bluuebunny/crossref_metadata_2025 huggingface dataset:
Winner of the SLS Annual Conference Best Paper Prize 2013: Bogeymen, lunatics and fanatics: collective actions and the private enforcement of European competition law
Authors: Wardhaugh Bruce
Published: February 2014

The European desire to ensure that bearers of EU rights are adequately compensated for any infringement of these rights, particularly in cases where the harm is widely diffused, and perhaps not even noticed by those affected by it, collides with another desire: to avoid the perceived excesses of an American-style system of class actions. The excesses of these American class actions are in European discourse presented as a sort of bogeyman, which is a source of irrational fear, often presented by parental or other authority figures. But when looked at critically, the bogeyman disappears. In this paper, I examine the European (and UK) proposals for collective action. I compare them to the American regime. The flaws and purported excesses of the American regime, I argue, are exaggerated. A close, objective examination of the American regime shows this. I conclude that it is not the mythical bogeyman of a US class action that is the barrier to effective collective redress; rather, the barriers to effective, wide-ranging group actions lie within European legal culture and traditions, particularly those mandating individual control over litigation.
Models for Seismic Vulnerability Analysis of Power Networks: Comparative Assessment
Authors: Cavalieri Francesco , Franchin Paolo , Buriticá Cortés Jessica A. M. , Tesfamariam Solomon
Published: February 2014

Electric power networks are spatially distributed systems, subject to different magnitude and recurrence of earthquakes, that play a fundamental role in the well‐being and safety of communities. Therefore, identification of critical components is of paramount importance in retrofit prioritization. This article presents a comparison of five seismic performance assessment models (M1 to M5) of increasing complexity. The first two models (M1 and M2) approach the problem from a connectivity perspective, whereas the last three (M3 to M5) consider also power flow analysis. To illustrate the utility of the five models, the well‐known IEEE‐118 test case, assumed to be located in the central United States, is considered. Performances of the five models are compared using both system‐level and component‐level measures. Spearman rank correlation ρ is computed between results of each model. Highest ρ values, at both system‐ and component‐level, are obtained, as expected, between M1 and M2, and within models M3 to M5. The ρ values between component‐level measures are relatively high across all models, indicating that simpler ones (M1 and M2) are appropriate for vulnerability assessment and retrofit prioritization. The complex flow‐based models (M3 to M5) are suitable if actual performance of the systems is desired, as it is the case when the power network is considered within a larger set of interconnected infrastructural systems.
Data‐Based Model‐Free Hysteretic Restoring Force and Mass Identification for Dynamic Systems
Authors: Xu Bin , He Jia , Masri Sami F.
Published: February 2014

Most of the currently available vibration‐based damage detection approaches identify structural damage in the form of decrease in structural stiffness based on extracted eigenparameters and/or their derivates, and the basic hypothesis behind them is the system should be linear and the mass distribution of the system is usually known. Different from the stiffness degradation, the hysteretic restoring force of a dynamic system provides a more informative and direct description on the initiation and development of damage in structures under dynamic loadings and can be employed to quantitatively evaluate the energy dissipation during vibration. In this study, a data‐based model‐free hysteretic behavior identification approach with incomplete external excitations was proposed for the identification of structural hysteretic restoring force without the prior knowledge of structural mass distribution and the numerical model of the nonlinearity of the structure. The accuracy and feasibility of the approach for both structural mass and hysteretic behavior identification was illustrated: first, via numerical simulation with a lumped‐mass multi‐degree‐of‐freedom structure incorporating nonlinear magnetorheological (MR) dampers and a consistent mass plane truss structure incorporating a pseudo‐elastic shape memory alloy model to mimic the nonlinearity in dynamic systems. Second, a dynamic test on a four‐story frame structure equipped with MR dampers was carried out and the corresponding dynamic response was employed to validate the reliability of the proposed approach for both structural mass and hysteretic behavior identification. The results show that the proposed approach is capable of identifying different types of structural nonlinearity, which numerical model is unknown, with incomplete inputs and unknown mass distribution. The approach provides a promising way for damage detection and monitoring in the form of hysteretic behavior and energy dissipation for engineering structures under dynamic loadings, which should be dealt with as nonlinear systems.
In Defense of the Modal Account of the Progressive
Authors: MAYERHOFER IVAN
Published: February 2014

When we talk about creation, we use the progressive and verbs of creation as in ‘Mary is building a house’. The modal account of the progressive says that a sentence such as ‘Mary is building a house’ is true just in case Mary eventually builds a house in all worlds in which her house‐building proceeds normally. Recently, the modal account has come under fire from those who claim that it over‐generates modal entailments and those who think the progressive should be treated as a predicate of events. By properly situating the modal account within a contemporary semantic framework for natural language modals, I argue that it gives the best semantic treatment of the progressive.
Fortification of corn masa flour with folic acid in the United States: an overview of the evidence
Authors: Hamner Heather C. , Tinker Sarah C.
Published: February 2014

