bluuebunny/crossref_metadata_2025 huggingface dataset:
Identity, Sustainability, and Local Setting at U.S. Botanical Gardens
Authors: Johnson Victoria
Published: September 2012

In the last decade, an increasing number of U.S. botanical gardens have adopted the concept of “sustainability” as an explicit element of their missions and practices. By reducing water, energy, and pesticide usage, these gardens seek to model environmental behavior that mitigates the destructive impact of human activities. However, botanical gardens are also complex organizations whose members have varying understandings of their organization’s identity. Through 52 interviews conducted at 10 botanical gardens, I examined the cognitive-cultural resources used by members as they explained new sustainability initiatives. I found that a key cognitive-cultural resource for respondents, overlooked in past studies of identity work, was an organization’s local setting, in both its “social” and “natural” aspects. I discuss the implications of this finding for organizational identity theory. I conclude by considering how this local setting can be mobilized in botanical gardens and other kinds of organizations trying to gain support for sustainability initiatives. I argue that the higher the salience of local natural settings for members, the more easily they can integrate environmental sustainability into their understanding of their organization’s identity.
Efficacy and safety of beta-interferon in Thai patients with demyelinating diseases
Authors: Jarernsook B , Siritho S , Prayoonwiwat N
Published: September 2012

Background:

The efficacy of beta-interferon (IFN-β) treatment in Thai patients with demyelinating diseases has not been reported.

Objectives:

To evaluate the efficacy and any adverse drug reactions of IFN-β therapy in Thai patients, for each group of demyelinating diseases.

Methods:

We retrospectively reviewed data of Thai patients with multiple sclerosis (MS), neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSDs) who attended the MS Clinic at Siriraj Hospital, Thailand from March 2000 to October 2011. We reviewed those 73 patients who received IFN-β. We evaluated the drug’s efficacy over 2 years and any adverse drug reactions among these patients.

Results:

Of the 40 MS patients who received IFN-β, 26 adhered to the medication for at least 2 years. In addition, 27 NMO/NMOSDs patients who had been diagnosed with MS were treated as such with IFN-β. In the true MS group, the pre- and post-treatment annualized relapse rates (ARR) were 1.25 and 0.59, respectively, so there was a reduction of 52.8% ( p = 0.004). In addition, in 69.2% of the patients, IFN-β also showed beneficial effects by prolonging the time to first relapse to 15.9 months and stabilizing or decreasing progression of the disease. In contrast, no significant benefit was seen in the NMO/NMOSDs group. On the contrary, an increase in EDSS was seen in 53.3 % of them. The most common side effects seen were local skin reactions and flu-like symptoms.

Conclusions:

Treatment with IFN-β was effective in reducing both ARR and disability progression in Thai patients with MS. In contrast, we observed that giving IFN-β treatment to NMO/NMOSDs patients may lead to a worsening of symptoms.
Critical reflections on some recent definitions of “culture”
Authors: Jahoda Gustav
Published: September 2012

At the outset the historical background of attempts to define “culture” is briefly sketched. Then the definitions found in cross-cultural texts published between 2009 and 2011 are roughly divided into three categories according to where they locate “culture”, and whether they present single or multiple definitions. Each definition is critically examined, as are the relationships between them, and it is shown that several of the definitions are logically and substantively incompatible. It is concluded (with Alfred Lang) that there can be no generally agreed definition of culture, and an alternative proposal is put forward.
On mind, mediation and meaning-making
Authors: Märtsin Mariann
Published: September 2012

This paper takes inspiration from the integrative model of human mind proposed by Brinkmann (2011, 2012) and argues that the kind of integration that he seeks to attain can only be achieved if the model focuses on the processes that underlie the functioning of the human mind and not on the entities that these processes produce or function by. An alternative integrative model is thus proposed. In the first part of the paper the process of meaning-making will be explored. It will be argued that an integrative conceptualisation of human mind needs to take into account pre-reflective and unmediated as well as reflective and mediated states through which meanings become constructed. In the second part of the paper the idea of semiotic mediation will be explored. It will be argued that an integrative model of human mind needs to focus not only on different kinds of mediators, but also explain how these are used reflectively and non-reflectively by individuals themselves and visibly or invisibly by others in our everyday interactions.
Who defines humanity? Psychological and cultural obstacles to omniculturalism
Authors: Bilewicz Michal , Bilewicz Aleksandra
Published: September 2012

In this article we discuss the social-psychological limitations of using omniculturalism as a tool to improve intercultural relations between majority and minority groups. The omnicultural imperative suggests that intercultural interactions be framed in terms of human commonalities. This strategy might face severe psychological and cultural obstacles. Due to automatic mechanisms of ingroup projection, such framing might have adverse effects: People tend to construe their concepts of “humanity” based on their impressions about their own group. Such projection has been shown to have detrimental effects on intergroup relations, especially between groups differing in status (such as minority–majority relations). Psychological and anthropological evidence is provided to argue that the lay concept of “humanity” is often used as a tool of ingroup favouritism and discrimination. An extension of the omnicultural imperative is proposed—based on the indefinable character of humanity (inspired by Jahoda’s remarks on the definition of culture and Wittgenstein’s concept of family resemblance) and humananimal similarities.
Connecting body and mind: The first interview with somatising patients and their families
Authors: Kozlowska Kasia , English Margaret , Savage Blanche
Published: September 2012

