bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of life-cycle assessment in optimisation of municipal waste management systems: the case of Lithuania
Authors: Miliūte Jūratė , Kazimieras Staniškis Jurgis
Published: August 2009

This paper discusses the ecological optimisation of municipal waste management systems. The purpose of this paper is to help local decision-makers in designing integrated waste management solutions that are ecologically optimal. The study uses life-cycle assessment (LCA) methodology to build a model and test different waste management scenarios in order to see whether the waste management hierarchy is influenced by regional conditions. The study also tests to which variables in waste management systems the end results of the LCA are most sensitive. The discussion is built around a case study in Lithuania where several waste management scenarios have been analysed and compared in the LCA framework. The paper reveals several methodology-related issues and discusses what implications waste-related policy intervention would have on the environmental outcomes of different waste management scenarios.
Psychometric Properties of a New Scale to Assess Family Violence in Older African American Women: The Family Violence Against Older Women (FVOW) Scale
Authors: Paranjape Anuradha , Rodríguez Michael , Gaughan John , Kaslow Nadine J.
Published: August 2009

Absence of a conceptually grounded, comprehensive measure for family violence in older women has hindered attempts to define the extent of the problem and its effects on older women’s health. This article reports the development and psychometrics of the Family Violence in Older African American Women Scale, a comprehensive scale to measure family violence in older women. The scale demonstrates two distinct factors: (a) “Abuse” and (b) “Caregiving Failure,” which measure abusive behaviors in the context of a family relationship and caring for older women, respectively. Implications for the use of this scale in research and practice settings are discussed.
A Reflection on the Significance of Numbers
Authors: Perriton Linda
Published: August 2009

This article reflects on what the author considers a curious absence of curiosity about, and research looking at the practices of, management development practitioners. Whilst appreciative of the breadth and depth of qualitative research presented in this journal over the course of the last 40 years the article suggests that we are far from having the measure of management learning as a practice and that it would now be helpful—perhaps even essential if the field is to be meaningful to academics, practitioners and policy makers—to establish the boundaries of the field with the help of quantitative data about the business of management learning.
Feminist Challenges and Futures: Women, Diversity and Management Learning
Authors: Swan Elaine , Stead Valerie , Elliott Carole
Published: August 2009

Drawing on the category of the ‘social’ in social learning theory as a ‘mini case study’, we argue in this article that gender, race and class are still neglected in the field and practices of management learning. We suggest that feminist work is a growing part of the journal and field of management learning but on limited terms. Thus we argue that feminism has not been mobilized to interrogate core categories and concepts in management learning, such as the ‘social’ in social learning. In addition, we outline how issues of race and class are even more marginalized and raise a number of questions to indicate how management learning might be researched and theorized if race, gender and class were taken seriously as mainstream issues.
Popular Critiques of Consultancy and a Politics of Management Learning?
Authors: Sturdy Andrew
Published: August 2009

In this short article, I argue that popular business discourse on the role of management consultancy in the promotion and translation of management ideas is often critical, informed by more or less implicit ethical and political concerns with employee security, equity, openness and the transparency and legitimacy of responsibility. These concerns are, in part, ‘sayable’ because their object is seen as a scapegoat for management. Nevertheless, combined with the popular form of their expression, they can support and legitimize critical studies of management learning, a discipline which otherwise has become overly concerned with processual and situational phenomena at the expense of broader political dynamics and of the content and consequences of management and management knowledge.
Reflection and Mindfulness in Organizations: Rationales and Possibilities for Integration
Authors: Jordan Silvia , Messner Martin , Becker Albrecht
Published: August 2009

The notion of reflection has featured strongly in Management Learning in recent years. While there is an important body of knowledge on how organizations can foster reflection-on-action, less seems to be known about how they can promote reflection-in-action. We suggest that reflection-in-action is closely linked to the phenomenon of mindfulness and we outline what existing research on mindfulness may teach us about understanding and organizing reflection-in-action. We believe that integrating the perspectives taken in these two streams of literature is important for a clear understanding of why some organizations seem to learn ‘better’ than others and why some initiatives to promote reflection and learning are more successful than others.
Improving hospital care for young children in the context of HIV/AIDS and poverty
Authors: Richter Linda , Chandan Upjeet , Rochat Tamsen
Published: August 2009

Paediatric wards in South African government hospitals are occupied predominantly by children with HIV and AIDS-related illnesses. Although access to anti-retroviral treatment for adults is being scaled up, it is likely to be many years before South Africa achieves anywhere near universal access for children. Currently, most children living with HIV or AIDS are identified only when they become acutely or chronically ill and/or hospitalized, if at all. In the absence of treatment, the stress of caring for ill and hospitalized HIV-positive children often results in emotional withdrawal among both health professionals and caregivers. The demoralizing cycle of repeated admissions, treatment failure and death also affect the quality of the care given to HIV-negative children in over-burdened wards. This article describes the development of simple, low-cost and context-relevant interventions to improve the care environment for young hospitalized children within the context of the HIV/AIDS epidemic and poverty.
Family—school connections and internalizing problems among children living with asthma in urban, low-income neighborhoods
Authors: Murdock Karla Klein , Robinson Elizabeth M. , Adams Sue K. , Berz Jennifer , Rollock Michael J.D.
Published: August 2009

