bluuebunny/crossref_metadata_2025 huggingface dataset:
Colonization of storm gaps by the spruce bark beetle: influence of gap and landscape characteristics
Authors: Schroeder Leif Martin
Published: September 2009

After storm disturbances, there is a risk for degradation of the quality of fallen trees, and for subsequent tree mortality caused by the spruce bark beetle Ips typographus (L.) (Coleoptera: Curculionidae). Models assessing the risk for bark beetle colonization of different kinds of storm gaps would be a valuable tool for management decisions.

The present study aimed to determine which gap and landscape characteristics are correlated with the probability of colonization of wind‐felled Norway spruce trees by I. typographus.

The study included 36 storm gaps, varying in size from three to 1168 wind‐felled spruces, created by the storm Gudrun in southern Sweden in January 2005.

In the first summer, on average, 5% of the wind‐felled spruces were colonized by I. typographus. The percentage of colonized wind‐felled trees per gap was negatively correlated with the total area of storm gaps within 2000 m in the surrounding forest landscape.

In the second summer, the proportion of colonized trees increased to 50%. Both gap (mean diameter of wind‐felled trees and basal area of living spruce trees) and landscape variables (amount of spruce forest) were significantly correlated with colonization percentage and explained almost 50% of the variation between gaps.

There was no relationship between gap area and colonization percentage. This implies that landscapes with many large storm gaps, where logging resources will be most effectively used, should be salvaged first.
Production and characterization of an orally immunogenic Plasmodium antigen in plants using a virus‐based expression system
Authors: Webster Diane E. , Wang Lina , Mulcair Mark , Ma Charles , Santi Luca , Mason Hugh S. , Wesselingh Steve L. , Coppel Ross L.
Published: September 2009

Increasing numbers of plant‐made vaccines and pharmaceuticals are entering the late stage of product development and commercialization. Despite the theoretical benefits of such production, expression of parasite antigens in plants, particularly those from Plasmodium, the causative parasites for malaria, have achieved only limited success. We have previously shown that stable transformation of tobacco plants with a plant‐codon optimized form of the Plasmodium yoelii merozoite surface protein 4/5 (PyMSP4/5) gene resulted in PyMSP4/5 expression of up to ∼0.25% of total soluble protein. In this report, we describe the rapid expression of PyMSP4/5 in Nicotiana benthamiana leaves using the deconstructed tobacco mosaic virus‐based magnICON® expression system. PyMSP4/5 yields of up to 10% TSP or 1–2 mg/g of fresh weight were consistently achieved. Characterization of the recombinant plant‐made PyMSP4/5 indicates that it is structurally similar to PyMSP4/5 expressed by Escherichia coli. It is notable that the plant‐made PyMSP4/5 protein retained its immunogenicity following long‐term storage at ambient temperature within freeze‐dried leaves. With assistance from a mucosal adjuvant the PyMSP4/5‐containing leaves induced PyMSP4/5‐specific antibodies when delivered orally to naïve mice or mice primed by a DNA vaccine. This study provides evidence that immunogenic Plasmodium antigens can be produced in large quantities in plants using the magnICON® viral vector system.
Intron‐mediated enhancement as a method for increasing transgene expression levels in barley
Authors: Bartlett Joanne G. , Snape John W. , Harwood Wendy A.
Published: September 2009

It is desirable to produce transgenic plants which have optimized and stable levels of transgene expression. Low levels of transgene expression may lead to an insufficient quantity of transgenic protein being produced for a particular purpose. This report demonstrates a means of enhancing transgene expression in barley beyond that conferred by the Ubi1 promoter, via the inclusion of an intron at a specific position within the transgene coding sequence. We independently cloned two different introns (RpoT‐i4 from maize and UBQ10‐i1 from Arabidopsis) into the same position within the firefly luciferase (luc) coding sequence. The constructs produced were transformed into barley (Hordeum vulgare) via Agrobacterium‐mediated transformation, and the resulting transformant populations (of between 119 and 123 independent plants for each construct) were assayed for luciferase activity. Both introns significantly increased luciferase activity, and a quantitative reverse‐transcription polymerase chain reaction assay revealed that the introns increased the accumulation of luciferase mRNA transcripts. The enhanced transgene expression levels were maintained in the T1 and T2 progenies. These findings show that intron‐mediated enhancement is a valuable additional tool for achieving high and stable levels of transgene expression in crop plants.
TheLP2leucine‐rich repeat receptor kinase gene promoter directs organ‐specific, light‐responsive expression in transgenic rice
Authors: Thilmony Roger , Guttman Mara , Thomson James G. , Blechl Ann E.
Published: September 2009

