bluuebunny/crossref_metadata_2025 huggingface dataset:
ExomeAI: detection of recurrent allelic imbalance in tumors using whole-exome sequencing data
Authors: Nadaf Javad , Majewski Jacek , Fahiminiya Somayyeh
Published: October 2014

Summary: Whole-exome sequencing (WES) has extensively been used in cancer genome studies; however, the use of WES data in the study of loss of heterozygosity or more generally allelic imbalance (AI) has so far been very limited, which highlights the need for user-friendly and flexible software that can handle low-quality datasets. We have developed a statistical approach, ExomeAI, for the detection of recurrent AI events using WES datasets, specifically where matched normal samples are not available.

Availability: ExomeAI is a web-based application, publicly available at: http://genomequebec.mcgill.ca/exomeai .

Contact:  JavadNadaf@gmail.com or somayyeh.fahiminiya@mcgill.ca

Supplementary information:  Supplementary data are available at Bioinformatics online.
In the Shadow of Tragedy: The Evolution of Safety Coregulation on America’s Uninspected Towing Vessels
Authors: Rust Daniel L.
Published: October 2014

Disasters often prompt debates regarding public policy and lead to changes in safety regulations. With the deaths of 47 passengers and crew, the 1993 Sunset Limited tragedy focused public and governmental attention upon safety practices aboard uninspected towing vessels operated on US inland waterways. The event shaped the policy debate as the federal government imposed new safety regulations upon the towing industry and the dominant industry trade organization, the American Waterways Operators, adopted an industry-driven safety program. Subsequent tragedies revealed the inadequacies of the AWO’s Responsible Carrier Program and pushed industry stakeholders toward the creation of a formal US Coast Guard inspection regime for all uninspected towing vessels. Set within the context of steamboat safety regulations dating from 1838 and drawn from diverse primary sources, this article traces the evolution of safety coregulation aboard America’s uninspected towing vessels, explores the Coast Guard’s reluctance to establish a formal inspection regime for uninspected towing vessels, and highlights why self regulation without a form of strong government or third-party involvement is often unsuccessful.
Application of Process Improvement Principles to Increase the Frequency of Complete Airway Management Documentation
Authors: McCarty L. Kelsey , Saddawi-Konefka Daniel , Gargan Lauren M. , Driscoll William D. , Walsh John L. , Peterfreund Robert A.
Published: October 2014

Background:

Process improvement in healthcare delivery settings can be difficult, even when there is consensus among clinicians about a clinical practice or desired outcome. Airway management is a medical intervention fundamental to the delivery of anesthesia care. Like other medical interventions, a detailed description of the management methods should be documented. Despite this expectation, airway documentation is often insufficient. The authors hypothesized that formal adoption of process improvement methods could be used to increase the rate of “complete” airway management documentation.

Methods:

The authors defined a set of criteria as a local practice standard of “complete” airway management documentation. The authors then employed selected process improvement methodologies over 13 months in three iterative and escalating phases to increase the percentage of records with complete documentation. The criteria were applied retrospectively to determine the baseline frequency of complete records, and prospectively to measure the impact of process improvements efforts over the three phases of implementation.

Results:

Immediately before the initial intervention, a retrospective review of 23,011 general anesthesia cases over 6 months showed that 13.2% of patient records included complete documentation. At the conclusion of the 13-month improvement effort, documentation improved to a completion rate of 91.6% (P < 0.0001). During the subsequent 21 months, the completion rate was sustained at an average of 90.7% (SD, 0.9%) across 82,571 general anesthetic records.

Conclusion:

Systematic application of process improvement methodologies can improve airway documentation and may be similarly effective in improving other areas of anesthesia clinical practice.
Intestinal and Gastric Permeability in Children With Eosinophilic Esophagitis and Reflux Esophagitis
Authors: Leung Aldrich J.T. , Persad Sujata , Slae Mordechai , Abdelradi Amr , Kluthe Cheryl , Shirton Leanne , Danchuk Ronda , Persad Rabin , Meddings Jon , Huynh Hien Q.
Published: October 2014

Objectives:

Eosinophilic esophagitis (EoE) is an allergic and immune‐mediated entity that leads to a characteristic inflammation of esophageal mucosa. Patients complain of dysphagia and reflux‐like symptoms. As many as 80% of patients with EoE may also have a history of atopy, and patients with asthma and eczema have previously been shown to have increased intestinal permeability. This study was designed to assess small intestinal and gastric permeability in patients with EoE and to see whether it differed from healthy individuals and patients with reflux esophagitis (RE).

Methods:

Gastric and small intestinal permeability was measured using sugar probe tests containing lactulose, mannitol, and sucrose. Lactulose‐to‐mannitol (L/M) ratios in the patient's urine were a measure for intestinal permeability, and total sucrose was a measure for gastric permeability.

Results:

We analyzed samples from 23 patients with EoE, 20 RE, 14 normal upper endoscopy with gastrointestinal symptoms, and 26 healthy controls. All of the 4 groups had L/M ratios less than the upper limit of normal (<0.025). There was no statistically significant difference in gastric permeability between the 4 groups (L/M P = 0.26, sucrose P = 0.46).

