bluuebunny/crossref_metadata_2025 huggingface dataset:
Silicon Migration from High‐barrier Coated Multilayer Polymeric Films to Selected Food Simulants after Microwave Processing Treatments
Authors: Dhawan Sumeet , Sablani Shyam S. , Tang Juming , Barbosa‐Cànovas Gustavo V. , Ullman Jeffrey L. , Bhunia Kanishka
Published: December 2013

The use of microwave (MW) technology for in‐package food sterilization and pasteurization has the potential for widespread use in the food industry. Because the use of MW technology requires that food be processed inside its packaging, the interaction between food and its packaging during processing must be studied to ensure package integrity as well as consumer safety. In this study, two commercially available multilayer films developed for retort sterilization were evaluated for their suitability to MW processing. Film A was composed of oriented nylon//coated polyethylene terephthalate//cast polypropylene (CPP); film B consisted of oriented nylon//coated nylon//CPP with overall oxygen transmission rates <0.2 cc/m2. day. Silicon (Si) was a major component in the coated polyethylene terephthalate layer and food‐contact CPP layer. This study evaluated the influence of MW processing on Si migration from films into selected food‐simulating liquids (FSLs; water and 3% acetic acid) using inductively coupled plasma‐mass spectroscopy, as compared with conventional thermal processing. This study also assessed migration of Si into FSL in terms of process temperature (70–123 °C) and time (18–34 min). A Fourier transform infrared spectrometer was used to evaluate the stability of the silicon–oxygen (Si–O) bonds in the metal‐oxide coated and food‐contact layer of the packaging film. Overall, there were no significant differences (p > 0.05) between the level of Si migration from films to FSL and the stability of Si–O–Si bonds during MW processing as compared with the conventional thermal processing. However, we found that the final processing temperature and time had a significant (p < 0.05) impact on Si migration into the FSL. Copyright © 2013 John Wiley & Sons, Ltd.
When land breezes collide: Converging diurnal winds over small bodies of water
Authors: Gille Sarah T. , Llewellyn Smith Stefan G.
Published: December 2013

Over enclosed and semi‐enclosed bodies of water, the land‐breeze/sea‐breeze circulation is expected to be modified by the presence of opposing coastlines. These effects are studied using satellite scatterometer surface wind observations from the QuikSCAT and ADEOS‐2 tandem mission from April–October 2003. Winds are studied for six bodies of water: the Red Sea, the Gulf of California, the Mediterranean, the Adriatic Sea, the Black Sea and the Caspian Sea. These bodies of water are large enough for the geographic orientation of the diurnal winds relative to the coastline to match the expected orientation for a straight coastline. Land breezes from opposite coastlines converge in the middle of these bodies of water, and in some cases the convergence line is shifted substantially away from the midpoint between opposite coastlines. Displacements in the convergence line appear likely to be explained by differences in the strength of the diurnal winds emanating from opposite coastlines associated with differential heating or island/peninsula effects, and by geographic displacements associated with large‐scale mean wind patterns.
Synthetic Phase II Shewhart‐type Attributes Control Charts When Process Parameters are Estimated
Authors: Castagliola Philippe , Wu Shu , Khoo Michael B. C. , Chakraborti S.
Published: December 2013

The performance of attributes control charts (such as c and np charts) is usually evaluated under the assumption of known process parameters (i.e., the nominal proportion of nonconforming units or the nominal number of nonconformities). However, in practice, these process parameters are rarely known and have to be estimated from an in‐control phase I data set. In this paper, we derive the run length properties of the phase II synthetic c and np charts with estimated parameters, and we investigate the number m of phase I samples that would be necessary for these charts in order to obtain similar in‐control average run lengths as in the known parameters case. We also propose new specific chart parameters that allow these charts to have approximately the same in‐control average run lengths as the ones obtained in the known parameter case. Copyright © 2013 John Wiley & Sons, Ltd.
A Tolerance Design Method for Electronic Circuits Based on Performance Degradation
Authors: Zhai Guofu , Zhou Yuege , Ye Xuerong
Published: December 2013

Due to the effects of manufacturing tolerances and environmental conditions, component parameters vary and degrade with time. This may cause performance measures of electronic circuits to deviate from design specifications. Therefore, a tolerance design method based on performance degradation is proposed for electronic circuits, so as to improve the robustness of output characteristics. First, sensitive components causing output fluctuation are determined via orthogonal experiment and PSpice simulation. Then, degradation path models are established to describe the degradation process of sensitive components. The predicted values worked out by the degradation path models are substituted into the simulation model for Monte Carlo analysis. Besides, output characteristics and performance reliability are evaluated according to Monte Carlo simulation. Finally, optimum allocation is carried out for component tolerances as per minimum life cycle cost. The proposed method is illustrated by a case study of light‐emitting diode (LED) driver. Copyright © 2013 John Wiley & Sons, Ltd.
Trajectory Tracking Controller Design for Unmanned Vehicles: A New Methodology
Authors: Cheein Fernando Auat , Scaglia Gustavo
Published: December 2013

