The inadequacy of embedded markup for cultural heritage texts

Embedded generalized markup, as applied by digital humanists to the recording and studying of our textual cultural heritage, suffers from a number of serious technical drawbacks. As a result of its evolution from early printer control languages, generalized markup can only express a document’s ‘logical’ structure via a repertoire of permissible printed format structures. In addition to the well-researched overlap problem, the embedding of markup codes into texts that never had them when written leads to a number of further difficulties: the inclusion of potentially obsolescent technical and subjective information into texts that are supposed to be archivable for the long term, the manual encoding of information that could be better computed automatically, and the obscuring of the text by highly complex technical data. Many of these problems can be alleviated by asserting a separation between the versions of which many cultural heritage texts are composed, and their content. In this way the complex inter-connections between versions can be handled automatically, leaving only simple markup for individual versions to be handled by the user.

Network structure, knowledge governance, and firm performance : evidence from innovation networks and SMEs in the UK

It is increasingly understood that learning and thus innovation often occurs via highly interactive, iterative, network-based processes. Simultaneously, economic development policy is increasingly focused on small and medium-sized enterprises (SMEs) as a means of generating growth, creating a clear research issue in terms of the roles and interactions of government policy, universities, and other sources of knowledge, SMEs, and the creation and dissemination of innovation. This paper analyses the contribution of a range of actors in an SME innovation creation and dissemination framework, reviewing the role of various institutions therein, exploring the contribution of cross-locality networks, and identifying the mechanisms required to operationalise such a framework. Bivariate and multivariate (regression) techniques are employed to investigate both innovation and growth outcomes in relation to these structures; data are derived from the survey responses of over 450 SMEs in the UK. Results are complex and dependent upon the nature of institutions involved, the type of knowledge sought, and the spatial level of the linkages in place but overall highlight the value of cross-locality networks, network governance structures, and certain spillover effects from universities. In general, we find less support for the factors predicting SME growth outcomes than is the case for innovation. Finally, we outline an agenda for further research in the area.

Design process : similarities and differences

The research is based on studying the early stage of the design process. It aims to identify differences in design approaches across two design domains. The research is based on the analysis of the observational data from the conceptual stage of (i) product and (ii) software design process. The activities captured from the analysis of the design process are utilized to outline similarities and differences across the two domains. This will contribute to a better understanding of the connections between, and integration of, design process variables, and to a better understanding of design expertise transfer to other domain (e.g., science or nursing).

Human atrial beta1L-adrenoceptor but not beta3-adrenoceptor activation increases force and Ca2+ current at physiological temperature

BACKGROUND AND PURPOSE It has been proposed that BRL37344, SR58611 and CGP12177 activate b3-adrenoceptors in human atrium to increase contractility and L-type Ca2+ current (ICa-L). b3-adrenoceptor agonists are potentially beneficial for the treatment of a variety of diseases but concomitant cardiostimulation would be potentially harmful. It has also been proposed that (-)-CGP12177 activates the low affinity binding site of the b1-adrenoceptor in human atrium. We therefore used BRL37344, SR58611 and (-)-CGP12177 with selective b-adrenoceptor subtype antagonists to clarify cardiostimulant b-adrenoceptor subtypes in human atrium. EXPERIMENTAL APPROACH Human right atrium was obtained from patients without heart failure undergoing coronary artery bypass or valve surgery. Cardiomyocytes were prepared to test BRL37344, SR58611 and CGP12177 effects on ICa-L. Contractile effects were determined on right atrial trabeculae. KEY RESULTS BRL37344 increased force which was antagonized by blockade of b1- and b2-adrenoceptors but not by blockade of b3-adrenoceptors with b3-adrenoceptor-selective L-748,337 (1 mM). The b3-adrenoceptor agonist SR58611 (1 nM–10 mM) did not affect atrial force. BRL37344 and SR58611 did not increase ICa-L at 37°C, but did at 24°C which was prevented by L-748,337. (-)-CGP12177 increased force and ICa-L at both 24°C and 37°C which was prevented by (-)-bupranolol (1–10 mM), but not L-748,337. CONCLUSIONS AND IMPLICATIONS We conclude that the inotropic responses to BRL37344 are mediated through b1- and b2-adrenoceptors. The inotropic and ICa-L responses to (-)-CGP12177 are mediated through the low affinity site b1L-adrenoceptor of the b1-adrenoceptor. b3-adrenoceptor-mediated increases in ICa-L are restricted to low temperatures. Human atrial b3-adrenoceptors do not change contractility and ICa-L at physiological temperature.