Conclusions:

Our data suggest that an alteration in gastric and intestinal permeability does not play a role in EoE or RE pathogenesis.
A systems biology analysis of the changes in gene expression via silencing of HPV-18 E1 expression in HeLa cells
Authors: Castillo Andres , Wang Lu , Koriyama Chihaya , Eizuru Yoshito , Jordan King , Akiba Suminori
Published: October 2014

Previous studies have reported the detection of a truncated E1 mRNA generated from HPV-18 in HeLa cells. Although it is unclear whether a truncated E1 protein could function as a replicative helicase for viral replication, it would still retain binding sites for potential interactions with different host cell proteins. Furthermore, in this study, we found evidence in support of expression of full-length HPV-18 E1 mRNA in HeLa cells. To determine whether interactions between E1 and cellular proteins play an important role in cellular processes other than viral replication, genome-wide expression profiles of HPV-18 positive HeLa cells were compared before and after the siRNA knockdown of E1 expression. Differential expression and gene set enrichment analysis uncovered four functionally related sets of genes implicated in host defence mechanisms against viral infection. These included the toll-like receptor, interferon and apoptosis pathways, along with the antiviral interferon-stimulated gene set. In addition, we found that the transcriptional coactivator E1A-binding protein p300 (EP300) was downregulated, which is interesting given that EP300 is thought to be required for the transcription of HPV-18 genes in HeLa cells. The observed changes in gene expression produced via the silencing of HPV-18 E1 expression in HeLa cells indicate that in addition to its well-known role in viral replication, the E1 protein may also play an important role in mitigating the host's ability to defend against viral infection.
On alternative wavelet reconstruction formula: a case study of approximate wavelets
Authors: Lebedeva Elena A. , Postnikov Eugene B.
Published: October 2014

The application of the continuous wavelet transform to the study of a wide class of physical processes with oscillatory dynamics is restricted by large central frequencies owing to the admissibility condition. We propose an alternative reconstruction formula for the continuous wavelet transform, which is applicable even if the admissibility condition is violated. The case of the transform with the standard reduced Morlet wavelet, which is an important example of such analysing functions, is discussed.
Asymptotic formulae for the Lommel and Bessel functions and their derivatives
Authors: Aleksandrova N. I.
Published: October 2014

We derive new approximate representations of the Lommel functions in terms of the Scorer function and approximate representations of the first derivative of the Lommel functions in terms of the derivative of the Scorer function. Using the same method, we obtain previously known approximate representations of the Nicholson type for Bessel functions and their first derivatives. We study also for what values of the parameters our representations have reasonable accuracy.
New dinosaur (Theropoda,
stem
-Averostra) from the earliest Jurassic of the La Quinta formation, Venezuelan Andes
Authors: Langer Max C. , Rincón Ascanio D. , Ramezani Jahandar , Solórzano Andrés , Rauhut Oliver W. M.
Published: October 2014

Dinosaur skeletal remains are almost unknown from northern South America. One of the few exceptions comes from a small outcrop in the northernmost extension of the Andes, along the western border of Venezuela, where strata of the La Quinta Formation have yielded the ornithischian
Laquintasaura venezuelae
and other dinosaur remains. Here, we report isolated bones (ischium and tibia) of a small new theropod,
Tachiraptor admirabilis
gen. et sp. nov., which differs from all previously known members of the group by an unique suite of features of its tibial articulations. Comparative/phylogenetic studies place the new form as the sister taxon to Averostra, a theropod group that is known primarily from the Middle Jurassic onwards. A new U–Pb zircon date (isotope dilution thermal-ionization mass spectrometry; ID-TIMS method) from the bone bed matrix suggests an earliest Jurassic maximum age for the La Quinta Formation. A dispersal–vicariance analysis suggests that such a stratigraphic gap is more likely to be filled by new records from north and central Pangaea than from southern areas. Indeed, our data show that the sampled summer-wet equatorial belt, which yielded the new taxon, played a pivotal role in theropod evolution across the Triassic–Jurassic boundary.
Stress fields in hollow core–shell spherical electrodes of lithium ion batteries
Authors: Liu Yingjie , Lv Pengyu , Ma Jun , Bai Ruobing , Duan Hui Ling
Published: October 2014

This paper presents a comprehensive model coupling the effects of hydrostatic stress, surface/interface stress, phase transformation and the structure of electrodes. First, the governing equation of moving phase interface with hydrostatic stress is established. Under the effect of hydrostatic stress, phase transformation process is much faster, which means phase transformation time is overestimated in previous publications. Then, a cross-scale analysis is presented to investigate the size effect owing to hydrostatic stress, surface stress and interface stress separately, which concludes that the effect of hydrostatic stress is significant for the stress field in microelectrode particles, whereas that of surface/interface stress is highlighted in nano-ones. Finally, an electrochemical variable ‘efficiency’ (ratio of effective capacity over total capacity) is defined. The advantages of hollow structure electrodes on stress and efficiency are analysed. The present model is helpful for the material and structure design of electrodes of lithium ion batteries.
Recurrence-Based Information Processing in Gene Regulatory Networks
Authors: Gabalda-Sagarra Marçal , Carey Lucas , Garcia-Ojalvo Jordi
Published: October 2014