A major issue in the automatic guidance of vehicles is the design of control laws dedicated to the specific mobile platform used. Thus, if the model associated with the mobile platform or its constraints change, a new control law must be designed. In this paper, the problem of designing trajectory tracking controllers for unmanned vehicles is addressed. The methodology proposed here is an algebraic approach for obtaining optimum and stable trajectory tracking controllers for nonholonomic vehicles. Such an algebraic formulation makes the proposal suitable for embedded applications. The stability and optimality of the proposed controllers design method is theoretically proven for both bicycle‐type and unicycle‐type mobile robots, although the methodology can be extended to other types of unmanned vehicles. Four tests were carried out in this work in order to show the advantages of the proposal: the step discontinuity test, the curvature test, the real world test, and navigation under disturbances in the control actions. The results obtained were compared with four trajectory tracking controllers previously published in the literature. Additionally, an agricultural application is included in order to show the performance of the proposed controller when applied to a service unit within an agricultural environment. Field experiments demonstrating the capabilities of our proposal are also reported and discussed.
Numerical Modelling of Dissipation Phenomena in a New Ladle Shroud for Fluidynamic Control and Its Effect on Inclusions Removal in a Slab Tundish
Authors: Solorio‐Diaz Gildardo , Davila‐Morales Rodolfo , de Jesus Barreto‐Sandoval Jose , Vergara‐Hernández Hector Javier , Ramos‐Banderas Angel , Galvan Sergio Ricardo
Published: December 2013

In the current research study, a mathematical model was developed to study the dissipation phenomena inside a new design of ladle shroud and its effects on flow patterns and inclusion removal rate. The New Ladle Shroud performance is evaluated in a conventional slab tundish, and the results are compared to different flow control arrangements. The velocity of the entry jet is decreased and the bulk flow is well controlled, the inclusion removal rate is improved, and compared to those arrangements where turbulence inhibitors are used.
Thermochemical Calculation of the Quaternary CaO–SiO2–Al2O3–MgO System at 1600°C for Predicting the MgO‐Saturation and MgO–MgO · Al2O3 Equilibrium of Secondary Metallurgical Slag
Authors: Goriupp Jürgen , Schenk Johannes , Klösch Gerald , Hiebler Martin
Published: December 2013

Different quaternary CaO–SiO2–Al2O3–MgO systems were calculated with thermochemical‐calculations at various temperatures by using FactSage6.2. The calculated systems provide enhanced knowledge of secondary metallurgical ladle slag conditions at process temperatures. These systems can also be used for predicting the MgO‐saturation and the MgO–MgO · Al2O3 equilibrium at various temperatures for commonly used ladle slag compositions.
Street Vending Phenomena: A Literature Review and Research Agenda
Authors: Wongtada Nittaya
Published: December 2013

Street vending is pervasive across the globe, especially in developing countries. It provides an important source of earnings for the unemployed in urban areas, as well as a source of relatively inexpensive goods and services for city residents. However, typical street vendors face a common set of problems, which range from tenuous property rights and harassment from civic authorities to subsistence living and earning. Under this precarious setting, street enterprises have been expanding. The objective of this article is to employ a systematic method to research the studies in this field, extract their findings, and integrate them in order to propose a model that incorporates factors affecting the success of street enterprises. Based on this model, major research issues are outlined to advance the knowledge in the field. © 2013 Wiley Periodicals, Inc.
“Use it or lose it”: Characterization, implications, and mitigation of female infertility in captive wildlife
Authors: Penfold Linda M. , Powell David , Traylor‐Holzer Kathy , Asa Cheryl S.
Published: December 2013

Zoos and other ex situ wildlife institutions can play an important role in species conservation by maintaining populations for education and research, as sources for potential re‐introduction or reinforcement, and as ambassadors for financial support of in situ conservation. However, many regional zoo associations are realizing that current captive populations are unsustainable, with many programs failing to meet demographic and genetic goals to ensure long‐term viability. Constraints on population size due to limited space often mandate delayed and/or less frequent breeding, but for females of many species this can have profound effects on fertility. A retrospective analysis combined with published literature and reliable anecdotal reports reveals that, when females are housed in a non‐breeding situation for extended periods of time, reproductive changes that negatively impact fertility have occurred in multiple species, including canids, elephants, white rhinoceros, Seba's bats, wildebeest, stingrays, and some felid species. Competing space needs and changing interest in taxa for exhibits over time compound the problem. Counter strategies to breed early and often have their own demographic and genetic consequences as well as logistical and political implications. Strategies to mitigate the sustainability crisis in these taxa might include a mixed strategy in which young, genetically valuable females are bred earlier and at more regular intervals to ensure reproductive success, in combination with the judicious use of available tools to manage the number of offspring produced, including contraception and culling. An understanding of the issues at stake is the first step towards developing management strategies for sustainable populations. Zoo Biol. 33:20–28, 2014. © 2013 Wiley Periodicals Inc.
All-aqueous multiphase microfluidics
Authors: Song Yang , Sauret Alban , Cheung Shum Ho
Published: December 2013