Children with asthma living in urban environments are at risk for experiencing internalizing problems and difficulties at school due to social context and health-related stressors. Parent confidence and participation in the school and children’s attitudes about school were explored in association with children’s depressed mood and school anxiety. Forty-five parent—child dyads were recruited from urban community health centers. Most participants were members of ethnic minority groups. Hierarchical multiple regression analyses revealed that higher levels of parent confidence in the school were associated with fewer symptoms of school anxiety in children. Children’s attitudes toward school moderated the relation between parent participation in the school and children’s depressed mood. Specifically, lower levels of parent participation were associated with higher levels of depressed mood only for children with the least positive school attitudes. Although preliminary, these results suggest the importance of attending to family—school connections to optimize the school-related psychological functioning of children living with asthma in urban environments.
The perceptions and preferences of parents of children with tracheostomies in a study of humidification therapy
Authors: McNamara David G. , Dickinson Annette R. , Byrnes Catherine A.
Published: August 2009

This article reports a grounded theory study which was the qualitative phase of a randomized-controlled trial in children with tracheostomies comparing two techniques for providing humidified inspired gases. Semi-structured interviews were conducted with eight mothers of children with tracheostomies recruited from the trial, one mother who was not involved in the trial and four experienced nurses. Data were analysed using open, selective and theoretical coding. A core category was identified of parents managing the child’s care in response to a set of problematic and constraining states. Parents were seen to utilize strategies of constant checking, becoming the expert, the family pulling together and electing to use preferred technology. The findings of this study mirror those of previous studies and reinforce the primacy of caregivers as managers of their child’s health care. Mothers elected to use or not use a given technology within this context, utilizing a process of balancing.
The National Programme for IT in England: Clinicians’ views on the impact of the Choose and Book service
Authors: Rabiei Reza , Bath Peter A. , Hutchinson Allen , Burke Derek
Published: August 2009

In England, the Choose and Book service, a main component of the England National Programme for IT (NPfIT), aims at empowering patients. Little research has been performed to evaluate clinicians’ perceptions of, and satisfaction with, the Choose and Book service. The aim of the research was to examine clinicians’ perceptions of, and satisfaction with, the Choose and Book service. A qualitative approach, using in-depth, semi-structured interviews, was used to collect data. Framework analysis was used to analyse the data. Twenty clinicians were interviewed, including 14 general practitioners (GPs) and six hospital consultants. Although clinicians were positive about the benefits of the Choose and Book service, they were concerned about the adverse impact of the electronic referral process on their job. Paying attention to the impact of the service on clinicians’ jobs, at both ends of the process, could help to improve the referral process and the use of the system.
‘Caught in the act’: ethics committee review and researching the sexual culture of schools
Authors: Allen Louisa
Published: August 2009

This article explores ethics committee review as part of a system of government directing the behaviour of researchers and possibilities of research. Drawing on the work of Halse and Honey (2007) it argues ethics committees represent one of the governing practices of an institutional discourse of ethical research. This discourse has constitutive effects for researcher identities that are ‘ethical’ and what in practice might represent ‘ethical’ research. This analysis is undertaken with reference to visual research with youth about ‘the sexual culture of schools’. How ethics review constituted this research as ‘risky’ and young people as ‘irresponsible’ and ‘recalcitrant’ is examined. These discursive practices undermined a youth-centred methodology committed to valuing the agency and competency of youth and left the researcher feeling she had acted ‘unethically’ towards participants. These effects demonstrate a paradox whereby compliance with ethics review can produce what this process seeks to prevent, ‘unethical’ researchers and research.
Looking at and looking back: visualization in mobile research
Authors: Murray Lesley
Published: August 2009

This article discusses mobile and visual methodologies and the use of visual and mobile methods in the context of a study exploring the negotiation of risk on the journey to school. It sets out an epistemological approach that encompasses the ‘mobilities turn’ in the social sciences and current debates on visual methods, arguing that ‘mobile’ and ‘visual’ methods are not only compatible, but often indivisible. This argument is developed through the researcher’s experience of using mobile and visual methods to explore the range of social, emotional and sensorial responses to mobile space. In particular, it is argued that methods that are both mobile and visual produce insights into everyday life experiences, especially of excluded groups such as children and young people, which are not available using more traditional methods.
Association of angiotensin-converting enzyme gene promoter single nucleotide polymorphisms and haplotype with major depression in a northeastern Thai population
Authors: Angunsri Rudee , Sritharathikhun Thapanut , Suttirat Sarawut , Tencomnao Tewin
Published: August 2009

Introduction. Angiotensin-converting enzyme (ACE) is thought to influence the activity of the hypothalamic-pituitary-adrenocortical system, which shows hyperactivity in the majority of patients with major depressive disorder (MDD). This study aimed at determining an association between two single nucleotide polymorphisms (SNPs) (rs4291;−240A/T and rs4292;−93T/C) of the ACE gene promoter and MDD in northeastern Thais.

