnetic fields. Consequently, we conclude that the switching mechanism implemented in the SSE does not induce traders to advance their trading programs in time.
Serotonin and Migraine: Biology and Clinical Implications
Authors: Hamel E , Currents Headache
Published: October 2007

Migraine is the most frequent neurological disorder in the adult population worldwide, affecting up to 12% of the general population and more frequent in women (~25%). It has a high impact on our society due to its disabling nature and, therein, reduced quality of life and increased absenteeism from work. Headache is the primary clinical manifestation and it has been associated with ‘a hereditary or predisposed sensitivity of neurovascular reactions to certain stimuli or to cyclic changes in the central nervous system’ (1). Amongst the many neurotransmitters in the brain, the serotonergic (serotonin, 5-HT) system from the brainstem raphe nucleus has been most convincingly implicated in migraine pathophysiology. The documented changes in 5-HT metabolism and in the processing of central 5-HT-mediated responses during and in between migraine attacks have led to the suggestion that migraine is a consequence of a central neurochemical imbalance that involves a low serotonergic disposition. Although the exact cascade of events that link abnormal serotonergic neurotransmission to the manifestation of head pain and the accompanying symptoms has yet to be fully understood, recent evidence suggests that a low 5-HT state facilitates activation of the trigeminovascular nociceptive pathway, as induced by cortical spreading depression. In this short review, we present and discuss the original and most recent findings that support a role for altered serotonergic neurotransmission in the manifestation of migraine headache.
Dopamine and Migraine: Biology and Clinical Implications
Authors: Akerman S , Goadsby PJ
Published: October 2007

In the last 30 years dopamine has been considered as playing a role in the pathogenesis of migraine. The literature indicates that migraineurs are hypersensitive to dopamine agonists with respect to some of the premonitory symptoms of migraine such as nausea and yawning. There are various nonspecific dopamine D2 receptor antagonists that show good clinical efficacy in migraine, and also a number of polymorphisms of dopaminergic genes related to migraine. Animal studies have also shown that dopamine receptors are present in the trigeminovascular system, the area believed to be involved in headache pain, and neuronal firing here is reduced by dopamine agonists. There appears to be little effect of dopamine on peripheral trigeminal afferents. We assess some of the limitations of the clinical studies with regard to the therapeutics, and those found in the studies that discovered differences in genetic polymorphisms in migraine, and consider the implications of this on a dopaminergic hypothesis of migraine.
A randomized, double‐blind, four‐arm parallel‐group, placebo‐controlled Phase II/III study to investigate the clinical efficacy of two galenic formulations of Polyphenon® E in the treatment of external genital warts
Authors: Gross G , Meyer K‐G , Pres H , Thielert C , Tawfik H , Mescheder A
Published: October 2007

Objective  Clinical efficacy and safety of Polyphenon® E, a defined green tea extract, in external genital warts.

Design  Randomized, double‐blind, placebo‐controlled study for up to 12 weeks with a 12‐week treatment‐free follow‐up.

Setting  Twenty‐eight hospitals and practices in Germany and Russia.

Patients  Two hundred forty‐two outpatients (125 men, 117 women) with 2 to 30 warts (total wart area, 12–600 mm2).

Intervention(s)  Topical application of Polyphenon® E 10% Cream, Polyphenon® E 15% Ointment or placebo to all external genital warts three times a day.

Main outcome measure(s)  Measurement of total wart area and local reactions/adverse events.

Results  For 15% ointment, statistically significant differences to placebo were achieved regarding complete clearance of all baseline external genital warts (61.0% vs. 40.5% in males, 56.8% vs. 34.1% in females; combined gender: P = 0.0066) and 75% to 100% clearance (80.8% vs. 51.8%; P = 0.0001) in both the intent‐to‐treat and per‐protocol populations. For 10% cream, 53.8% males and 39.5% females achieved complete clearance. Recurrence rates 12 weeks after end of treatment were 10.6%, 11.8% and 10.3% for 15% ointment, 10% cream and placebo, respectively.

Adverse events were observed in only 7.9% of patients, with no serious adverse events or deaths reported. Local skin reactions were generally mild to moderate and resolved with continued treatment without sequelae.