In this article we outline the framework our consultation-liaison team has developed for interviewing families whose children present with medically unexplained symptoms. The framework was developed over many years in the context of our work with a large number of families, who collectively taught us to be more sensitive with regard to the experience of such families in the medical system, and who reacted strongly when we moved prematurely to the use of psychological language or to questions about family relationships or emotional functioning. Throughout the interview we maintain a focus on the body: the family history of illness and, in particular, the story of the child’s symptoms. We take a detailed, temporally ordered history of the symptom and ask for collateral information – family illness, family life events, events at school, family emotional responses – all in relation to the story of the symptoms. In the assessment interview and in our work in general, we focus on the body. We move very carefully and very slowly from the physical to the psychological, from talking about the body to talking about relationships and about the mind.
The Interpretability Hypothesis again: A partial replication of Tsimpli and Dimitrakopoulou (2007)
Authors: Leal Méndez Tania , Slabakova Roumyana
Published: September 2012

Tsimpli and Dimitrakopoulou (2007) propose the Interpretability Hypothesis (IH), according to which uninterpretable features present an insurmountable difficulty in adult second language acquisition. The experimental study supporting the IH examines Greek native speakers’ knowledge of gaps versus resumptive pronouns in English wh-movement. A crucial assumption is that Greek allows resumptives optionally. Alexopoulou and Keller’s (2002, 2007) findings confirm that assumption. In our replication of Tsimpli and Dimitrakopoulou’s study, we divide Spanish native speakers into those who accept resumptives and those who do not; then we look at their acceptance of gaps and resumptives in English. The results indicate that both groups of advanced learners, those that do and those that don’t have resumptives in their individual grammars, have acquired the ungrammaticality of resumptives in English, although there may be lingering native language effects. The effects of d-linking, animacy, syntactic function of the resumptive/gap (subject vs. object), and presence of the complementizer that are also examined.
Archival anarchies: Online fandom, subcultural conservation, and the transformative work of digital ephemera
Authors: Lothian Alexis
Published: September 2012

This article explores the politics of digital memory and traceability, drawing on Jacques Derrida’s Archive Fever and on queer theories of performance and ephemerality. Its primary example is the Organization for Transformative Works, a successful advocacy group for creative media fans whose main project has been an online fan fiction archive. I am concerned both with this public face and with the activities that fans would prefer to keep out of the official record. For scholars of subcultural artistic and cultural production, the mixed blessings of conservation and legitimacy are necessary considerations for the archiving and meaning-making work of cultural theory. Paying attention to the technological and social specificities that contextualize fandom as a digital archive culture, I trace contradictions and contestations around what fannish and scholarly archivable content is and should be: what’s trivial, what’s significant, what legally belongs to whom, and what deserves to be preserved.
It’s a game of give and take: Modeling behavior in a give-or-take-some social dilemma
Authors: Budescu David V. , McCarter Matthew W.
Published: September 2012

We investigate a new give-or-take-some (GOTS) dilemma paradigm that merges traditional give-some and take-some dilemmas. In this hybrid social dilemma, individuals can choose to give or to take resources from a shared resource pool. Previous empirical work by McCarter, Budescu, and Scheffran (2011) found that the composition of the group and the individuals’ endowments influenced their tendency to give and/or take. We reanalyze results from two experiments from McCarter, Budescu, et al. (2011) using the new paradigm and propose a simple model of individual behavior based on the players’ perceptions of their relative standing in the group and their perception of fair allocations. We also use these data to fit the model at the individual level and use it to provide a general framework for interpreting the group results.
Is consensus-seeking unique to humans? A selective review of animal group decision-making and its implications for (human) social psychology
Authors: Kameda Tatsuya , Wisdom Thomas , Toyokawa Wataru , Inukai Keigo
Published: September 2012

Recent research on animal behavior suggests that group decision-making may not be uniquely human. Based on Tinbergen’s (1963) “four questions,” this paper proposes that linking biological- and social-science approaches is important to a better understanding of human group decisions. Toward this end, we first review some recent findings on collective behavior by social insects (ants and honeybees in particular). We then argue that several fundamental processes (e.g., positive feedback, nonlinear responses to social frequency information, and use of quorums) commonly underlie human and non-human group decision-making under uncertainty, while key prerequisites for the emergence of collective intelligence may be more vulnerable to social nuances in human contexts. We sketch some future research directions to promote cross-fertilizations between the two fields.
Motivated information processing and group decision refusal
Authors: Nijstad Bernard A. , Oltmanns Jan
Published: September 2012