Subjects and methods. In the present case-control study, genotyping of 187 unrelated patients with MDD (44.89±12.92 years) and 207 unrelated healthy controls (41.34±9.76 years) from the northeastern part of Thailand was performed using polymerase chain reaction-restriction fragment length polymorphism technique.

Results. Comparing the two groups, no significant difference was observed with regard to either genotype distributions or allele frequencies of the −93T/C SNP of ACE. For the −240A/T SNP, a significant difference in genotype distributions was found (χ2=6.65, d f=2, p=0.036).The presence of the −240A allele of ACE was associated with a decreased risk for MDD compared with the −240T allele (χ2=4.24, d f=1, p=0.040, odds ratio=0.702 [95% confidence interval=0.508—0.971]). Moreover, haplotype frequency analysis revealed that the −240T/—93T combination was significantly over-represented in patients with MDD in comparison with controls (13.6% and 6.8%, p=0.002 on χ2 test, empirical p=0.004).

Conclusions. In the present investigation, an association between the −240A allele and a reduced risk for MDD was observed, but the genotype distributions of controls were only just in marginal agreement with Hardy-Weinberg equilibrium.The T-T haplotype in the ACE gene was significantly associated with an increased risk for MDD.
Interleukin-6 is associated with liver lipid homeostasis but not with cell death in experimental hepatic steatosis
Authors: Sánchez-Garrido Miguel A. , Chico Yolanda , González Raúl , Ranchal Isidora , González-Rubio Sandra , Hidalgo Ana B. , Díaz-López Cesar , Costán Guadalupe , Padillo Francisco J. , De la Mata Manuel , Ochoa Begoña , Muntané Jordi
Published: August 2009

Hepatic steatosis is a risk factor for the progression of non-alcoholic fatty liver disease. The role of pro-inflammatory interleukin (IL)-6 in hepatic steatosis etiology is controversial. We investigated in vivo and in primary hepatocyte cultures whether IL-6 has a modulator role in liver and mitochondria lipid composition and cell death in a choline-deficient (CD) diet rat model of hepatic steatosis. Dietary choline deficiency increased triglycerides and cholesterol, and reduced phosphatidylcholine (PC), phosphatidylethanolamine (PE) and the membrane integrity marker PC:PE ratio in liver. Choline-deficient diet enhanced systemic IL-6, and IL-6 receptor expression and cell death vulnerability in hepatocytes. Derangement of the mitochondrial electron transport chain and of its phospholipid environment was found in CD rat liver mitochondria, which exhibited elevated concentrations of triglycerides, cardiolipin and PC and elevated PC:PE ratio. The cell treatment with IL-6, but not PC, eliminated much of the CD-promoted lipid imbalance in mitochondria but not tumor-necrosis factor (TNF)-α-induced cell death. However, PC supplementation prevented the TNF-α-induced DNA fragmentation, cytochrome-c release and caspase-3 activity in control and CD hepatocytes. In conclusion, IL-6 ameliorated the mitochondria lipid disturbance in hepatocytes isolated from steatotic animals. Furthermore, PC is identified as a new survival agent that reverses several TNFα-inducible responses that are likely to promote steatosis and necrosis.
Expression of UDP-glucuronosyltransferase 1A6 isoform in Caco-2 cells stimulated with lipopolysaccharide
Authors: Panaro Maria Antonietta , Cavallo Pasqua , Acquafredda Angela , Cianciulli Antonia , Calvello Rosa , Mitolo Vincenzo
Published: August 2009

Glucuronidation is an important metabolic process of detoxification in all vertebrates. The reaction is catalyzed by a multigene family of UDP-glucuronosyltransferases (UGTs) able to convert many xenobiotics and endobiotics (hydrophobic substances) to inactive, water-soluble glucuronides. The UGTs play a protective role, facilitating the elimination of potentially toxic metabolites via urine, bile and feces; therefore, impairment of UGTs may have important toxicological consequences. The regulation of UGTs during bacterial infection or inflammation is not well described. In this study, we investigated the in vitro effect of lipopolysaccharide (LPS) on the expression of the UGT1A6 isoform in human colon carcinoma Caco-2 cells. Results demonstrated a significant down-regulation of UGT1A6 expression, both in terms of mRNA and protein levels, and a reduced UGT activity after LPS exposure of cell cultures, suggesting a role for endotoxins on UGT regulation mechanisms.
Nd:YAG laser cladding Ni base alloy/nano-h-BN self-lubricating composite coatings
Authors: Yan H. , Wang A. H. , Zhang X. L. , Huang Z. W. , Wang W. Y. , Xie J. P.
Published: August 2009

