bluuebunny/crossref_metadata_2025 huggingface dataset:
Using high‐dimensional propensity scores to automate confounding control in a distributed medical product safety surveillance system
Authors: Rassen Jeremy A. , Schneeweiss Sebastian
Published: January 2012

Distributed medical product safety monitoring systems such as the Sentinel System, to be developed as a part of Food and Drug Administration's Sentinel Initiative, will require automation of large parts of the safety evaluation process to achieve the necessary speed and scale at reasonable cost without sacrificing validity. Although certain functions will require investigator intervention, confounding control is one area that can largely be automated. The high‐dimensional propensity score (hd‐PS) algorithm is one option for automated confounding control in longitudinal healthcare databases. In this article, we discuss the use of hd‐PS for automating confounding control in sequential database cohort studies, as applied to safety monitoring systems. In particular, we discuss the robustness of the covariate selection process, the potential for over‐ or under‐selection of variables including the possibilities of M‐bias and Z‐bias, the computation requirements, the practical considerations in a federated database network, and the cases where automated confounding adjustment may not function optimally. We also outline recent improvements to the algorithm and show how the algorithm has performed in several published studies. We conclude that despite certain limitations, hd‐PS offers substantial advantages over non‐automated alternatives in active product safety monitoring systems. Copyright © 2012 John Wiley & Sons, Ltd.
A protocol for active surveillance of acute myocardial infarction in association with the use of a new antidiabetic pharmaceutical agent
Authors: Fireman Bruce , Toh Sengwee , Butler Melissa G. , Go Alan S. , Joffe Hylton V. , Graham David J. , Nelson Jennifer C. , Daniel Gregory W. , Selby Joe V.
Published: January 2012

Purpose

To describe a protocol for active surveillance of acute myocardial infarction (AMI) in users of a recently approved oral antidiabetic medication, saxagliptin, and to provide the rationale for decisions made in drafting the protocol.

Methods

A new‐user cohort design is planned for evaluating data from at least four Mini‐Sentinel data partners from 1 August 2009 (following US Food and Drug Administration's approval of saxagliptin) through mid‐2013. New users of saxagliptin will be compared in separate analyses with new users of sitagliptin, pioglitazone, long‐acting insulins, and second‐generation sulfonylureas. Two approaches to controlling for confounding will be evaluated: matching by exposure propensity score and stratification by AMI risk score. The primary analyses will use Cox regression models specified in a way that does not require pooling of patient‐level data from the data partners. The Cox models are fit to summarized data on risk sets composed of saxagliptin users and similar comparator users at the time of an AMI. Secondary analyses will use alternative methods including Poisson regression and will explore whether further adjustment for covariates available only at some data partners (e.g., blood pressure) modifies results.

Results

The results of this study are pending.

Conclusions

The proposed protocol describes a design for surveillance to evaluate the safety of a newly marketed agent as postmarket experience accrues. It uses data from multiple partner organizations without requiring sharing of patient‐level data and compares alternative approaches to controlling for confounding. It is hoped that this initial active surveillance project of the Mini‐Sentinel will provide insights that inform future population‐based surveillance of medical product safety. Copyright © 2012 John Wiley & Sons, Ltd.
A Study on the Triazole Crosslinked Polymeric Binder Based on Glycidyl Azide Polymer and Dipolarophile Curing Agents
Authors: Min Byoung Sun , Park Young Chul , Yoo Ji Chang
Published: January 2012

Instead of using urethane curing systems, which have long been used as solid propellants, a triazole curing system has been introduced into a new binder recipe in which azide groups in the polymer react with triple bonds of a dipolarophile curing agent. Commercially available glycidyl azide polymers (GAP) were used and an aliphatic curing agent, bispropargyl succinate (BPS), as well as an aromatic curing agent, 1,4‐bis(1‐hydroxypropargyl)benzene (BHPB), were synthesized as dipolarophile curing agent. Together with networks prepared under the triazole curing system, the networks under dual curing systems, which consist of an isocyanate curing agent and a dipolarophile curing agent, were prepared. Through swelling experiments, solubility parameters and crosslinking densities of the triazole crosslinked networks were determined by using Gee’s theory and Flory–Rhener theory. The mechanical properties of the triazole crosslinked networks were also investigated with different contents of the dipolarophile curing agent, along with the type of dipolarophile curing agent. The networks prepared under the triazole curing system did not show good mechanical properties. However, GAP‐based networks prepared under a dual curing system showed excellent mechanical properties with only a small amount of dipolarophile curing agent used. The effects of BPS and BHPB on the mechanical properties of the networks were much more distinguishable in networks prepared under a dual curing system rather than a single curing system.
Ballistic transport through a semiconducting magnetic nanocontact in the presence of Rashba and Dresselhaus spin–orbit interactions
Authors: Fallahi V. , Ghanaatshoar M.
Published: January 2012