Group decision making has attracted much scientific interest, but few studies have investigated group decisions that do not get made. Based on the Motivated Information Processing in Groups model, this study analysed the effect of epistemic motivation (low vs. high) and social motivation (proself vs. prosocial) on group decision refusal (the decision to delay choice and refuse all options). In a laboratory experiment, groups had to negotiate diverse preferences and choose one of three options or refuse all. When epistemic motivation was low decisions were made quickly, whereas high epistemic motivation more often led to refusal. This effect was partly mediated by perceived information insufficiency. Social motivation did not affect refusal, but proself motivation led to longer discussions, greater task conflict and more forcing behavior than prosocial motivation. Further, forcing was negatively related to decision refusal, but only when epistemic motivation was low.
Good and bad group performance: Same process—different outcomes
Authors: Tindale R. Scott , Smith Christine M. , Dykema-Engblade Amanda , Kluwe Katharina
Published: September 2012

Much of the research on small group performance shows that groups tend to outperform individuals in most task domains. However, there is also evidence that groups sometimes perform worse than individuals, occasionally with severe negative consequences. Theoretical attempts to explain such negative performance events have tended to point to characteristics of the group or the group process that were different than those found for better performing groups. We argue that typical group processes can be used to explain both good and bad group performance in many instances. Results from a pair of experiments focusing on two different task domains are reported and used to support our arguments.
Land Diagrams: the new twinned studies
Authors: Cutler Amy E.
Published: September 2012

As interdisciplinary geographers we find ourselves taking part in conversations, conferences and collaborations that are structured to focus on commonalities across ways of knowing. The unchecked rhetoric of interdisciplinarity often refers to underthought, benign activities that prioritize the congruent topics and lexis by which two or more disciplines are able to be mutually supplementary. If the complex environments of the modern world are one of the major stakes in interdisciplinary conversations, then alternative methods of organizing cross-disciplinary geographical enquiry are needed. Land Diagrams, the new online series of non-collaborative ‘twinned studies’, uses found diagrams as ‘machines of translation’ to provoke divergent specialist interpretations. The series refers to the intellectual and practical uses of visual methodologies, as well as to a history of philosophical work in ekphrastics and diagrammatology, using diagrams as migratory objects that reveal diverse understandings of the multiple systems of knowledge attached to the land.
Complications Related to Femoral Artery Access for Transcatheter Procedures
Authors: Stone Patrick A. , Campbell John E.
Published: September 2012

Percutaneous-based procedures continue to increase as endovascular techniques improve and provide a less morbid approach than the open vascular procedures. The most common complications associated with either cardiac interventions or peripheral interventions involve the access point of the procedure. The retrograde femoral access has and is currently the most frequently used arterial access. Vascular surgeons have been responsible for management of complications following femoral-based procedures and now are a significant contributor to catheter-based diagnostic and interventional procedures. This review provides in-depth review of the literature on specific complications encountered during percutaneous femoral artery puncture. This review includes access complications related to the method of obtaining access (ie, best pulse fluoroscopic guided), direction of access either retrograde or antegrade, risk factors and incidence of complications based on best literature sources, and management strategies for specific complications.
Professional Transitions in the Academy: A Conversation
Authors: Jones Peter , Galloway Kate
Published: September 2012

Journeys are funny things—they do not always take you were you were expecting them to, or even where you want to go. But if you are open to the experience, and committed to reflection, there are interesting lessons to be learned. What does it mean to shift from a practising professional (a lawyer–a social worker) to a discipline-based academic? Or to move beyond a narrow discipline to become a scholar of teaching and learning? What dangers lurk in the swamp of managerialism? How can we escape from the towers of solitude and isolation that characterise debates around academic identity and become true barrier breakers and boundary blenders? The key, for these two travellers, lies in recognising the transformative potential of epistemological fusion.
Editors’ Introduction to the Special Issue on Exploring Cognitive Readiness in Complex Operational Environments
Authors: Schmorrow Dylan D. , Bolstad Cheryl A. , May Katrina A. , Cuevas Haydee M.
Published: September 2012

The previous special issue featured articles on the theme of presenting the latest advances in cognitive readiness research in terms of both theory development and practical applications across domains. For researchers, this translates into addressing important research gaps and identifying areas warranting further investigation. For practitioners, this translates into useful and practical recommendations and lessons learned for promoting cognitive readiness in complex domains. The editors continue this theme in this special issue with two more articles that address this important topic. It is their hope that the findings and lessons learned presented in this three-part special issue will provide a basis for future research aimed at creating more cognitively ready individuals and teams.
Racially Discriminatory Service in Full-Service Restaurants
Authors: Brewster Zachary W.
Published: September 2012