Biotechnologists seeking to limit gene expression to nonseed tissues of genetically engineered cereal crops have only a few choices of well characterized organ‐specific promoters. We have isolated and characterized the promoter of the riceLeaf Panicle 2gene (LP2, Os02g40240). TheLP2gene encodes a leucine‐rich repeat‐receptor kinase‐like protein that is strongly expressed in leaves and other photosynthetic tissues. Transgenic rice plants containing anLP2promoter‐GUS::GFPbifunctional reporter gene displayed an organ‐specific pattern of expression. This expression corresponded to transcript levels observed on RNA blots of various rice organs and microarray gene expression data. The strongest β‐glucuronidase activity was observed in histochemically stained mesophyll cells, but other green tissues and leaf cell types including epidermal cells also exhibited expression. Low or undetectable levels ofLP2transcript andLP2‐mediated reporter gene expression were observed in roots, mature seeds, and reproductive tissues. TheLP2promoter is highly responsive to light and only weak expression was detected in etiolated rice seedlings. The specificity and strength of theLP2promoter suggests that this promoter will be a useful control element for green tissue‐specific expression in rice and potentially other plants. Organ‐specific promoters likeLP2will enable precise, localized expression of transgenes in biotechnology‐derived crops and limit the potential of unintended impacts on plant physiology and the environment.
Exploring the learning mechanism of web‐based question‐answering systems and their design
Authors: Zhang Yin
Published: September 2009

In recent years, a number of models concerning question‐answering (QA) systems have been put forward. But many of them stress technology and neglect the research of QA itself. In this paper, we analyse the essence of QA and discuss the relationship between technology and QA. On that basis, we propose that when designing web‐based QA systems, more attention should be paid to the learning mechanism involved in the QA process than to technology. Some new ideas on the design of QA systems are also put forward in order to promote the rapid development of web‐based QA systems.
Improved Prediction Intervals and Distribution Functions
Authors: VIDONI PAOLO
Published: September 2009

Abstract.  The plug‐in solution is usually not entirely adequate for computing prediction intervals, as their coverage probability may differ substantially from the nominal value. Prediction intervals with improved coverage probability can be defined by adjusting the plug‐in ones, using rather complicated asymptotic procedures or suitable simulation techniques. Other approaches are based on the concept of predictive likelihood for a future random variable. The contribution of this paper is the definition of a relatively simple predictive distribution function giving improved prediction intervals. This distribution function is specified as a first‐order unbiased modification of the plug‐in predictive distribution function based on the constrained maximum likelihood estimator. Applications of the results to the Gaussian and the generalized extreme‐value distributions are presented.
Extensions of a Conflict Measure of Inconsistencies in Bayesian Hierarchical Models
Authors: GÅSEMYR JØRUND , NATVIG BENT
Published: September 2009

Abstract. In a recent paper we extended and refined some tools introduced by O'Hagan for criticism of Bayesian hierarchical models. Especially, avoiding double use of data by a data‐splitting approach was a main concern. Such tools can be applied at each node of the model, with a view to diagnosing problems of model fit at any point in the model structure. As O'Hagan, we investigated a Gaussian model of one‐way analysis of variance. Through extensive Markov chain Monte Carlo simulations it was shown that our method detects model misspecification about as well as the one of O'Hagan, when this is properly calibrated, while retaining the desired false warning probability for data generated from the assumed model. In the present paper, we suggest some new measures of conflict based on tail probabilities of the so‐called integrated posterior distributions introduced in our recent paper. These new measures are equivalent to the measure applied in the latter paper in simple Gaussian models, but seem more appropriately adjusted to deviations from normality and to conflicts not concerning location parameters. A general linear normal model with known covariance matrices is considered in detail.
The Judge Specificity of Evaluations of Youth Social Behavior: The Case of Peer Provocation
Authors: Dirks Melanie A. , Treat Teresa A. , Weersing V. Robin
Published: September 2009

Increasingly, theorists have suggested that social competence is an evaluative construct that will vary as a function of who is judging behavior. This study examined how two key groups in children's social environments—peers (N = 663, age range = 10.83–15.25 years) and teachers (N = 49)—rated the effectiveness of different behaviors generated by youth in response to physical, verbal, and relational provocation by peers. Results indicated that youth evaluated aggressive responses as more effective than teachers whereas teachers evaluated seeking an explanation as more effective than youth. Both groups judged responses combining assertive and aggressive elements to be more effective than ‘pure’ aggression. Implications for measurement and intervention models of social competence are discussed.
BAYSIAN INFERENCE FOR ORDERED RESPONSE DATA WITH A DYNAMIC SPATIAL‐ORDERED PROBIT MODEL
Authors: Wang Xiaokun , Kockelman Kara M.
Published: September 2009