Cellular information processing is generally attributed to the complex networks of genes and proteins that regulate cell behavior. It is still unclear, however, what are the main features of those networks that allow a cell to encode and interpret its ever changing environment. Here we address this question by studying the computational capabilities of the transcriptional regulatory networks of five evolutionary distant organisms. We identify in all cases a cyclic recurrent structure, formed by a small core of genes, that is essential for dynamical encoding and information integration. The recent history of the cell is encoded by the transient dynamics of this recurrent reservoir of nodes, while the rest of the network forms a readout layer devoted to decode and interpret the high-dimensional dynamical state of the recurrent core. This separation of roles allows for the integration of temporal information, while facilitating the learning of new environmental conditions and preventing catastrophic interference between those new inputs and the previously stored information. This resembles the reservoir-computing paradigm recently proposed in computational neuroscience and machine learning. Our results reveal that gene regulatory networks act as echo-state networks that perform optimally in standard memory-demanding tasks, and confirms that most of their memory resides in the recurrent reservoir. We also show that the readout layer can learn to decode the information stored in the reservoir via standard evolutionary strategies. Our work thus suggests that recurrent dynamics is a key element for the processing of complex time-dependent information by cells.

Cells must monitor the dynamics of their environment continuously, in order to adapt to present conditions and anticipate future changes. But anticipation requires processing temporal information, which in turn requires memory. Here we propose that cells can perform such dynamical information processing via the reservoir computing paradigm. According to this concept, a structure with recurrent (cyclic) paths, known as the reservoir, stores in its dynamics a record of the cell’s recent history. A much simpler feedforward structure then reads and decodes that information. We show that the transcriptional gene regulatory networks of five evolutionary distant organisms are organized in this manner, allowing them to store complex time-dependent signals entering the cell in a biologically realistic manner.
Cost benefit analysis on SVC and UPFC in a dynamic economic dispatch problem
Authors: Sreejith Sekharan , P. Simon Sishaj
Published: October 2014

Purpose

– The aim of this paper is to compare the performance of static VAR compensator (SVC) and unified power flow controller (UPFC) in dynamic economic dispatch (DED) problem. DED schedules the online generator outputs with the predicted load demands over a certain period so that the electric power system is operated most economically. During last decade, flexible alternating current transmission systems (FACTS) devices are broadly used for maximizing the loadability of existing power system transmission networks. However, based on the literature survey, the performance of SVC and UPFC incorporated in the DED problem and its cost–benefit analysis are not discussed earlier in any of the literature.

Design/methodology/approach

– Here, the DED problem is solved applying ABC algorithm incorporating SVC and UPFC. The following conditions are investigated with the incorporation of SVC and UPFC into DED problem: the role of SVC and UPFC for improving the power flow and voltage profile and the approximate analysis on cost recovery and payback period with SVC and UPFC in DED problem.

Findings

– The incorporation of FACTS devices reduces the generation cost and improves the stability of the system. The percentage cost recovered with FACTS devices is estimated approximately using equated monthly installment (EMI) and non-EMI scheme. It is clear from the illustrations that the installation of FACTS devices is profitable after a certain period.

Research limitations/implications

– In this research work, the generation cost with FACTS devices is only taken into account while calculating the profit. The other benefits like congestion management, cost gained due to land and cost due to stability issues are not considered. For future work, these things can be considered while calculating the benefit.

Originality/value

– The originality of the work is incorporation of FACTS devices in DED problem and approximate estimation of recovery cost with FACTS devices in DED problem.
Sector size, technical change and stability in the USA (1957-2006): a Schumpeterian approach
Authors: Konstantakis Konstantinos , G. Michaelides Panayotis , Papageorgiou Theofanis
Published: October 2014

Purpose

– The purpose of this paper is to investigate two famous postulates of the Schumpeterian doctrine and its implications for the US economy.

Design/methodology/approach

– Analytically, the authors investigate whether sector size matters for sectoral: technological change and stability, as expressed through the relevant quantitative measures and variables. To this end, the authors test a number of relevant models that express the various forms of this relationship. More precisely, the authors use panel data for the 14 main sectors of economic activity in the USA over the period 1957-2006, just before the first signs of the US and global recession made their appearance.

Findings

– The results seem to be in line with the Schumpeterian postulate that market size matters for technological change and economic stability, for the US economy (1957-2006). Clearly, further research would be of great interest.