Most of the scholarly and popular discourse to date on the topic of racial discrimination within the restaurant industry has centered on the unjust treatment experienced by employees who are racial minorities. However, discriminatory service based on race also is—or should be—an industry concern. Based on a review of evidence, race-based discrimination in restaurants is a systemic, industry-wide problem. One source of this problem is a social psychological process involving the diffusion and reinforcement of racial stereotypes that servers use to inform the nature of their interactions with customers. Using social psychological principles, restaurateurs should first interdict the diffusion of inappropriate stereotypes by immediately squelching all such talk. Then management must reverse existing damage, by demonstrating the inaccuracy or exaggerated nature of certain beliefs. This article concludes with a call for increased engagement with the issue of racially motivated discriminatory service in our nation’s restaurants.
Diuretic drugs benefit patients with hypertension more with night-time dosing
Authors: Okeahialam Basil N , Ohihoin Esther N , Ajuluchukwu Jayne NA
Published: September 2012

Objectives:

Night-time chronotherapy in antihypertensive drugs has been shown to produce better blood pressure control and protect from cardiovascular morbidity and mortality. To date, this has been proven for several drug classes excluding thiazides diuretics. Given the peculiar response of blood pressure to thiazides in black people we sought to determine whether night-time chronotherapy with thiazides produces better control as already shown with other drug classes.

Methods:

A subanalysis of a larger chronotherapy study with antihypertensive drugs in Nigerian Africans was done. The subpopulation of those whose disease was controlled after 12 weeks of diuretic monotherapy was analysed. Those who received drugs in the morning and at night were compared along control lines and some cardiac indices.

Results:

Both groups were similar on all scores at baseline. After 12 weeks of monotherapy patients who received drugs at night had significantly lower systolic and diastolic blood pressure though control was achieved with both morning and night-time dosing. Also the left ventricular posterior and septal walls regressed better as well as left ventricular mass in the night-time group.

Conclusion:

Though equally effective in reducing blood pressure and cardiac indices related to hypertension, patients taking their drugs at night recorded better values. This makes diuretics equally amenable to night-time chronotherapy as other drug classes. This effect should be explored to reduce the morbidity and mortality consequences of hypertension.
Public relations and the Northern Ireland peace process: Dissemination, reconciliation and the ‘Good Friday Agreement’ referendum campaign
Authors: Somerville Ian , Kirby Shane
Published: September 2012

This study analyses the public relations strategies employed by the mainstream political parties during the ‘Good Friday Agreement’ referendum campaign in Northern Ireland in April/May 1998. Using data from elite interviews, triangulated with content analysis from campaign literature, we assess the communication strategies of the pro- and anti-Agreement parties who were attempting to persuade the people of Northern Ireland to vote Yes or No to the Agreement. Key findings of the research include: first, in comparison to the ‘normal’ political culture in Northern Ireland, there was a significant increase in the deployment of public relations expertise in the referendum campaign; indeed, for many of the political parties it represented their first major investment in political public relations. A second key finding pertains to the communicative model adopted by the key actors. All parties, in different ways, adopted a ‘dissemination’ model rather than a ‘dialogic’ one to communicate with allies, rivals and the general public. In our view this is an entirely appropriate approach to political public relations and we suggest that the communication model of the Social Democratic and Labour Party is particularly noteworthy because it was an approach underpinned, we argue, by dissemination and reconciliation. Moreover, we also suggest that public relations based on dissemination and reconciliation to difference offers a more realistic and appropriate approach, than the currently fashionable dialogic model, for the kinds of communication and information exchange required in contemporary democratic societies.
The global shadow of functionalism and Excellence Theory: An analysis of Australasian PR
Authors: Macnamara Jim
Published: September 2012

There are increasing claims and, in some quarters, celebration of a ‘sociocultural turn’ in public relations that has allegedly shifted the locus of scholarship and practice from US-originating functionalist and organization-centric models to more socially and culturally orientated approaches. However, this article presents a critical analysis of PR education and scholarship in Australasia which shows that, despite a claimed ‘sociocultural turn’ and a number of emergent postmodern models identified by contemporary scholars around the world, Excellence Theory, including its various constituent theories, remains a dominant paradigm of PR in Australia and many South East Asian countries. The ontological and epistemological characteristics of PR in Australasia, and the influences that have created and sustained them, as well as the progress of alternative postmodern and critical conceptualizations, are explored in this article based on two stages of research. In the first, a broad exploratory study was undertaken using ethnography and elements of autoethnography to provide reflective insights into the nature of and influences on PR scholarship and practice in the region. In the second stage, the findings of this exploratory analysis were tested and further contextualized with empirical data from structured textual analysis of the PR texts and reference books most commonly used today.
Asenapine Safety, Tolerability, and Pharmacokinetics After Single and Multiple Doses in Healthy Volunteers
Authors: Dogterom Peter , Timmer Cees , de Greef Rik , Spaans Edwin , de Vries Dick , van Vliet Andre , Peeters Pierre
Published: September 2012