ABSTRACT Many databases involve ordered discrete responses in a temporal and spatial context, including, for example, land development intensity levels, vehicle ownership, and pavement conditions. An appreciation of such behaviors requires rigorous statistical methods, recognizing spatial effects and dynamic processes. This study develops a dynamic spatial‐ordered probit (DSOP) model in order to capture patterns of spatial and temporal autocorrelation in ordered categorical response data. This model is estimated in a Bayesian framework using Gibbs sampling and data augmentation, in order to generate all autocorrelated latent variables. It incorporates spatial effects in an ordered probit model by allowing for interregional spatial interactions and heteroskedasticity, along with random effects across regions or any clusters of observational units. The model assumes an autoregressive, AR(1), process across latent response values, thereby recognizing time‐series dynamics in panel data sets. The model code and estimation approach is tested on simulated data sets, in order to reproduce known parameter values and provide insights into estimation performance, yielding much more accurate estimates than standard, nonspatial techniques. The proposed and tested DSOP model is felt to be a significant contribution to the field of spatial econometrics, where binary applications (for discrete response data) have been seen as the cutting edge. The Bayesian framework and Gibbs sampling techniques used here permit such complexity, in world of two‐dimensional autocorrelation.
Structural and Parameter Uncertainty in Bayesian Cost-Effectiveness Models
Authors: Jackson Christopher H. , Sharples Linda D. , Thompson Simon G.
Published: September 2009

Health economic decision models are subject to various forms of uncertainty, including uncertainty about the parameters of the model and about the model structure. These uncertainties can be handled within a Bayesian framework, which also allows evidence from previous studies to be combined with the data. As an example, we consider a Markov model for assessing the cost-effectiveness of implantable cardioverter defibrillators. Using Markov chain Monte Carlo posterior simulation, uncertainty about the parameters of the model is formally incorporated in the estimates of expected cost and effectiveness. We extend these methods to include uncertainty about the choice between plausible model structures. This is accounted for by averaging the posterior distributions from the competing models using weights that are derived from the pseudo-marginal-likelihood and the deviance information criterion, which are measures of expected predictive utility. We also show how these cost-effectiveness calculations can be performed efficiently in the widely used software WinBUGS.
Interest‐Rate Reforms and Financial Deepening in Botswana: An Empirical Investigation
Authors: Odhiambo Nicholas M. , Akinboade Oludele A.
Published: September 2009

In this paper, we examine the impact of interest‐rate reforms on financial deepening in Botswana, one of Africa's economic development success stories. We employ three proxies of financial deepening against deposit rate, a proxy for interest‐rate reforms. The financial deepening in this study is defined as the increase in the relative size and role of the financial system in an economy. The empirical results of our study show that the impact of interest‐rate reforms on financial deepening is sensitive to the variable used as a proxy for financial deepening. When the ratio of bank deposits to GDP (BD/GDP) is used as a proxy for financial deepening, the interest‐rate reforms impact positively on the level of financial deepening. However, when the monetization variable (M2/GDP) and the ratio of the private sector credit to GDP (DCP/GDP) are used, the coefficient of the deposit rate in the financial deepening model turns out to be statistically insignificant. Overall, our results show that the positive impact of interest‐rate reforms on financial deepening in Botswana is minimal. This outcome, though contrary to our expectations, is not surprising given the high level of population dependency in Botswana. Our results show that there is a strong negative relationship between the dependency ratio and financial deepening in Botswana.
The multi‐professional approach: front‐line professionals' behaviours and interactions
Authors: Sousa Liliana , Costa Tânia
Published: September 2009

Sousa L, Costa T. The multi‐professional approach: front‐line professionals' behaviours and interactions

Int J Soc Welfare 2010: 19: 444–454 © 2009 The Author, Journal compilation © 2009 Blackwell Publishing Ltd and the International Journal of Social Welfare.

Given the complexity of social problems, the multi‐professional approach has been generally adopted in the Western world as a desirable work practice. This study aimed at identifying front‐line professionals' behaviours and interactions that significantly influenced (positively or negatively) multi‐professional processes and outcomes. The study was conducted using the critical incidents technique administered to 117 front‐line professionals involved in multi‐professional approaches from different agencies and areas of expertise. The main findings suggest that the multi‐professional approach among front‐line professionals is facilitated by the professionals' commitment and complementarity and inhibited by the absence of complementarity, professionals being aggressive and insensitive to other professionals, and incompetence. The multi‐professional approach emerges as a context in which it is necessary to articulate professionals' personal and professional similarities and differences. The results suggest that professionals need to develop new competencies, particularly interdependence, flexibility and reflection on the process and outcomes of the multi‐professional approach.
Determinants of the Pension Curtailment Decisions of UK Firms
Authors: Klumpes Paul , Whittington Mark , Li Yong
Published: September 2009

Abstract:  During the last ten years of regulatory change, many UK companies have curtailed their defined benefit pension scheme. We test three competing explanations of UK corporate pension curtailments: integration, separation and risk management. We predict and find an association between the use of managerial discretion over changes in UK firms' expected rate of return on pension assets (ERR) assumptions, and subsequent decisions to curtail future defined benefit pension obligations. These findings are consistent with a risk management‐based explanation, even after controlling for other factors identified by prior literature as significant in explaining pension benefit reductions. We also find that curtailments and the risk management of ERR assumptions are associated with subsequent corporate restructuring decisions. The findings support the view that pension curtailment decisions are driven by the failure to adapt to new economic and regulatory pressures and that they are ultimately determined by strategic corporate risk management considerations.
Earnings Conservatism and Value Relevance Across the Business Cycle
Authors: Jenkins David S. , Kane Gregory D. , Velury Uma
Published: September 2009