Approximate Bayesian computation using indirect inference

We present a novel approach for developing summary statistics for use in approximate Bayesian computation (ABC) algorithms by using indirect inference. ABC methods are useful for posterior inference in the presence of an intractable likelihood function. In the indirect inference approach to ABC the parameters of an auxiliary model fitted to the data become the summary statistics. Although applicable to any ABC technique, we embed this approach within a sequential Monte Carlo algorithm that is completely adaptive and requires very little tuning. This methodological development was motivated by an application involving data on macroparasite population evolution modelled by a trivariate stochastic process for which there is no tractable likelihood function. The auxiliary model here is based on a beta–binomial distribution. The main objective of the analysis is to determine which parameters of the stochastic model are estimable from the observed data on mature parasite worms.

In vitro and in vivo examination of the cell surface glycoprotein CDCP1

A number of reports have demonstrated the importance of the CUB domaincontaining protein 1 (CDCP1) in facilitating cancer progression in animal models and the potential of this protein as a prognostic marker in several malignancies. CDCP1 facilitates metastasis formation in animal models by negatively regulating anoikis, a type of apoptosis triggered by the loss of attachment signalling from cell-cell contacts or cell-extra cellular matrix (ECM) contacts. Due to the important role CDCP1 plays in cancer progression in model systems, it is considered a potential drug target to prevent the metastatic spread of cancers. CDCP1 is a highly glycosylated 836 amino acid cell surface protein. It has structural features potentially facilitating protein-protein interactions including 14 N-glycosylation sites, three CUB-like domains, 20 cysteine residues likely to be involved in disulfide bond formation and five intracellular tyrosine residues. CDCP1 interacts with a variety of proteins including Src family kinases (SFKs) and protein kinase C ä (PKCä). Efforts to understand the mechanisms regulating these interactions have largely focussed on three CDCP1 tyrosine residues Y734, Y743 and Y762. CDCP1-Y734 is the site where SFKs phosphorylate and bind to CDCP1 and mediate subsequent phosphorylation of CDCP1-Y743 and -Y762 which leads to binding of PKCä at CDCP1-Y762. The resulting trimeric protein complex of SFK•CDCP1•PKCä has been proposed to mediate an anti-apoptotic cell phenotype in vitro, and to promote metastasis in vivo. The effect of mutation of the three tyrosines on interactions of CDCP1 with SFKs and PKCä and the consequences on cell phenotype in vitro and in vivo have not been examined. CDCP1 has a predicted molecular weight of ~90 kDa but is usually detected as a protein which migrates at ~135 kDa by Western blot analysis due to its high degree of glycosylation. A low molecular weight form of CDCP1 (LMWCDCP1) of ~70 kDa has been found in a variety of cancer cell lines. The mechanisms leading to the generation of LMW-CDCP1 in vivo are not well understood but an involvement of proteases in this process has been proposed. Serine proteases including plasmin and trypsin are able to proteolytically process CDCP1. In addition, the recombinant protease domain of the serine protease matriptase is also able to cleave the recombinant extracellular portion of CDCP1. Whether matriptase is able to proteolytically process CDCP1 on the cell surface has not been examined. Importantly, proteolytic processing of CDCP1 by trypsin leads to phosphorylation of its cell surface-retained portion which suggests that this event leads to initiation of an intracellular signalling cascade. This project aimed to further examine the biology of CDCP1 with a main of focus on exploring the roles played by CDCP1 tyrosine residues. To achieve this HeLa cells stably expressing CDCP1 or the CDCP1 tyrosine mutants Y734F, Y743F and Y762F were generated. These cell lines were used to examine: • The roles of the tyrosine residues Y734, Y743 and Y762 in mediating interactions of CDCP1 with binding proteins