Ni base alloy/nano-hexagonal boron nitride (nano-h-BN) self-lubricating composite coatings were successfully produced on medium carbon steel substrate by means of Nd:YAG laser cladding. A novel high energy ball milling method was adopted to clad nano-Ni onto nano-h-BN with an aim to enhance the compatibility between the h-BN and the metal matrix during laser cladding process. The microhardness profile of the composite coatings along the depth direction was measured, while its cross-sectional microstructures and phase compositions were analysed by means of SEM incorporating EDX and XRD. The friction behaviour of the composite coatings sliding against GCr15 steel at room temperature was evaluated using a ball on disc friction and wear tester, and the worn surface morphologies of the composite coatings were observed using SEM. It was found that nano-h-BN was hardly to be composed into Ni45 matrix coating even if increasing the weight percentage of h-BN from 5 to 10 wt-% with a conventional mechanical mixing. The high energy ball milling of nano-Ni onto nano-h-BN significantly improved the interfacial compatibility between h-BN and Ni60 matrix. The friction coefficient of the laser clad Ni60/nano-Ni-clad h-BN coating was reduced obviously.
Reduction characteristics of iron oxide in nanoscale
Authors: Abdel Halim K. S. , Khedr M. H. , Soliman N. K.
Published: August 2009

Nanosized iron oxide powder with an average crystallite size of 35, 100 and 150 nm was prepared by thermal evaporation and coprecipitation techniques. The synthesised powders were characterised by X-ray diffraction analysis technique, reflected light microscope, TEM and scanning electron microscope. The powder was pressed into compacts which then isothermally reduced in hydrogen atmosphere at 400–600°C. The reduction course was followed up by means of weight loss technique. The effect of crystal size and reduction temperature on the reduction behaviour of nanosized iron oxides compacts was investigated. The values of apparent activation energy calculated from the experimental results together with the application of gas solid reaction model were used to elucidate the reduction mechanism of iron oxide in nanoscale. It was observed that both the reduction temperature and crystal size of the compact greatly affect the reduction mechanism of iron oxide. It can be reported that the complete reduction process of nanosized iron oxides can be performed at relatively low temperatures (450–600°C). At the initial stages of reduction, the reduction rate is controlled by combined effect of gas diffusion and interfacial chemical reaction mechanism for all nanosized compacts whereas the controlled mechanism was varied at the final stages of reduction according to the crystal size of iron oxides.
A novel interplay between Epac/Rap1 and mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) regulates thrombospondin to control angiogenesis
Authors: Doebele Robert C. , Schulze-Hoepfner Frank T. , Hong Jia , Chlenski Alexandre , Zeitlin Benjamin D. , Goel Kushboo , Gomes Suzana , Liu Yuru , Abe Mark K. , Nor Jacques E. , Lingen Mark W. , Rosner Marsha Rich
Published: August 2009

Tumors depend upon angiogenesis for growth and metastasis. It is therefore critical to understand the inhibitory signaling mechanisms in endothelial cells that control angiogenesis. Epac is a cyclic adenosine 5′-monophosphate–activated guanine nucleotide exchange factor for Rap1. In this study, we show that activation of Epac or Rap1 leads to potent inhibition of angiogenesis in vivo. Epac/Rap1 activation down-regulates inhibitor of differentiation 1 (Id1), which negatively regulates thrombospondin-1 (TSP1), an inhibitor of angiogenesis. Consistent with this mechanism, activation of Epac/Rap 1 induces expression of TSP1; conversely, depletion of Epac reduces TSP1 levels in endothelial cells. Blockade of TSP1 binding to its receptor, CD36, rescues inhibition of chemotaxis or angiogenesis by activated Epac/Rap1. Mitogen-activated protein kinase kinase 5, a downstream mediator of vascular endothelial growth factor, antagonizes the effects of Epac/Rap1 by inducing Id1 and suppressing TSP1 expression. Finally, TSP1 is also secreted by fibroblasts in response to Epac/Rap1 activation. These results identify Epac and Rap1 as inhibitory regulators of the angiogenic process, implicate Id1 and TSP1 as downstream mediators of Epac/Rap1, and highlight a novel interplay between pro- and antiangiogenic signaling cascades involving multiple cell types within the angiogenic microenvironment.
Decatenation: fixing your knots
Authors: Clarke Duncan J.
Published: August 2009

How tumor cells gain resistance to drugs is critically important to elucidate for developing better cancer therapy. In this issue of Blood, Wray and colleagues have identified a mechanism whereby acute leukemia cells use a stimulator of topoisomerase II activity to allow proliferation despite drug inhibition of this essential enzyme.
The antitumorigenic trifecta
Authors: Mowery Yvonne M. , Pizzo Salvatore V.
Published: August 2009

The laboratory of Judah Folkman identified the potent endogenous antiangiogenic protein angiostatin in 1994.1 In this issue of Blood, Lee and colleagues propose 2 new mechanisms of action for angiostatin that may represent promising targets for new cancer therapeutics.2
CD20-targeted tetrameric interferon-α, a novel and potent immunocytokine for the therapy of B-cell lymphomas
Authors: Rossi Edmund A. , Goldenberg David M. , Cardillo Thomas M. , Stein Rhona , Chang Chien-Hsing
Published: August 2009