Originality/value

– This work contributes to the literature in the following ways: first, it provides an extensive review of the literature on the subject and adopts two relevant methodological approaches. Second, based on these quantitative approaches, the paper offers a complete investigation of two famous postulates of the Schumpeterian theory for the US economy, and it is the first, to the best of the authors’ knowledge, to do so by sector of economic activity, in a panel data framework. Third, the paper uses a wide data set (1957-2006) to examine the US economy up until the first signs of the US and global economic recession made their appearance.
Student engagement with sustainability: understanding the value–action gap
Authors: Chaplin Gareth , Wyton Paul
Published: October 2014

Purpose

– The purpose of this paper is to present the findings of research that aimed to determine what university students living in Unite accommodation in the UK understand about the concept of sustainable living. It considers what barriers they perceive to be standing in the way of following sustainable living practices. In particular, the research aimed to explore any value–action gap for the student population with a view to informing future actions to help close any gap.

Design/methodology/approach

– The study was completed through an online questionnaire survey of students living in halls of residence operated by provider The Unite Group Plc. The survey informed semi-structured interviews and focus groups that explored the issues raised in greater detail.

Findings

– It was found that students living in Unite properties believed sustainable living to be important, yet levels of understanding were very low and there appeared to be a wide value–action gap. Reasons for this are varied; however, an unexpected theme emerged around the association of effort and importance. There was a very strong association between sustainable living and recycling, which, therefore, saw the lack of adequate recycling facilities as a significant barrier to sustainable living. There were also issues around a lack of information, cost and respondents’ flatmates as further barriers. However, the most significant barrier was the displacement of responsibility for sustainable living to other people or organisations.

Originality/value

– Gaining an insight into the complexity of attitude and behaviour of students with the sustainability agenda will enable understanding that can be applied to activities that promote sustainability.
Cognitive styles and the use of electronic journals in a mobile context
Authors: Chan Chu-Han , Hsieh Chen-Wei , Y. Chen Sherry
Published: October 2014

Purpose

– The purpose of this paper is to examine how different cognitive style groups use electronic journals via mobile devices, with an emphasis on the use of search mechanisms, the approaches to judge the relevance and to refine the results, the use of horizontal screens, and on the influence of negative emotions.

Design/methodology/approach

– Participants’ cognitive styles were identified as Holists and Serialists with Ford's Study Preference Questionnaire. The behaviour of the participants interacting with theScienceDirectwas observed and was analysed with both traditional statistics and data mining.

Findings

– Holists prefer to use multiple searches when undertaking the Expert Search only, which is a complex search mechanism. Conversely, Serialists have a tendency to use multiple searches, irrespective of the complexity of search mechanisms. Additionally, the Expert Search may be helpful for Serialists while the Basic Search seems beneficial to Holists. Regarding the judgement of relevance, Holists tend to use a variety of approaches while Serialists prefer to use a single approach. In general, the major results of this study confirm those of Vilar and Žumer (2008).

Originality/value

– The novelty of this study covers two aspects. One is to examine the behaviour of Holists and Serialists in the mobile context of electronic journals and the other is to analyse data with an integrative approach that combines both traditional statistics and data mining. The former contributes to the understandings of how to design mobile electronic journals that can accommodate the needs of different cognitive style groups. The latter can not only strengthen the reliability of the results obtained from traditional statistics, but also discover findings neglected by traditional statistics.
Prestack exploding reflector modelling and migration for anisotropic media
Authors: Alkhalifah T.
Published: October 2014

The double‐square‐root equation is commonly used to image data by downward continuation using one‐way depth extrapolation methods. A two‐way time extrapolation of the double‐square‐root‐derived phase operator allows for up and downgoing wavefields but suffers from an essential singularity for horizontally travelling waves. This singularity is also associated with an anisotropic version of the double‐square‐root extrapolator. Perturbation theory allows us to separate the isotropic contribution, as well as the singularity, from the anisotropic contribution to the operator. As a result, the anisotropic residual operator is free from such singularities and can be applied as a stand alone operator to correct for anisotropy. We can apply the residual anisotropy operator even if the original prestack wavefield was obtained using, for example, reverse‐time migration. The residual correction is also useful for anisotropic parameter estimation. Applications to synthetic data demonstrate the accuracy of the new prestack modelling and migration approach. It also proves useful in approximately imaging the Vertical Transverse Isotropic Marmousi model.
Loss of Dfg5 glycosylphosphatidylinositol‐anchored membrane protein confers enhanced heat tolerance in Saccharomyces cerevisiae
Authors: Nasution Olviyani , Lee Jaok , Srinivasa Kavitha , Choi In‐Geol , Lee Young Mi , Kim Eunjung , Choi Wonja , Kim Wankee
Published: October 2014

The protein product of Saccharomyces cerevisiae DFG5 gene is a glycosylphosphatidylinositol (GPI)‐anchored plasma membrane protein and a putative glycosidase/glycosyltransferase that links other GPI‐anchored proteins to β‐glucans in the cell wall. Upon exposure to heat (41°C), DFG5 deletion mutant dfg5Δ displayed significantly enhanced heat tolerance as well as lowered level of reactive oxygen species and decreased membrane permeability compared with those in the control (BY4741). Comparative transcriptome profiles of BY4741 and dfg5Δ revealed that 38 and 23 genes were up‐ and down‐regulated in dfg5Δ respectively. Of the 23 down‐regulated genes, 11 of 13 viable deletion mutants were identified to be tolerant to heat, suggesting that the down‐regulation of those genes might have contributed to the enhanced heat tolerance in dfg5Δ. Deletion of DFG5 caused slight activation of mitogen‐activated protein kinases Hog1 in the high‐osmolarity glycerol pathway and Slt2 in the cell wall integrity pathway. Therefore, a model is proposed on the signal transduction pathways associated with deletion of DFG5 upon heat stress.
Treatment and prognostic analysis of patients with leptomeningeal metastases from non‐small cell lung cancer
Authors: Xu Qinghua , Chen Xiu , Qian Danwen , Wang Yongsheng , Meng Shuyan , Liu Hui , Zhou Caicun
Published: October 2014