We study the magnetoresistance (MR) of a one‐dimensional electron gas in a ferromagnetic semiconducting nanocontact containing an atomic‐size domain wall, and in the presence of the Rashba and the Dresselhaus spin–orbit interactions. The MR is calculated in the ballistic regime, within the Landauer–Büttiker formalism. It is shown that, the Dresselhaus spin–orbit interaction which is the result of bulk‐induced inversion asymmetry makes a reduction in the domain wall MR. In contrast, the Rashba coupling may lead to a negative or positive change in the domain wall MR, depending on the Fermi energy and the lateral confinement potentials which can be induced by both parabolic lateral confinement and lateral gate potentials.
Survey of advances in guidance, navigation, and control of unmanned rotorcraft systems
Authors: Kendoul Farid
Published: January 2012

Recently, there has been growing interest in developing unmanned aircraft systems (UAS) with advanced onboard autonomous capabilities. This paper describes the current state of the art in autonomous rotorcraft UAS (RUAS) and provides a detailed literature review of the last two decades of active research on RUAS. Three functional technology areas are identified as the core components of an autonomous RUAS. Guidance, navigation, and control (GNC) have received much attention from the research community, and have dominated the UAS literature from the nineties until now. This paper first presents the main research groups involved in the development of GNC systems for RUAS. Then it describes the development of a framework that provides standard definitions and metrics characterizing and measuring the autonomy level of a RUAS using GNC aspects. This framework is intended to facilitate the understanding and the organization of this survey paper, but it can also serve as a common reference for the UAS community. The main objective of this paper is to present a comprehensive survey of RUAS research that captures all seminal works and milestones in each GNC area, with a particular focus on practical methods and technologies that have been demonstrated in flight tests. These algorithms and systems have been classified into different categories and classes based on the autonomy level they provide and the algorithmic approach used. Finally, the paper discusses the RUAS literature in general and highlights challenges that need to be addressed in developing autonomous systems for unmanned rotorcraft. © 2012 Wiley Periodicals, Inc.
Microstructural evolution during oxidative ablation in air for polyacrylonitrile based carbon fibers with different graphite degrees
Authors: Li Zhaorui , Wang Jianbin , Tong Yuanjian , Xiao Shijie , Xu Lianghua
Published: January 2012

Polyacrylonitrile‐based carbon fibers with different graphite degrees were oxidative ablated at 500 and 600 °C in air. By Thermal gravimetric (TG), Raman spectroscopy, X‐ray diffraction, and SEM, the mass loss, microstructure, and surface morphology of carbon fibers were investigated. The mass loss of carbon fiber increases linearly with increasing oxidative ablated time under 500 and 600 °C. The carbon fiber with higher graphite degree shows higher oxidative resistance, and the surface roughness increases gradually because of chemical ablation during the whole oxidation. A gloss morphology appears on the surface primarily because of physical denudation for carbon fibers with lower graphite degree and then burn off according to carbon and oxygen reaction. The crystallite size (La) decreases significantly, while interlayer spacing(d002) remains nearly unchanged. SEM observation suggests the two kinds of ablation mechanisms for carbon fibers with different graphite degrees indicating that CC band in sp3 hybridization prefers to be attacked by oxygen molecule more than that in sp2 hybridization during oxidation ablation in air. Copyright © 2012 John Wiley & Sons, Ltd.
Development of reference materials for the investigation of local mechanical properties at the nanoscale
Authors: Campbell Anna Charvátová , Klapetek Petr , Valtr Miroslav , Buršíková Vilma
Published: January 2012

At present, local mechanical properties can be measured not only for macroscopic objects but also for nano‐objects and thin films with dimensions of only a few tens of nanometers. For these purposes, special indentation devices can be used. In past decades, many special data measurement and processing methods for thin film characterization have been developed. In addition, the method is no longer restricted to materials science but now also has a wide range of applications for biological problems in which the hardness/modulus values are quite different from those in materials science for which the method was originally designed. Data interpretation in the field of metrology is not so straightforward and care is required in dealing with quantitative results, especially if dealing with very soft samples. Therefore, it is necessary to use reference samples that would enable the comparison of different instruments and the validation of the applied methods. In this contribution, we present the results of our effort on preparing and testing thin film–based reference materials prepared using plasma technologies. We describe a deposition procedure that allows us to produce samples with a large range of hardness and modulus values. From these, we choose a very soft but stable sample that is then further tested to verify its suitability as a reference sample. The major issues discussed in this article are the repeatability of the deposition process, time stability, and homogeneity. Copyright © 2012 John Wiley & Sons, Ltd.
A Longitudinal Study of the Relationship between Work Engagement and Symptoms of Anxiety and Depression
Authors: Innstrand Siw Tone , Langballe Ellen Melbye , Falkum Erik
Published: January 2012

This longitudinal study examined the dynamic relationship between work engagement (vigour and dedication) and symptoms of anxiety and depression. A sample of 3475 respondents from eight different occupational groups (lawyers, physicians, nurses, teachers, church ministers, bus drivers, people working in advertising and people working in information technology) in Norway supplied data at two points in time with a 2‐year time interval. The advantages of longitudinal design were utilized, including testing of reversed causation and controlling for unmeasured third variables. In general, the results showed that the hypothesized normal causal relationship was superior to a reversed causation model. In other words, this study supported the assumption that work engagement is more likely to be the antecedent for symptoms of depression and anxiety than the outcome. In particular, the vigour facet of work engagement provides lower levels of depression and anxiety 2 years later. However, additional analyses modelling unmeasured third variables indicate that unknown third variables may have created some spurious effects on the pattern of the observed relationship. Implications of the findings are discussed in the paper. Copyright © 2011 John Wiley & Sons, Ltd.
Amaranth, millet and buckwheat flours affect the physical properties of extruded breakfast cereals and modulates their potential glycaemic impact
Authors: Brennan Margaret A. , Menard Carine , Roudaut Gaëlle , Brennan Charles S.
Published: January 2012