Interferon-α (IFN-α) has direct inhibitory effects on some tumors and is a potent stimulator of both the innate and adaptive immune systems. A tumor-targeting antibody-IFN-α conjugate (mAb-IFN-α) could kill by direct actions of the monoclonal antibody (mAb) and IFN-α on tumor cells and also potentiate a tumor-directed immune response. The modular Dock-and-Lock method (DNL) was used to generate 20-2b, the first immunocytokine having 4 cytokine (IFN-α2b) groups that are fused to the humanized anti-CD20 mAb, veltuzumab. Additional mAb-IFN-α constructs, each retaining potent IFN-α2b biologic activity, also were produced by DNL. The 20-2b shows enhanced antibody-dependent cellular cytotoxicity compared with veltuzumab but lacks complement-dependent cytotoxicity. The 20-2b inhibits in vitro proliferation of lymphoma cells and depletes them from whole human blood more potently than the combination of veltuzumab and a nontargeting, irrelevant, mAb-IFN-α. The 20-2b demonstrated superior therapeutic efficacy compared with veltuzumab or nontargeting mAb-IFN-α in 3 human lymphoma xenograft models, even though mouse immune cells respond poorly to human IFN-α2b. Targeting IFN-α with an anti-CD20 mAb makes the immunocytokine more potent than either agent alone. These findings suggest that 20-2b merits clinical evaluation as a new candidate antilymphoma therapeutic.
Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the eye?
Authors: Pullarkat Vinod
Published: August 2009

The role of iron chelation therapy in myelodysplastic syndrome (MDS) remains controversial. Averting cardiac dysfunction in low-grade MDS patients who have sufficient longevity to experience deleterious cardiac effects of iron overload has been the major argument in favor of iron chelation. Although there is significant evidence showing the adverse impact of transfusion dependency on survival in MDS, direct evidence linking tissue iron overload to poor survival or in particular to cardiac dysfunction is lacking. Given the heterogeneity of MDS, it is likely that the pathophysiology of iron overload is equally heterogeneous and complex in these patients. In this article, I argue that prevention of cardiac dysfunction in patients with lower grades of MDS may not be the major benefit of iron chelation therapy, and present evidence suggesting a potential benefit of iron chelation on 3 other outcomes, namely (1) lowering infection risk, (2) improving the outcome of allogeneic hematopoietic stem cell transplantation, and (3) delaying leukemic transformation. These outcomes have particular relevance for patients with higher grades of MDS and should be evaluated in future prospective clinical trials that include patients with all grades of MDS to fully evaluate the benefit of iron chelation therapy.
QPCR: Application for real-time PCR data management and analysis
Authors: Pabinger Stephan , Thallinger Gerhard G , Snajder René , Eichhorn Heiko , Rader Robert , Trajanoski Zlatko
Published: August 2009

Background

Since its introduction quantitative real-time polymerase chain reaction (qPCR) has become the standard method for quantification of gene expression. Its high sensitivity, large dynamic range, and accuracy led to the development of numerous applications with an increasing number of samples to be analyzed. Data analysis consists of a number of steps, which have to be carried out in several different applications. Currently, no single tool is available which incorporates storage, management, and multiple methods covering the complete analysis pipeline.

Results

QPCR is a versatile web-based Java application that allows to store, manage, and analyze data from relative quantification qPCR experiments. It comprises a parser to import generated data from qPCR instruments and includes a variety of analysis methods to calculate cycle-threshold and amplification efficiency values. The analysis pipeline includes technical and biological replicate handling, incorporation of sample or gene specific efficiency, normalization using single or multiple reference genes, inter-run calibration, and fold change calculation. Moreover, the application supports assessment of error propagation throughout all analysis steps and allows conducting statistical tests on biological replicates. Results can be visualized in customizable charts and exported for further investigation.

Conclusion

We have developed a web-based system designed to enhance and facilitate the analysis of qPCR experiments. It covers the complete analysis workflow combining parsing, analysis, and generation of charts into one single application. The system is freely available at http://genome.tugraz.at/QPCR
Pairwise and higher-order correlations among drug-resistance mutations in HIV-1 subtype B protease
Authors: Haq Omar , Levy Ronald M , Morozov Alexandre V , Andrec Michael
Published: August 2009

Background

The reaction of HIV protease to inhibitor therapy is characterized by the emergence of complex mutational patterns which confer drug resistance. The response of HIV protease to drugs often involves both primary mutations that directly inhibit the action of the drug, and a host of accessory resistance mutations that may occur far from the active site but may contribute to restoring the fitness or stability of the enzyme. Here we develop a probabilistic approach based on connected information that allows us to study residue, pair level and higher-order correlations within the same framework.

Results

We apply our methodology to a database of approximately 13,000 sequences which have been annotated by the treatment history of the patients from which the samples were obtained. We show that including pair interactions is essential for agreement with the mutational data, since neglect of these interactions results in order-of-magnitude errors in the probabilities of the simultaneous occurence of many mutations. The magnitude of these pair correlations changes dramatically between sequences obtained from patients that were or were not exposed to drugs. Higher-order effects make a contribution of as much as 10% for residues taken three at a time, but increase to more than twice that for 10 to 15-residue groups. The sequence data is insufficient to determine the higher-order effects for larger groups. We find that higher-order interactions have a significant effect on the predicted frequencies of sequences with large numbers of mutations. While relatively rare, such sequences are more prevalent after multi-drug therapy. The relative importance of these higher-order interactions increases with the number of drugs the patient had been exposed to.