Corn masa flour, used to make products such as corn tortillas, is a staple food for Hispanic populations residing in the United States, particularly among Mexican Americans and Central Americans. Research has indicated that Hispanic women in the United States continue to be at a higher risk of having a neural tube defect–affected pregnancy than women of other races/ethnicities, even after the introduction of folic acid fortification of cereal grain products labeled as “enriched.” Corn masa flour has, therefore, been suggested as a potential food vehicle for folic acid in the United States. This paper explores the potential impact that folic acid fortification of corn masa flour could have on the Hispanic population in the United States.
Topoisomerase II and leukemia
Authors: Pendleton MaryJean , Lindsey R. Hunter , Felix Carolyn A. , Grimwade David , Osheroff Neil
Published: February 2014

Type II topoisomerases are essential enzymes that modulate DNA under‐ and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase II poisons) in clinical use. Topoisomerase II poisons kill cells by increasing levels of covalent enzyme‐cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use also is associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase II–active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type II topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential.
Itraconazole inhibits TNF‐α‐induced CXCL10 expression in oral fibroblasts
Authors: Ohta K , Ishida Y , Fukui A , Nishi H , Naruse T , Takechi M , Kamata N
Published: February 2014

Objective

Itraconazole (ICZ) has a broad spectrum of antifungal activity including a wide range of Candida spp. TNF‐α, an inflammatory cytokine associated with Th1‐mediated oral inflammatory disease, enhances inflammatory mediators, such as CXCR3‐agonistic chemokines including CXCL10. We examined the anti‐inflammatory potential of ICZ against TNF‐α‐induced chemokines in oral fibroblasts.

Materials and methods

We investigated the effects of ICZ on mRNA expressions of various TNF‐α‐induced chemokines in immortalized oral keratinocytes (RT7) and oral fibroblasts (GT1) using quantitative PCR analysis. Subsequently, the effects of ICZ and fluconazole (FLZ) on TNF‐α‐induced CXCL10 proteins in GT1 and primary fibroblasts were examined using enzyme‐linked immunosorbent assays (ELISA). The effect of ICZ on signal transduction protein phosphorylation involved in CXCL10 production from TNF‐α‐stimulated GT1 was examined by western blotting.

Results

ICZ inhibited TNF‐α‐induced CXCL10 mRNA in GT1, but not RT7. Although ICZ did not affect TNF‐α‐induced IL‐8 mRNA, the mRNAs of TNF‐α‐induced CXCR3‐agonistic chemokines such as CXCL9 and CXCL11 were inhibited by ICZ in GT1. TNF‐α‐induced CXCL10 protein production in GT1 and primary fibroblasts was inhibited by ICZ, but not FLZ. Finally, ICZ inhibited TNF‐α‐induced phosphorylation of c‐JUN, which is related to CXCL10 production by TNF‐α‐stimulated GT1.

Conclusion

ICZ may be useful as therapy for Th1‐mediated oral inflammatory disease.
Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines
Authors: Young Richard J. , Waldeck Kelly , Martin Claire , Foo Jung H. , Cameron Donald P. , Kirby Laura , Do Hongdo , Mitchell Catherine , Cullinane Carleen , Liu Wendy , Fox Stephen B. , Dutton‐Regester Ken , Hayward Nicholas K. , Jene Nicholas , Dobrovic Alexander , Pearson Richard B. , Christensen James G. , Randolph Sophia , McArthur Grant A. , Sheppard Karen E.
Published: February 2014

We have investigated the potential for the p16‐cyclin D‐CDK4/6‐retinoblastoma protein pathway to be exploited as a therapeutic target in melanoma. In a cohort of 143 patients with primary invasive melanoma, we used fluorescence in situ hybridization to detect gene copy number variations (CNVs) in CDK4, CCND1, and CDKN2A and immunohistochemistry to determine protein expression. CNVs were common in melanoma, with gain of CDK4 or CCND1 in 37 and 18% of cases, respectively, and hemizygous or homozygous loss of CDKN2A in 56%. Three‐quarters of all patients demonstrated a CNV in at least one of the three genes. The combination of CCND1 gain with either a gain of CDK4 and/or loss of CDKN2A was associated with poorer melanoma‐specific survival. In 47 melanoma cell lines homozygous loss, methylation or mutation of CDKN2A gene or loss of protein (p16INK4A) predicted sensitivity to the CDK4/6 inhibitor PD0332991, while RB1 loss predicted resistance.
Molecular data and ecological niche modelling reveal the phylogeographic pattern ofCotinus coggygria(Anacardiaceae) in China's warm‐temperate zone
Authors: Wang W. , Tian C. Y. , Li Y. H. , Li Y.
Published: February 2014

The phylogeography of common and widespread species helps to elucidate the history of local flora and vegetation. In this study, we selectedCotinus coggygria, a species widely distributed in China's warm‐temperate zone. One chloroplastDNA(cpDNA) region and ecological niche modelling were used to examine the phylogeographic pattern ofC. coggygria. The cpDNAdata revealed two phylogeographic groups (Southern and Northern) corresponding to the geographic regions. Divergence time analyses revealed that divergence of the two groups occurred at approximately 147,000 years before the present (BP), which coincided with the formation of the downstream area of the Yellow River, indicating that the Yellow River was a weak phylogeographic divide forC. coggygria. The molecular data and ecological niche modelling also indicated thatC. coggyriadid not experience population expansion after glaciations. This study thus supports the fact that Pleistocene glacial cycles only slightly affectedC. coggygria, which survivedin situand occupied multiple localised glacial refugia during glaciations. This finding is contrary to the hypothesis of large‐scale range habitat contraction and retreat into a few main refugia.
Managing Perishables with Time and Temperature History
Authors: Ketzenberg Michael , Bloemhof Jacqueline , Gaukler Gary
Published: February 2014