Conclusions  Polyphenon® E 15% ointment, composed of a defined green tea extract, proved to be efficacious and safe for both gender in the treatment of external genital warts.
Mitral annular excursion during exercise in endurance athletes
Authors: Sundstedt Milena , Hedberg Pär , Henriksen Egil
Published: October 2007

The aim of the present study was to quantify the left ventricular (LV) longitudinal motion during exercise at rest and during upright exercise in 24 healthy male endurance athletes. By using M‐mode and two‐dimensional echocardiography, the relative mitral annular motion and the absolute LV longitudinal axis was measured at end‐diastole and end‐systole at rest and during exercise. From rest to peak exercise at a heart rate of 160 beats per minute (bpm) the mitral annular motion increased in the septal and lateral annular borders by 68% and 49% respectively. At rest, mitral annular excursion was significantly (13%) higher in the lateral than in the septal wall but at peak exercise at a heart rate of 160 bpm there was no difference between the septal and lateral annular motion. The total end‐diastolic LV axial length did not increase from rest to peak exercise. In conclusion, during upright exercise, mitral annular motion increased significantly with no difference between the septal and lateral annular excursion at peak exercise. The absolute increase in mitral annular motion during exercise was explained by a decrease in axial end‐systolic length.
Detection of Subclinical Cardiac Involvement in Systemic Sclerosis by Echocardiographic Strain Imaging
Authors: Kepez Alper , Akdogan Ali , Sade L. Elif , Deniz Ali , Kalyoncu Umut , Karadag Omer , Hayran Mutlu , Aytemir Kudret , Ertenli Ihsan , Kiraz Sedat , Calguneri Meral , Kabakcı Giray , Tokgozoglu Lale
Published: October 2007

Background: Cardiac involvement is one of the major problems in systemic sclerosis (SSc). Subclinical cardiac involvement has a higher frequency than thought previously. In this study we investigated whether subclinical cardiac involvement can be detected by using echocardiographic strain imaging in SSc patients without pulmonary hypertension. Methods: Echocardiographic examinations were performed to 27 SSc patients and 26 healthy controls. Left ventricular strain parameters were obtained from apical views and average strain value was calculated from these measurements. Results: There were no significant differences between patients and controls regarding two‐dimensional (2D), conventional Doppler and tissue Doppler velocity measurements. Strain was reduced in 6 of 12 segments of the left ventricle (LV) and in 1 of 2 segments of the right ventricle (RV). Strain rate (SR) was reduced in 2 of 12 segments of the LV and 1 of 2 segments of the RV in SSc patients as compared to controls (P < 0.05 for all). These involvements did not match any particular coronary artery distribution. More important differences were detected by average strain and SR values of the LV between patients and controls (19.78 ± 3.00% vs 23.41 ± 2.73%, P < 0.001; 2.01 ± 0.41 vs 2.23 ± 0.27/sec, P = 0.026, respectively). Furthermore, carbon monoxide diffusion capacity (DLCO) in scleroderma patients significantly correlated with LV average strain (r = 0.59; P = 0.001). Conclusion: Evaluation of ventricular function by using echocardiographic strain imaging appears to be useful to detect subclinical cardiac involvement in SSc patients with normal standard echocardiographic and tissue Doppler velocity findings.
RESEARCH FROM THE UNIVERSITY OF ALABAMA AT BIRMINGHAM: Patent Foramen Ovale in a Large Population of Ischemic Stroke Patients: Diagnosis, Age Distribution, Gender, and Race
Authors: Gupta Vishal , Yesilbursa Dilek , Huang Wen Ying , Aggarwal Kul , Gupta Vijaya , Gomez Camilo , Patel Vinod , Miller Andrew P. , Nanda Navin C.
Published: October 2007