Three non‐traditional pseudo‐cereal flours (amaranth, buckwheat and millet) were used in the manufacture of extruded breakfast cereal products as a replacement for wheat and maize flour. The use of these flours altered the physical and nutritional quality of extruded breakfast cereals. Extruded products made using the flours exhibited an increased product and bulk density. However the extruded products were not significantly different compared to the control sample in terms of expansion ratio (excepting Amaranth at the 65% inclusion rate). All of the extruded products made with the inclusion of pseudo‐cereals showed a significant reduction in readily digestible carbohydrates and slowly digestible carbohydrates compared to the control product during predictive in vitro glycaemic profiling. The results illustrate the potential use of these non‐traditional cereal flours in lowering the glycaemic response to the ingestion of extruded breakfast cereals.
Cortical rotation and messenger RNA localization in Xenopus axis formation
Authors: Houston Douglas W.
Published: January 2012

In Xenopus eggs, fertilization initiates a rotational movement of the cortex relative to the cytoplasm, resulting in the transport of critical determinants to the future dorsal side of the embryo. Cortical rotation is mediated by microtubules, resulting in activation of the Wnt/β‐catenin signaling pathway and expression of organizer genes on the dorsal side of the blastula. Similar cytoplasmic localizations resulting in β‐catenin activation occur in many chordate embryos, suggesting a deeply conserved mechanism for patterning early embryos. This review summarizes the experimental evidence for the molecular basis of this model, focusing on recent maternal loss‐of‐function studies that shed light on two main unanswered questions: (1) what regulates microtubule assembly during cortical rotation and (2) how is Wnt/β‐catenin signaling activated dorsally? In addition, as these processes depend on vegetally localized molecules in the oocyte, the mechanisms of RNA localization and novel roles for localized RNAs in axis formation are discussed. The work reviewed here provides a beginning framework for understanding the coupling of asymmetry in oogenesis with the establishment of asymmetry in the embryo. WIREs Dev Biol 2012, 1:371–388. doi: 10.1002/wdev.29

This article is categorized under:

Establishment of Spatial and Temporal Patterns > Cytoplasmic Localization

Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms

Signaling Pathways > Cell Fate Signaling

Early Embryonic Development > Fertilization to Gastrulation
Child Mobility, Maternal Status, and Household Composition in Rural South Africa
Authors: Madhavan Sangeetha , Schatz Enid , Clark Samuel , Collinson Mark
Published: January 2012

This article examines the influence of maternal status, socioeconomic status of the household, and household composition on the mobility of children aged 0–14 in Mpumalanga Province, South Africa, from 1999 to 2008. Using data from the Agincourt Health and Demographic Surveillance System, we found that children whose mothers were temporary migrants, living elsewhere, or dead had higher odds of moving than children whose mothers were coresident. Older children and children living in richer households faced lower odds of mobility. For children whose mothers were coresident, there was no effect of maternal substitutes on child mobility. However, among children whose mothers were temporary migrants or living elsewhere, the presence of prime-aged and elderly females lowered the odds of mobility. For maternal orphans, the presence of elderly women in the household lowered their odds of mobility. The results underscore the importance of examining the conditions under which children move in order to strengthen service delivery targeted at safeguarding children’s well-being.
MONEY-GO-ROUND: PERSONAL ECONOMIES OF WEALTH, ASPIRATION AND INDEBTEDNESS
Authors: James Deborah
Published: January 2012

Considerable attempts to create a single economy of credit, in part through regularizing microlenders (especially the much-demonized loansharks or mashonisas), have been made by the South African government, notably through the National Credit Act. This article explores how borrowing and indebtedness are seen from the point of view of consumers and of those who aim to protect them. It suggests that we should speak of moneylending rather than moneylenders; that lending is often done by groups rather than by individuals (in a variant of the well-known stokvel); and that it may represent a response to so-called ‘formalization’ (Guyer 2004) of financial arrangements by those who have considerable experience of this, rather than being a bulwark against it. Based on research in Gauteng and Mpumalanga, the article critically explores prevalent stereotypes of the ‘overindebted consumer’ and the ‘black diamond’, seeking evidence both in support and in refutation of them. It discusses those factors which are conducive to and those which obstruct the achieving of the status of upwardly mobile – and simultaneously overindebted – person; demonstrates that aspiration and upward mobility, and the problems of credit or debt that accompany these, have much longer histories; and that these matters can give us insights into the contradictory character of the South African state. Its ‘neo-liberal’ dimension allows and encourages free engagement with the market and advocates the freedom to spend, even to become excessively acquisitive of material wealth. But it simultaneously attempts to regulate this in the interests of those unable to participate in this dream of conspicuous consumption. Informalization intensifies as all manner of means are devised to tap into state resources. Neo-liberal means are used to ensure the wide spread of redistribution.
Heartfelt Driving: Discourses on Manners, Safety, and Emotion in Japan's Era of Mass Motorization
Authors: Roth Joshua Hotaka
Published: January 2012