We address the use and value of time and temperature information to manage perishables in the context of a retailer that sells a random lifetime product subject to stochastic demand and lost sales. The product's lifetime is largely determined by the temperature history and the flow time through the supply chain. We compare the case in which information on flow time and temperature history is available and used for inventory management to a base case in which such information is not available. We formulate the two cases as Markov Decision Processes and evaluate the value of information through an extensive simulation using representative, real world supply chain parameters.
A Comparison of Product Take‐Back Compliance Schemes
Authors: Esenduran Gökçe , Kemahlıoğlu‐Ziya Eda
Published: February 2014

Product take‐back regulation, under which firms finance the collection and treatment of their end‐of‐life products, is a widely used environmental program. One of the most common compliance schemes is collectively with cost allocation by market share. As an alternative, individual compliance scheme is considered. Assuming that firms can choose their compliance scheme, we compare these two schemes with respect to the costs they impose on firms and environmental benefits. We show that high collection targets and large market shares among firms in a collective compliance scheme make it more cost‐effective. From an environmental benefits perspective, the prevailing intuition is that collection rates will be higher under collective schemes but individual compliance will provide more incentive for higher recyclability levels. Our results challenge both of these premises. We identify conditions under which collection rates are higher when firms comply individually and recyclability levels are higher when firms comply collectively and allocate costs with respect to market shares.
Does a Store Brand Always Hurt the Manufacturer of a Competing National Brand?
Authors: Ru Jun , Shi Ruixia , Zhang Jun
Published: February 2014

It is generally believed that store brands hurt the manufacturers of competing national brands while benefiting retailers. In this study, we challenge this notion by studying the impacts of a store brand when it is introduced by a power retailer. We show that a store brand may benefit the manufacturer when the interaction between the manufacturer and retailer is modeled as a retailer‐led Stackelberg game. This phenomenon occurs because the store brand changes the nature of the strategic interaction between the manufacturer and retailer in our model. In particular, while the interaction is always vertical strategic substitutability without a store brand, it may become vertical strategic independence with one. With the store brand, the demand for the national brand becomes larger, and the wholesale price for the national brand may increase, both of which benefit the manufacturer. Finally, the store brand may lessen the double marginalization problem of the supply chain for the national brand in the retailer‐led Stackelberg game, but does so in an unconventional way: The reduction in the double marginalization effect may come from a lowered retail markup instead of a lowered wholesale price. Our results reconcile some discrepancies between theoretical predictions and empirical findings regarding the impacts of store brands on manufacturers.
Dynamic Pricing and Inventory Management with Dual Suppliers of Different Lead Times and Disruption Risks
Authors: Gong Xiting , Chao Xiuli , Zheng Shaohui
Published: February 2014

It is common for a firm to make use of multiple suppliers of different delivery lead times, reliabilities, and costs. In this study, we are concerned with the joint pricing and inventory control problem for such a firm that has a quick‐response supplier and a regular supplier that both suffer random disruptions, and faces price‐sensitive random demands. We aim at characterizing the optimal ordering and pricing policies in each period over a planning horizon, and analyzing the impacts of supply source diversification. We show that, when both suppliers are unreliable, the optimal inventory policy in each period is a reorder point policy and the optimal price is decreasing in the starting inventory level in that period. In addition, we show that having supply source diversification or higher supplier reliability increases the firm's optimal profit and lowers the optimal selling price. We also demonstrate that, with the selling price as a decision, a supplier may receive even more orders from the firm after an additional supplier is introduced. For the special case where the quick‐response supplier is perfectly reliable, we further show that the optimal inventory policy is of a base‐stock type and the optimal pricing policy is a list‐price policy with markdowns.
Systems biology approaches to understand the role of auxin in root growth and development
Authors: Goh Tatsuaki , Voβ Ute , Farcot Etienne , Bennett Malcolm J. , Bishopp Anthony
Published: February 2014

The past decade has seen major advances in our understanding of auxin regulated root growth and developmental processes. Key genes have been identified that regulate and/or mediate auxin homeostasis, transport, perception and response. The molecular and biochemical reactions that underpin auxin signalling are non‐linear, with feed‐forward and feedback loops contributing to the robustness of the system. As our knowledge of auxin biology becomes increasingly complex and their outputs less intuitive, modelling is set to become much more important. For the last several decades modelling efforts have focused on auxin transport and, latterly, on auxin response. Recently researchers have employed multi‐scale modelling approaches to predict emergent properties at the tissue and organ scales. Such innovative modelling approaches are proving very promising, revealing new mechanistic insights about how auxin functions within a multicellular context to control plant growth and development. In this review we initially describe examples of models capturing auxin transport and response pathways, and then discuss increasingly complex models that integrate multiple hormone response pathways, tissues and/or scales.
Electroejaculation Increases Low Molecular Weight Proteins in Seminal Plasma Modifying Sperm Quality inCorriedaleRams
Authors: Ledesma A , Manes J , Cesari A , Alberio R , Hozbor F
Published: February 2014