This double‐blind, placebo‐controlled, randomized study is the first in healthy volunteers to describe the safety, tolerability, and pharmacokinetics of sublingual asenapine at therapeutic dosages. After a 2‐day placebo run‐in phase, healthy male volunteers received placebo or asenapine escalated to dosages of 3, 5, 10, or 15 mg bid. Another group received single doses (2 and 5 mg) 1 week apart. Serial blood samples were obtained for pharmacokinetic analysis. The single asenapine doses and multiple bid doses up to 10 mg were well tolerated. The most frequent treatment‐emergent adverse events were somnolence, oral paresthesia, fatigue, headache, dizziness, and dyspnea. Clinically relevant abnormalities or trends in laboratory and vital signs measures, physical examinations, or electrocardiograms were not observed. Asenapine was rapidly absorbed, with a tmax of ∼1 hour, and was biphasically eliminated with a terminal elimination half‐life of 20 to 30 hours. In the range of 3 to 10 mg bid, increases in plasma concentrations were less than dose proportional. Asenapine appears to be well tolerated at single doses up to 5 mg and multiple doses up to 10 mg bid and can be administered to healthy volunteers in clinical pharmacology studies using the dosing regimens described.
Contemporary approaches to reducing weld induced residual stress
Authors: Coules H E
Published: September 2012

Self-equilibrating residual stresses may occur in materials in the absence of external loading due to internal strain inhomogeneity. While favourable distributions of residual stress can bestow an object with the appearance of superior material properties, most welding processes leave behind residual stresses in particularly unfavourable patterns, causing a greater susceptibility to fracture based failure mechanisms and unintended deformation. Currently, heat treatment is the primary means of removing these stresses, but since the formation of residual stress is dependent upon many material and process factors, there are several other viable mechanisms (using thermal, mechanical or phase transformation effects) by which it may be modified. It is only now, using relevant advances in numerical and experimental methods, that these techniques are being fully explored. This article gives a brief introduction to weld induced residual stresses and reviews the current state of the art with regard to their reduction. Emphasis is placed on the recent development of unconventional techniques, and the mechanisms by which they act.
Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival
Authors: Ranuncolo Stella M. , Pittaluga Stefania , Evbuomwan Moses O. , Jaffe Elaine S. , Lewis Brian A.
Published: September 2012

We have analyzed the role of the REL family members in Hodgkin lymphoma (HL). shRNA targeting of each REL member showed that HL was uniquely dependent on relB, in contrast to several other B-cell lymphomas. In addition, relA and c-rel shRNA expression also decreased HL cell viability. In exploring relB activation further, we found stable NF-κB inducing kinase (NIK) protein in several HL cell lines and that NIK shRNA also affected HL cell line viability. More importantly, 49 of 50 HL patient biopsies showed stable NIK protein, indicating that NIK and the noncanonical pathway are very prevalent in HL. Lastly, we have used a NIK inhibitor that reduced HL but not other B-cell lymphoma cell viability. These data show that HL is uniquely dependent on relB and that the noncanonical pathway can be a therapeutic target for HL. Furthermore, these results show that multiple REL family members participate in the maintenance of a HL phenotype.
PAGED: a pathway and gene-set enrichment database to enable molecular phenotype discoveries
Authors: Huang Hui , Wu Xiaogang , Sonachalam Madhankumar , Mandape Sammed N , Pandey Ragini , MacDorman Karl F , Wan Ping , Chen Jake Y
Published: September 2012

Background

Over the past decade, pathway and gene-set enrichment analysis has evolved into the study of high-throughput functional genomics. Owing to poorly annotated and incomplete pathway data, researchers have begun to combine pathway and gene-set enrichment analysis as well as network module-based approaches to identify crucial relationships between different molecular mechanisms.

Methods

To meet the new challenge of molecular phenotype discovery, in this work, we have developed an integrated online database, the P athway A nd G ene E nrichment D atabase (PAGED), to enable comprehensive searches for disease-specific pathways, gene signatures, microRNA targets, and network modules by integrating gene-set-based prior knowledge as molecular patterns from multiple levels: the genome, transcriptome, post-transcriptome, and proteome.

Results

The online database we developed, PAGED http://bio.informatics.iupui.edu/PAGED is by far the most comprehensive public compilation of gene sets. In its current release, PAGED contains a total of 25,242 gene sets, 61,413 genes, 20 organisms, and 1,275,560 records from five major categories. Beyond its size, the advantage of PAGED lies in the explorations of relationships between gene sets as gene-set association networks (GSANs). Using colorectal cancer expression data analysis as a case study, we demonstrate how to query this database resource to discover crucial pathways, gene signatures, and gene network modules specific to colorectal cancer functional genomics.