This paper explores the contradictory discourses on manners, safety and emotion that arose with mass motorization in Japan in the 1960s and which continue through the present. It documents the way in which multiple government entities end up working at cross-purposes in their attempts to cultivate safer drivers and slow the epidemic of traffic accidents. On the one hand, the discourse on driving manners suggests a widespread embrace of the Traffic Bureau's and other government agencies' concern with safety. On the other hand, the emphasis on manners may lead to angrier driving, which promotes accidents according to psychological studies of driving. The picture that emerges is one in which attempts at social control are complicated by the often unpredictable emotional reactions of subjects caught in a web of institutional and ideological processes. By exploring the relationship of emotion to driving school curricula and the discourse on manners, this article extends previous studies of self, social control, and social management in Japan.
IDENTIFYING THE BROWNIAN COVARIATION FROM THE CO-JUMPS GIVEN DISCRETE OBSERVATIONS
Authors: Mancini Cecilia , Gobbi Fabio
Published: January 2012

When the covariance between the risk factors of asset prices is due to both Brownian and jump components, the realized covariation (RC) approaches the sum of theintegrated covariation(IC) with the sum of the co-jumps, as the observation frequency increases to infinity, in a finite and fixed time horizon. In this paper the two components are consistently separately estimated within a semimartingale framework with possibly infinite activity jumps. The threshold (or truncated) estimator$I\hat C_n $is used, which substantially excludes from RC all terms containing jumps. Unlike in Jacod (2007, Universite de Paris-6) and Jacod (2008,Stochastic Processes and Their Applications118, 517–559), no assumptions on the volatilities’ dynamics are required. In the presence of only finite activity jumps: 1) central limit theorems (CLTs) for$I\hat C_n $and for further measures of dependence between the two Brownian parts are obtained; the estimation error asymptotic variance is shown to be smaller than for the alternative estimators of IC in the literature; 2) by also selecting the observations as in Hayashi and Yoshida (2005,Bernoulli11, 359–379), robustness to nonsynchronous data is obtained. The proposed estimators are shown to have good finite sample performances in Monte Carlo simulations even with an observation frequency low enough to make microstructure noises’ impact on data negligible.
A CONSISTENT NONPARAMETRIC TEST FOR CAUSALITY IN QUANTILE
Authors: Jeong Kiho , Härdle Wolfgang K. , Song Song
Published: January 2012

This paper proposes a nonparametric test of Granger causality in quantile. Zheng (1998, Econometric Theory 14, 123–138) studied the idea to reduce the problem of testing a quantile restriction to a problem of testing a particular type of mean restriction in independent data. We extend Zheng’s approach to the case of dependent data, particularly to the test of Granger causality in quantile. Combining the results of Zheng (1998) and Fan and Li (1999, Journal of Nonparametric Statistics 10, 245–271), we establish the asymptotic normal distribution of the test statistic under a β-mixing process. The test is consistent against all fixed alternatives and detects local alternatives approaching the null at proper rates. Simulations are carried out to illustrate the behavior of the test under the null and also the power of the test under plausible alternatives. An economic application considers the causal relations between the crude oil price, the USD/GBP exchange rate, and the gold price in the gold market.
Researching Parent Abuse: A Critical Review of the Methods
Authors: Holt Amanda
Published: January 2012

‘Parent abuse’ is the most under-researched form of family abuse and the research that exists is characterised by diverse and discrete methodological approaches which have produced somewhat inconsistent findings. This critical review examines these different research approaches and discusses the methodological challenges which they present. The review concludes by suggesting how research might develop to produce a more coherent and contextual methodology which does justice to the complexities of the topic.
Airborne lidar measurements of wave energy dissipation in a coral reef lagoon system
Authors: Huang Zhi‐Cheng , Reineman Benjamin D. , Lenain Luc , Melville W. Kendall , Middleton Jason H.
Published: January 2012

Quantification of the turbulent kinetic energy dissipation rate in the water column, ε, is very important for assessing nutrient uptake rates of corals and therefore the health of coral reef lagoon systems. However, the availability of such data is limited. Recently, at Lady Elliot Island (LEI), Australia, we showed that there was a strong correlation between in situ measurements of surface‐wave energy dissipation and ε. Previously, Reineman et al. (2009), we showed that a small airborne scanning lidar system could measure the surface wavefield remotely. Here we present measurements demonstrating the use of the same airborne lidar to remotely measure surface wave energy fluxes and dissipation and thereby estimate ε in the LEI reef‐lagoon system. The wave energy flux and wave dissipation rate across the fore reef and into the lagoon are determined from the airborne measurements of the wavefield. Using these techniques, observed spatial profiles of energy flux and wave energy dissipation rates over the LEI reef‐lagoon system are presented. The results show that the high lidar backscatter intensity and point density coming from the high reflectivity of the foam from depth‐limited breaking waves coincides with the high wave‐energy dissipation rates. Good correlations between the airborne measurements and in situ observations demonstrate that it is feasible to apply airborne lidar systems for large‐scale, long‐term studies in monitoring important physical processes in coral reef environments. When added to other airborne techniques, the opportunities for efficient monitoring of large reef systems may be expanded significantly.
Multimodality of a particle size distribution of cohesive suspended particulate matters in a coastal zone
Authors: Lee Byung Joon , Fettweis Michael , Toorman Erik , Molz Fred J.
Published: January 2012