Immiscible aqueous phases, formed by dissolving incompatible solutes in water, have been used in green chemical synthesis, molecular extraction and mimicking of cellular cytoplasm. Recently, a microfluidic approach has been introduced to generate all-aqueous emulsions and jets based on these immiscible aqueous phases; due to their biocompatibility, these all-aqueous structures have shown great promises as templates for fabricating biomaterials. The physico-chemical nature of interfaces between two immiscible aqueous phases leads to unique interfacial properties, such as an ultra-low interfacial tension. Strategies to manipulate components and direct their assembly at these interfaces needs to be explored. In this paper, we review progress on the topic over the past few years, with a focus on the fabrication and stabilization of all-aqueous structures in a multiphase microfluidic platform. We also discuss future efforts needed from the perspectives of fluidic physics, materials engineering, and biology for fulfilling potential applications ranging from materials fabrication to biomedical engineering.
Non-Markovian properties and multiscale hidden Markovian network buried in single molecule time series
Authors: Sultana Tahmina , Takagi Hiroaki , Morimatsu Miki , Teramoto Hiroshi , Li Chun-Biu , Sako Yasushi , Komatsuzaki Tamiki
Published: December 2013

We present a novel scheme to extract a multiscale state space network (SSN) from single-molecule time series. The multiscale SSN is a type of hidden Markov model that takes into account both multiple states buried in the measurement and memory effects in the process of the observable whenever they exist. Most biological systems function in a nonstationary manner across multiple timescales. Combined with a recently established nonlinear time series analysis based on information theory, a simple scheme is proposed to deal with the properties of multiscale and nonstationarity for a discrete time series. We derived an explicit analytical expression of the autocorrelation function in terms of the SSN. To demonstrate the potential of our scheme, we investigated single-molecule time series of dissociation and association kinetics between epidermal growth factor receptor (EGFR) on the plasma membrane and its adaptor protein Ash/Grb2 (Grb2) in an in vitro reconstituted system. We found that our formula successfully reproduces their autocorrelation function for a wide range of timescales (up to 3 s), and the underlying SSNs change their topographical structure as a function of the timescale; while the corresponding SSN is simple at the short timescale (0.033–0.1 s), the SSN at the longer timescales (0.1 s to ∼3 s) becomes rather complex in order to capture multiscale nonstationary kinetics emerging at longer timescales. It is also found that visiting the unbound form of the EGFR-Grb2 system approximately resets all information of history or memory of the process.
High precision micro-impulse measurements for micro-thrusters based on torsional pendulum and sympathetic resonance techniques
Authors: Zhang Daixian , Wu Jianjun , Zhang Rui , Zhang Hua , He Zhen
Published: December 2013

A sympathetic resonance theory is analyzed and applied in a newly developed torsional pendulum to measure the micro-impulse produced by a μN s-class ablative pulsed plasma thruster. According to theoretical analysis on the dynamical behaviors of a torsional pendulum, the resonance amplification effect of micro-signals is presented. In addition, a new micro-impulse measurement method based on sympathetic resonance theory is proposed as an improvement of the original single pulse measurement method. In contrast with the single pulse measurement method, the advantages of sympathetic resonance method are significant. First, because of the magnification of vibration signals due to resonance processes, measurement precision for the sympathetic resonance method becomes higher especially in reducing reading error. With an increase in peak number, the relative errors induced by readout of voltage signals decrease to approximately ±1.9% for the sympathetic resonance mode, whereas the relative error in single pulse mode is estimated as ±13.4%. Besides, by using the resonance amplification effect the sympathetic resonance method makes it possible to measure an extremely low-impulse beyond the resolution of a thrust stand without redesigning or purchasing a new one. Moreover, because of the simple operational principle and structure the sympathetic resonance method is much more convenient and inexpensive to be implemented than other high-precision methods. Finally, the sympathetic resonance measurement method can also be applied in other thrust stands to improve further the ability to measure the low-impulse bits.
The thermodynamic properties of hydrated γ-Al2O3 nanoparticles
Authors: Spencer Elinor C. , Huang Baiyu , Parker Stewart F. , Kolesnikov Alexander I. , Ross Nancy L. , Woodfield Brian F.
Published: December 2013