Abstract:  Prior research has demonstrated higher value relevance of current earnings during economic expansions relative to contractions. We largely attribute such a result to expected growth prospects being captured in the current earnings coefficient when a direct proxy for expected future earnings is omitted from the returns‐earnings model. We demonstrate that the conservatism and value relevance of current earnings is actually higher during economic contractions when including a proxy for future earnings expectations. We further demonstrate that the value‐relevance of expected future earnings is higher during expansions, when the association between historical accounting information and future growth opportunities likely weakens.
Do Firms Manage Fair Value Estimates? An Examination of SFAS 142 Goodwill Impairments
Authors: Jarva Henry
Published: September 2009

Abstract:  I find that goodwill write‐offs under Statement of Financial Accounting Standards No. 142 (SFAS 142) are associated with future expected cash flows as mandated by the standard. However, there are indications that goodwill write‐offs lag behind the economic impairment of goodwill. Additional analysis reveals that the association between goodwill write‐offs and future cash flows is insignificant for firms with contemporaneous restructuring. I hypothesize that this finding is due to agency‐based motives. Finally, I examine a sample of non‐impairment firms in which there are indications that goodwill is impaired. I fail to find convincing evidence that these firms are opportunistically avoiding impairments.
Comorbidity of learning disorders: prevalence and familial transmission
Authors: Landerl Karin , Moll Kristina
Published: September 2009

Background:  In order to fully specify the profiles of risk and protective factors of developmental disorders, a better understanding of the conditions under which they co‐occur is required. So far, empirical evidence on comorbidities of specific learning disorders in arithmetic, reading and spelling is scarce.

Methods:  Prevalence and gender ratios of specific learning disorders in arithmetic (AD), reading (RD), and spelling (SD) and their co‐occurrence were assessed in a large (N = 2586) population‐based sample of elementary school children and in a subsample of 293 children with at least one learning disorder (LD‐sample). A questionnaire on familial transmission was given to a subsample of 256 parents of children with a learning disorder and 146 typically developing children.

Results:  The rates of deficits in arithmetic, reading, or spelling were four to five times higher in samples already experiencing marked problems in one academic domain compared to the full population. Thus, comorbidity of learning disorders was confirmed in a fairly standard school population. Rates of co‐occurrence decreased for AD and RD, but not isolated SD when more stringent cutoff criteria were applied, suggesting that the comorbidity of arithmetic and spelling disorder may be more strongly biologically mediated than the comorbidity of arithmetic and reading disorder. We found a preponderance of girls with AD and boys with SD. These imbalanced gender ratios were especially marked for isolated problems, while for comorbid problems gender ratios were mostly balanced with the exception of deficits in arithmetic and reading (but not spelling) which were more typical for girls. The parental questionnaire provided evidence for disorder‐specific familial transmission and co‐segregation of arithmetic and literacy deficits.

Conclusions:  Comorbidities of learning disorders are not artificial. They are the result of a complex interplay between both general and disorder‐specific aetiological factors.
Dynamics of emotion regulation in infants of clinically depressed and nondepressed mothers
Authors: Manian Nanmathi , Bornstein Marc H.
Published: September 2009

Background:  Emotion regulation (ER) has been conceptualized as an ongoing process of the individual’s emotion patterns in relation to moment‐to‐moment contextual demands. In contrast to traditional approaches of descriptively quantizing ER, we employed a dynamic approach to ER by examining key transitions in infants of clinically depressed and nondepressed mothers in the context of maternal still‐face (SF).

Methods:  Mothers with (n = 48) and without a clinical diagnosis of depression (n = 68) were seen in a modified SF paradigm with their 5‐month‐olds. Infant states and self‐soothing behaviors were coded in 1‐sec time intervals.

Results:  Infants of nondepressed mothers used attentional regulatory strategies, whereas infants of depressed mothers used internally directed strategies of self‐soothing to reduce negativity and maintain engagement with mother.

Conclusions:  This study advances our understanding of processes underlying infant ER and points to possible mechanisms for the development of long‐term maladaptive ER strategies in infants of depressed mothers.
Reduced electrodermal fear conditioning from ages 3 to 8 years is associated with aggressive behavior at age 8 years
Authors: Gao Yu , Raine Adrian , Venables Peter H. , Dawson Michael E. , Mednick Sarnoff A.
Published: September 2009

Background:  Poor fear conditioning characterizes adult psychopathy and criminality, but it is not known whether it is related to aggressive/antisocial behavior in early childhood.

Methods:  Using a differential, partial reinforcement conditioning paradigm, electrodermal activity was recorded from 200 male and female children at ages 3, 4, 5, 6, and 8 years. Antisocial/aggressive and hyperactive‐inattentive measures were collected at age 8.

Results:  Poor electrodermal fear conditioning from ages 3 to 8 years was associated with aggressive behavior at age 8 in both males and females.