Background

Leptomeningeal metastases (LM) from non‐small cell lung cancer (NSCLC) are associated with poor prognosis and optimal treatment for this subgroup of NSCLC patients is controversial. The purpose of this study is to evaluate treatment options and prognostic factors of NSCLC patients with LM.

Methods

We retrospectively analyzed data of 108 patients who had been diagnosed with LM from NSCLC between May 2006 and August 2013.

Results

The median survival time (MST) of the 108 patients was 5.3 months, and the one‐year survival rate was 23.7%. Forty‐nine patients received whole brain radiotherapy (WBRT) and the MST of patients who received WBRT and those who did not were 6.4 and 4.3 months, respectively. Forty‐two patients were treated with epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) after being diagnosed with LM. These patients had prolonged survival (11.1 vs. 4.4 months). Patients who received concomitant WBRT and EGFR‐TKIs had the longest MST (12.3 months). Eastern Cooperative Oncology Group performance status, whether patients received WBRT, and/or EGFR‐TKIs were independent prognostic factors for patients with LM from NSCLC.

Conclusion

WBRT, EGFR‐TKIs or combined therapy, could lead to better clinical outcomes for NSCLC patients with LM. EGFR‐TKIs plus WBRT has the potential to be the standard strategy for LM in NSCLC patients.
A method for calculating minimum biodiversity offset multipliers accounting for time discounting, additionality and permanence
Authors: Laitila Jussi , Moilanen Atte , Pouzols Federico M.
Published: October 2014

Biodiversity offsetting, which means compensation for ecological and environmental damage caused by development activity, has recently been gaining strong political support around the world. One common criticism levelled at offsets is that they exchange certain and almost immediate losses for uncertain future gains. In the case of restoration offsets, gains may be realized after a time delay of decades, and with considerable uncertainty.

Here we focus on offset multipliers, which are ratios between damaged and compensated amounts (areas) of biodiversity. Multipliers have the attraction of being an easily understandable way of deciding the amount of offsetting needed. On the other hand, exact values of multipliers are very difficult to compute in practice if at all possible.

We introduce a mathematical method for deriving minimum levels for offset multipliers under the assumption that offsetting gains must compensate for the losses (no net loss offsetting). We calculate absolute minimum multipliers that arise from time discounting and delayed emergence of offsetting gains for a one‐dimensional measure of biodiversity. Despite the highly simplified model, we show that even the absolute minimum multipliers may easily be quite large, in the order of dozens, and theoretically arbitrarily large, contradicting the relatively low multipliers found in literature and in practice.

While our results inform policy makers about realistic minimal offsetting requirements, they also challenge many current policies and show the importance of rigorous models for computing (minimum) offset multipliers. The strength of the presented method is that it requires minimal underlying information. We include a supplementary spreadsheet tool for calculating multipliers to facilitate application.
An examination of when and how leader political skill influences team performance in China: A cultural value perspective
Authors: Yang Fu , Zhang Lihua
Published: October 2014

This study examined the relationship between leader political skill and team performance, as well as the mediating (team cohesion) and moderating (power distance) variables of the relationship. Our theoretical model was tested using data collected from employees in a food service company. Analyses of multisource and lagged data from 59 teams and 276 members indicated that leader political skill was positively related to team performance via team cohesion. Further, both the relationship between leader political skill and team cohesion and the indirect relationship between leader political skill and team performance were stronger when teams exhibited lower power distance.
Recent advances and future directions in targeting the secretory apparatus in multiple myeloma
Authors: Auner Holger W. , Cenci Simone
Published: October 2014

Multiple myeloma is a genetically heterogeneous tumour of transformed plasma cells, terminally differentiated effectors of the B cell lineage specialized in producing large amounts of immunoglobulins. The uniquely well‐developed secretory apparatus that equips normal and transformed plasma cells with the capacity for high‐level protein secretion constitutes a distinctive therapeutic target. In this review we discuss how fundamental cellular processes, such as the unfolded protein response (UPR), endoplasmic reticulum (ER)‐associated degradation and autophagy, maintain intracellular protein homeostasis (proteostasis) and regulate plasma cell ontogeny and malignancy. We summarize our current understanding of the cellular effects of proteasome inhibitors and the molecular bases of resistance to them. Furthermore, we discuss how improvements in our understanding of the secretory apparatus and of the complex interactions between intracellular protein synthesis and degradation pathways can disclose novel drug targets for multiple myeloma, defining a paradigm of general interest for cancer biology and disorders of altered proteostasis.
CardiacNOsignalling in the metabolic syndrome
Authors: Pechánová O , Varga Z V , Cebová M , Giricz Z , Pacher P , Ferdinandy P
Published: October 2014