Particle size distributions (PSDs) of suspended particulate matters in a coastal zone are lognormal and multimodal in general. The multimodal PSD, which is caused by the mixing of multiple particle and aggregate size groups under flocculation and erosion/resuspension, is a record of the particle and aggregate dynamics in a coastal zone. Curve‐fitting software was used to decompose the multimodal PSD into subordinate lognormal PSDs of primary particles, flocculi, microflocs, and macroflocs. The curve‐fitting analysis for a time series of multimodal PSDs in the Belgian coastal zone showed the dependency of the multimodality on (1) shear‐dependent flocculation in a flood and ebb tide, (2) breakage‐resistant flocculation in the spring season, and (3) silt‐sized particle erosion and advection in a storm surge. Also, for modeling and simulation purposes, the curve‐fitting analysis and the settling flux estimation for the multimodal PSDs showed the possibility of using discrete groups of primary particles, flocculi, microflocs, and macroflocs as an approximation of a continuous multimodal PSD.
Observations of ozone transport from the free troposphere to the Los Angeles basin
Authors: Neuman J. A. , Trainer M. , Aikin K. C. , Angevine W. M. , Brioude J. , Brown S. S. , de Gouw J. A. , Dube W. P. , Flynn J. H. , Graus M. , Holloway J. S. , Lefer B. L. , Nedelec P. , Nowak J. B. , Parrish D. D. , Pollack I. B. , Roberts J. M. , Ryerson T. B. , Smit H. , Thouret V. , Wagner N. L.
Published: January 2012

Analysis of in situ airborne measurements from the CalNex 2010 field experiment (Research at the Nexus of Air Quality and Climate Change) show that ozone in the boundary layer over Southern California was increased by downward mixing of air from the free troposphere (FT). The chemical composition, origin, and transport of air upwind and over Los Angeles, California, were studied using measurements of carbon monoxide (CO), ozone, reactive nitrogen species, and meteorological parameters from the National Oceanic and Atmospheric Administration WP‐3D aircraft on 18 research flights in California in May and June 2010. On six flights, multiple vertical profiles from 0.2–3.5 km above ground level were conducted throughout the Los Angeles (LA) basin and over the Pacific Ocean. Gas phase compounds measured in 32 vertical profiles are used to characterize air masses in the FT over the LA basin, with the aim of determining the source of increased ozone observed above the planetary boundary layer (PBL). Four primary air mass influences were observed regularly in the FT between approximately 1 and 3.5 km altitude: upper tropospheric air, long‐range transport of emissions, aged regional emissions, and marine air. The first three air mass types accounted for 89% of the FT observations. Ozone averaged 71 ppbv in air influenced by the upper troposphere, 69 ppbv in air containing emissions transported long distances, and 65 ppbv in air with aged regional emissions. Correlations between ozone and CO, and ozone and nitric acid, demonstrate entrainment of ozone from the FT into the LA PBL. Downward transport of ozone‐rich air from the FT into the PBL contributes to the ozone burden at the surface in this region and makes compliance with air quality standards challenging.
Honors
Authors: Anonymous
Published: January 2012

Donald Boesch, president of the University of Maryland Center for Environmental Science, received the Maryland‐Asia Environmental Partnership's 2011 Maryland Energy and Environmental Leadership Award on 7 December. The award recognized Boesch, an estuarine scientist, for providing state and national leadership on energy and environment issues. Russell Harmon has been appointed director of the International Research Office of the U.S. Army Corps of Engineers' Engineer Research and Development Center in London, United Kingdom. Russell had been program manager for terrestrial sciences at the Army Research Office in Durham, N. C.
Gulledge receives 2011 Charles S. Falkenberg Award: Response
Authors: Gulledge Jay
Published: January 2012

Jay Gulledge received the Charles S. Falkenberg Award at the 2011 AGU Fall Meeting Honors Ceremony, held on 7 December in San Francisco, Calif. The award honors a “scientist under 45 years of age who has contributed to the quality of life, economic opportunities, and stewardship of the planet through the use of Earth science information and to the pubic awareness of the importance of understanding our planet.”
Steenhuis receives 2011 International Award: Citation
Authors: van de Giesen Nick
Published: January 2012

Tammo Steenhuis received the International Award at the 2011 Fall Meeting Honors Ceremony, held on 7 December 2011 in San Francisco, Calif. The award honors “an individual scientist or a small team for making an outstanding contribution to furthering the Earth and space sciences and using science for the benefit of society in less favored nations.”
The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates
Authors: Zoetendal Erwin G , Raes Jeroen , van den Bogert Bartholomeus , Arumugam Manimozhiyan , Booijink Carien C G M , Troost Freddy J , Bork Peer , Wels Michiel , de Vos Willem M , Kleerebezem Michiel
Published: January 2012