Conclusions:  Results indicate that the relationship between poor fear conditioning and aggression occurs early in childhood. Enhanced electrodermal fear conditioning may protect children against future aggressive/violent behavior. Abnormal amygdala functioning, as indirectly assessed by fear conditioning, may be one of the factors influencing the development of childhood aggression.
ACCESS TO TREATMENT IN HIV PREVENTION TRIALS: PERSPECTIVES FROM A SOUTH AFRICAN COMMUNITY
Authors: BARSDORF NICOLA , MAMAN SUZANNE , KASS NANCY , SLACK CATHERINE
Published: September 2009

Access to treatment, in HIV vaccine trials (HVTs), remains ethically controversial. In most prevention trials, including in South Africa, participants who seroconvert are referred to publicly funded programmes for treatment. This strategy is problematic when there is inadequate and uneven access to public sector antiretroviral therapy (ART) and support resources. The responsibilities, if any, of researchers, sponsors and public health authorities involved in HVTs has been hotly debated among academics, scholars, representatives of international organizations and sponsors. However, there is little published on community perceptions. Recent guidance asserts that communities should make inputs into treatment and care decisions. This qualitative study explored a South African community's perceptions of who should provide what to HVT participants as well as how and why this should be done. Twenty‐nine adults working at or attending five primary health care clinics in two rural areas in KwaZulu‐Natal participated in in‐depth interviews. Respondents expressed that researchers should ‘help participants to access’ treatment and care ‘because they are in a position to do so’ and ‘are in a relationship with’ trial participants. Respondents suggested that researchers could help by ‘facilitating referral’ until such time that participants can access care and treatment on their own. We highlight a series of implications for researchers in HVTs, including their need to be aware of prospective participants' considerable trust in and respect for researchers, the responsibility that this places on them, and the need for clear communication with communities so as not to erode community trust.
Prototype analysis of the concept of compassionate love
Authors: FEHR BEVERLEY , SPRECHER SUSAN
Published: September 2009

Social scientists are turning their attention to compassionate love, arguing that this kind of love may promote the greatest social good. The central thesis of this research was that compassionate love might be best understood as a prototype rather than a classically defined concept. Six studies were conducted with in Canada and the United States. In Study 1, participants generated features of compassionate love. Studies 2 and 3 revealed that some features (e.g., trust, caring) are considered more central to the concept of compassionate love than others (e.g., sacrifice, sympathy). This prototype structure was confirmed in studies of reaction time (Study 4), memory (Study 5), and logical inferences (Study 6). The implications of a prototype conceptualization of compassionate love for theorizing and research in this relatively new area are discussed.
Temporal discounting for monetary and close relationship outcomes
Authors: TAYLER SOPHIE , ARANTES JOANA , GRACE RANDOLPH C.
Published: September 2009

The present study extended research on intertemporal choice—in which individuals choose between outcomes that may be received immediately or after a delay—to close relationships. In Experiment 1, New Zealand university students aged 18 to 25 made decisions about hypothetical monetary and relationship outcomes, and in Experiment 2, about relationship outcomes which emphasized companionate or sexual aspects (Ns = 64). Both experiments found effects of delay and magnitude on temporal discounting rates, and domain independence for choices about close relationships, similar to previous studies with monetary outcomes. There were no significant gender differences. Overall, results suggest that people make intertemporal choices about relationships according to a similar process used to make decisions involving other types of outcomes.
Attachment, marital satisfaction, and divorce during the first fifteen years of parenthood
Authors: HIRSCHBERGER GILAD , SRIVASTAVA SANJAY , MARSH PENNY , COWAN CAROLYN PAPE , COWAN PHILIP A.
Published: September 2009

This study examines 2 overlapping longitudinal samples of U.S. couples with children, covering a period of 15 years after the first child's birth. The first sample extended from the pregnancy with a first child until that child was 5.5 years old and the second from ages 4.5 to 14.5. Growth curve analyses revealed that marital satisfaction declined over 15 years for both husbands and wives. Attachment security measured in the second sample was associated with greater marital satisfaction but did not buffer against declines in marital satisfaction over time. Husbands' lower initial level of marital satisfaction measured around the first child's transition to school was the only significant predictor of marital dissolution. The discussion emphasizes theoretical and practical implications of these findings.
Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti‐cancer effects and pharmacological properties
Authors: Hegedűs C , Özvegy‐Laczka C , Apáti Á , Magócsi M , Német K , Őrfi L , Kéri G , Katona M , Takáts Z , Váradi A , Szakács G , Sarkadi B
Published: September 2009

Background and purpose:  ABC multidrug transporters (MDR‐ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti‐cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first‐generation, small‐molecule, tyrosine kinase inhibitors (TKIs), including the Bcr‐Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second‐generation inhibitors of the Bcr‐Abl tyrosine kinase activity.

Experimental approach:  MDR‐ABC transporter function was screened in both membrane‐ and cell‐based (K562 cells) systems. Cytotoxicity measurements in Bcr‐Abl‐positive model cells were coupled with direct determination of intracellular TKI concentrations by high‐pressure liquid chromatography‐mass spectrometry and analysis of the pattern of Bcr‐Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity.