In this paper we report a combined calorimetric and inelastic neutron scattering (INS) study of hydrated γ-Al2O3 (γ-alumina) nanoparticles. These complementary techniques have enabled a comprehensive evaluation of the thermodynamic properties of this technological and industrially important metal oxide to be achieved. The isobaric heat capacity (Cp) data presented herein provide further critical insights into the much-debated chemical composition of γ-alumina nanoparticles. Furthermore, the isochoric heat capacity (Cv) of the surface water, which is so essential to the stability of all metal-oxides at the nanoscale, has been extracted from the high-resolution INS data and differs significantly from that of ice‑Ih due to the dominating influence of strong surface-water interactions. This study also encompassed the analysis of four γ-alumina samples with differing pore diameters [4.5 (1), 13.8 (2), 17.9 (3), and 27.2 nm (4)], and the results obtained allow us to unambiguously conclude that the water content and pore size have no influence on the thermodynamic behaviour of hydrated γ-alumina nanoparticles.
Epitaxial lift-off of II–VI semiconductors from III–V substrates using a MgS release layer
Authors: Rajan Akhil , Davidson Ian A. , Moug Richard T. , Prior Kevin A.
Published: December 2013

Epitaxial lift-off (ELO) is a post-growth process that allows an epitaxial layer to be removed from its original substrate and transferred to a new one. ELO has previously been successfully demonstrated for III–V materials and also ZnSe based II–VI semiconductors using a MgS sacrificial layer. Following the recent successful growth of epitaxial MgS layers on GaP and InP substrates, in this paper we compare ELO of II–VI epilayers grown on GaP, GaAs, and InP substrates using MgS sacrificial layers in the range of 7–15 nm thick. Good quality lifted layers are obtained rapidly from InP and GaAs substrates. For GaP substrates, ELO is much slower and good quality lifts have only been achieved with ZnSe epilayers. Photoluminescence spectra obtained from epitaxial layers before and after ELO show changes in peak positions, which are compatible with changes of strain in the layer. The layers produced by ELO are flat and free of cracks, suggesting that this is an efficient and convenient method for the transfer of II–VI epitaxial layers to other substrates.
Direct current voltage sweep and alternating current impedance analysis of SrZrO3 memory device in ON and OFF states
Authors: Lai Chun-Hung , Liu Chih-Yi
Published: December 2013

The resistive switching (RS) effect of sputtered SrZrO3 memory cell is investigated by current-voltage (I-V) and impedance spectroscopy (IS) measurements for ON and OFF states. While the ON-state conduction in I-V exhibits ohmic relation of slightly temperature dependence, the OFF-state transport follows Frenkel-Poole mechanism and Arrhenius plot detects a single trap at 0.37 eV. An equivalent circuit model derived from the combined impedance-modulus spectra is proposed to characterize the real IS response. The extracted film capacitance and contact resistance keep constant at 25–100 °C and, by contrast, the film resistance reveals activation energy of 0.08 eV. Both I-V and IS analyses indicate the domination of the OFF-state film conduction on the observed RS behavior and thermal effect. For doped perovskites, the OFF-state electrical property is associated with the presence of film-interior oxygen vacancies.
Origins of
R
2
∗
orientation dependence in gray and white matter
Authors: Rudko David A. , Klassen L. Martyn , de Chickera Sonali N. , Gati Joseph S. , Dekaban Gregory A. , Menon Ravi S.
Published: December 2013

Significance

Differences in the apparent transverse relaxation rate (

) between tissues are exploited in numerous magnetic resonance imaging (MRI) techniques from functional MRI to susceptibility weighted imaging. Recent results show a surprising dependence of tissue

on orientation. This study demonstrates that the orientation dependence of

in both white and cortical gray matter has a sinusoidal dependence on tissue orientation and a linear dependence on the perturber volume fraction (measured by quantitative histology). A biophysical model is used to relate the observed orientation dependence to the local Larmor frequency shift and volume magnetic susceptibility of the tissue.
Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach
Authors: You Sungyong , Yoo Seung-Ah , Choi Susanna , Kim Ji-Young , Park Su-Jung , Ji Jong Dae , Kim Tae-Hwan , Kim Ki-Jo , Cho Chul-Soo , Hwang Daehee , Kim Wan-Uk
Published: December 2013

Significance

Rheumatoid arthritis (RA) is an autoimmune disorder that affects ∼1% of the population. Macrophage- and fibroblast-like synoviocytes are thought to play central roles in the pathogenesis of RA. They have shared and distinct features defining RA pathology. However, these features have not been systematically explored. Using global gene expression profiling, we identified molecular signature and biological network models underlying the pathologic features of macrophage-like vs. fibroblast-like synoviocytes. Based on the network models, we selected key regulators, including POSTN and TWIST1, responsible for synoviocyte migration/invasion causing joint destruction, and their validity was experimentally confirmed. Our findings provide a comprehensive and systematic basis for mechanisms explaining RA pathogenesis and also for identification of therapeutic targets for RA.
NOTCH1–RBPJ complexes drive target gene expression through dynamic interactions with superenhancers
Authors: Wang Hongfang , Zang Chongzhi , Taing Len , Arnett Kelly L. , Wong Yinling Joey , Pear Warren S. , Blacklow Stephen C. , Liu X. Shirley , Aster Jon C.
Published: December 2013