Contents

This study was conducted to evaluate the effect of seminal collection method (artificial vagina or electroejaculation) on the protein composition of seminal plasma and sperm quality parameters inCorriedalerams. To address this question, we assessed the effect of seminal collection method on motility, plasma membrane integrity and functionality, mitochondrial functionality and the decondensation state of nuclear chromatin in sperm cells. Volume,pH, osmolarity, protein concentration, total protein content and protein profile using sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS‐PAGE) and 2‐D polyacrylamide electrophoresis of seminal plasma collected with artificial vagina and electroejaculation were also analysed. The main findings from this study were that ejaculates obtained with electroejaculation had (i) a higher number of spermatozoa with intact plasma membrane and functional mitochondria and (ii) a higher proportion of seminal plasma, total protein content and relative abundance of low molecular weight proteins than ejaculates obtained with artificial vagina. Five of these proteins were identified by mass spectrometry: binder of sperm 5 precursor;RSVP14;RSVP22; epididymal secretory protein E1 and clusterin. One protein spot with molecular weight of approximately 31 kDa and isoelectric point of 4.8 was only found in the seminal plasma from electroejaculation.
Multitype Point Process Analysis of Spines on the Dendrite Network of a Neuron
Authors: Baddeley Adrian , Jammalamadaka Aruna , Nair Gopalan
Published: February 2014

We develop methods for analysing the spatial pattern of events, classified into several types, that occur on a network of lines. The motivation is the study of small protrusions called ‘spines’ which occur on the dendrite network of a neuron. The spatially varying density of spines is modelled by using relative distributions and regression trees. Spatial correlations are investigated by using counterparts of the K-function and pair correlation function, where the main problem is to compensate for the network geometry. This application illustrates the need for careful analysis of spatial variation in the intensity of points, before assessing any evidence of clustering.
Estimation of the Intensity Parameter of the Germ‐Grain Quermass‐Interaction Model when the Number of Germs is not Observed
Authors: Dereudre David , Lavancier Frédéric , Helisová Kateřina Staňková
Published: February 2014

The Quermass‐interaction model allows to generalize the classical germ‐grain Boolean model in adding a morphological interaction between the grains. It enables to model random structures with specific morphologies, which are unlikely to be generated from a Boolean model. The Quermass‐interaction model depends in particular on an intensity parameter, which is impossible to estimate from classical likelihood or pseudo‐likelihood approaches because the number of points is not observable from a germ‐grain set. In this paper, we present a procedure based on the Takacs–Fiksel method, which is able to estimate all parameters of the Quermass‐interaction model, including the intensity. An intensive simulation study is conducted to assess the efficiency of the procedure and to provide practical recommendations. It also illustrates that the estimation of the intensity parameter is crucial in order to identify the model. The Quermass‐interaction model is finally fitted by our method to P. Diggle's heather data set.
Basic Psychological Needs, Suicidal Ideation, and Risk for Suicidal Behavior in Young Adults
Authors: Britton Peter C. , Van Orden Kimberly A. , Hirsch Jameson K. , Williams Geoffrey C.
Published: February 2014

Associations between the satisfaction of basic psychological needs of autonomy, competence, and relatedness with current suicidal ideation and risk for suicidal behavior were examined. Two logistic regressions were conducted with a cross‐sectional database of 440 university students to examine the association of need satisfaction with suicidal ideation and risk for suicidal behavior, while controlling for demographics and depressive symptoms. Suicidal ideation was reported by 15% of participants and 18% were found to be at risk for suicidal behavior. A one standard deviation increase in need satisfaction reduced the odds of suicidal ideation by 53%,OR(95%CI) = 0.47 (0.33–0.67), and the odds of being at risk for suicidal behavior by 50%,OR(95%CI) = 0.50 (0.37–0.69). Young adults whose basic psychological needs are met may be less likely to consider suicide and engage in suicidal behavior. Prospective research is needed to confirm these associations.
Suicidal Ideation and Behavior in Adolescents Aged 12–16 Years: A 17‐Year Follow‐Up
Authors: Joffe Benjamin I. , Van Lieshout Ryan J. , Duncan Laura , Boyle Michael H.
Published: February 2014

The prevalence of suicidal ideation/behavior in 1983 or 1987 and its association with future mental health in 2001 were evaluated in a provincially representative sample of Canadian adolescents (n = 1,248) aged 12 to 16 years. Approximately 13.3% (95% CI = 11.5–15.3) of adolescents self‐reported suicidal ideation/behavior. Adolescent agreement with parent (κ = .07) and teacher (κ = .05) reports at baseline was low because adults identified so few subjects. In adulthood, the associations between adolescent self‐reports of suicidal behavior/ideation and major depression and other mental health indicators were explained by respondent sex and adolescent emotional problems reported in 1983/1987. Adolescents with suicidal behavior/ideation often are not recognized by their parents and teachers and may be at risk for persistent psychiatric problems attributable to coexisting mental health problems early‐on.
Temperament, Hopelessness, and Attempted Suicide: Direct and Indirect Effects
Authors: Rosellini Anthony J. , Bagge Courtney L.
Published: February 2014