Conclusion

Correlations are critical for the understanding of mutation patterns in HIV protease. Pair interactions have substantial qualitative effects, while higher-order interactions are individually smaller but may have a collective effect. Together they lead to correlations which could have an important impact on the dynamics of the evolution of cross-resistance, by allowing the virus to pass through otherwise unlikely mutational states. These findings also indicate that pairwise and possibly higher-order effects should be included in the models of protein evolution, instead of assuming that all residues mutate independently of one another.
Improved mutation tagging with gene identifiers applied to membrane protein stability prediction
Authors: Winnenburg Rainer , Plake Conrad , Schroeder Michael
Published: August 2009

Background

The automated retrieval and integration of information about protein point mutations in combination with structure, domain and interaction data from literature and databases promises to be a valuable approach to study structure-function relationships in biomedical data sets.

Results

We developed a rule- and regular expression-based protein point mutation retrieval pipeline for PubMed abstracts, which shows an F-measure of 87% for the mutation retrieval task on a benchmark dataset. In order to link mutations to their proteins, we utilize a named entity recognition algorithm for the identification of gene names co-occurring in the abstract, and establish links based on sequence checks. Vice versa, we could show that gene recognition improved from 77% to 91% F-measure when considering mutation information given in the text. To demonstrate practical relevance, we utilize mutation information from text to evaluate a novel solvation energy based model for the prediction of stabilizing regions in membrane proteins. For five G protein-coupled receptors we identified 35 relevant single mutations and associated phenotypes, of which none had been annotated in the UniProt or PDB database. In 71% reported phenotypes were in compliance with the model predictions, supporting a relation between mutations and stability issues in membrane proteins.

Conclusion

We present a reliable approach for the retrieval of protein mutations from PubMed abstracts for any set of genes or proteins of interest. We further demonstrate how amino acid substitution information from text can be utilized for protein structure stability studies on the basis of a novel energy model.
Labelling and targeted ablation of specific bipolar cell types in the zebrafish retina
Authors: Zhao Xiao-Feng , Ellingsen Staale , Fjose Anders
Published: August 2009

Background

Development of a functional retina depends on regulated differentiation of several types of neurons and generation of a highly complex network between the different types of neurons. In addition, each type of retinal neuron includes several distinct morphological types. Very little is known about the mechanisms responsible for generating this diversity of retinal neurons, which may also display specific patterns of regional distribution.

Results

In a screen in zebrafish, using a trapping vector carrying an engineered yeast Gal4 transcription activator and a UAS:eGFP reporter cassette, we have identified two transgenic lines of zebrafish co-expressing eGFP and Gal4 in specific subsets of retinal bipolar cells. The eGFP-labelling facilitated analysis of axon terminals within the inner plexiform layer of the adult retina and showed that the fluorescent bipolar cells correspond to previously defined morphological types. Strong regional restriction of eGFP-positive bipolar cells to the central part of the retina surrounding the optic nerve was observed in adult zebrafish. Furthermore, we achieved specific ablation of the labelled bipolar cells in 5 days old larvae, using a bacterial nitroreductase gene under Gal4-UAS control in combination with the prodrug metronidazole. Following prodrug treatment, nitroreductase expressing bipolar cells were efficiently ablated without affecting surrounding retina architecture, and recovery occurred within a few days due to increased generation of new bipolar cells.

Conclusion

This report shows that enhancer trapping can be applied to label distinct morphological types of bipolar cells in the zebrafish retina. The genetic labelling of these cells yielded co-expression of a modified Gal4 transcription activator and the fluorescent marker eGFP. Our work also demonstrates the potential utility of the Gal4-UAS system for induction of other transgenes, including a bacterial nitroreductase fusion gene, which can facilitate analysis of bipolar cell differentiation and how the retina recovers from specific ablation of these cells.
Electric pulses used in electrochemotherapy and electrogene therapy do not significantly change the expression profile of genes involved in the development of cancer in malignant melanoma cells
Authors: Mlakar Vid , Todorovic Vesna , Cemazar Maja , Glavac Damjan , Sersa Gregor
Published: August 2009

Background

Electroporation is a versatile method for in vitro or in vivo delivery of different molecules into cells. However, no study so far has analysed the effects of electric pulses used in electrochemotherapy (ECT pulses) or electric pulses used in electrogene therapy (EGT pulses) on malignant cells. We studied the effect of ECT and EGT pulses on human malignant melanoma cells in vitro in order to understand and predict the possible effect of electric pulses on gene expression and their possible effect on cell behaviour.

Methods

We used microarrays with 2698 different oligonucleotides to obtain the expression profile of genes involved in apoptosis and cancer development in a malignant melanoma cell line (SK-MEL28) exposed to ECT pulses and EGT pulses.