Significance

Studies focused on understanding how transcription factors control gene expression have shown that transcription-factor binding sites generally greatly exceed the number of regulated genes, making it challenging to identify functional binding sites. Using Notch pathway inhibitors, we identified a subset of Notch-binding sites in leukemia cell genomes that are dynamic, changing in occupancy relatively rapidly when Notch signaling is perturbed. Dynamic Notch sites are highly associated with genes that are directly regulated by Notch and mainly lie in large regulatory switches termed superenhancers, which control genes with key roles in development and cancer. This work links Notch signaling to superenhancers and suggests that assessment of transcription factor–genome dynamics can help to identify functionally important regulatory sites.
β-Catenin induces T-cell transformation by promoting genomic instability
Authors: Dose Marei , Emmanuel Akinola Olumide , Chaumeil Julie , Zhang Jiangwen , Sun Tianjiao , Germar Kristine , Aghajani Katayoun , Davis Elizabeth M. , Keerthivasan Shilpa , Bredemeyer Andrea L. , Sleckman Barry P. , Rosen Steven T. , Skok Jane A. , Le Beau Michelle M. , Georgopoulos Katia , Gounari Fotini
Published: December 2013

Significance

Understanding molecular mechanisms that underlie genomic instability will remove a major obstacle to effective treatment of cancer. Here we characterize a unique animal model that allows insight into mechanisms of genomic instability leading to oncogenic translocations. We show that thymocyte-specific activation of β-catenin induces genomically unstable lymphomas with
Tcra/Myc
translocations, reminiscent of human leukemia. Tcf-1, the partner of β-catenin, colocalized throughout the genome with the RAG2 recombinase at DNA sites thought to be vulnerable to illegitimate recombination. Pretransformed thymocytes showed increased DNA damage at the translocating loci and altered DNA repair. These cells survived despite DNA damage. These surprising observations show that activated β-catenin promotes genomic instability and cancer by compromising DNA repair and enhancing cell survival.
Roles of common subunits within distinct multisubunit complexes
Authors: Nakabayashi Yu , Kawashima Satoshi , Enomoto Takemi , Seki Masayuki , Horikoshi Masami
Published: December 2013

Significance

The same protein is often a subunit of more than one multisubunit protein complex, each of which has a distinct function within cells. Mutating such a protein would cause multiple cellular defects; therefore, it is difficult to distinguish between the function of a protein in one complex from its functions in other complexes. Here, we developed a unique strategy to overcome this problem, which will help to analyze a variety of biological processes by revealing the specific roles played by such proteins within multisubunit protein complexes.
Observation time scale, free-energy landscapes, and molecular symmetry
Authors: Wales David J. , Salamon Peter
Published: December 2013

Significance

This work explains how the experimental time scale determines our perception of the free-energy landscape for a molecular system. Greater temporal resolution naturally resolves more free-energy minima, although this structure may be averaged out over longer time scales. Hence shorter observation times may resolve more states, but result in broken ergodicity. A consistent treatment of the thermodynamics that corresponds with a given experiment must therefore account for the feasibility of different rearrangement mechanisms on the relevant observation time scale. Hence we establish a connection between the concepts of molecular symmetry, ergodicity, and local equilibrium.
Structure-based cleavage mechanism of
Thermus thermophilus
Argonaute DNA guide strand-mediated DNA target cleavage
Authors: Sheng Gang , Zhao Hongtu , Wang Jiuyu , Rao Yu , Tian Wenwen , Swarts Daan C. , van der Oost John , Patel Dinshaw J. , Wang Yanli
Published: December 2013

Significance

We have solved crystal structures of ternary
Thermus thermophilus
Argonaute (Ago) complexes with guide and target DNA in cleavage-incompatible, cleavage-compatible, and postcleavage states in the 2.2- to 2.3-Å resolution range, thereby identifying the relative positions of catalytic residues, a pair of Mg
2+
cations, and the nucleophilic water poised for in-line attack on the cleavable phosphate. These higher resolution structures represent snapshots of distinct key steps in the catalytic RNase H-mediated cleavage pathway, providing additional detailed insights into Ago-mediated cleavage chemistry of target strands. Importantly, a Glu residue shifts from an “outside” to an “inside” conformation where it inserts into the catalytic pocket to complete a catalytic tetrad during the transition from a cleavage-incompatible to a cleavage-compatible conformation.
Redirecting splicing with bifunctional oligonucleotides
Authors: Brosseau Jean-Philippe , Lucier Jean-François , Lamarche Andrée-Anne , Shkreta Lulzim , Gendron Daniel , Lapointe Elvy , Thibault Philippe , Paquet Éric , Perreault Jean-Pierre , Abou Elela Sherif , Chabot Benoit
Published: December 2013

