bluuebunny/crossref_metadata_2025 huggingface dataset:
Roles of individual domains in the function of DHX29, an essential factor required for translation of structured mammalian mRNAs
Authors: Dhote Vidya , Sweeney Trevor R. , Kim Natalia , Hellen Christopher U. T. , Pestova Tatyana V.
Published: October 2012

On most eukaryotic mRNAs, initiation codon selection involves base-by-base inspection of 5′ UTRs by scanning ribosomal complexes. Although the eukaryotic initiation factors 4A/4B/4G can mediate scanning through medium-stability hairpins, scanning through more stable structures additionally requires DHX29, a member of the superfamily 2 DEAH/RNA helicase A (RHA) helicase family that binds to 40S subunits and possesses 40S-stimulated nucleoside triphosphatase (NTPase) activity. Here, sequence alignment and structural modeling indicated that DHX29 comprises a unique 534-aa–long N-terminal region (NTR), central catalytic RecA1/RecA2 domains containing a large insert in the RecA2 domain, and the C-terminal part, which includes winged-helix, ratchet, and oligonucleotide/oligosaccharide-binding (OB) domains that are characteristic of DEAH/RHA helicases. Functional characterization revealed that specific ribosomal targeting is required for DHX29’s activity in initiation and is determined by elements that map to the NTR and to the N-terminal half of the winged-helix domain. The ribosome-binding determinant located in the NTR was identified as a putative double-stranded RNA-binding domain. Mutational analyses of RecA1/RecA2 domains confirmed the essential role of NTP hydrolysis for DHX29’s function in initiation and validated the significance of a β-hairpin protruding from RecA2. The large RecA2 insert played an autoinhibitory role in suppressing DHX29’s intrinsic NTPase activity but was not essential for its 40S-stimulated NTPase activity and function in initiation. Deletion of the OB domain also increased DHX29's basal NTPase activity, but more importantly, abrogated the responsiveness of the NTPase activity to stimulation, which abolished DHX29's function in initiation. This finding suggests that the OB domain, which is specific for DEAH/RHA helicases, plays an important role in their NTPase cycle.
Quantitative imaging of endosome acidification and single retrovirus fusion with distinct pools of early endosomes
Authors: Padilla-Parra Sergi , Matos Pedro M. , Kondo Naoyuki , Marin Mariana , Santos Nuno C. , Melikyan Gregory B.
Published: October 2012

Diverse enveloped viruses enter host cells through endocytosis and fuse with endosomal membranes upon encountering acidic pH. Currently, the pH dynamics in virus-carrying endosomes and the relationship between acidification and viral fusion are poorly characterized. Here, we examined the entry of avian retrovirus that requires two sequential stimuli—binding to a cognate receptor and low pH—to undergo fusion. A genetically encoded sensor incorporated into the viral membrane was used to measure the pH in virus-carrying endosomes. Acid-induced virus fusion was visualized as the release of a fluorescent viral content marker into the cytosol. The pH values in early acidic endosomes transporting the virus ranged from 5.6 to 6.5 but were relatively stable over time for a given vesicle. Analysis of viral motility and luminal pH showed that cells expressing the transmembrane isoform of the receptor (TVA950) preferentially sorted the virus into slowly trafficking, less acidic endosomes. In contrast, viruses internalized by cells expressing the GPI-anchored isoform (TVA800) were uniformly distributed between stationary and mobile compartments. We found that the lag times between acidification and fusion were significantly shorter and fusion pores were larger in dynamic endosomes than in more stationary compartments. Despite the same average pH within mobile compartments of cells expressing alternative receptor isoforms, TVA950 supported faster fusion than TVA800 receptor. Collectively, our results suggest that fusion steps downstream of the low-pH trigger are modulated by properties of intracellular compartments harboring the virus.
Reverse engineering the euglenoid movement
Authors: Arroyo Marino , Heltai Luca , Millán Daniel , DeSimone Antonio
Published: October 2012

Euglenids exhibit an unconventional motility strategy amongst unicellular eukaryotes, consisting of large-amplitude highly concerted deformations of the entire body (euglenoid movement or metaboly). A plastic cell envelope called pellicle mediates these deformations. Unlike ciliary or flagellar motility, the biophysics of this mode is not well understood, including its efficiency and molecular machinery. We quantitatively examine video recordings of four euglenids executing such motions with statistical learning methods. This analysis reveals strokes of high uniformity in shape and pace. We then interpret the observations in the light of a theory for the pellicle kinematics, providing a precise understanding of the link between local actuation by pellicle shear and shape control. We systematically understand common observations, such as the helical conformations of the pellicle, and identify previously unnoticed features of metaboly. While two of our euglenids execute their stroke at constant body volume, the other two exhibit deviations of about 20% from their average volume, challenging current models of low Reynolds number locomotion. We find that the active pellicle shear deformations causing shape changes can reach 340%, and estimate the velocity of the molecular motors. Moreover, we find that metaboly accomplishes locomotion at hydrodynamic efficiencies comparable to those of ciliates and flagellates. Our results suggest new quantitative experiments, provide insight into the evolutionary history of euglenids, and suggest that the pellicle may serve as a model for engineered active surfaces with applications in microfluidics.
Cathode diameter and operating parameter effects on hafnium cathode evaporation for oxygen plasma cutting arc
Authors: Long Nguyen Phi , Katada Yusuke , Tanaka Yasunori , Uesugi Yoshihiko , Yamaguchi Yoshihiro
Published: October 2012