The human gastrointestinal tract (GI tract) harbors a complex community of microbes. The microbiota composition varies between different locations in the GI tract, but most studies focus on the fecal microbiota, and that inhabiting the colonic mucosa. Consequently, little is known about the microbiota at other parts of the GI tract, which is especially true for the small intestine because of its limited accessibility. Here we deduce an ecological model of the microbiota composition and function in the small intestine, using complementing culture-independent approaches. Phylogenetic microarray analyses demonstrated that microbiota compositions that are typically found in effluent samples from ileostomists (subjects without a colon) can also be encountered in the small intestine of healthy individuals. Phylogenetic mapping of small intestinal metagenome of three different ileostomy effluent samples from a single individual indicated that Streptococcus sp., Escherichia coli, Clostridium sp. and high G+C organisms are most abundant in the small intestine. The compositions of these populations fluctuated in time and correlated to the short-chain fatty acids profiles that were determined in parallel. Comparative functional analysis with fecal metagenomes identified functions that are overrepresented in the small intestine, including simple carbohydrate transport phosphotransferase systems (PTS), central metabolism and biotin production. Moreover, metatranscriptome analysis supported high level in-situ expression of PTS and carbohydrate metabolic genes, especially those belonging to Streptococcus sp. Overall, our findings suggest that rapid uptake and fermentation of available carbohydrates contribute to maintaining the microbiota in the human small intestine.
The Golgi-associated long coiled-coil protein NECC1 participates in the control of the regulated secretory pathway in PC12 cells
Authors: Cruz-García David , Díaz-Ruiz Alberto , Rabanal-Ruiz Yoana , Peinado Juan R. , Gracia-Navarro Francisco , Castaño Justo P. , Montero-Hadjadje Maité , Tonon Marie-Christine , Vaudry Hubert , Anouar Youssef , Vázquez-Martínez Rafael , Malagón María M.
Published: January 2012

Golgi-associated long coiled-coil proteins, often referred to as golgins, are involved in the maintenance of the structural organization of the Golgi apparatus and the regulation of membrane traffic events occurring in this organelle. Little information is available on the contribution of golgins to Golgi function in cells specialized in secretion such as endocrine cells or neurons. In the present study, we characterize the intracellular distribution as well as the biochemical and functional properties of a novel long coiled-coil protein present in neuroendocrine tissues, NECC1 (neuroendocrine long coiled-coil protein 1). The present study shows that NECC1 is a peripheral membrane protein displaying high stability to detergent extraction, which distributes across the Golgi apparatus in neuroendocrine cells. In addition, NECC1 partially localizes to post-Golgi carriers containing secretory cargo in PC12 cells. Overexpression of NECC1 resulted in the formation of juxtanuclear aggregates together with a slight fragmentation of the Golgi and a decrease in K+-stimulated hormone release. In contrast, NECC1 silencing did not alter Golgi architecture, but enhanced K+-stimulated hormone secretion in PC12 cells. In all, the results of the present study identify NECC1 as a novel component of the Golgi matrix and support a role for this protein as a negative modulator of the regulated trafficking of secretory cargo in neuroendocrine cells.
n−3 polyunsaturated fatty acids suppress phosphatidylinositol 4,5-bisphosphate-dependent actin remodelling during CD4+ T-cell activation
Authors: Hou Tim Y. , Monk Jennifer M. , Fan Yang-Yi , Barhoumi Rola , Chen Yong Q. , Rivera Gonzalo M. , McMurray David N. , Chapkin Robert S.
Published: January 2012

n−3 PUFA (polyunsaturated fatty acids), i.e. DHA (docosahexaenoic acid), found in fish oil, exhibit anti-inflammatory properties; however, the molecular mechanisms remain unclear. Since PtdIns(4,5)P2 resides in raft domains and DHA can alter the size of rafts, we hypothesized that PtdIns(4,5)P2 and downstream actin remodelling are perturbed by the incorporation of n−3 PUFA into membranes, resulting in suppressed T-cell activation. CD4+ T-cells isolated from Fat-1 transgenic mice (membranes enriched in n−3 PUFA) exhibited a 50% decrease in PtdIns(4,5)P2. Upon activation by plate-bound anti-CD3/anti-CD28 or PMA/ionomycin, Fat-1 CD4+ T-cells failed to metabolize PtdIns(4,5)P2. Furthermore, actin remodelling failed to initiate in Fat-1 CD4+ T-cells upon stimulation; however, the defect was reversed by incubation with exogenous PtdIns(4,5)P2. When Fat-1 CD4+ T-cells were stimulated with anti-CD3/anti-CD28-coated beads, WASP (Wiskott–Aldrich syndrome protein) failed to translocate to the immunological synapse. The suppressive phenotype, consisting of defects in PtdIns(4,5)P2 metabolism and actin remodelling, were recapitulated in CD4+ T-cells isolated from mice fed on a 4% DHA triacylglycerol-enriched diet. Collectively, these data demonstrate that n−3 PUFA, such as DHA, alter PtdIns(4,5)P2 in CD4+ T-cells, thereby suppressing the recruitment of WASP to the immunological synapse, and impairing actin remodelling in CD4+ T-cells.
Novel control of cAMP-regulated transcription in vascular endothelial cells
Authors: Milne Gillian R. , Palmer Timothy M. , Yarwood Stephen J.
Published: January 2012