Ectopic modulators of alternative splicing are important tools to study the function of splice variants and for correcting mis-splicing events that cause human diseases. Such modulators can be bifunctional oligonucleotides made of an antisense portion that determines target specificity, and a non-hybridizing tail that recruits proteins or RNA/protein complexes that affect splice site selection (TOSS and TOES, respectively, for targeted oligonucleotide silencer of splicing and targeted oligonucleotide enhancer of splicing). The use of TOSS and TOES has been restricted to a handful of targets. To generalize the applicability and demonstrate the robustness of TOSS, we have tested this approach on more than 50 alternative splicing events. Moreover, we have developed an algorithm that can design active TOSS with a success rate of 80%. To produce bifunctional oligonucleotides capable of stimulating splicing, we built on the observation that binding sites for TDP-43 can stimulate splicing and improve U1 snRNP binding when inserted downstream from 5′ splice sites. A TOES designed to recruit TDP-43 improved exon 7 inclusion in SMN2. Overall, our study shows that bifunctional oligonucleotides can redirect splicing on a variety of genes, justifying their inclusion in the molecular arsenal that aims to alter the production of splice variants.
c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs
Authors: Gustems Montse , Woellmer Anne , Rothbauer Ulrich , Eck Sebastian H. , Wieland Thomas , Lutter Dominik , Hammerschmidt Wolfgang
Published: December 2013

CpG methylation in mammalian DNA is known to interfere with gene expression by inhibiting the binding of transactivators to their cognate sequence motifs or recruiting proteins involved in gene repression. An Epstein–Barr virus-encoded transcription factor, Zta, was the first example of a sequence-specific transcription factor that preferentially recognizes and selectively binds DNA sequence motifs with methylated CpG residues, reverses epigenetic silencing and activates gene transcription. The DNA binding domain of Zta is homologous to c-Fos, a member of the cellular AP-1 (activator protein 1) transcription factor family, which regulates cell proliferation and survival, apoptosis, transformation and oncogenesis. We have identified a novel AP-1 binding site termed meAP-1, which contains a CpG dinucleotide. If methylated, meAP-1 sites are preferentially bound by the AP-1 heterodimer c-Jun/c-Fos in vitro and in cellular chromatin in vivo. In activated human primary B cells, c-Jun/c-Fos locates to these methylated elements in promoter regions of transcriptionally activated genes. Reminiscent of the viral Zta protein, c-Jun/c-Fos is the first identified cellular member of the AP-1 family of transactivators that can induce expression of genes with methylated, hence repressed promoters, reversing epigenetic silencing.
Targeting and tracing of specific DNA sequences with dTALEs in living cells
Authors: Thanisch Katharina , Schneider Katrin , Morbitzer Robert , Solovei Irina , Lahaye Thomas , Bultmann Sebastian , Leonhardt Heinrich
Published: December 2013

Epigenetic regulation of gene expression involves, besides DNA and histone modifications, the relative positioning of DNA sequences within the nucleus. To trace specific DNA sequences in living cells, we used programmable sequence-specific DNA binding of designer transcription activator-like effectors (dTALEs). We designed a recombinant dTALE (msTALE) with variable repeat domains to specifically bind a 19-bp target sequence of major satellite DNA. The msTALE was fused with green fluorescent protein (GFP) and stably expressed in mouse embryonic stem cells. Hybridization with a major satellite probe (3D-fluorescent in situ hybridization) and co-staining for known cellular structures confirmed in vivo binding of the GFP-msTALE to major satellite DNA present at nuclear chromocenters. Dual tracing of major satellite DNA and the replication machinery throughout S-phase showed co-localization during mid to late S-phase, directly demonstrating the late replication timing of major satellite DNA. Fluorescence bleaching experiments indicated a relatively stable but still dynamic binding, with mean residence times in the range of minutes. Fluorescently labeled dTALEs open new perspectives to target and trace DNA sequences and to monitor dynamic changes in subnuclear positioning as well as interactions with functional nuclear structures during cell cycle progression and cellular differentiation.
Dissecting pollinator responses to a ubiquitous ultraviolet floral pattern in the wild
Authors: Koski Matthew H. , Ashman Tia‐Lynn
Published: December 2013

Colour patterns on flowers can increase pollinator visitation and enhance foraging behaviour. Flowers uniform in colour to humans, however, can appear patterned to insects due to spatial variation in UV reflectance on petals. A UV ‘bullseye’ pattern that is common among angiosperms – UV‐absorbing petal bases and UV‐reflective apices – purportedly functions as a nectar guide, enhancing pollinator orientation and experimental evidence suggests that UV reflectance increases floral apparency to pollinators.