and to examine the effect of the stable expression on HeLa cell morphology. • The ability of the serine protease matriptase to proteolytically process cell surface CDCP1 and to examine the consequences of this event on HeLa cell phenotype and cell signalling in vitro. • The importance of these residues in processes associated with cancer progression in vitro including adhesion, proliferation and migration. • The role of these residues on metastatic phenotype in vivo and the ability of a function-blocking anti-CDCP1 antibody to inhibit metastasis in the chicken embryo chorioallantoic membrane (CAM) assay. Interestingly, biochemical experiments carried out in this study revealed that mutation of certain CDCP1 tyrosine residues impacts on interactions of this protein with binding proteins. For example, binding of SFKs as well as PKCä to CDCP1 was markedly decreased in HeLa-CDCP1-Y734F cells, and binding of PKCä was also reduced in HeLa-CDCP1-Y762F cells. In contrast, HeLa-CDCP1-Y743F cells did not display altered interactions with CDCP1 binding proteins. Importantly, observed differences in interactions of CDCP1 with binding partners impacted on basal phosphorylation of CDCP1. It was found that HeLa-CDCP1, HeLa-CDCP1-Y743F and -Y762F displayed strong basal levels of CDCP1 phosphorylation. In contrast, HeLa-CDCP1-Y734F cells did not display CDCP1 phosphorylation but exhibited constitutive phosphorylation of focal adhesion kinase (FAK) at tyrosine 861. Significantly, subsequent investigations to examine this observation suggested that CDCP1-Y734 and FAK-Y861 are competitive substrates for SFK-mediated phosphorylation. It appeared that SFK-mediated phosphorylation of CDCP1- Y734 and FAK-Y861 is an equilibrium which shifts depending on the level of CDCP1 expression in HeLa cells. This suggests that the level of CDCP1 expression may act as a regulatory mechanism allowing cells to switch from a FAK-Y861 mediated pathway to a CDCP1-Y734 mediated pathway. This is the first time that a link between SFKs, CDCP1 and FAK has been demonstrated. One of the most interesting observations from this work was that CDCP1 altered HeLa cell morphology causing an elongated and fibroblastic-like appearance. Importantly, this morphological change depended on CDCP1- Y734. In addition, it was observed that this change in cell morphology was accompanied by increased phosphorylation of SFK-Y416. This suggests that interactions of SFKs with CDCP1-Y734 increases SFK activity since SFKY416 is critical in regulating kinase activity of these proteins. The essential role of SFKs in mediating CDCP1-induced HeLa cell morphological changes was demonstrated using the SFK-selective inhibitor SU6656. This inhibitor caused reversion of HeLa-CDCP1 cell morphology to an epithelial appearance characteristic of HeLa-vector cells. Significantly, in vitro studies revealed that certain CDCP1-mediated cell phenotypes are mediated by cellular pathways dependent on CDCP1 tyrosine residues whereas others are independent of these sites. For example, CDCP1 expression caused a marked increase in HeLa cell motility that was independent of CDCP1 tyrosine residues. In contrast, CDCP1- induced decrease in HeLa cell proliferation was most prominent in HeLa- CDCP1-Y762F cells, potentially indicating a role for this site in regulating proliferation in HeLa cells. Another cellular event which was identified to require phosphorylation of a particular CDCP1 tyrosine residue is adhesion to fibronectin. It was observed that the CDCP1-mediated strong decrease in adhesion to fibronectin is mostly restored in HeLa-CDCP1-Y743F cells. This suggests a possible role for CDCP1-Y743 in causing a CDCP1-mediated decrease in adhesion. Data from in vivo experiments indicated that HeLa-CDCP1-Y734F cells are more metastic than HeLa-CDCP1 cells in vivo. This indicates that interaction of CDCP1 with SFKs and PKCä may not be required for CDCP1-mediated metastasis formation of HeLa cells in vivo. The metastatic phenotype of these cells may be caused by signalling involving FAK since HeLa-CDCP1- Y734F cells are the only CDCP1 expressing cells displaying constitutive phosphorylation of FAK-Y861. HeLa-CDCP1-Y762F cells displayed a very low