Conclusions

This integrated online database lays a foundation for developing tools beyond third-generation pathway analysis approaches on for discovering molecular phenotypes, especially for disease-associated pathway/gene-set enrichment analysis.
Implementation of multiple-instance learning in drug activity prediction
Authors: Fu Gang , Nan Xiaofei , Liu Haining , Patel Ronak Y , Daga Pankaj R , Chen Yixin , Wilkins Dawn E , Doerksen Robert J
Published: September 2012

Background

In the context of drug discovery and development, much effort has been exerted to determine which conformers of a given molecule are responsible for the observed biological activity. In this work we aimed to predict bioactive conformers using a variant of supervised learning, named multiple-instance learning. A single molecule, treated as a bag of conformers, is biologically active if and only if at least one of its conformers, treated as an instance, is responsible for the observed bioactivity; and a molecule is inactive if none of its conformers is responsible for the observed bioactivity. The implementation requires instance-based embedding, and joint feature selection and classification. The goal of the present project is to implement multiple-instance learning in drug activity prediction, and subsequently to identify the bioactive conformers for each molecule.

Methods

We encoded the 3-dimensional structures using pharmacophore fingerprints which are binary strings, and accomplished instance-based embedding using calculated dissimilarity distances. Four dissimilarity measures were employed and their performances were compared. 1-norm SVM was used for joint feature selection and classification. The approach was applied to four data sets, and the best proposed model for each data set was determined by using the dissimilarity measure yielding the smallest number of selected features.

Results

The predictive abilities of the proposed approach were compared with three classical predictive models without instance-based embedding. The proposed approach produced the best predictive models for one data set and second best predictive models for the rest of the data sets, based on the external validations. To validate the ability of the proposed approach to find bioactive conformers, 12 small molecules with co-crystallized structures were seeded in one data set. 10 out of 12 co-crystallized structures were indeed identified as significant conformers using the proposed approach.

Conclusions

The proposed approach was proven not to suffer from overfitting and to be highly competitive with classical predictive models, so it is very powerful for drug activity prediction. The approach was also validated as a useful method for pursuit of bioactive conformers.
Investigating drug repositioning opportunities in FDA drug labels through topic modeling
Authors: Bisgin Halil , Liu Zhichao , Kelly Reagan , Fang Hong , Xu Xiaowei , Tong Weida
Published: September 2012

Background

Drug repositioning offers an opportunity to revitalize the slowing drug discovery pipeline by finding new uses for currently existing drugs. Our hypothesis is that drugs sharing similar side effect profiles are likely to be effective for the same disease, and thus repositioning opportunities can be identified by finding drug pairs with similar side effects documented in U.S. Food and Drug Administration (FDA) approved drug labels. The safety information in the drug labels is usually obtained in the clinical trial and augmented with the observations in the post-market use of the drug. Therefore, our drug repositioning approach can take the advantage of more comprehensive safety information comparing with conventional de novo approach.

Method

A probabilistic topic model was constructed based on the terms in the Medical Dictionary for Regulatory Activities (MedDRA) that appeared in the Boxed Warning, Warnings and Precautions, and Adverse Reactions sections of the labels of 870 drugs. Fifty-two unique topics, each containing a set of terms, were identified by using topic modeling. The resulting probabilistic topic associations were used to measure the distance (similarity) between drugs. The success of the proposed model was evaluated by comparing a drug and its nearest neighbor (i.e., a drug pair) for common indications found in the Indications and Usage Section of the drug labels.

Results

Given a drug with more than three indications, the model yielded a 75% recall, meaning 75% of drug pairs shared one or more common indications. This is significantly higher than the 22% recall rate achieved by random selection. Additionally, the recall rate grows rapidly as the number of drug indications increases and reaches 84% for drugs with 11 indications. The analysis also demonstrated that 65 drugs with a Boxed Warning, which indicates significant risk of serious and possibly life-threatening adverse effects, might be replaced with safer alternatives that do not have a Boxed Warning. In addition, we identified two therapeutic groups of drugs (Musculo-skeletal system and Anti-infective for systemic use) where over 80% of the drugs have a potential replacement with high significance.

Conclusion

Topic modeling can be a powerful tool for the identification of repositioning opportunities by examining the adverse event terms in FDA approved drug labels. The proposed framework not only suggests drugs that can be repurposed, but also provides insight into the safety of repositioned drugs.
Metabolic and enzymatic changes associated with carbon mobilization, utilization and replenishment triggered in grain amaranth (Amaranthus cruentus) in response to partial defoliation by mechanical injury or insect herbivory
Authors: Castrillón-Arbeláez Paula Andrea , Martínez-Gallardo Norma , Arnaut Hamlet Avilés , Tiessen Axel , Délano-Frier John Paul
Published: September 2012

Background

Amaranthus cruentus and A. hypochondriacus are crop plants grown for grain production in subtropical countries. Recently, the generation of large-scale transcriptomic data opened the possibility to study representative genes of primary metabolism to gain a better understanding of the biochemical mechanisms underlying tolerance to defoliation in these species. A multi-level approach was followed involving gene expression analysis, enzyme activity and metabolite measurements.