Evaporation of hafnium cathode in a plasma cutting arc torch was investigated numerically and experimentally to assess the effects of cathode diameter and operating parameters such as gas pressure, gas flow rate and arc current. A numerical model was developed for arc plasma with consideration of hafnium cathode evaporation. Using this model, the surface cathode temperature and the amount of cathode mass loss caused by evaporation were predicted for different operating parameters. Simulated results show that the cathode surface temperature decreases at the hafnium cathode centre with increasing gas flow rate and cathode diameter. However, an increase in gas pressure elevates the surface cathode temperature in the radial range of 0.35 mm. The total amount of mass loss of hafnium cathode evaporation was predicted to be enhanced with increasing gas flow rate, gas pressure and cathode diameter as well. Comparison of the calculated results with experimentally obtained results shows good agreement in terms of the average surface cathode temperature, with variation in gas pressure and cathode diameter.
Application of asymmetric statistical potentials to antibody–protein docking
Authors: Brenke Ryan , Hall David R. , Chuang Gwo-Yu , Comeau Stephen R. , Bohnuud Tanggis , Beglov Dmitri , Schueler-Furman Ora , Vajda Sandor , Kozakov Dima
Published: October 2012

Motivation: An effective docking algorithm for antibody–protein antigen complex prediction is an important first step toward design of biologics and vaccines. We have recently developed a new class of knowledge-based interaction potentials called Decoys as the Reference State (DARS) and incorporated DARS into the docking program PIPER based on the fast Fourier transform correlation approach. Although PIPER was the best performer in the latest rounds of the CAPRI protein docking experiment, it is much less accurate for docking antibody–protein antigen pairs than other types of complexes, in spite of incorporating sequence-based information on the location of the paratope. Analysis of antibody–protein antigen complexes has revealed an inherent asymmetry within these interfaces. Specifically, phenylalanine, tryptophan and tyrosine residues highly populate the paratope of the antibody but not the epitope of the antigen.

Results: Since this asymmetry cannot be adequately modeled using a symmetric pairwise potential, we have removed the usual assumption of symmetry. Interaction statistics were extracted from antibody–protein complexes under the assumption that a particular atom on the antibody is different from the same atom on the antigen protein. The use of the new potential significantly improves the performance of docking for antibody–protein antigen complexes, even without any sequence information on the location of the paratope. We note that the asymmetric potential captures the effects of the multi-body interactions inherent to the complex environment in the antibody–protein antigen interface.

Availability: The method is implemented in the ClusPro protein docking server, available at http://cluspro.bu.edu.

Contact:  midas@bu.edu or vajda@bu.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
An unbiased evaluation of gene prioritization tools
Authors: Börnigen Daniela , Tranchevent Léon-Charles , Bonachela-Capdevila Francisco , Devriendt Koenraad , De Moor Bart , De Causmaecker Patrick , Moreau Yves
Published: October 2012

Motivation: Gene prioritization aims at identifying the most promising candidate genes among a large pool of candidates—so as to maximize the yield and biological relevance of further downstream validation experiments and functional studies. During the past few years, several gene prioritization tools have been defined, and some of them have been implemented and made available through freely available web tools. In this study, we aim at comparing the predictive performance of eight publicly available prioritization tools on novel data. We have performed an analysis in which 42 recently reported disease-gene associations from literature are used to benchmark these tools before the underlying databases are updated.

Results: Cross-validation on retrospective data provides performance estimate likely to be overoptimistic because some of the data sources are contaminated with knowledge from disease-gene association. Our approach mimics a novel discovery more closely and thus provides more realistic performance estimates. There are, however, marked differences, and tools that rely on more advanced data integration schemes appear more powerful.

Contact:  yves.moreau@esat.kuleuven.be

Supplementary information:  Supplementary data are available at Bioinformatics online.
Optimal design of stimulus experiments for robust discrimination of biochemical reaction networks
Authors: Flassig R. J. , Sundmacher K.
Published: October 2012

Motivation: Biochemical reaction networks in the form of coupled ordinary differential equations (ODEs) provide a powerful modeling tool for understanding the dynamics of biochemical processes. During the early phase of modeling, scientists have to deal with a large pool of competing nonlinear models. At this point, discrimination experiments can be designed and conducted to obtain optimal data for selecting the most plausible model. Since biological ODE models have widely distributed parameters due to, e.g. biologic variability or experimental variations, model responses become distributed. Therefore, a robust optimal experimental design (OED) for model discrimination can be used to discriminate models based on their response probability distribution functions (PDFs).