Results

Cells exposed to ECT pulses showed a 68.8% average survival rate, while cells exposed to EGT pulses showed a 31.4% average survival rate. Only seven common genes were found differentially expressed in cells 16 h after exposure to ECT and EGT pulses. We found that ECT and EGT pulses induce an HSP70 stress response mechanism, repress histone protein H4, a major protein involved in chromatin assembly, and down-regulate components involved in protein synthesis.

Conclusion

Our results show that electroporation does not significantly change the expression profile of major tumour suppressor genes or oncogenes of the cell cycle. Moreover, electroporation also does not changes the expression of genes involved in the stability of DNA, supporting current evidence that electroporation is a safe method that does not promote tumorigenesis. However, in spite of being considered an isothermal method, it does to some extent induce stress, which resulted in the expression of the environmental stress response mechanism, HSP70.
Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)
Authors: Glaysher Sharon , Yiannakis Dennis , Gabriel Francis G , Johnson Penny , Polak Marta E , Knight Louise A , Goldthorpe Zoe , Peregrin Katharine , Gyi Mya , Modi Paul , Rahamim Joe , Smith Mark E , Amer Khalid , Addis Bruce , Poole Matthew , Narayanan Ajit , Gulliford Tim J , Andreotti Peter E , Cree Ian A
Published: August 2009

Background

NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors.

Methods

The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue.

Results

There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents.

Conclusion

Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.
Upregulation of miRNA hsa-miR-342-3p in experimental and idiopathic prion disease
Authors: Montag Judith , Hitt Reiner , Opitz Lennart , Schulz-Schaeffer Walter J , Hunsmann Gerhard , Motzkus Dirk
Published: August 2009

The aim of our study was to analyze the differential expression of miRNAs in the brains of BSE-infected cynomolgus macaques as a model for Creutzfeldt-Jakob disease (CJD). MicroRNAs (miRNAs) are small noncoding RNAs regulating gene expression by mRNA targeting. Among other functions they contribute to neuronal development and survival. Recently, the lack of miRNA processing has been shown to promote neurodegeneration and deregulation of several miRNAs has been reported to be associated with Scrapie in mice. Therefore, we hypothesized that miRNAs are also regulated in response to human prion disease. We have applied miRNA-microarrays to identify deregulated miRNA candidates in brains of BSE-infected macaques. Shock-frozen brain sections of six BSE-infected and five non-infected macaques were used to validate regulated miRNA candidates by two independent qRT-PCR-based methods. Our study revealed significant upregulation of hsa-miR-342-3p and hsa-miR-494 in the brains of BSE-infected macaques compared to non-infected animals. In a pilot study we could show that hsa-miR-342-3p was also upregulated in brain samples of human type 1 and type 2 sporadic CJD. With respect to the reported regulation of this miRNA in Scrapie-infected mice, we propose that upregulation of hsa-miR-342-3p may be a general phenomenon in late stage prion disease and might be used as a novel marker for animal and human TSEs.
Comprehensibility, reliability, validity, and responsiveness of the Thai version of the Health Assessment Questionnaire in Thai patients with rheumatoid arthritis
Authors: Osiri Manathip , Wongchinsri Jeerapat , Ukritchon Sitthichai , Hanvivadhanakul Punchong , Kasitanon Nuntana , Siripaitoon Boonjing
Published: August 2009

Introduction

The Health Assessment Questionnaire Disability Index (HAQ-DI) is a commonly used instrument to assess functional status of patients with rheumatoid arthritis (RA). Translations and adaptations of the HAQ-DI have been carried out for use with RA patients in several countries. The objective of this study was to evaluate the psychometric properties of the Thai version of the HAQ-DI (Thai HAQ) in Thai patients with RA.

Methods

Comprehensibility of the Thai HAQ was assessed by 126 patients with RA from 6 medical centers in Thailand. Another group of 115 patients with active RA was enrolled to test the reliability (internal reliability and 1-week test-retest reliability), construct validity (correlations with other measures of RA disease activity), floor and ceiling effects, and sensitivity to change of the Thai HAQ at 3 months of treatment with disease-modifying antirheumatic drugs.

Results

More than 98% of the patients regarded the Thai HAQ as comprehensible. The internal consistency of the Thai HAQ was satisfactory with the overall Cronbach alpha of 0.91. The test-retest reliability of the Thai HAQ was acceptable with the intraclass correlation coefficient of 0.89. Moderate correlations between the Thai HAQ and other outcomes of RA disease activity were observed, except erythrocyte sedimentation rate, with the Spearman correlation coefficients ranging from 0.42 to 0.57. The responsiveness of the Thai HAQ was moderate, with a standardized response mean of 0.75 (95% confidence interval 0.56 to 0.94).