This study evaluated whether hopelessness mediated the relations between temperament and recent suicide attempter status in a psychiatric sample. Negative temperament and positive temperament (particularly the positive emotionality subscale) uniquely predicted levels of hopelessness. Although these temperament constructs also demonstrated significant indirect effects on recent suicide attempter status, the effects were partially (for the broad temperament scales) or fully (for the positive emotionality subscale) mediated by the levels of hopelessness. These findings indicate that a tendency to experience excessive negative emotions as well as a paucity of positive emotions may lead individuals to experience hopelessness. Although temperament may also indirectly influence suicide attempter status, hopelessness mediates these relations.
Antisense gene inhibition by phosphorothioate antisense oligonucleotide in Arabidopsis pollen tubes
Authors: Mizuta Yoko , Higashiyama Tetsuya
Published: February 2014

Sexual reproduction is an essential biological event for proliferation of plants. The pollen tube (PT) that contained male gametes elongates and penetrates into the pistils for successful fertilization. However, the molecular mechanisms of plant fertilization remain largely unknown. Here, we report a transient inhibition of gene function using phosphorothioate antisense oligodeoxynucleotides (AS‐ODNs) without cytofectin, which is a simple way to study gene function in Arabidopsis thaliana PTs. The PTs treated with AS‐ODNs against both ANX1 and ANX2 showed short, knotted, and ruptured morphology in vitro/semi‐in vitro, whereas normal PT growth was shown in its sense control in vitro/semi‐in vitro. PT growth was impaired in a manner dependent on the dose of AS‐ODNs against both ANX1 and ANX2 above 10 μm. The treatment with AS‐ODNs against ROP1 and CalS5 resulted in waving PTs and in short PTs with a few callose plugs, respectively. The expression levels of the target genes in PTs treated with their AS‐ODNs were lower than or similar to those in the sense control, indicating that the inhibition was directly or indirectly related to the expression of each mRNA. The AS‐ODN against fluorescent protein (sGFP) led to reduced sGFP expression, suggesting that the AS‐ODN suppressed protein expression. This method will enable the identification of reproductively important genes in Arabidopsis PTs.
Escherichia coli Exposure Inhibits Exocytic SNARE‐Mediated Membrane Fusion in Mast Cells
Authors: Wesolowski Jordan , Paumet Fabienne
Published: February 2014

Mast cells orchestrate the allergic response through the release of proinflammatory mediators, which is driven by the fusion of cytoplasmic secretory granules with the plasma membrane. During this process, SNARE proteins including Syntaxin4, SNAP23 and VAMP8 play a key role. Following stimulation, the kinase IKKβ interacts with and phosphorylates the t‐SNARE SNAP23. Phosphorylated SNAP23 then associates with Syntaxin4 and the v‐SNARE VAMP8 to form a ternary SNARE complex, which drives membrane fusion and mediator release. Interestingly, mast cell degranulation is impaired following exposure to bacteria such as Escherichia coli. However, the molecular mechanism(s) by which this occurs is unknown. Here, we show that E. coli exposure rapidly and additively inhibits degranulation in the RBL‐2H3 rat mast cell line. Following co‐culture with E. coli, the interaction between IKKβ and SNAP23 is disrupted, resulting in the hypophosphorylation of SNAP23. Subsequent formation of the ternary SNARE complex between SNAP23, Syntaxin4 and VAMP8 is strongly reduced. Collectively, these results demonstrate that E. coli exposure inhibits the formation of VAMP8‐containing exocytic SNARE complexes and thus the release of VAMP8‐dependent granules by interfering with SNAP23 phosphorylation.
GABAergic and glycinergic inputs modulate rhythmogenic mechanisms in the lamprey respiratory network
Authors: Cinelli Elenia , Mutolo Donatella , Robertson Brita , Grillner Sten , Contini Massimo , Pantaleo Tito , Bongianni Fulvia
Published: February 2014

Key points

In this study we investigated the role of GABA and glycine receptors within the respiratory central pattern generator, i.e. the paratrigeminal respiratory group (pTRG), and the vagal motoneuron region of the lamprey.

Only GABA‐mediated inhibition modulates the pTRG both during apnoea induced by blockade of glutamatergic transmission and under basal conditions.

Both GABA‐ and glycine‐mediated inhibition within the vagal region are involved in the regulation of respiratory frequency via ascending excitatory projections to the pTRG.

Projecting neurons are retrogradely labelled from the pTRG, and intense GABA immunoreactivity is present within the pTRG and the vagal motoneuron region.

Inhibitory mechanisms, which appear to be evolutionarily conserved, regulate network excitability and may provide an important contribution to rhythmic activities, such as respiration and locomotion.