Results: In this work, we present an optimal control-based methodology for designing optimal stimulus experiments aimed at robust model discrimination. For estimating the time-varying model response PDF, which results from the nonlinear propagation of the parameter PDF under the ODE dynamics, we suggest using the sigma-point approach. Using the model overlap (expected likelihood) as a robust discrimination criterion to measure dissimilarities between expected model response PDFs, we benchmark the proposed nonlinear design approach against linearization with respect to prediction accuracy and design quality for two nonlinear biological reaction networks. As shown, the sigma-point outperforms the linearization approach in the case of widely distributed parameter sets and/or existing multiple steady states. Since the sigma-point approach scales linearly with the number of model parameter, it can be applied to large systems for robust experimental planning.

Availability: An implementation of the method in MATLAB/AMPL is available at http://www.uni-magdeburg.de/ivt/svt/person/rf/roed.html.

Contact: flassig@mpi-magdeburg.mpg.de

Supplementary information: Supplementary data are are available at Bioinformatics online.
Global network alignment using multiscale spectral signatures
Authors: Patro Rob , Kingsford Carl
Published: October 2012

Motivation: Protein interaction networks provide an important system-level view of biological processes. One of the fundamental problems in biological network analysis is the global alignment of a pair of networks, which puts the proteins of one network into correspondence with the proteins of another network in a manner that conserves their interactions while respecting other evidence of their homology. By providing a mapping between the networks of different species, alignments can be used to inform hypotheses about the functions of unannotated proteins, the existence of unobserved interactions, the evolutionary divergence between the two species and the evolution of complexes and pathways.

Results: We introduce GHOST, a global pairwise network aligner that uses a novel spectral signature to measure topological similarity between subnetworks. It combines a seed-and-extend global alignment phase with a local search procedure and exceeds state-of-the-art performance on several network alignment tasks. We show that the spectral signature used by GHOST is highly discriminative, whereas the alignments it produces are also robust to experimental noise. When compared with other recent approaches, we find that GHOST is able to recover larger and more biologically significant, shared subnetworks between species.

Availability: An efficient and parallelized implementation of GHOST, released under the Apache 2.0 license, is available at http://cbcb.umd.edu/kingsford_group/ghost

Contact:  rob@cs.umd.edu
Promoter-proximal CCCTC-factor binding is associated with an increase in the transcriptional pausing index
Authors: Paredes Sur Herrera , Melgar Michael F. , Sethupathy Praveen
Published: October 2012

Motivation: It has been known for more than 2 decades that after RNA polymerase II (RNAPII) initiates transcription, it can enter into a paused or stalled state immediately downstream of the transcription start site before productive elongation. Recent advances in high-throughput genomic technologies facilitated the discovery that RNAPII pausing at promoters is a widespread physiologically regulated phenomenon. The molecular underpinnings of pausing are incompletely understood. The CCCTC-factor (CTCF) is a ubiquitous nuclear factor that has diverse regulatory functions, including a recently discovered role in promoting RNAPII pausing at splice sites.

Results: In this study, we analyzed CTCF binding sites and nascent transcriptomic data from three different cell types, and found that promoter-proximal CTCF binding is significantly associated with RNAPII pausing.

Contact:  praveen_sethupathy@med.unc.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Membrane-Based Oligonucleotide Array Developed from Multiple Markers for the Detection of Many Phytophthora Species
Authors: Chen Wen , Djama Zeinab Robleh , Coffey Michael D. , Martin Frank N. , Bilodeau Guillaume J. , Radmer Lorien , Denton Geoff , Lévesque C. André
Published: October 2012

Most Phytophthora spp. are destructive plant pathogens; therefore, effective monitoring and accurate early detection are important means of preventing potential epidemics and outbreaks of diseases. In the current study, a membrane-based oligonucleotide array was developed that can detect Phytophthora spp. reliably using three DNA regions; namely, the internal transcribed spacer (ITS), the 5′ end of cytochrome c oxidase 1 gene (cox1), and the intergenic region between cytochrome c oxidase 2 gene (cox2) and cox1 (cox2-1 spacer). Each sequence data set contained ≈250 sequences representing 98 described and 15 undescribed species of Phytophthora. The array was validated with 143 pure cultures and 35 field samples. Together, nonrejected oligonucleotides from all three markers have the ability to reliably detect 82 described and 8 undescribed Phytophthora spp., including several quarantine or regulated pathogens such as Phytophthora ramorum. Our results showed that a DNA array containing signature oligonucleotides designed from multiple genomic regions provided robustness and redundancy for the detection and differentiation of closely related taxon groups. This array has the potential to be used as a routine diagnostic tool for Phytophthora spp. from complex environmental samples without the need for extensive growth of cultures.
Evidence for Permo-Triassic colonization of the deep sea by isopods
Authors: Lins Luana S. F. , Ho Simon Y. W. , Wilson George D. F. , Lo Nathan
Published: October 2012