Chronic inflammatory diseases, such as atherosclerosis, are a major cause of death and disability in the developed world. In this respect, although cholesterol obviously plays a predominant role in atherosclerosis, targeting inflammation at lesion sites may be just as important. Indeed, elevated IL-6 (interleukin 6) levels are as strongly associated with coronary heart disease as increased cholesterol. We have been investigating novel cAMP-regulated pathways that combat the action of pro-inflammatory cytokines, such as IL-6 and leptin, in the VECs (vascular endothelial cells) of the circulatory system. In this respect, we have begun to unravel new molecular mechanisms by which the cAMP/Epac1 (exchange protein directly activated by cAMP 1)/Rap1 pathway can initiate a rigorous programme of protective anti-inflammatory responses in VECs. Central to this is the coupling of cAMP elevation to the mobilization of two C/EBP (CCAAT/enhancer-binding protein) family transcription factors, resulting in the induction of the SOCS3 (suppressor of cytokine signalling 3) gene, which attenuates pro-inflammatory cytokine signalling in VECs. These novel ‘protective’ mechanisms of cAMP action will inform the development of the next generation of pharmaceuticals specifically designed to combat endothelial inflammation associated with cardiovascular disease.
Regulation of store-operated calcium entry during cell division
Authors: Smyth Jeremy T. , Putney James W.
Published: January 2012

Store-operate Ca2+ channels gate Ca2+ entry into the cytoplasm in response to the depletion of Ca2+ from endoplasmic reticulum Ca2+ stores. The major molecular components of store-operated Ca2+ entry are STIM (stromal-interacting molecule) 1 (and in some instances STIM2) that serves as the endoplasmic reticulum Ca2+ sensor, and Orai (Orai1, Orai2 and Orai3) which function as pore-forming subunits of the store-operated channel. It has been known for some time that store-operated Ca2+ entry is shut down during cell division. Recent work has revealed complex mechanisms regulating the functions and locations of both STIM1 and Orai1 in dividing cells.
The emerging role of PtdIns5P: another signalling phosphoinositide takes its place
Authors: Grainger Deborah L. , Tavelis Christodoulos , Ryan Alexander J. , Hinchliffe Katherine A.
Published: January 2012

Of the seven phosphoinositides, PtdIns5P remains the most enigmatic. However, recent research has begun to elucidate its physiological functions. It is now clear that PtdIns5P is found in several distinct subcellular locations, and the identification of a number of PtdIns5P-binding proteins points to its involvement in a variety of key processes, including signal transduction, membrane trafficking and regulation of gene expression. Although the mechanisms that control its turnover are not yet fully understood, the existence of multiple pathways for PtdIns5P regulation is consistent with this emerging versatility.
The roles of ATF2 (activating transcription factor 2) in tumorigenesis
Authors: Gozdecka Malgorzata , Breitwieser Wolfgang
Published: January 2012

MAPK (mitogen-activated protein kinase) pathways are among the most frequently deregulated signalling events in cancer. Among the critical targets of MAPK activities are members of the AP-1 (activator protein 1) transcription factor, a dimeric complex consisting of Jun, Fos, Maf and ATF (activating transcription factor) family DNA-binding proteins. Depending on the cellular context, the composition of the dimeric complexes determines the regulation of growth, survival or apoptosis. JNK (c-Jun N-terminal kinase), p38 and a number of Jun and Fos family proteins have been analysed for their involvement in oncogenic transformation and tumour formation. These data are also emerging for the ATF components of the AP-1 factor. The aim of the present review is to provide an overview of the functions of two ATF family proteins, ATF2 and ATF7, in mammalian development and their potential functions in tumour formation.
Immediate-early gene activation by the MAPK pathways: what do and don't we know?
Authors: O'Donnell Amanda , Odrowaz Zaneta , Sharrocks Andrew D.
Published: January 2012

The study of IE (immediate-early) gene activation mechanisms has provided numerous paradigms for how transcription is controlled in response to extracellular signalling. Many of the findings have been derived from investigating one of the IE genes, FOS, and the models extrapolated to regulatory mechanisms for other IE genes. However, whereas the overall principles of activation appear similar, recent evidence suggests that the underlying mechanistic details may differ depending on cell type, cellular stimulus and IE gene under investigation. In the present paper, we review recent advances in our understanding of IE gene transcription, chiefly focusing on FOS and its activation by ERK (extracellular-signal-regulated kinase) MAPK (mitogen-activated protein kinase) pathway signalling. We highlight important fundamental regulatory principles, but also illustrate the gaps in our current knowledge and the potential danger in making assumptions based on extrapolation from disparate studies.
Decoding neurohormone pulse frequency by convergent signalling modules
Authors: Tsaneva-Atanasova Krasimira , Caunt Christopher J. , Armstrong Stephen P. , Perrett Rebecca M. , McArdle Craig A.
Published: January 2012