Key results:  Nilotinib and dasatinib were high‐affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters.

Conclusions and implications:  A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti‐cancer TKIs, even in multidrug‐resistant cancer. The pattern of MDR‐ABC transporter–TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.
Actions of hydrogen sulphide on ion transport across rat distal colon
Authors: Hennig B , Diener M
Published: September 2009

Background and purpose: The aim of this study was to identify the actions of H2S on ion transport across rat distal colon.

Experimental approach: Changes in short‐circuit current (Isc) induced by the H2S‐donor, NaHS, were measured in Ussing chambers. Cytosolic Ca2+concentration was evaluated using fura‐2.

Key results: NaHS concentration‐dependently induced a change in Isc, that was only partially inhibited by the neurotoxin, tetrodotoxin. Lower concentrations (≤10−3 mol·L−1) of NaHS induced a monophasic increase in Isc, whereas higher concentrations induced an additional, secondary fall of Isc, before a third phase when Isc rose again. Blockers of H2S‐producing enzymes (expression demonstrated immunohistochemically) decreased basal Isc, suggesting that endogenous production of H2S contributes to spontaneous anion secretion. The positive Isc phases induced by NaHS were due to Cl‐secretion as shown by anion substitution and transport inhibitor experiments, whereas the transient negative Isc induced by higher concentrations of the H2S‐donor was inhibited by mucosal tetrapentylammonium suggesting a transient K+secretion. When applied from the serosal side, glibenclamide, an inhibitor of ATP‐sensitive K+channels, and tetrapentylammonium, a blocker of Ca2+‐dependent K+channels, suppressed NaHS‐induced Cl‐secretion suggesting different types of K+channels are stimulated by the H2S‐donor. NaHS‐induced increase in cytosolic Ca2+concentration was confirmed in isolated, fura‐2‐loaded colonic crypts. This response was not dependent on extracellular Ca2+, but was inhibited by blockers of intracellular Ca2+channels present on Ca2+storage organelles.

Conclusions and implications: H2S induces colonic ion secretion by stimulation of apical as well as basolateral epithelial K+channels.
Activation of the lung S1P1 receptor reduces allergen‐induced plasma leakage in mice
Authors: Blé F‐X , Cannet C , Zurbruegg S , Gérard C , Frossard N , Beckmann N , Trifilieff A
Published: September 2009

Background and purpose:  It has been suggested that intratracheal administration of the immunomodulator, FTY720, could have anti‐inflammatory effects without causing a decrease in blood lymphocyte counts. However, the receptor responsible for this effect has not been defined.

Experimental approach:  We have described, in a mouse model of allergen‐induced inflammation, the use of proton magnetic resonance imaging to non‐invasively assess lung fluid accumulation and inflammation. Here, we used this model to investigate the sphingosine‐1‐phosphate (S1P) receptor responsible for the anti‐inflammatory effect of FTY720.

Key results:  When given intranasally, FTY720 (3 and 10 µg·kg−1) inhibited by approximately 50% the allergen‐induced accumulation of fluid in the lung detected by magnetic resonance imaging, but had no effect on the cellular inflammation in the airway space or on circulating blood lymphocytes. Inhibition of the infiltration of inflammatory cells into the airways was only observed at a dose of FTY720 that induced lymphopenia (100 µg·kg−1). Similar results were observed in S1P3‐deficient mice. The effect of FTY720 was mimicked by intranasal treatment of wild‐type mice with a S1P1‐specific agonist, AUY954.

Conclusions and implications:  Thus, in contrast to previously published work, our results suggest that systemic exposure of FTY720 is necessary to obtain an airway anti‐inflammatory effect. On the contrary, inhibition of the allergen‐induced accumulation of fluid in the lung, via activation of the S1P1 receptor, is obtainable without systemic effects.
Integrated risk assessment and predictive value to humans of non‐clinical repolarization assays
Authors: Wallis Robert M
Published: September 2009

The potential for drugs to be associated with the life‐threatening arrhythmia, Torsades de Pointes (TdeP), continues to be a topic of regulatory, academic and industrial concern. Despite being an imperfect biomarker, prolongation of the QT interval of the surface ECG is used to assess the risk of a drug being associated with TdeP such that a thorough examination of drug effects on the QT interval is required for all new chemical entities. Numerous studies have investigated the relationship between non‐clinical findings and the risk of TdeP and QT prolongation in the general population. There are many literature references supporting the strong correlation between the clinical safety margin over humanether‐a‐go‐go(hERG) inhibitory potency and the risk of drug‐induced arrhythmia and sudden death. A quantitative analysis of the relationship between non‐clinical studies and the outcome of a human Thorough QT study has also been reported. In the current manuscript, based on the outcome of the non‐clinical assays the sensitivity and specificity of each assay and an integrated risk assessment for predicting the outcome of the human Thorough QT study has been conducted. The data suggest that for QT prolongation mediated through inhibition of the hERG current the non‐clinical assays are highly predictive of drug effects on the QT interval. Based on the literature review and specific quantitative analysis reported above it is concluded that non‐clinical assays predict the risk of compounds to prolong the QT interval and cause TdeP in humans if the mechanism is through inhibition of the hERG current.