The deep sea is one of the largest ecosystems on Earth and is home to a highly diverse fauna, with polychaetes, molluscs and peracarid crustaceans as dominant groups. A number of studies have proposed that this fauna did not survive the anoxic events that occurred during the Mesozoic Era. Accordingly, the modern fauna is thought to be relatively young, perhaps having colonized the deep sea after the Eocene/Oligocene boundary. To test this hypothesis, we performed phylogenetic analyses of nuclear ribosomal
18S
and
28S
and mitochondrial cytochrome oxidase I and
16S
sequences from isopod crustaceans. Using a molecular clock calibrated with multiple isopod fossils, we estimated the timing of deep-sea colonization events by isopods. Our results show that some groups have an ancient origin in the deep sea, with the earliest estimated dates spanning 232–314 Myr ago. Therefore, anoxic events at the Permian–Triassic boundary and during the Mesozoic did not cause the extinction of all the deep-sea fauna; some species may have gone extinct while others survived and proliferated. The monophyly of the ‘munnopsid radiation’ within the isopods suggests that the ancestors of this group evolved in the deep sea and did not move to shallow-water refugia during anoxic events.
Prey field switching based on preferential behaviour can induce Lévy flights
Authors: Lundy Mathieu G. , Harrison Alan , Buckley Daniel J. , Boston Emma S. , Scott David D. , Teeling Emma C. , Montgomery W. Ian , Houghton Jonathan D. R.
Published: October 2012

Using the foraging movements of an insectivorous bat,Myotis mystacinus, we describe temporal switching of foraging behaviour in response to resource availability. These observations conform to predictions of optimized search under the Lévy flight paradigm. However, we suggest that this occurs as a result of a preference behaviour and knowledge of resource distribution. Preferential behaviour and knowledge of a familiar area generate distinct movement patterns as resource availability changes on short temporal scales. The behavioural response of predators to changes in prey fields can elicit different functional responses, which are considered to be central in the development of stable predator–prey communities. Recognizing how the foraging movements of an animal relate to environmental conditions also elucidates the evolution of optimized search and the prevalence of discrete strategies in natural systems. Applying techniques that use changes in the frequency distribution of movements facilitates exploration of the processes that underpin behavioural changes.
Cell signalling regulates dynamics of Nanog distribution in embryonic stem cell populations
Authors: Luo Yang , Lim Chea Lu , Nichols Jennifer , Martinez-Arias Alfonso , Wernisch Lorenz
Published: October 2012

A population of mouse embryonic stem (ES) cells is characterized by a distribution of Nanog, a gene whose expression is associated with the degree of pluripotency. Cells exhibiting high levels of Nanog maintain a state of pluripotency, while those with low levels are more likely to undergo differentiation. Using a cell line with a fluorescence tag for Nanog enables measurements of the distribution of Nanog in an ES cell culture in a stationary state or after a perturbation. In order to model the dynamics of the system, we assume that the distribution of Nanog-GFP for single cells shows distinct attractor steady states of Nanog levels, with individual cells moving between these states stochastically. The addition of synthetic inhibitors of signal transduction induces strong shifts in the distribution of Nanog. In particular, the addition of Chiron and PD03, inhibitors for the ERK and GSK3 signalling pathways, induces a high level of Nanog. In this study, we placed ES cells in different culture conditions, including the above inhibitors, and recorded the change in Nanog-GFP distribution over several days. In order to interpret the measurements of Nanog levels, we propose a new stochastic modelling strategy for the dynamics of the system not requiring detailed knowledge of regulatory or signalling mechanisms, while still capturing the stochastic and the deterministic components of the stochastic dynamical system. Despite its relative simplicity, the model provides an insight into key features of the cell population under various conditions, including the level of noise and occupancy and location of attractor steady states, without the need for strong assumptions about the underlying cellular mechanisms. By applying the model to our experimental data, we infer the existence of three stable steady states for Nanog levels, which are the same in all the different conditions of the cell-culture medium. Noise, on the other hand, and the proportion of cells in each steady state are subject to large shifts. Surprisingly, the isolated effects of PD03 and Chiron on noise and dynamics of the system are quite different from their combined effect. Our results show that signalling determines the occupancy of each state, with a particular role for GSK3 in the regulation of the noise across the population.
Synthetic gene circuits for metabolic control: design trade-offs and constraints
Authors: Oyarzún Diego A. , Stan Guy-Bart V.
Published: October 2012

A grand challenge in synthetic biology is to push the design of biomolecular circuits from purely genetic constructs towards systems that interface different levels of the cellular machinery, including signalling networks and metabolic pathways. In this paper, we focus on a genetic circuit for feedback regulation of unbranched metabolic pathways. The objective of this feedback system is to dampen the effect of flux perturbations caused by changes in cellular demands or by engineered pathways consuming metabolic intermediates. We consider a mathematical model for a control circuit with an operon architecture, whereby the expression of all pathway enzymes is transcriptionally repressed by the metabolic product. We address the existence and stability of the steady state, the dynamic response of the network under perturbations, and their dependence on common tuneable knobs such as the promoter characteristic and ribosome binding site (RBS) strengths. Our analysis reveals trade-offs between the steady state of the enzymes and the intermediates, together with a separation principle between promoter and RBS design. We show that enzymatic saturation imposes limits on the parameter design space, which must be satisfied to prevent metabolite accumulation and guarantee the stability of the network. The use of promoters with a broad dynamic range and a small leaky expression enlarges the design space. Simulation results with realistic parameter values also suggest that the control circuit can effectively upregulate enzyme production to compensate flux perturbations.
Jan Swammerdam's frogs
Authors: Sleigh Charlotte
Published: October 2012