metastatic ability which suggests that this CDCP1 tyrosine residue is important in mediating a pro-metastatic phenotype in HeLa cells. More detailed exploration of cellular events occurring downstream of CDCP1-Y734 and -Y762 may provide important insights into the mechanisms altering the metastatic ability of CDCP1 expressing HeLa cells. Complementing the in vivo studies, anti-CDCP1 antibodies were employed to assess whether these antibodies are able to inhibit metastasis of CDCP1 and CDCP1 tyrosine mutants expressing HeLa cells. It was found that HeLa- CDCP1-Y734F cells were the only cell line which was markedly reduced in the ability to metastasise. In contrast, the ability of HeLa-CDCP1, HeLa- CDCP1-Y743F and -Y762F cells to metastasise in vivo was not inhibited. These data suggest a possible role of interactions of CDCP1 with SFKs, occurring at CDCP1-Y734, in preventing an anti-metastatic effect of anti- CDCP1 antibodies in vivo. The proposal that SFKs may play a role in regulating anti-metastatic effects of anti-CDCP1 antibodies was supported by another experiment where differences between HeLa-CDCP1 cells and CDCP1 expressing HeLa cells (HeLa-CDCP1-S) from collaborators at the Scripps Research Institute were examined. It was found that HeLa-CDCP1-S cells express different SFKs than CDCP1 expressing HeLa cells generated for this study. This is important since HeLa-CDCP1-S cells can be inhibited in their metastatic ability using anti-CDCP1 antibodies in vivo. Importantly, these data suggest that further examinations of the roles of SFKs in facilitating anti-metastatic effects of anti-CDCP1 antibodies may give insights into how CDCP1 can be blocked to prevent metastasis in vivo. This project also explored the ability of the serine protease matriptase to proteolytically process cell surface localised CDCP1 because it is unknown whether matriptase can cleave cell surface CDCP1 as it has been reported for other proteases such as trypsin and plasmin. Furthermore, the consequences of matriptase-mediated proteolysis on cell phenotype in vitro and cell signalling were examined since recent reports suggested that proteolysis of CDCP1 leads to its phosphorylation and may initiate cell signalling and consequently alter cell phenotype. It was found that matriptase is able to proteolytically process cell surface CDCP1 at low nanomolar concentrations which suggests that cleavage of CDCP1 by matriptase may facilitate the generation of LWM-CDCP1 in vivo. To examine whether matriptase-mediated proteolysis induced cell signalling anti-phospho Erk 1/2 Western blot analysis was performed as this pathway has previously been examined to study signalling in response to proteolytic processing of cell surface proteins. It was found that matriptase-mediated proteolysis in CDCP1 expressing HeLa cells initiated intracellular signalling via Erk 1/2. Interestingly, this increase in phosphorylation of Erk 1/2 was also observed in HeLa-vector cells. This suggested that initiation of cell signalling via Erk 1/2 phosphorylation as a result of matriptase-mediated proteolysis occurs by pathways independent of CDCP1. Subsequent investigations measuring the flux of free calcium ions and by using a protease-activated receptor 2 (PAR2) agonist peptide confirmed this hypothesis. These data suggested that matriptase-mediated proteolysis results in cell signalling via a pathway induced by the activation of PAR2 rather than by CDCP1. This indicates that induction of cell signalling in HeLa cells as a consequence of matriptase-mediated proteolysis occurs via signalling pathways which do not involve phosphorylation of Erk 1/2. Consequently, it appears that future attempts should focus on the examination of cellular pathways other than Erk 1/2 to elucidate cell signalling initiated by matriptase-mediated proteolytic processing of CDCP1. The data presented in this thesis has explored in vitro and in vivo aspects of the biology of CDCP1. The observations summarised above will permit the design of future studies to more precisely determine the role of CDCP1 and its binding partners in processes relevant to cancer progression. This may contribute to further defining CDCP1 as a target for cancer treatment.