We have previously shown that GABA and glycine modulate respiratory activity in the in vitro brainstem preparations of the lamprey and that blockade of GABAA and glycine receptors restores the respiratory rhythm during apnoea caused by blockade of ionotropic glutamate receptors. However, the neural substrates involved in these effects are unknown. To address this issue, the role of GABAA, GABAB and glycine receptors within the paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator, and the vagal motoneuron region was investigated both during apnoea induced by blockade of glutamatergic transmission and under basal conditions through microinjections of specific antagonists. The removal of GABAergic, but not glycinergic transmission within the pTRG, causes the resumption of rhythmic respiratory activity during apnoea, and reveals the presence of a modulatory control of the pTRG under basal conditions. A blockade of GABAA and glycine receptors within the vagal region strongly increases the respiratory frequency through disinhibition of neurons projecting to the pTRG from the vagal region. These neurons were retrogradely labelled (neurobiotin) from the pTRG. Intense GABA immunoreactivity is observed both within the pTRG and the vagal area, which corroborates present findings. The results confirm the pTRG as a primary site of respiratory rhythm generation, and suggest that inhibition modulates the activity of rhythm‐generating neurons, without any direct role in burst formation and termination mechanisms.
Asymmetric resistive switching characteristics of In2O3:SiO2 cosputtered thin film memories
Authors: Hsieh Wei-Kang , Lam Kin-Tak , Chang Shoou-Jinn
Published: February 2014

The authors report the fabrication and characterization of resistance switching for a resistance random access memory with a Ti/In2O3:SiO2/Pt structure. It was found that the device exhibited bipolar resistance switching behavior over one hundred switching cycles and showed stable retention characteristics for over 104 s under 100 mV stress condition. The asymmetric phenomenon of the carrier conduction mechanism at high resistance state was also explored by fitting the current–voltage (I–V) curves and explained by the schematic energy band diagram. It was also found that the switching behavior is due to the migration of oxygen ions and the formation of SiO2 with higher quality at the interface of top electrode and insulator.
Effects of Submaximal Eccentric Exercise on Muscle Activity at Different Elbow Joint Angles
Authors: Kisiel-Sajewicz Katarzyna , Jaskólska Anna , Janecki Damian , Andrzejewska Renata , Marusiak Jarosław , Jaskólski Artur
Published: February 2014

Our study aimed to determine whether electrical and mechanical factors contributing to acute or long-term maximal torque reduction and muscle soreness due to submaximal eccentric exercise (ECC) are elbow-joint-angle specific and to what extent the joint angle affects the contribution of antagonist coactivation to this torque reduction. Maximal isometric torque (MIT), muscle soreness assessment, agonist electromechanical activities, and antagonist coactivation during the maximal voluntary contraction (MVC) were measured at elbow joint angles of 60°, 90°, and 150° before ECC, immediately after exercise, and 24, 48, 72, and 120 hr after exercise. ECC causes an immediate decrease in MIT as well as increased antagonist coactivation at three angles. Antagonist coactivation returned to its baseline level at 24 hr regardless of joint angle. The most rapid torque recovery and the highest force level at which pain occurred were found after ECC at a joint angle of 60°. During the recovery period, no mechanomyographical changes were observed when measuring surface mechanomyography changes at three angles, while the electrical activity differed between angles.
Dual Task Performance of the Stroop Color-Word Test and Stepping in Place
Authors: Ikeda Yoshifumi , Okuzumi Hideyuki , Kokubun Mitsuru
Published: February 2014

This study investigated whether cognitive processing is influenced by stepping in place, particularly according to its frequency. Fourteen healthy young participants performed the Stroop test during stepping in place at various frequencies. Results showed the following: (a) performances on the Stroop test and at stepping in place at 1, 2, and 3 Hz were not so mutually influential, (b) performing the Stroop test degraded the timing of stepping in place at 4 Hz, (c) stepping at 0.5 Hz interfered with the cognitive processing involved with perceiving and naming colors but not with inhibitory control. These results imply that stepping in place is differentially controlled between walking at 1–4 Hz and at 0.5 Hz, the latter of which demands more attention.
Force Control in Manipulation Tasks: Comparison of Two Common Methods of Grip Force Calculation
Authors: Uygur Mehmet , Prebeg Goran , Jaric Slobodan
Published: February 2014

We compared two standard methods routinely used to assess the grip force (GF; perpendicular force that hand exerts upon the hand-held object) in the studies of coordination of GF and load force (LF; tangential force) in manipulation tasks. A variety of static tasks were tested, and GF-LF coupling (i.e., the maximum cross-correlation between the forces) was assessed. GF was calculated either as the minimum value of the two opposing GF components acting upon the hand-held object (GFmin) or as their average value (GFavg). Although both methods revealed high GF-LF correlation coefficients, most of the data revealed the higher values for GFavg than for GFmin. Therefore, we conclude that the CNS is more likely to take into account GFavg than GFmin when controlling static manipulative actions as well as that GFavg should be the variable of choice in kinetic analyses of static manipulation tasks.
Noncanonical NF-κB Signaling Is Limited by Classical NF-κB Activity
Authors: Gray Carolyn M. , Remouchamps Caroline , McCorkell Kelly A. , Solt Laura A. , Dejardin Emmanuel , Orange Jordan S. , May Michael J.
Published: February 2014

Disrupting crosstalk between classical and noncanonical NF-κB signaling pathways may contribute to symptoms of immunodeficiency.
Science Signaling
Podcast: 4 February 2014
Authors: Iyengar Ravi , He John Cijiang , VanHook Annalisa M.
Published: February 2014