Having discussed insect metamorphosis at length, Jan Swammerdam's
Bybel der Natuure
(1679/1737) reached its climax with a substantial description of the generation and muscular activity of frogs. This paper explores the rhetorical role of frogs in Swammerdam's ‘great work’, showing how they were the Archimedean point from which he aimed to reorder all of creation—from insects to humans—within one glorious, God-ordained natural history and philosophy. Swammerdam linked insects to frogs through a demonstration that all underwent epigenesis; and frogs were then linked to humans through a demonstration of their identical muscular activity. The success of Swammerdam's strategy required a theological reconstruction of the frog, traditionally an ungodly creature, such that trustworthy knowledge could be obtained from its body. Perhaps surprisingly, this act of theological cleansing is shown to be somewhat prefigured in the distinctly non-experimental natural history of Edward Topsell (1608). The paper also examines Swammerdam's interactions with the mystic Antoinette Bourignon, and his challenges in reconciling a spirituality of meletetics with a material epistemology in natural philosophy. Differences are revealed between the natural analogies given by Swammerdam in his published and unpublished writings, undermining to a certain extent the triumphal insect–frog–human rhetorical structure of the
Bybel
.
Three-dimensional thermal analysis of wirelessly powered light-emitting systems
Authors: Zhang Y. H. , Li Y. H. , Kim R.-H. , Tao H. , Kim T.-I. , Omenetto F. G. , Rogers J. A. , Huang Y.
Published: October 2012

A theoretical model of heat conduction is developed for wirelessly powered microscale inorganic light-emitting diodes (μ-ILEDs). Analytical solutions are obtained for the three-dimensional temperature distribution of each component in the system, which agree reasonably well with the finite-element analyses and experiment results. A simplified scaling law is presented between the non-dimensional temperature of the μ-ILEDs, and the combined geometrical parameters and thermal conductivities of the inductive receiver coil and the substrate. These results provide useful design guidelines for avoiding adverse heating of wireless μ-ILEDs systems, of critical importance for bio-implanted applications.
Pre-adaptations and the evolution of pollination by sexual deception: Cope's rule of specialization revisited
Authors: Vereecken Nicolas J. , Wilson Carol A. , Hötling Susann , Schulz Stefan , Banketov Sergey A. , Mardulyn Patrick
Published: October 2012

Pollination by sexual deception is arguably one of the most unusual liaisons linking plants and insects, and perhaps the most illustrative example of extreme floral specialization in angiosperms. While considerable progress has been made in understanding the floral traits involved in sexual deception, less is known about how this remarkable mimicry system might have arisen, the role of pre-adaptations in promoting its evolution and its extent as a pollination mechanism outside the few groups of plants (primarily orchids) where it has been described to date. In the Euro-Mediterranean region, pollination by sexual deception is traditionally considered to be the hallmark of the orchid genusOphrys. Here, we introduce two new cases outside ofOphrys, in plant groups dominated by generalized, shelter-mimicking species. On the basis of phylogenetic reconstructions of ancestral pollination strategies, we provide evidence for independent and bidirectional evolutionary transitions between generalized (shelter mimicry) and specialized (sexual deception) pollination strategies in three groups of flowering plants, and suggest that pseudocopulation has evolved from pre-adaptations (floral colours, shapes and odour bouquets) that selectively attract male pollinators through shelter mimicry. These findings, along with comparative analyses of floral traits (colours and scents), shed light on particular phenotypic changes that might have fuelled the parallel evolution of these extraordinary pollination strategies. Collectively, our results provide the first substantive insights into how pollination sexual deception might have evolved in the Euro-Mediterranean region, and demonstrate that even the most extreme cases of pollinator specialization can reverse to more generalized interactions, breaking ‘Cope's rule of specialization’.
Quantifying introgression risk with realistic population genetics
Authors: Ghosh Atiyo , Meirmans Patrick G. , Haccou Patsy
Published: October 2012

Introgression is the permanent incorporation of genes from the genome of one population into another. This can have severe consequences, such as extinction of endemic species, or the spread of transgenes. Quantification of the risk of introgression is an important component of genetically modified crop regulation. Most theoretical introgression studies aimed at such quantification disregard one or more of the most important factors concerning introgression: realistic genetical mechanisms, repeated invasions and stochasticity. In addition, the use of linkage as a risk mitigation strategy has not been studied properly yet with genetic introgression models. Current genetic introgression studies fail to take repeated invasions and demographic stochasticity into account properly, and use incorrect measures of introgression risk that can be manipulated by arbitrary choices. In this study, we present proper methods for risk quantification that overcome these difficulties. We generalize a probabilistic risk measure, the so-called hazard rate of introgression, for application to introgression models with complex genetics and small natural population sizes. We illustrate the method by studying the effects of linkage and recombination on transgene introgression risk at different population sizes.
The epithelial sodium channel in the Australian lungfish,
Neoceratodus forsteri
(Osteichthyes: Dipnoi)
Authors: Uchiyama Minoru , Maejima Sho , Yoshie Sumio , Kubo Yoshihiro , Konno Norifumi , Joss Jean M. P.
Published: October 2012