On the optimality of sample-based estimates of the expectation of the empirical minimizer

We study sample-based estimates of the expectation of the function produced by the empirical minimization algorithm. We investigate the extent to which one can estimate the rate of convergence of the empirical minimizer in a data dependent manner. We establish three main results. First, we provide an algorithm that upper bounds the expectation of the empirical minimizer in a completely data-dependent manner. This bound is based on a structural result due to Bartlett and Mendelson, which relates expectations to sample averages. Second, we show that these structural upper bounds can be loose, compared to previous bounds. In particular, we demonstrate a class for which the expectation of the empirical minimizer decreases as O(1/n) for sample size n, although the upper bound based on structural properties is Ω(1). Third, we show that this looseness of the bound is inevitable: we present an example that shows that a sharp bound cannot be universally recovered from empirical data.

Functional heterogeneity as a two-dimensional concept : empirical evidence for new venture teams

Previous research on entrepreneurial teams has failed to settle the controversy over whether team heterogeneity helps or hinders new venture performance. Reconciling this inconsistency, this paper suggests a new conceptual approach to disentangle differential effects of team heterogeneity by modeling two separate heterogeneity dimensions, namely knowledge scope and knowledge disparity. Analyzing unique data on functional experiences of the members of 337 start-up teams, we find support for our contention of team heterogeneity as a two-dimensional concept. Results suggest that knowledge disparity negatively relates to both start-ups’ entrepreneurial and innovative performance. In contrast, we find knowledge scope to positively affect entrepreneurial performance, while it shows an inverse U-shaped relationship to innovative start-up performance.

Mechanical behaviours of pumpkin peel under compression test

Mechanical damages such as bruising, collision and impact during food processing stages diminish quality and quantity of productions as well as efficiency of operations. Studying mechanical characteristics of food materials will help to enhance current industrial practices. Mechanical properties of fruits and vegetables describe how these materials behave under loading in real industrial operations. Optimizing and designing more efficient equipments require accurate and precise information of tissue behaviours. FE modelling of food industrial processes is an effective method of studying interrelation of variables during mechanical operation. In this study, empirical investigation has been done on mechanical properties of pumpkin peel. The test was a part of FE modelling and simulation of mechanical peeling stage of tough skinned vegetables. The compression test has been conducted on Jap variety of pumpkin. Additionally, stress strain curve, bio-yield and toughness of pumpkin skin have been calculated. The required energy for reaching bio-yield point was 493.75, 507.71 and 451.71 N.mm for 1.25, 10 and 20 mm/min loading speed respectively. Average value of force in bio-yield point for pumpkin peel was 310 N.

Developing a conceptual framework of strategic entrepreneurship

Purpose: This paper aims to examine the integration of entrepreneurship and strategy to develop a conceptual framework of strategic entrepreneurship. The framework is developed through an analysis of theory and refined through an examination of practice. Design/methodology/approach: This framework is considered in the context of potentially entrepreneurial and strategic activity undertaken by 12 of the 17 state-owned enterprises (SOEs) operating in New Zealand in 2006-2007. Based on a review of documents, observation, and interviews with SOE executives, cases of 12 SOE activities were analysed to compare and contrast strategic entrepreneurship in practice. Findings: The findings reveal distinct elements within the four activities classified as strategic entrepreneurship, activities, such as leveraging from core skills and resources from a strategic perspective, and innovation from an entrepreneurial perspective. Originality/value: This study is one of the first to examine the nature of strategic entrepreneurship in practice and the associated financial returns.

Train service timetabling in railway open markets by particle swarm optimisation

Railway timetabling is an important process in train service provision as it matches the transportation demand with the infrastructure capacity while customer satisfaction is also considered. It is a multi-objective optimisation problem, in which a feasible solution, rather than the optimal one, is usually taken in practice because of the time constraint. The quality of services may suffer as a result. In a railway open market, timetabling usually involves rounds of negotiations among a number of self-interested and independent stakeholders and hence additional objectives and constraints are imposed on the timetabling problem. While the requirements of all stakeholders are taken into consideration simultaneously, the computation demand is inevitably immense. Intelligent solution-searching techniques provide a possible solution. This paper attempts to employ a particle swarm optimisation (PSO) approach to devise a railway timetable in an open market. The suitability and performance of PSO are studied on a multi-agent-based railway open-market negotiation simulation platform.

Communicating with the coroner : how religion, culture, and family concerns may influence autopsy decision making

Based on coronial data gathered in the state of Queensland in 2004, this article reviews how a change in legislation may have impacted autopsy decision making by coroners. More specifically, the authors evaluated whether the requirement that coronial autopsy orders specify the level of invasiveness of an autopsy to be performed by a pathologist was affected by the further requirement that coroners take into consideration a known religion, culture, and/or raised family concern before making such an order. Preliminary data reveal that the cultural status of the deceased did not affect coronial autopsy decision making. However, a known religion with a proscription against autopsy and a raised family concern appeared to be taken into account by coroners when making autopsy decisions and tended to decrease the invasiveness of the autopsy ordered from a full internal examination to either a partial internal examination or an external-only examination of the body. The impact of these findings is briefly discussed.