This article is part of a themed section on QT safety. To view this issue visithttp://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010
Phosphorylation alters the pharmacology of Ca2+‐activated Cl‐ channels in rabbit pulmonary arterial smooth muscle cells
Authors: Wiwchar M , Ayon R , Greenwood IA , Leblanc N
Published: September 2009

Background and purpose:  Ca2+‐activated Cl‐ currents (ICl(Ca)) in arterial smooth muscle cells are inhibited by phosphorylation. The Ca2+‐activated Cl‐ channel (ClCa) blocker niflumic acid (NFA) produces a paradoxical dual effect on ICl(Ca), causing stimulation or inhibition at potentials below or above 0 mV respectively. We tested whether the effects of NFA on ICl(Ca) were modulated by phosphorylation.

Experimental approach:  ICl(Ca) was elicited with 500 nM free internal Ca2+ in rabbit pulmonary artery myocytes. The state of global phosphorylation was altered by cell dialysis with either 5 mM ATP or 0 mM ATP with or without an inhibitor of calmodulin‐dependent protein kinase type II, KN‐93 (10 µM).

Key results:  Dephosphorylation enhanced the ability of 100 µM NFA to inhibit ICl(Ca). This effect was attributed to a large negative shift in the voltage‐dependence of block, which was converted to stimulation at potentials <−50 mV, ∼70 mV more negative than cells dialysed with 5 mM ATP. NFA dose‐dependently blocked ICl(Ca) in the range of 0.1–250 µM in cells dialysed with 0 mM ATP and KN‐93, which contrasted with the stimulation induced by 0.1 µM, which converted to block at concentrations >1 µM when cells were dialysed with 5 mM ATP.

Conclusions and implications:  Our data indicate that the presumed state of phosphorylation of the pore‐forming or regulatory subunit of ClCa channels influenced the interaction of NFA in a manner that obstructs interaction of the drug with an inhibitory binding site.
Long‐term blockade of L/N‐type Ca2+channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart
Authors: Takahara A , Nakamura Y , Wagatsuma H , Aritomi S , Nakayama A , Satoh Y , Akie Y , Sugiyama A
Published: September 2009

Background and purpose: The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death.

Experimental approach: The L‐type Ca2+channel blocker amlodipine (2.5 mg·day−1), L/N‐type Ca2+channel blocker cilnidipine (5 mg·day−1), or the angiotensin II receptor blocker candesartan (12 mg·day−1) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration.

Key results: Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat‐to‐beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed.

Conclusions and implications: Long‐term blockade of L/N‐type Ca2+channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases.
Evidence that 5‐hydroxytryptamine7 receptors play a role in the mediation of afferent transmission within the nucleus tractus solitarius in anaesthetized rats
Authors: Oskutyte Diana , Jordan David , Ramage Andrew G
Published: September 2009

Background and purpose:  Central 5‐hydroxytryptamine (5‐HT)‐containing pathways utilizing 5‐HT7 receptors are known to be critical for the mediation of cardiovascular reflexes. The nucleus tractus solitarius (NTS) is a site involved in the integration of cardiovascular afferent information. The present experiments examined the involvement of the 5‐HT7 receptor in the processing of cardiovascular reflexes in the NTS.

Experimental approach:  In anaesthetized rats extracellular recordings were made from 104 NTS neurones that were excited by electrical stimulation of the vagus nerve and/or activation of cardiopulmonary afferents. Drugs were applied ionophoretically in the vicinity of these neurones.

Key results:  The non‐selective 5‐HT7 receptor agonist 5‐carboxamidotryptamine maleate (5‐CT) applied to 78 neurones increased the firing rate in 18 by 59% and decreased it in 38 neurones by 47%. Similarly, the 5‐HT1A agonist 8‐OH‐DPAT applied to 20 neurones had an excitatory (8), inhibitory (7) or no effect (5) on the 20 neurones tested. In the presence of the 5‐HT7 antagonist SB 258719 the 5‐CT excitation was attenuated. Furthermore, the excitatory response of NTS neurones evoked by electrical stimulation of the vagus nerve or activation of cardiopulmonary afferents with intra atrial phenylbiguanide was attenuated by SB 258719. The inhibitory action of 5‐CT was unaffected by SB 258719 and the 5‐HT1A antagonist WAY‐100635. WAY‐100635 failed to have any effect on 5‐CT and vagal afferent‐evoked excitations.