Epithelial sodium channel (ENaC) is a Na
+
-selective, aldosterone-stimulated ion channel involved in sodium transport homeostasis. ENaC is rate-limiting for Na
+
absorption in the epithelia of osmoregulatory organs of tetrapods. Although the ENaC/degenerin gene family is proposed to be present in metazoans, no orthologues or paralogues for ENaC have been found in the genome databases of teleosts. We studied full-length cDNA cloning and tissue distributions of ENaCα, β and γ subunits in the Australian lungfish,
Neoceratodus forsteri
, which is the closest living relative of tetrapods.
Neoceratodus
ENaC (
n
ENaC) comprised three subunits:
n
ENaCα, β and γ proteins. The
n
ENaCα, β and γ subunits are closely related to amphibian ENaCα, β and γ subunits, respectively. Three ENaC subunit mRNAs were highly expressed in the gills, kidney and rectum. Amiloride-sensitive sodium current was recorded from
Xenopus
oocytes injected with the
n
ENaCαβγ subunit complementary RNAs under a two-electrode voltage clamp.
n
ENaCα immunoreactivity was observed in the apical cell membrane of the gills, kidney and rectum. Thus,
n
ENaC may play a role in regulating sodium transport of the lungfish, which has a renin–angiotensin–aldosterone system. This is interesting because there may have been an ENaC sodium absorption system controlled by aldosterone before the conquest of land by vertebrates.
Early warning signals and the prosecutor's fallacy
Authors: Boettiger Carl , Hastings Alan
Published: October 2012

Early warning signals have been proposed to forecast the possibility of a critical transition, such as the eutrophication of a lake, the collapse of a coral reef or the end of a glacial period. Because such transitions often unfold on temporal and spatial scales that can be difficult to approach by experimental manipulation, research has often relied on historical observations as a source of natural experiments. Here, we examine a critical difference between selecting systems for study based on the fact that we have observed a critical transition and those systems for which we wish to forecast the approach of a transition. This difference arises by conditionally selecting systems known to experience a transition of some sort and failing to account for the bias this introduces—a statistical error often known as the prosecutor's fallacy. By analysing simulated systems that have experienced transitions purely by chance, we reveal an elevated rate of false-positives in common warning signal statistics. We further demonstrate a model-based approach that is less subject to this bias than those more commonly used summary statistics. We note that experimental studies with replicates avoid this pitfall entirely.
Strategies for Service Quality II
Authors: Fojt Martin
Published: October 2012

That someone can make you feel good is a quality in itself. There has been much talk within British government circles, for example, about “the feel‐good
factor”, which is constantly reminding us that it is just around the corner! Whether or not we can believe in this is another matter, but it certainly displays
an awareness that making other people feel good can have positive benefits for you also. How this can be achieved will differ depending on your particular line of business. Having a good quality product does not in itself guarantee success as service quality must also be taken into account. This is where the feel‐good factor comes into play. It is all very well, for example, going to a restaurant to have a top‐class meal (in that the food was good), only to have it thrown at you. Quality, therefore, must not be seen as a separate entity, but more as a package deal.
Strategies for Service Quality
Authors: Sandelands Eric
Published: October 2012

For many, quality circles have been a struggle, total quality management has been something to “get around to one day” and continuous improvement has just been another expression meaning total quality management, which, of course is something that we will “get around to one day”. Worse, the acronyms used ‐ QC,
TQM, CI ‐ have joined such exotic practices as JIT (Just‐in‐Time inventory), CAD‐CAM (computer‐aided development and
manufacturing) and more recently BPR (business process re‐engineering) in an alphabet soup of consultant‐led packages, available to the discerning manager ‐ at a price.
National Perspectives in Multinational Headquarters: The Case of EUFOR Tchad/RCA
Authors: Ekman Olof
Published: October 2012

Recent studies of the European Union crisis management capability argue for establishing a permanent Operations Headquarters (OHQ) instead of the temporary alternatives currently available. These studies picture temporary OHQs as slow starters hampered by multiple interests and a lack of common grounds. This paper corroborates these studies by reporting on the empirical findings of a year‐long case study of the EUFOR Tchad/RCA OHQ. The combined results of observations, interviews, and surveys indicate that national perspectives not only existed in the OHQ, but were also asymmetric in the sense that staff members from France and Ireland nations displayed stronger national perspectives than staff members from other nations. However, the general trust between staff members seems to have been largely unaffected by this. The findings also indicate a process of familiarization spanning over several months. This paper argues that temporary multinational headquarters are likely to work around frictions and mature into well‐functioning organization, but that this is a time‐consuming process in which national parallel chains of command may remain. Prior training should prepare staff members for this. In addition, leading nations need to understand their strong visibility and to be careful not to dominate the day‐to‐day staff work.
Case of pleural metastasis of prostate cancer
Authors: Yasuda Koichiro , Maeda Ai , Yukawa Takuro , Saisho Shinsuke , Okita Riki , Hirami Yuji , Shimizu Katsuhiko , Nakata Masao
Published: October 2012