Conclusions

The Thai HAQ is comprehensible, reliable, valid and sensitive to change in the evaluation of functional status of Thai patients with RA. The Thai HAQ is an essential tool to measure treatment effects and progression of disability in RA patients and should be applied in both clinical trials and routine clinical care settings.
Glucose absorption and gastric emptying in critical illness
Authors: Chapman Marianne J , Fraser Robert JL , Matthews Geoffrey , Russo Antonietta , Bellon Max , Besanko Laura K , Jones Karen L , Butler Ross , Chatterton Barry , Horowitz Michael
Published: August 2009

Introduction

Delayed gastric emptying occurs frequently in critically ill patients and has the potential to adversely affect both the rate, and extent, of nutrient absorption. However, there is limited information about nutrient absorption in the critically ill, and the relationship between gastric emptying (GE) and absorption has hitherto not been evaluated. The aim of this study was to quantify glucose absorption and the relationships between GE, glucose absorption and glycaemia in critically ill patients.

Methods

Studies were performed in nineteen mechanically-ventilated critically ill patients and compared to nineteen healthy subjects. Following 4 hours fasting, 100 ml of Ensure, 2 g 3-O-methyl glucose (3-OMG) and 99mTc sulphur colloid were infused into the stomach over 5 minutes. Glucose absorption (plasma 3-OMG), blood glucose levels and GE (scintigraphy) were measured over four hours. Data are mean ± SEM. A P-value < 0.05 was considered significant.

Results

Absorption of 3-OMG was markedly reduced in patients (AUC240: 26.2 ± 18.4 vs. 66.6 ± 16.8; P < 0.001; peak: 0.17 ± 0.12 vs. 0.37 ± 0.098 mMol/l; P < 0.001; time to peak; 151 ± 84 vs. 89 ± 33 minutes; P = 0.007); and both the baseline (8.0 ± 2.1 vs. 5.6 ± 0.23 mMol/l; P < 0.001) and peak (10.0 ± 2.2 vs. 7.7 ± 0.2 mMol/l; P < 0.001) blood glucose levels were higher in patients; compared to healthy subjects. In patients; 3-OMG absorption was directly related to GE (AUC240; r = -0.77 to -0.87; P < 0.001; peak concentrations; r = -0.75 to -0.81; P = 0.001; time to peak; r = 0.89-0.94; P < 0.001); but when GE was normal (percent retention240 < 10%; n = 9) absorption was still impaired. GE was inversely related to baseline blood glucose, such that elevated levels were associated with slower GE (ret 60, 180 and 240 minutes: r > 0.51; P < 0.05).

Conclusions

In critically ill patients; (i) the rate and extent of glucose absorption are markedly reduced; (ii) GE is a major determinant of the rate of absorption, but does not fully account for the extent of impaired absorption; (iii) blood glucose concentration could be one of a number of factors affecting GE.
Finite-difference frequency-domain modeling of viscoacoustic wave propagation in 2D tilted transversely isotropic (TTI) media
Authors: Operto Stéphane , Virieux Jean , Ribodetti A. , Anderson J. E.
Published: August 2009

A 2D finite-difference, frequency-domain method was developed for modeling viscoacoustic seismic waves in transversely isotropic media with a tilted symmetry axis. The medium is parameterized by the P-wave velocity on the symmetry axis, the density, the attenuation factor, Thomsen’s anisotropic parameters [Formula: see text] and [Formula: see text], and the tilt angle. The finite-difference discretization relies on a parsimonious mixed-grid approach that designs accurate yet spatially compact stencils. The system of linear equations resulting from discretizing the time-harmonic wave equation is solved with a parallel direct solver that computes monochromatic wavefields efficiently for many sources. Dispersion analysis shows that four grid points per P-wavelength provide sufficiently accurate solutions in homogeneous media. The absorbing boundary conditions are perfectly matched layers (PMLs). The kinematic and dynamic accuracy of the method wasassessed with several synthetic examples which illustrate the propagation of S-waves excited at the source or at seismic discontinuities when [Formula: see text]. In frequency-domain modeling with absorbing boundary conditions, the unstable S-wave mode is not excited when [Formula: see text], allowing stable simulations of the P-wave mode for such anisotropic media. Some S-wave instabilities are seen in the PMLs when the symmetry axis is tilted and [Formula: see text]. These instabilities are consistent with previous theoretical analyses of PMLs in anisotropic media; they are removed if the grid interval is matched to the P-wavelength that leads to dispersive S-waves. Comparisons between seismograms computed with the frequency-domain acoustic TTI method and a finite-difference, time-domain method for the vertical transversely isotropic elastic equation show good agreement for weak to moderate anisotropy. This suggests the method can be used as a forward problem for viscoacoustic anisotropic full-waveform inversion.
Power-gradient velocity model
Authors: Stovas Alexey
Published: August 2009

A proposed power-gradient velocity model incorporates several well-known velocity models as special cases. The model covers a wide range of possible velocity distributions and has four parameters, giving more flexibility in velocity-model manipulation. For this nonlinear model, the kinematic characteristics — offset-traveltime parameteric equations, traveltime parameters, relative geometric spreading, and propagator phase — are computed. The characteristics are investigated with respect to a parameter responsible for nonlinearity of velocity distribution. The inversion of travel-time parameters was studied in three- and four-parameter frameworks.