It is well documented that metabolic syndrome (i.e. a group of risk factors, such as abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides and low cholesterol level in high‐density lipoprotein), which raises the risk for heart disease and diabetes, is associated with increased reactive oxygen and nitrogen species (ROS/RNS) generation.ROS/RNScan modulate cardiacNOsignalling and trigger various adaptive changes inNOS and antioxidant enzyme expressions/activities. While initially these changes may represent protective mechanisms in metabolic syndrome, later with more prolonged oxidative, nitrosative and nitrative stress, these are often exhausted, eventually favouring myocardialRNSgeneration and decreasedNObioavailability. The increased oxidative and nitrative stress also impairs theNO‐soluble guanylate cyclase (sGC) signalling pathway, limiting the ability ofNOto exert its fundamental signalling roles in the heart. EnhancedROS/RNSgeneration in the presence of risk factors also facilitates activation of redox‐dependent transcriptional factors such asNF‐κB, promoting myocardial expression of various pro‐inflammatory mediators, and eventually the development of cardiac dysfunction and remodelling. While the dysregulation ofNOsignalling may interfere with the therapeutic efficacy of conventional drugs used in the management of metabolic syndrome, the modulation ofNOsignalling may also be responsible for the therapeutic benefits of already proven or recently developed treatment approaches, such asACEinhibitors, certain β‐blockers, andsGCactivators. Better understanding of the above‐mentioned pathological processes may ultimately lead to more successful therapeutic approaches to overcome metabolic syndrome and its pathological consequences in cardiacNOsignalling.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2015.172.issue-6
Kv11.1 (hERG)‐induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv11.1 (hERG) inhibitors
Authors: Yu Z , IJzerman A P , Heitman L H
Published: October 2014

Background and Purpose

Drug‐induced arrhythmia due to blockade of the Kv11.1 channel (also known as the hERG K+ channel) is a frequent side effect. Previous studies have primarily focused on equilibrium parameters, i.e. affinity or potency, of drug candidates at the channel. The aim of this study was to determine the kinetics of the interaction with the channel for a number of known Kv11.1 blockers and to explore a possible correlation with the affinity or physicochemical properties of these compounds.

Experimental Approach

The affinity and kinetic parameters of 15 prototypical Kv11.1 inhibitors were evaluated in a number of [3H]‐dofetilide binding assays. The lipophilicity (logKW‐C8) and membrane partitioning (logKW‐IAM) of these compounds were determined by means of HPLC analysis.

Key Results

A novel [3H]‐dofetilide competition association assay was set up and validated, which allowed us to determine the binding kinetics of the Kv11.1 blockers used in this study. Interestingly, the compounds' affinities (Ki values) were correlated to their association rates rather than dissociation rates. Overall lipophilicity or membrane partitioning of the compounds were not correlated to their affinity or rate constants for the channel.

Conclusions and Implications

A compound's affinity for the Kv11.1 channel is determined by its rate of association with the channel, while overall lipophilicity and membrane affinity are not. In more general terms, our findings provide novel insights into the mechanism of action for a compound's activity at the Kv11.1 channel. This may help to elucidate how Kv11.1‐induced cardiotoxicity is governed and how it can be circumvented in the future.
The effects of microRNA on the absorption, distribution, metabolism and excretion of drugs
Authors: He Y , Chevillet J R , Liu G , Kim T K , Wang K
Published: October 2014

The importance of genetic factors (e.g. sequence variation) in the absorption, distribution, metabolism, excretion (ADME) and overall efficacy of therapeutic agents is well established. Our ability to identify, interpret and utilize these factors is the subject of much clinical investigation and therapeutic development. However, drug ADME and efficacy are also heavily influenced by epigenetic factors such as DNA/histone methylation and non‐coding RNAs [especially microRNAs (miRNAs)]. Results from studies using tools, such as in silico miRNA target prediction, in vitro functional assays, nucleic acid profiling/sequencing and high‐throughput proteomics, are rapidly expanding our knowledge of these factors and their effects on drug metabolism. Although these studies reveal a complex regulation of drug ADME, an increased understanding of the molecular interplay between the genome, epigenome and transcriptome has the potential to provide practically useful strategies to facilitate drug development, optimize therapeutic efficacy, circumvent adverse effects, yield novel diagnostics and ultimately become an integral component of personalized medicine.

Linked Articles

This article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐11
Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside‐perpetrated herb–drug interactions on OATP1B3
Authors: Jiang Rongrong , Dong Jiajia , Li Xiuxue , Du Feifei , Jia Weiwei , Xu Fang , Wang Fengqing , Yang Junling , Niu Wei , Li Chuan
Published: October 2014

Background and Purpose

Ginsenosides are bioactive saponins derived from Panax notoginseng roots (Sanqi) and ginseng. Here, the molecular mechanisms governing differential pharmacokinetics of 20(S)‐protopanaxatriol‐type ginsenoside Rg1, ginsenoside Re and notoginsenoside R1 and 20(S)‐protopanaxadiol‐type ginsenosides Rb1, Rc and Rd were elucidated.