The most frequent sites of prostate cancer metastases are the bone and lung. Pleural metastasis of prostate cancer is clinically rare. We report a case with solitary pleural thickening arising from the metastasis of prostate cancer. A 71‐year‐old man was referred to our hospital for further examination of pleural thickening detected during a chest computed tomography (CT) examination. A video‐assisted pleural biopsy was performed. The pathological findings showed that the tumor cells had spread from the parietal pleura to adipose tissue around the costal muscles. The tumor cells were positive for prostate‐specific antigen (PSA) and negative for calretinin, cytokeratin (Ck5/6) and D2‐40. These findings suggested that the pleural lesion was a metastasis of the prostate cancer.
Adipose stromal cell and sarpogrelate orchestrate the recovery of inflammation‐induced angiogenesis in aged hindlimb ischemic mice
Authors: Fan Weiwei , Li Chengxiang , Qin Xing , Wang Shenxu , Da Hu , Cheng Kang , Zhou Ri , Tong Chao , Li Xiujuan , Bu Qingting , Li Congye , Han Yaling , Ren Jun , Cao Feng
Published: October 2012

Aging population displays a much higher risk of peripheral arterial disease (PAD) possibly due to the higher susceptibility, poor prognosis, and fewer therapeutic options. This study was designed to examine the impact of combined multipotent adipose‐derived stromal cells (mADSCs) and sarpogrelate treatment on aging hindlimb ischemia and the mechanism of action involved. mADSCs (1.0 × 107) constitutively expressing enhanced green fluorescent protein (eGFP) or firefly luciferase (Fluc) reporter were engrafted into the hindlimb of aged Vegfr2‐luc transgenic or FVB/N mice subjected to unilateral femoral artery occlusion, followed by a further administration of sarpogrelate. Multimodality molecular imaging was employed to noninvasively evaluate mADSCs' survival and therapeutic efficacy against aging hindlimb ischemia. Aged Tg(Vegfr2‐luc) mice exhibited decreased inflammatory response, and downregulation of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor‐2 (VEGFR2) compared with young ones following hindlimb ischemia induction, resulting in angiogenesis insufficiency and decompensation for ischemia recovery. Engrafted mADSCs augmented inflammation‐induced angiogenesis to yield pro‐angiogenic/anti‐apoptotic effects partly via the VEGF/VEGFR2/mTOR/STAT3 pathway. Nonetheless, mADSCs displayed limited survival and efficacy following transplantation. Sarpogrelate treatment with mADSCs further upregulated mammalian target of rapamycin (mTOR)/STAT3 signal and modulated pro‐/anti‐inflammatory markers including IL‐1β/TNF‐α/IFN‐γ and IL‐6/IL‐10, which ultimately facilitated mADSCs' survival and therapeutic benefit in vivo. Sarpogrelate prevented mADSCs from hypoxia/reoxygenation‐induced cell death via a mTOR/STAT3‐dependent pathway in vitro. This study demonstrated a role of in vivo kinetics of VEGFR2 as a biomarker to evaluate cell‐derived therapeutic angiogenesis in aging. mADSCs and sarpogrelate synergistically restored impaired angiogenesis and inflammation modulatory capacity in aged hindlimb ischemic mice, indicating its therapeutic promise for PAD in the elderly.
Uneven implementation of the National Perinatal Depression Initiative: findings from a survey of Australian women's hospitals
Authors: Fisher Jane , Chatham Elizabeth , Haseler Sally , McGaw Beth , Thompson Jane
Published: October 2012

Background

Australia is a leader in recognising that perinatal mental health problems are prevalent and constitute a significant burden of disease among women. In 2009, the Australian government launched the National Perinatal Depression Initiative (NPDI) to address this.

Aims

To investigate implementation of Australia's NPDI.

Materials and Methods

Data were collected by a structured online survey assessing: screening for depression and depression risk in women receiving antenatal and postnatal care; staff training about perinatal depression; barriers and enablers to implementing the NPDI recommendations. All Australian members of Women's Healthcare Australasia (WHA) were invited to complete the survey in March 2011.

Results

Of 30 Australian WHA members, 14 (46.6%) completed the survey. The sample included a representative distribution of small, medium and large hospitals. All respondents had introduced some NPDI recommendations. Most (80%) reported using the Edinburgh Postnatal Depression Scale (EPDS) to screen for antenatal depression and for risk of developing depression but at varied gestational ages, and with differing cut‐off scores for follow‐up or referral. Only one assessed depression status postpartum. Responsibility for screening and feedback was predominantly assigned to midwives, most of whom were offered <4 h training. Implementation barriers included insufficient personnel; per‐client time requirements; insufficient clarity about screening protocols; difficulties modifying the medical record; few referral options and a lack of training resources.

Conclusions

Implementation of the NPDI is uneven among Australian maternity hospitals. Little is known about perinatal mental health screening practices in the private sector and hospitals with <1000 births annually.
Patterns of weight gain in pregnant women with and without gestational diabetes mellitus: An observational study
Authors: Stewart Zoe A. , Wallace Euan M. , Allan Carolyn A.
Published: October 2012

Objective

To quantify late‐pregnancy weight gain in women with and without gestational diabetes mellitus (GDM) and to determine factors associated with gestational weight gain.

Study design

A prospective clinical audit of 212 women (115 GDM and 97 non‐GDM) who were weighed at each antenatal visit from 24–32 weeks gestation until delivery. Women received routine antenatal clinical care. For women with GDM, this included a 2‐h lifestyle counselling session, capillary blood glucose testing and frequent clinical review.