Results

Defoliation by insect herbivory (HD) or mechanical damage (MD) led to a rapid and transient reduction of non-structural carbohydrates (NSC) in all tissues examined. This correlated with a short-term induction of foliar sucrolytic activity, differential gene expression of a vacuolar invertase and its inhibitor, and induction of a sucrose transporter gene. Leaf starch in defoliated plants correlated negatively with amylolytic activity and expression of a β-amylase-1 gene and positively with a soluble starch synthase gene. Fatty-acid accumulation in roots coincided with a high expression of a phosphoenolpyruvate/phosphate transporter gene. In all tissues there was a long-term replenishment of most metabolite pools, which allowed damaged plants to maintain unaltered growth and grain yield. Promoter analysis of ADP-glucose pyrophosphorylase and vacuolar invertase genes indicated the presence of cis-regulatory elements that supported their responsiveness to defoliation. HD and MD had differential effects on transcripts, enzyme activities and metabolites. However, the correlation between transcript abundance and enzymatic activities was very limited. A better correlation was found between enzymes, metabolite levels and growth and reproductive parameters.

Conclusions

It is concluded that a rapid reduction of NSC reserves in leaves, stems and roots followed by their long-term recovery underlies tolerance to defoliation in grain amaranth. This requires the coordinate action of genes/enzymes that are differentially affected by the way leaf damage is performed. Defoliation tolerance in grain is a complex process that can’t be fully explained at the transcriptomic level only.
Plasma nuclear and mitochondrial DNA levels as predictors of outcome in severe sepsis patients in the emergency room
Authors: Kung Chia-Te , Hsiao Sheng-Yuan , Tsai Tsung-Cheng , Su Chih-Min , Chang Wen-Neng , Huang Chi-Ren , Wang Hung-Chen , Lin Wei-Che , Chang Hsueh-Wen , Lin Yu-Jun , Cheng Ben-Chung , Su Ben Yu-Jih , Tsai Nai-Wen , Lu Cheng-Hsien
Published: September 2012

Background and aim

The sensitivity and specificity of biomarkers and scoring systems used for predicting fatality of severe sepsis patients remain unsatisfactory. This study aimed to determine the prognostic value of circulating plasma DNA levels in severe septic patients presenting at the Emergency Department (ED).

Methods

Sixty-seven consecutive patients with severe sepsis and 33 controls were evaluated. Plasma DNA levels were estimated by real-time quantitative polymerase chain reaction assay using primers for the human β-hemoglobin and ND2 gene. The patients’ clinical and laboratory data on admission were analyzed.

Results

The median plasma nuclear and mitochondria DNA levels for severe septic patients on admission were significantly higher than those of the controls. The mean plasma nuclear DNA level on admission correlated with lactate concentration (γ = 0.36, p = 0.003) and plasma mitochondrial DNA on admission (γ = 0.708, p < 0.001). Significant prognostic factors for fatality included mechanical ventilation within the first 24 hours (p = 0.013), mean sequential organ failure assessment (SOFA) score on admission (p = 0.04), serum lactate (p < 0.001), and both plasma nuclear and mitochondrial DNA on admission (p < 0.001). Plasma mitochondrial DNA was an independent predictor of fatality by stepwise logistic regression such that an increase by one ng/mL in level would increase fatality rate by 0.7%.

Conclusion

Plasma DNA has potential use for predicting outcome in septic patients arriving at the emergency room. Plasma mitochondrial DNA level on admission is a more powerful predictor than lactate concentration or SOFA scores on admission.
LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors
Authors: Hinkle Kelly M , Yue Mei , Behrouz Bahareh , Dächsel Justus C , Lincoln Sarah J , Bowles Erin E , Beevers Joel E , Dugger Brittany , Winner Beate , Prots Iryna , Kent Caroline B , Nishioka Kenya , Lin Wen-Lang , Dickson Dennis W , Janus Christopher J , Farrer Matthew J , Melrose Heather L
Published: September 2012

Mutations in theLRRK2gene are the most common cause of genetic Parkinson’s disease. Although the mechanisms behind the pathogenic effects ofLRRK2mutations are still not clear, data emerging fromin vitroandin vivomodels suggests roles in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation.

We created mice lacking exon 41 that encodes the activation hinge of the kinase domain of LRRK2. We have performed a comprehensive analysis of these mice up to 20 months of age, including evaluation of dopamine storage, release, uptake and synthesis, behavioral testing, dendritic spine and proliferation/neurogenesis analysis.