Experimental Approach

Interactions of ginsenosides with human and rat hepatobiliary transporters were characterized at the cellular and vesicular levels. A rifampin‐based inhibition study in rats evaluated the in vivo role of organic anion‐transporting polypeptide (Oatp)1b2. Plasma protein binding was assessed by equilibrium dialysis. Drug–drug interaction indices were calculated to estimate potential for clinically relevant ginsenoside‐mediated interactions due to inhibition of human OATP1Bs.

Key Results

All the ginsenosides were bound to human OATP1B3 and rat Oatp1b2 but only the 20(S)‐protopanaxatriol‐type ginsenosides were transported. Human multidrug resistance‐associated protein (MRP)2/breast cancer resistance protein (BCRP)/bile salt export pump (BSEP)/multidrug resistance protein‐1 and rat Mrp2/Bcrp/Bsep also mediated the transport of the 20(S)‐protopanaxatriol‐type ginsenosides. Glomerular‐filtration‐based renal excretion of the 20(S)‐protopanaxatriol‐type ginsenosides was greater than that of the 20(S)‐protopanaxadiol‐type counterparts due to differences in plasma protein binding. Rifampin‐impaired hepatobiliary excretion of the 20(S)‐protopanaxatriol‐type ginsenosides was effectively compensated by the renal excretion in rats. The 20(S)‐protopanaxadiol‐type ginsenosides were potent inhibitors of OATP1B3.

Conclusion and Implications

Differences in hepatobiliary and in renal excretory clearances caused markedly different systemic exposure and different elimination kinetics between the two types of ginsenosides. Caution should be exercised with the long‐circulating 20(S)‐protopanaxadiol‐type ginsenosides as they could induce hepatobiliary herb–drug interactions, particularly when patients receive long‐term therapies with high‐dose i.v. Sanqi or ginseng extracts.
Support and monitoring of families after child abuse detection based on parental characteristics at the Emergency Department
Authors: Diderich H. M. , Pannebakker F. D. , Dechesne M. , Buitendijk S. E. , Oudesluys‐Murphy A. M.
Published: October 2014

Background

The ‘Hague Protocol’ enables professionals at the adult Emergency Department (ED) to detect child abuse based on three parental characteristics: (i) suicide attempt or self‐harm, (ii) domestic violence or (iii) substance abuse, and to refer them to the Reporting Centre for Child Abuse and Neglect (RCCAN). This study investigates what had happened to the families three months after this referral.

Method

ED referrals based on parental characteristics (N = 100) in which child abuse was confirmed after investigation by the RCCAN were analysed. Information was collected regarding type of child abuse, reason for reporting, duration of problems prior to the ED referral, previous involvement of support services or other agencies, re‐occurrence of the problems and outcome of the RCCAN monitoring according to professionals and the families.

Results

Of the 100 referred cases, 68 families were already known to the RCCAN, the police or family support services, prior to the ED referral. Of the 99 cases where information was available, existing support was continued or intensified in 31, a Child Protection Services (CPS) report had to be made in 24, new support was organized for 27 cases and in 17 cases support was not necessary, because the domestic problems were already resolved. Even though the RCCAN is mandated to monitor all referred families after three months, 31 cases which were referred internally were not followed up.

Conclusion

Before referral by the ED two thirds of these families were already known to organizations. Monitoring may help provide a better, more sustained service and prevent and resolve domestic problems. A national database could help to link data and to streamline care for victims and families. We recommend a Randomized Controlled Trial to test the effectiveness of this Protocol in combination with the outcomes of the provided family support.
Suspected flunixin poisoning of a wild Eurasian Griffon Vulture from Spain
Authors: Zorrilla Irene , Martinez Rosa , Taggart Mark A. , Richards Ngaio
Published: October 2014

Exposure to residues of the nonsteroidal anti‐inflammatory drug (NSAID) diclofenac present in livestock carcasses has caused extensive declines in 3 Gyps vulture species across Asia. The carcass of a wild Eurasian Griffon Vulture (Gyps fulvus) was found in 2012 on an Andalucian (Spain) game hunting reserve and examined forensically. The bird had severe visceral gout, a finding consistent with Gyps vultures from Asia that have been poisoned by diclofenac. Liver and kidney samples from this Eurasian Griffon Vulture contained elevated flunixin (an NSAID) levels (median = 2.70 and 6.50 mg/kg, respectively). This is the first reported case of a wild vulture being exposed to and apparently killed by an NSAID outside Asia. It is also the first reported instance of mortality in the wild resulting from environmental exposure to an NSAID other than diclofenac.