Results

Women with GDM gained less weight than nondiabetic women (GDM: 1.18 kg (1.6%) [range, 3.8–7.1 kg]; non‐GDM: 4.0 kg (4.8%) [range, 0.7–18.5 kg]; P < 0.0001). Weight gain was influenced by body mass index and country of birth. Women with GDM showed reduced weight gain at weeks 1–4 postrecruitment, relative to weeks 4–8 (0.04 kg/week vs 0.45 kg/week; P < 0.0001). Nondiabetic women gained weight at a constant rate. GDM status was the only independent predictor of postrecruitment weight gain.

Conclusions

Application of a model of care for GDM (lifestyle advice and regular clinical review, in addition to home glucose monitoring) may reduce weight gain in women with GDM. The potential for applying a modified version of this model to all women in pregnancy warrants further study.
HPV vaccination of adult women: An audit of Australian general practitioners
Authors: Mazza Danielle , Petrovic Katja , Chakraborty Samantha
Published: October 2012

Background

While initial Human Papillomavirus (HPV) vaccine uptake estimates are encouraging, especially in the school‐aged population, it is unclear to what extent general practitioners (GPs) have been recommending and administering the vaccine to adult women and what the uptake has been.

Methods

A mixed methods study of Australian GPs consisting of a knowledge and attitudes questionnaire and an audit which assessed overall vaccination rates since commencement of the Australian National HPV program and in the last 50 female patients aged 27–45 years who consulted them.

Results

GPs have a good level of knowledge regarding HPV vaccination and are strongly committed to it for women until 27 years but are much less so for women aged 27–45 years. From 2007 to 2010, only 1.9% of women aged 27–45 who consulted the GPs commenced HPV vaccination. Of those, however, the majority completed all three doses. Higher rates of commencement of HPV vaccination (11.4%) were demonstrated by auditing the last 50 consecutive patients seen by the GP. In this group of women, 63% had received a Pap test in the last two years. Female GPs had significantly higher rates of vaccination.

Conclusions

There is relatively low HPV vaccine uptake in women aged 27–45. Once HPV vaccination is commenced, however, completion rates are high in women in this age group. Low uptake may be due to lack of opportunistic awareness raising in relevant consultations. Clear guidance together with further exploration of patient factors and GP barriers and enablers would assist implementation of HPV vaccination.
Asthma phenotypes identified by latent class analysis in the ISAAC phase II Spain study
Authors: Weinmayr G. , Keller F. , Kleiner A. , du Prel J. B. , Garcia‐Marcos L. , Batllés‐Garrido J. , Garcia‐Hernandez G. , Suarez‐Varela M. M. , Strachan D. P. , Nagel G.
Published: October 2012

Background

Classification of respiratory symptoms may help to identify different underlying asthma phenotypes reflecting differences in aetiology and prognosis of wheezing disease among children.

Objective

To determine childhood asthma phenotypes based on respiratory symptoms from a widely used questionnaire to further classify phenotypes in international settings.

Methods

Between 2000 and 2002 cross‐sectional studies were performed in four centres in Spain. Parental questionnaires were used to collect information on allergic diseases in more than 4000 children aged 8–12 years. In addition, objective markers for allergic sensitization and bronchial hyperresponsiveness (BHR) were measured. Latent class analyses (LCA) were applied to identify subgroups of children according to respiratory symptoms, and then the association of these groups with relevant clinical features such as concomitant allergic disease symptoms, atopy and BHR was studied.

Results

We found seven classes, one corresponding to healthy children, three classes related to wheeze and three other classes mainly related to congestion and coughed‐up phlegm. These tentative phenotypes differed in severity of symptoms and also in clinical correlates such as BHR and allergic sensitization. Atopy was more predominant in the ‘wheeze phenotypes’ whereas concomitant ‘allergic’ symptoms were most frequent in two of the ‘wheeze phenotypes’ and one of the ‘cough phenotypes’.

Conclusions

LCA on reported symptoms in a cross‐sectional survey allowed different subgroups with meaningful clinical correlates to be defined. It remains to be investigated to what extent these groups also have different aetiologies, prognoses and therapeutic needs.
Down syndrome and personalized medicine: Changing paradigms from genotype to phenotype to treatment
Authors: McCabe Linda L. , McCabe Edward R. B.
Published: October 2012

Abstract 

Personalized Medicine represents a paradigm shift in the conceptual framework of research and clinical care. This shift argues that Down syndrome is a treatable condition, and therefore we must invest in research to improve outcomes. Individuals with Down syndrome have varying levels of increased risk for a number of co‐morbidities, including infantile spasms and early onset Alzheimer's disease. We will review research in these associated conditions to show how investigators are attempting to identify biomarkers, including genomic, epigenomic, proteomic and metabolomic “signatures” that will predict who may be at risk to develop a specific co‐morbidity prior to onset and will provide novel targets for therapeutic development. This Personalized Medicine approach will permit predictive and preventive approaches for individuals at increased risk for co‐morbidities. The support for clinical trials among individuals with Down syndrome is beginning to overcome the “culture of intractability” that has surrounded this disorder.