Our results show that the dopaminergic system was not functionally comprised inLRRK2knockout mice. However,LRRK2knockout mice displayed abnormal exploratory activity in the open-field test. Moreover,LRRK2knockout mice stayed longer than their wild type littermates on the accelerated rod during rotarod testing. Finally, we confirm that loss of LRRK2 caused degeneration in the kidney, accompanied by a progressive enhancement of autophagic activity and accumulation of autofluorescent material, but without evidence of biphasic changes.
URDME: a modular framework for stochastic simulation of reaction-transport processes in complex geometries
Authors: Drawert Brian , Engblom Stefan , Hellander Andreas
Published: September 2012

Background

Experiments in silico using stochastic reaction-diffusion models have emerged as an important tool in molecular systems biology. Designing computational software for such applications poses several challenges. Firstly, realistic lattice-based modeling for biological applications requires a consistent way of handling complex geometries, including curved inner- and outer boundaries. Secondly, spatiotemporal stochastic simulations are computationally expensive due to the fast time scales of individual reaction- and diffusion events when compared to the biological phenomena of actual interest. We therefore argue that simulation software needs to be both computationally efficient, employing sophisticated algorithms, yet in the same time flexible in order to meet present and future needs of increasingly complex biological modeling.

Results

We have developed URDME, a flexible software framework for general stochastic reaction-transport modeling and simulation. URDME uses U nstructured triangular and tetrahedral meshes to resolve general geometries, and relies on the R eaction-D iffusion M aster E quation formalism to model the processes under study. An interface to a mature geometry and mesh handling external software (Comsol Multiphysics) provides for a stable and interactive environment for model construction. The core simulation routines are logically separated from the model building interface and written in a low-level language for computational efficiency. The connection to the geometry handling software is realized via a Matlab interface which facilitates script computing, data management, and post-processing. For practitioners, the software therefore behaves much as an interactive Matlab toolbox. At the same time, it is possible to modify and extend URDME with newly developed simulation routines. Since the overall design effectively hides the complexity of managing the geometry and meshes, this means that newly developed methods may be tested in a realistic setting already at an early stage of development.

Conclusions

In this paper we demonstrate, in a series of examples with high relevance to the molecular systems biology community, that the proposed software framework is a useful tool for both practitioners and developers of spatial stochastic simulation algorithms. Through the combined efforts of algorithm development and improved modeling accuracy, increasingly complex biological models become feasible to study through computational methods. URDME is freely available at http://www.urdme.org.
Interventions in Wnt signaling as a novel therapeutic approach to improve myocardial infarct healing
Authors: Hermans Kevin CM , Daskalopoulos Evangelos P , Blankesteijn W Matthijs
Published: September 2012

Following myocardial infarction, wound healing takes place in the infarct area where the non-viable cardiac tissue is replaced by a scar. Inadequate wound healing or insufficient maintenance of the extracellular matrix in the scar can lead to excessive dilatation of the ventricles, one of the hallmarks of congestive heart failure. Therefore, it is important to better understand the wound-healing process in the heart and to develop new therapeutic agents that target the infarct area in order to maintain an adequate cardiac function. One of these potential novel therapeutic targets is Wnt signaling. Wnt signaling plays an important role in embryonic myocardial development but in the adult heart the pathway is thought to be silent. However, there is increasing evidence that components of the Wnt pathway are re-expressed during cardiac repair, implying a regulatory role. Recently, several studies have been published where the effect of interventions in Wnt signaling on infarct healing has been studied. In this review, we will summarize the results of these studies and discuss the effects of these interventions on the different cell types that are involved in the wound healing process.
Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation
Authors: Lowthert Lori , Leffert Janine , Lin Aiping , Umlauf Sheila , Maloney Kathleen , Muralidharan Anjana , Lorberg Boris , Mane Shrikant , Zhao Hongyu , Sinha Rajita , Bhagwagar Zubin , Beech Robert
Published: September 2012

Background

Lithium is considered by many as the gold standard medication in the management of bipolar disorder (BD). However, the clinical response to lithium is heterogeneous, and the molecular basis for this difference in response is unknown. In the present study, we sought to determine how the peripheral blood gene expression profiles of patients with bipolar disorder (BD) changed over time following intitiation of treatment with lithium, and whether differences in those profiles over time were related to the clinical response.

Methods

Illumina Sentrix Beadchip (Human-6v2) microarrays containing > 48,000 transcript probes were used to measure levels of expression of gene-expression in peripheral blood from 20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label treatment with lithium.

Changes in gene-expression were compared between treatment responders (defined as a decrease in the Hamilton Depression Rating Scale of 50% or more) and non-responders. Pathway analysis was conducted using GeneGO Metacore software.

Results

127 genes showed a differential response in responders vs. non-responders. Pathway analysis showed that regulation of apoptosis was the most significantly affected pathway among these genes. Closer examination of the time-course of changes among BCL2 related genes showed that in lithium-responders, one month after starting treatment with lithium, several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2) were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1) and BCL2-associated agonist of cell death (BAD), were down-regulated. In contrast, in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated at the one-month time-point.

Conclusions

These results suggest that differential changes in the balance of pro- and anti- apoptotic gene-expression following treatment with lithium may explain some of the heterogeneity in clinical response in BD patients.