GnRH (gonadotropin-releasing hormone) mediates control of reproduction. It is secreted in pulses and acts via intracellular effectors to activate gene expression. Submaximal GnRH pulse frequency can elicit maximal responses, yielding bell-shaped frequency–response curves characteristic of genuine frequency decoders. GnRH frequency decoding is therapeutically important (pulsatile GnRH can drive ovulation in assisted reproduction, whereas sustained activation can treat breast and prostate cancers), but the mechanisms are unknown. In the present paper, we review recent work in this area, placing emphasis on the regulation of transcription, and showing how mathematical modelling of GnRH effects on two effectors [ERK (extracellular-signal-regulated kinase) and NFAT (nuclear factor of activated T-cells)] reveals the potential for genuine frequency decoding as an emergent feature of the GnRH signalling network, rather than an intrinsic feature of a given protein or pathway within it.
Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling
Authors: Little Annette S. , Balmanno Kathryn , Sale Matthew J. , Smith Paul D. , Cook Simon J.
Published: January 2012

The Raf/MEK1/2 [mitogen-activated protein kinase/ERK (extracellular-signal-regulated kinase) kinase 1/2]/ERK1/2 signalling pathway is frequently activated in human tumours due to mutations in BRAF or KRAS. B-Raf and MEK1/2 inhibitors are currently undergoing clinical evaluation, but their ultimate success is likely to be limited by acquired drug resistance. We have used colorectal cancer cell lines harbouring mutations in B-Raf or K-Ras to model acquired resistance to the MEK1/2 inhibitor selumetinib (AZD6244). Selumetinib-resistant cells were refractory to other MEK1/2 inhibitors in cell proliferation assays and exhibited a marked increase in MEK1/2 and ERK1/2 activity and cyclin D1 abundance when assessed in the absence of inhibitor. This was driven by a common mechanism in which resistant cells exhibited an intrachromosomal amplification of their respective driving oncogene, B-Raf V600E or K-RasG13D. Despite the increased signal flux from Raf to MEK1/2, resistant cells maintained in drug actually exhibited the same level of ERK1/2 activity as parental cells, indicating that the pathway is remodelled by feedback controls to reinstate the normal level of ERK1/2 signalling that is required and sufficient to maintain proliferation in these cells. These results provide important new insights into how tumour cells adapt to new therapeutics and highlight the importance of homoeostatic control mechanisms in the Raf/MEK1/2/ERK1/2 signalling cascade.
MKP-2: out of the DUSP-bin and back into the limelight
Authors: Lawan Ahmed , Torrance Emma , Al-Harthi Sameer , Shweash Muhannad , Alnasser Sulaiman , Neamatallah Thikryat , Schroeder Juliane , Plevin Robin
Published: January 2012

The MKPs (mitogen-activated protein kinase phosphatases) are a family of at least ten DUSPs (dual-specificity phosphatases) which function to terminate the activity of the MAPKs (mitogen-activated protein kinases). Several members have already been demonstrated to have distinct roles in immune function, cancer, fetal development and metabolic disorders. One DUSP of renewed interest is the inducible nuclear phosphatase MKP-2, which dephosphorylates both ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase) in vitro. Recently, the understanding of MKP-2 function has been advanced due to the development of mouse knockout models, which has resulted in the discovery of novel roles for MKP-2 in the regulation of sepsis, infection and cell-cycle progression that are distinct from those of other DUSPs. However, many functions for MKP-2 still await to be characterized.
ERK phosphorylation and nuclear accumulation: insights from single-cell imaging
Authors: Caunt Christopher J. , McArdle Craig A.
Published: January 2012

Many stimuli mediate activation and nuclear translocation of ERK (extracellular-signal-regulated kinase) by phosphorylation on the TEY (Thr-Glu-Tyr) motif. This is necessary to initiate transcriptional programmes controlling cellular responses, but the mechanisms that govern ERK nuclear targeting are unclear. Single-cell imaging approaches have done much to increase our understanding of input–output relationships in the ERK cascade, but few studies have addressed how the range of ERK phosphorylation responses observed in cell populations influences subcellular localization. Using automated microscopy to explore ERK regulation in single adherent cells, we find that nuclear localization responses increase in proportion to stimulus level, but not the level of TEY phosphorylation. This phosphorylation-unattributable nuclear localization response occurs in the presence of tyrosine phosphatase and protein synthesis inhibitors. It is also seen with a catalytically inactive ERK2–GFP (green fluorescent protein) mutant, and with a mutant incapable of binding the DEF (docking site for ERK, F/Y-X-F/Y-P) domains found in many ERK-binding partners. It is, however, reduced by MEK (mitogen-activated protein kinase/ERK kinase) inhibition and by mutations preventing TEY phosphorylation or in the ERK common docking region. We therefore show that TEY phosphorylation of ERK is necessary, but not sufficient, for the full nuclear accumulation response and that this ‘phosphorylation-unattributable’ component of stimulus-mediated ERK nuclear localization requires association with partner proteins via the common docking motif.