Background: Patent foramen ovale (PFO) is a well‐recognized risk factor for ischemic strokes. The true prevalence of PFO among stroke patients is still under debate. Transesophageal echocardiography (TEE) is the “gold standard” in diagnosing PFO but the physiology requires right‐to‐left atrial shunting. In this report, we evaluate the prevalence of PFO in a diverse group of ischemic stroke patients studied by TEE. Methods: TEE of 1,663 ischemic stroke patients were reviewed for cardiac source of embolism, including PFO and atrial septal aneurysm (ASA). Agitated saline bubble injection was performed to look for right to left atrial shunting. Success of maneuvers to elevate right atrial pressure (RAP) was noted by looking at the atrial septal bulge. Results: Among 1,435 ischemic stroke patients analyzed, the presence or absence of PFO could not be determined in 32.1% because bulging of the septum could not be demonstrated in patients with negative contrast study despite aggressive maneuvers to elevate RAP. Of the remaining 974 patients, 294 patients (30.2%) had a PFO. The mean age was 61.5 years in both groups, with a bimodal distribution of PFO and the highest prevalence occurring in ≤30‐year‐old group. Prevalence of PFO was similar in men (32.4%) and women (28.15%, P = 0.15); and in Caucasian (32.1%) and African American (27.7%; P = 0.15). ASA was present in 2.02% and hypermobile septum in 2.49% of the 1,435 patients. PFO was seen in 79.3% of the patients with ASA. Conclusion: Successful elevation of RAP cannot be achieved in a significant number of patients undergoing TEE and determination of PFO may be difficult. In our series, the true prevalence of PFO among ischemic stroke patients was 30.2% taking into account only those patients who showed no shunting despite bulging of the atrium septum into the left atrium (PFO absent group) during the contrast study. There was no gender or racial difference in the prevalence of PFO, but there was a bimodal distribution in prevalence with age.
Membranes of Left Atrial Appendage: Real Appearance or “Pitfall”
Authors: Correale Michele , Ieva Riccardo , Deluca Giovanni , Di Biase Matteo
Published: October 2007

The membranes of left atrial appendage (LAA) cavity are very rare entity. To date, only five cases of a membrane involving LAA have been described. In this report, we describe two different cases: in Case 1, we show image of a “real” nonobstructive membrane within the body of LAA, but in Case 2 we show a linear image, mimicking a membrane within the body of LAA. It really is a “pitfall” of transesophageal echocardiography (TEE).
Effect of absorbable membranes on sandwich bone augmentation
Authors: Park Sang‐Hoon , Lee Kwang‐won , Oh Tae‐Ju , Misch Carl E. , Shotwell Jeffrey , Wang Hom‐Lay
Published: October 2007

Objectives: This study was conducted to evaluate the effect of barrier membranes on sandwich bone augmentation (SBA) for the treatment of implant dehiscence defects.

Material and methods: Twenty‐six implant‐associated buccal dehiscence defects in 22 patients were treated according to the SBA concept – mineralized human cancellous allograft (inner layer), mineralized human cortical allograft (outer layer) and coverage with barrier membrane. The defects were randomly assigned to the bovine collagen membrane (BME) group; acellular dermal matrix (ADM) group; and no membrane group. Measurements at baseline and 6 months re‐entry included defect height (DH: from smooth–rough junction to the most apical part of the defect), defect width (DW: at the widest part of the defect), and horizontal defect depth (HDD: at three locations – smooth–rough junction, middle, and most apical portion of the defect). All measurements were taken from a reference stent. Statistical analyses were performed for comparison of intra‐ and inter‐group comparisons.

Results: All implants placed were successfully osseointegrated. DH at baseline for three groups were not significantly different (P=0.858). Mean % DH reductions for ADM, BME, and control groups at 6 months were 73.9±17.6%, 68.1±30.1%, and 63.6±23.9%, respectively, with no significant difference among the groups (P=0.686). Mean horizontal bone gain, however, was significantly greater for membrane groups (1.7 mm for ADM, 1.6 mm for BME) compared with control group (1 mm) (P=0.044). Implant exposure resulted in significant reduction in total height gain (79.1±14.3% vs. 57±23.5%, P=0.021).

Conclusions: Within the limit of this study, it is concluded that SBA technique achieved predictable clinical outcomes. The addition of absorbable membranes enhanced bone gain in thickness compared with membrane‐treated sites.