Conclusions and implications:  Vagal afferent‐evoked excitation of NTS neurones can be blocked by SB 258719, a selective 5‐HT7 antagonist. This observation further supports the involvement of 5‐HT neurotransmission in NTS afferent processing.
GENETIC MAPPING OF THE LAMINARIA JAPONICA (LAMINARALES, PHAEOPHYTA) USING AMPLIFIED FRAGMENT LENGTH POLYMORPHISM MARKERS1
Authors: Liu Fuli , Wang Xiuliang , Liu Jidong , Fu Wandong , Duan Delin , Yang Yingxia
Published: September 2009

To establish a molecular‐marker‐assisted system of breeding and genetic study for Laminaria japonica Aresch., amplified fragment length polymorphism (AFLP) was used to construct a genetic linkage map of L. japonica featuring 230 progeny of F2 cross population. Eighteen primer combinations produced 370 polymorphic loci and 215 polymorphic loci segregated in a 3:1 Mendelian segregation ratio (P ≤ 0.05). Of the 215 segregated loci, 142 were ordered into 27 linkage groups. The length of the linkage groups ranged from 6.7 to 90.3 centimorgans (cM) with an average length of 49.6 cM, and the total length was 1,085.8 cM, which covered 68.4% of the estimated 1,586.9 cM genome. The number of mapped markers on each linkage group ranged from 2 to 12, averaging 5.3 markers per group. The average density of the markers was 1 per 9.4 cM. Based on the marker density and the resolution of the map, the constructed linkage map can satisfy the need for quantitative trait locus (QTL) location and molecular‐marker‐assisted breeding for Laminaria.
INORGANIC CARBON ACQUISITION BY CHRYSOPHYTES1
Authors: Maberly Stephen C. , Ball Lucy A. , Raven John A. , Sültemeyer Dieter
Published: September 2009

Twelve species, representing 12 families of the chrysophytes sensu lato, were tested for their ability to take up inorganic carbon. Using the pH‐drift technique, CO2 compensation points generally varied between 1 and 20 μmol · L−1 with a mean concentration of 5 μmol · L−1. Neither pH nor alkalinity affected the CO2 compensation point. The concentration of oxygen had a relatively minor effect on CO2‐uptake kinetics, and the mean CO2 compensation point calculated from the kinetic curves was 3.6 μmol · L−1 at 10–15 kPa starting oxygen partial pressure and 3.8 μmol · L−1 at atmospheric starting oxygen partial pressure (21 kPa). Similarly, uptake kinetics were not affected by alkalinity, and hence concentration of bicarbonate. Membrane inlet mass spectrometry (MIMS) in the presence and absence of acetazolamide suggested that external carbonic anhydrase in Dinobryon sertularia Ehrenb. and Synura petersenii Korschikov was either very low or absent. Rates of net HCO3− uptake were very low (∼5% of oxygen evolution) using MIMS and decreased rather than increased with increasing HCO3− concentration, suggesting that it was not a real uptake. The CO2 compensation points determined by MIMS for CO2 uptake and oxygen evolution were similar to those determined in pH‐drift and were >1 μmol · L−1. Overall, the results suggest that chrysophytes as a group lack a carbon‐concentrating mechanism (CCM), or an ability to make use of bicarbonate as an alternative source of inorganic carbon. The possible evolutionary and ecological consequences of this are briefly discussed.
ULTRASTRUCTURE AND LSU rDNA–BASED REVISION OF PERIDINIUM GROUP PALATINUM (DINOPHYCEAE) WITH THE DESCRIPTION OF PALATINUS GEN. NOV.1
Authors: Craveiro Sandra C. , Calado António J. , Daugbjerg Niels , Moestrup Øjvind
Published: September 2009

The name Peridinium palatinum Lauterborn currently designates a freshwater peridinioid with 13 epithecal and six cingular plates, and no apical pore complex. Freshwater dinoflagellate floras classify it in Peridinium group palatinum together with P. pseudolaeve M. Lefèvre. General ultrastructure, flagellar apparatus, and pusular components of P. palatinum were examined by serial section TEM and compared to P. cinctum (O. F. Müll.) Ehrenb. and Peridiniopsis borgei Lemmerm., respectively, types of Peridinium and Peridiniopsis. Partial LSU rDNA sequences from P. palatinum, P. pseudolaeve and several peridinioids, woloszynskioids, gymnodinioids, and other dinoflagellates were used for a phylogenetic analysis. General morphology and tabulation of taxa in group palatinum were characterized by SEM. Differences in plate numbers, affecting both the epitheca and the cingulum, combine with differences in plate ornamentation and a suite of internal cell features to suggest a generic‐level distinction between Peridinium group palatinum and typical Peridinium. The branching pattern of the phylogenetic tree is compatible with this conclusion, although with low support from bootstrap values and posterior probabilities, as are sequence divergences estimated between species in group palatinum, and typical Peridinium and Peridiniopsis. Palatinus nov. gen. is proposed with the new combinations Palatinus apiculatus nov. comb. (type species; syn. Peridinium palatinum), P. apiculatus var. laevis nov. comb., and P. pseudolaevis nov. comb. Distinctive characters for Palatinus include a smooth or slightly granulate, but not areolate, plate surface, a large central pyrenoid penetrated by cytoplasmic channels and radiating into chloroplast lobes, and the presence of a peduncle‐homologous microtubular strand. Palatinus cells exit the theca through the antapical‐postcingular area.