Proteomic analysis and computational methods identify potential targets for reversing kidney damage.
Big MACs
Authors: Ash Caroline
Published: February 2014

Benthic marine larval development is triggered by a bacterially expressed structure of phage origin.
Building a Heart with Cyclin
Authors: Berndt Jason D.
Published: February 2014

Cyclin and cyclin-dependent kinase activity play independent roles in the stimulation of the transcription factor GATA4.
Dronedarone, an Amiodarone Analog with Improved Anti-Leishmania mexicana Efficacy
Authors: Benaim Gustavo , Casanova Paola , Hernandez-Rodriguez Vanessa , Mujica-Gonzalez Sheira , Parra-Gimenez Nereida , Plaza-Rojas Lourdes , Concepcion Juan Luis , Liu Yi-Liang , Oldfield Eric , Paniz-Mondolfi Alberto , Suarez Alirica I.
Published: February 2014

Dronedarone and amiodarone are cationic lipophilic benzofurans used to treat cardiac arrhythmias. They also have activity against the parasitic protozoan
Trypanosoma cruzi
, the causative agent of Chagas' disease. They function by disrupting intracellular Ca
2+
homeostasis of the parasite and by inhibiting membrane sterol (ergosterol) biosynthesis. Amiodarone also has activity against
Leishmania mexicana
, suggesting that dronedarone might likewise be active against this organism. This might be of therapeutic interest, since dronedarone is thought to have fewer side effects in humans than does amiodarone. We show here that dronedarone effectively inhibits the growth of
L. mexicana
promastigotes in culture and, more importantly, has excellent activity against amastigotes inside infected macrophages (the clinically relevant form) without affecting the host cell, with the 50% inhibitory concentrations against amastigotes being 3 orders of magnitude lower than those obtained previously with
T. cruzi
amastigotes (0.65 nM versus 0.75 μM). As with amiodarone, dronedarone affects intracellular Ca
2+
homeostasis in the parasite, inducing an elevation of intracellular Ca
2+
levels. This is achieved by rapidly collapsing the mitochondrial membrane potential and inducing an alkalinization of acidocalcisomes at a rate that is faster than that observed with amiodarone. We also show that dronedarone inhibits parasite oxidosqualene cyclase, a key enzyme in ergosterol biosynthesis known to be vital for survival. Overall, our results suggest the possibility of repurposing dronedarone as a treatment for cutaneous, and perhaps other, leishmaniases.
Fungicidal Mechanisms of Cathelicidins LL-37 and CATH-2 Revealed by Live-Cell Imaging
Authors: Ordonez Soledad R. , Amarullah Ilham H. , Wubbolts Richard W. , Veldhuizen Edwin J. A. , Haagsman Henk P.
Published: February 2014

Antifungal mechanisms of action of two cathelicidins, chicken CATH-2 and human LL-37, were studied and compared with the mode of action of the salivary peptide histatin 5 (Hst5).
Candida albicans
was used as a model organism for fungal pathogens. Analysis by live-cell imaging showed that the peptides kill
C. albicans
rapidly. CATH-2 is the most active peptide and kills
C. albicans
within 5 min. Both cathelicidins induce cell membrane permeabilization and simultaneous vacuolar expansion. Minimal fungicidal concentrations (MFC) are in the same order of magnitude for all three peptides, but the mechanisms of antifungal activity are very different. The activity of cathelicidins is independent of the energy status of the fungal cell, unlike Hst5 activity. Live-cell imaging using fluorescently labeled peptides showed that both CATH-2 and LL-37 quickly localize to the
C. albicans
cell membrane, while Hst5 was mainly directed to the fungal vacuole. Small amounts of cathelicidins internalize at sub-MFCs, suggesting that intracellular activities of the peptide could contribute to the antifungal activity. Analysis by flow cytometry indicated that CATH-2 significantly decreases
C. albicans
cell size. Finally, electron microscopy showed that CATH-2 affects the integrity of the cell membrane and nuclear envelope. It is concluded that the general mechanisms of action of both cathelicidins are partially similar (but very different from that of Hst5). CATH-2 has unique features and possesses antifungal potential superior to that of LL-37.
Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients
Authors: Valade Elodie , Tréluyer Jean-Marc , Bouazza Naïm , Ghosn Jade , Foissac Frantz , Benaboud Sihem , Fauchet Floris , Viard Jean-Paul , Urien Saïk , Hirt Déborah
Published: February 2014

The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CL
CR
), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC
0-24
) was 12.5 mg · h/liter for patients with normal renal function (CL
CR
, >80 ml/min), 14.7 mg · h/liter for patients with mild renal impairment (CL
CR
, 79 to 50 ml/min), and 17.9 mg · h/liter for patients with moderate renal impairment (CL
CR
, 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC
0-48
, 17.2 mg · h/liter) than for patients with normal renal function (median AUC
0-48
, 25.6 mg · h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function.
Impact of Renal Function on the Pharmacokinetics and Safety of Ceftolozane-Tazobactam
Authors: Wooley Myra , Miller Benjamin , Krishna Gopal , Hershberger Ellie , Chandorkar Gurudatt
Published: February 2014