We test the pollinator‐attracting and pollinator‐orienting functions of floral UV pattern and UV reflectance under natural conditions. Specifically, we address whether UV reflection alone, or UV pattern influences small bee and syrphid fly attraction rates (approaching, landing and foraging visits), foraging rates, and likelihood of foraging and orienting to the centre of flowers, using Argentina anserina, a species whose flowers exhibit variability in the size of the UV bullseye. We manipulated UV properties while maintaining uniformly yellow petals to create three phenotypes – uniformly UV‐absorptive, uniformly UV‐reflective, and inversed bullseye (reflective bases and absorptive apices) and compared insect visitation and behaviour to control flowers with the common UV bullseye phenotype.

The presence of UV pattern increased attraction rates by both bees and syrphid flies relative to either fully UV reflective or absorptive flowers. However, only in the inverse array did the bullseye phenotype elicit higher foraging rates than the test flower. Neither the presence of pattern, nor the reversal of the common pattern influenced the likelihood of pollinator foraging or orientating to the flowers' centre during a visit.

We provide some of the first evidence to suggest that flowers with spatial variation in UV reflectance may be more conspicuous to insects than those with petals that uniformly absorb or reflect UV, all of which are naturally occurring phenotypes. Further, we verify that the most common UV pattern in nature increases insect attraction and foraging rate relative to the inverse pattern. Results confirm a distance apparency function of the UV bullseye, but we argue for reconsideration of the notion that pollinators benefit from this ubiquitous floral motif through enhanced foraging efficiency.
Actors, patients and agency: a recent history
Authors: Armstrong David
Published: December 2013

This article examines the history of patients’ behaviour since the middle of the 20th century. It describes a number of strategies that have served to encourage patients to exercise increasingly autonomous behaviour. The effect has been to instil a sense of agency in previously passive patients.
The pursuit of preventive care for chronic illness: turning healthy people into chronic patients
Authors: Kreiner Meta J. , Hunt Linda M.
Published: December 2013

Preventive health care has become prominent in clinical medicine in the US, emphasising risk assessment and control, rather than addressing the signs and symptoms of pathology. Current clinical guidelines, reinforced by evidence‐based decision aids and quality of care assessment, encourage clinicians to focus on maintaining rigid test thresholds that are based on population norms. While achieving these goals may benefit the total population, this may be of no benefit or even harmful to individual patients. In order to explore how this phenomenon is manifested in clinical care and consider some factors that promote and sustain this trend, we analysed observations of over 100 clinical consultations, and open‐ended interviews with 58 primary care clinicians and 70 of their patients. Both clinicians and patients equated at‐risk states with illness and viewed the associated interventions not as prevention, but as treatment. This conflation of risk and disease redefines clinical success such that reducing the threat of anticipated future illness requires the acceptance of aggressive treatments and any associated adverse effects in the present. While the expanding emphasis on preventive medicine may improve the health profile of the total population, the implications of these innovations for the wellbeing of individual patients merits careful reconsideration.
Organisational innovation and control practices: the case of public–private mix in tuberculosis control in India
Authors: Engel Nora , van Lente Harro
Published: December 2013

Partnerships between public and private healthcare providers are often seen as an important way to improve health care in resource‐constrained settings. Despite the reconfirmed policy support for including private providers into public tuberculosis control in India, the public–private mix (PPM) activities continue to face apprehension at local implementation sites. This article investigates the causes for those difficulties by examining PPM initiatives as cases of organisational innovation. It examines findings from semi‐structured interviews, observations and document analyses in India around three different PPM models and the attempts of innovating and scaling up. The results reveal that in PPM initiatives underlying problem definitions and different control practices, including supervision, standardisation and culture, continue to clash and ultimately hinder the scaling up of PPM. Successful PPM initiatives require organisational control practices which are rooted in different professions to be bridged. This entails difficult balancing acts between innovation and control. The innovators handle those differently, based on their own ideas of the problem that PPM should address and their own control practices. We offer new perspectives on why collaboration is so difficult and show a possible way to mitigate the established apprehensions between professions in order to make organisational innovations, such as PPM, sustainable and scalable.
No microsatellite instability using Bethesda panel and revised markers in uterine leiomyomas
Authors: Hong Ja‐Min , Lee Jae‐Ho , Gwon Gi‐Jeong , Kim Dae‐Kwang
Published: December 2013