Caso de Sospecha de Envenenamiento por Flunixin de un Buitre Leonado en España
Children's Developing Intuitions About the Truth Conditions and Implications of Novel Generics Versus Quantified Statements
Authors: Brandone Amanda C. , Gelman Susan A. , Hedglen Jenna
Published: October 2014

Generic statements express generalizations about categories and present a unique semantic profile that is distinct from quantified statements. This paper reports two studies examining the development of children's intuitions about the semantics of generics and how they differ from statements quantified byall,most, andsome. Results reveal that, like adults, preschoolers (a) recognize that generics have flexible truth conditions and are capable of representing a wide range of prevalence levels; and (b) interpret novel generics as having near‐universal prevalence implications. Results further show that by age 4, children are beginning to differentiate the meaning of generics and quantified statements; however, even 7‐ to 11‐year‐olds are not adultlike in their intuitions about the meaning ofmost‐quantified statements. Overall, these studies suggest that by preschool, children interpret generics in much the same way that adults do; however, mastery of the semantics of quantified statements follows a more protracted course.
Is Probabilistic Evidence a Source of Knowledge?
Authors: Friedman Ori , Turri John
Published: October 2014

We report a series of experiments examining whether people ascribe knowledge for true beliefs based on probabilistic evidence. Participants were less likely to ascribe knowledge for beliefs based on probabilistic evidence than for beliefs based on perceptual evidence (Experiments 1 and 2A) or testimony providing causal information (Experiment 2B). Denial of knowledge for beliefs based on probabilistic evidence did not arise because participants viewed such beliefs as unjustified, nor because such beliefs leave open the possibility of error. These findings rule out traditional philosophical accounts for why probabilistic evidence does not produce knowledge. The experiments instead suggest that people deny knowledge because they distrust drawing conclusions about an individual based on reasoning about the population to which it belongs, a tendency previously identified by “judgment and decision making” researchers. Consistent with this, participants were more willing to ascribe knowledge for beliefs based on probabilistic evidence that is specific to a particular case (Experiments 3A and 3B).
Sensitization, pathologic, and imaging findings comparing symptomatic and quiescent failed renal allografts
Authors: Singh Pooja , Feld Rick I. , Colombe Beth W. , Farber John L. , Herman Jay H. , Gulati Rakesh , Maley Warren R. , Frank Adam M.
Published: October 2014

Late allograft failure (LAF) is a common cause of end stage renal disease. These patients face interrelated challenges regarding immunosuppression management, risk of graft intolerance syndrome (GIS), and sensitization. This retrospective study analyzes sensitization, pathology, imaging, and transfusion requirements in 33 LAFs presenting either with GIS (22) or grafts remaining quiescent (11). All patients underwent immunosuppression weaning to discontinuation at LAF. Profound increases in sensitization were noted for all groups and occurred in the GIS group prior to transplant nephrectomy (TxN). Patients with GIS experienced a major upswing in sensitization at, or before the time of their symptomatic presentation. For both GIS and quiescent grafts, sensitization appeared to be closely linked to immunosuppression withdrawal. Most transfusion naïve patients became highly sensitized. Fourteen patients in the GIS group underwent TxN which revealed grade II acute cellular rejection or worse, with grade 3 chronic active T‐cell‐mediated rejection. Blinded comparisons of computed tomography scan of GIS group revealed swollen allografts with fluid collections compared with the quiescent allografts (QAs), which were shrunken and atrophic. The renal volume on imaging and weight of explants nearly matched. Future studies should focus on interventions to avoid sensitization and GIS.
Behavioural thermoregulation and bioenergetics of riverine smallmouth bass associated with ambient cold‐period thermal refuge
Authors: Westhoff Jacob T. , Paukert Craig , Ettinger‐Dietzel Sarah , Dodd Hope , Siepker Michael
Published: October 2014

Smallmouth bass in thermally heterogeneous streams may behaviourally thermoregulate during the cold period (i.e., groundwater temperature greater than river water temperature) by inhabiting warm areas in the stream that result from high groundwater influence or springs. Our objectives were to determine movement of smallmouth bass (Micropterus dolomieu) that use thermal refuge and project differences in growth and consumption among smallmouth bass exhibiting different thermal‐use patterns. We implanted radio transmitters in 29 smallmouth bass captured in Alley Spring on the Jacks Fork River, Missouri, USA, during the winter of 2012. Additionally, temperature archival tags were implanted in a subset of nine fish. Fish were tracked using radio telemetry monthly from January 2012 through January of 2013. The greatest upstream movement was 42.5 km, and the greatest downstream movement was 22.2 km. Most radio tagged fish (69%) departed Alley Spring when daily maximum river water temperature first exceeded that of the spring (14 °C) and during increased river discharge. Bioenergetic modelling predicted that a 350 g migrating smallmouth bass that used cold‐period thermal refuge would grow 16% slower at the same consumption level as a fish that did not seek thermal refuge. Contrary to the bioenergetics models, extrapolation of growth scope results suggested migrating fish grow 29% more than fish using areas of stream with little groundwater influence. Our results contradict previous findings that smallmouth bass are relatively sedentary, provide information about potential cues for migratory behaviour, and give insight to managers regarding use and growth of smallmouth bass in thermally heterogeneous river systems.