Ceftolozane-tazobactam is a novel antipseudomonal cephalosporin with a β-lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, open-label studies, a single dose of ceftolozane-tazobactam was administered as a 1-h intravenous infusion to 24 subjects with normal, mild, or moderate renal impairment (1,000/500 mg) and six subjects with severe renal impairment (500/250 mg). Six subjects with end-stage renal disease (ESRD) received two doses of ceftolozane-tazobactam (500/250 mg each), pre- and posthemodialysis (post-HD). PK parameters were determined by noncompartmental methods. Plasma exposure to ceftolozane-tazobactam increased as renal function declined with only slightly increased exposures in subjects with mild renal impairment; the median area under the concentration-time curve from time zero to infinity (AUC
0-∞
) for ceftolozane and tazobactam increased 1.4- and 1.2-fold, respectively. In subjects with moderate renal impairment, the AUC
0-∞
increased 2.5- and 2.2-fold for ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC
0-∞
for ceftolozane and tazobactam increased 4.4- and 3.8-fold, respectively. In ESRD subjects, ceftolozane and tazobactam concentrations declined rapidly following the start of HD, with approximately 66 and 56% reductions in overall exposure based on the AUC
0-∞
before and after dialysis. Slight increases in exposure with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on HD require a decrease in the dose, a change in the frequency of administration, or both to achieve exposures within the established safety and efficacy margins of ceftolozane-tazobactam. Ceftolozane-tazobactam was well tolerated by all renal impairment groups.
Isavuconazole Therapy Protects Immunosuppressed Mice from Mucormycosis
Authors: Luo Guanpingsheng , Gebremariam Teclegiorgis , Lee Hongkyu , Edwards John E. , Kovanda Laura , Ibrahim Ashraf S.
Published: February 2014

We studied the
in vitro
and
in vivo
efficacies of the investigational drug isavuconazole against mucormycosis due to
Rhizopus delemar
. Isavuconazole was effective, with MIC and minimal fungicidal concentration (MFC) values ranging between 0.125 and 1.00 μg/ml. A high dose of isavuconazole prolonged the survival time and lowered the tissue fungal burden of cyclophosphamide/cortisone acetate-treated mice infected with
R. delemar
and was as effective as a high-dose liposomal amphotericin B treatment. These results support the further development of this azole against mucormycosis.
CYP2B6
18492T→C Polymorphism Compromises Efavirenz Concentration in Coinfected HIV and Tuberculosis Patients Carrying
CYP2B6
Haplotype *1/*1
Authors: Manosuthi Weerawat , Sukasem Chonlaphat , Thongyen Supeda , Nilkamhang Samruay , Manosuthi Sukanya , Sungkanuparph Somnuek
Published: February 2014

Data regarding the effect of the
CYP2B6
18492T→C polymorphism on plasma efavirenz concentrations and 96-week virologic responses in patients coinfected with HIV and tuberculosis (TB) are still unavailable. A total of 139 antiretroviral-naive HIV-infected adults with active TB were prospectively enrolled to receive efavirenz 600 mg-tenofovir 300 mg-lamivudine 300 mg. Eight single nucleotide polymorphisms (SNPs) within
CYP2B6
were genotyped. Seven SNPs, including 64C→T, 499C→G, 516G→T, 785A→G, 1375A→G, 1459C→T, and 21563C→T, were included for
CYP2B6
haplotype determination. The
CYP2B6
18492T→C polymorphism was studied in 48 patients who carried haplotype *1/*1. At 12 and 24 weeks after antiretroviral therapy, plasma efavirenz concentrations at 12 h after dosing were measured. Plasma HIV RNA was monitored every 12 weeks for 96 weeks. Of 48 patients {body weight [mean ± standard deviation (SD)], 56 ± 10 kg}, 77% received a rifampin-containing anti-TB regimen. No drug resistance-associated mutation was detected at baseline. The frequencies of the wild type (18492TT) and the heterozygous (18492TC) and homozygous (18492CC) mutants of the
CYP2B6
18492T→C polymorphism were 39%, 42%, and 19%, respectively. At 12 weeks, mean (±SD) efavirenz concentrations of patients who carried the 18492TT, 18492TC, and 18492CC mutants were 2.8 ± 1.6, 1.7 ± 0.9, and 1.4 ± 0.5 mg/liter, respectively (
P
= 0.005). At 24 weeks, the efavirenz concentrations of the corresponding groups were 2.4 ± 0.8, 1.7 ± 0.8, and 1.2 ± 0.4 mg/liter, respectively (
P
= 0.003). A low efavirenz concentration was independently associated with 18492T→C (β = −0.937,
P
= 0.004) and high body weight (β = −0.032,
P
= 0.046). At 96 weeks, 19%, 17%, and 28% of patients carrying the 18492TT, 18492TC, and 18492CC mutants, respectively, had plasma HIV RNA levels of >40 copies/ml and developed efavirenz-associated mutations (
P
= 0.254). In summary, the
CYP2B6
18492T→C polymorphism compromises efavirenz concentrations in patients who carry
CYP2B6
haplotype *1/*1 and are coinfected with HIV and tuberculosis.