Uterine leiomyomas are benign tumors of the uterus that arise clonally from smooth muscle cells of the myometrium and are very common reason for hysterectomy. The aim of this study was to evaluate microsatellite instability (MSI) in uterine leiomyomas using a set of MSI markers by Promega Corporation (Madison, WI, USA) and the Bethesda guideline. DNA was isolated from paired normal and tumoral tissues in 50 patients with uterine leiomyomas and MSI was analyzed by using seven microsatellite markers. Our result showed that microsatellite stability was found in all uterine leiomyomas. These data confirm the genetic status of uterine leiomyomas for the first time in Korean populations, and suggest that uterine leiomyomas have genetic stability in Korean.
Neurotoxicological Profile Assessment of Lobeline after Acute Treatment in Mice
Authors: Verde Rodrigues Laise C. Lima , Decker Natália , Picada Jaqueline N. , Pereira Patrícia
Published: December 2013

Lobeline is a natural alkaloid with high affinity for nicotinic acetylcholine receptors, and it is a promising candidate for addiction treatment in human beings. This work evaluated the toxicological profile of lobeline with different behavioural models and investigated its effect on DNA damage (comet assay and micronucleus test) in mice. Acute administration of lobeline (5 or 10 mg/kg; i.p.) did not impair the parameters measured in the habituation and inhibitory avoidance test, suggesting that it has no effect on memory acquisition in these tasks. Lobeline did not affect the number or the latency to the first head‐dip in the hole board test, indicating that it was not anxiolytic/anxiogenic in this model. No genotoxic effects were observed in blood, liver and brain tissues collected 24 hr after the single injection of lobeline (both doses). There was no increase in micronucleus frequency in mice treated with lobeline, indicating the absence of toxicity in bone marrow of the animals. Therefore, the acute treatment with high doses of lobeline did not impair the behavioural parameters measured in this work. Additionally, the drug was not able to produce DNA damage.
Pilot investigation of isradipine in the treatment of bipolar depression motivated by genome‐wide association
Authors: Ostacher Michael J , Iosifescu Dan V , Hay Aleena , Blumenthal Sarah R , Sklar Pamela , Perlis Roy H
Published: December 2013

Objectives

Motivated by genetic association data implicating L‐type calcium channels in bipolar disorder liability, we sought to estimate the tolerability, safety, and efficacy of isradipine in the adjunctive treatment of bipolar depression.

Methods

A total of 12 patients with bipolar I or II depression entered this pilot, proof‐of‐concept eight‐week investigation and 10 returned for at least one post‐baseline visit. They were initiated on isradipine at 2.5 mg and titrated up to 10 mg daily, with blinded assessments of depression using the Montgomery–Åsberg Depression Rating Scale (MADRS) as well as adverse effects.

Results

Among the 10 patients, three had bipolar II disorder; all but two reported current episode duration longer than six months. In all, four of 10 completed the study; no significant adverse events were observed, although one subject discontinued treatment per protocol because of possible hypomanic symptoms which had resolved prior to study visit. In a mixed‐effects model, mean improvement in depression severity, assessed by MADRS, was 2.1 (standard error = 0.36) points/week (p < 0.001). Two of the 10 subjects remitted and four of the 10 subjects experienced 50% or greater symptomatic improvement with treatment.

Conclusions

Isradipine merits further investigation for the treatment of bipolar depression. This preliminary trial illustrates the potential utility of genetic investigation in identifying psychiatric treatment targets.
Why do alternative ways of responding improve children's performance on tests of strategic reasoning?
Authors: Carroll Daniel J. , FitzGibbon Lily , Critchley Anna
Published: December 2013

Changing the way in which children respond significantly improves performance across a variety of cognitive domains. However, the basis for this response‐mode effect is unknown. To address this issue, the current study tested 78 preschool children on a measure of executive functioning (the windows task: Hala & Russell, ). The task requires children to point to an empty box to receive a box with a treat in it. There were four versions of the task, differing only in the way in which children made their responses. Children in the baseline condition, who pointed with their finger, performed poorly. However, children in three alternative response‐mode conditions won the treat significantly more often. Strikingly, even children who pretended to be pointing with an arrow – but were in reality pointing with their finger – performed significantly better than baseline. We suggest that non‐standard response modes encourage children to reflect on their actions and that this reduces the number of unreflective errors they make. The findings demonstrate that response‐mode effects do not depend on the presence of a physical means of responding (such as an arrow), but can be achieved via a purely cognitive means (such as engaging in pretence).
G6PD deficiency: a classic example of pharmacogenetics with on‐going clinical implications
Authors: Luzzatto Lucio , Seneca Elisa
Published: December 2013

That primaquine and other drugs can trigger acute haemolytic anaemia in subjects who have an inherited mutation of the glucose 6‐phosphate dehydrogenase (G6PD) gene has been known for over half a century: however, these events still occur, because when giving the drug either the G6PD status of a person is not known, or the risk of this potentially life‐threatening complication is under‐estimated. Here we review briefly the genetic basis of G6PD deficiency, and then the pathophysiology and the clinical features of drug‐induced haemolysis; we also update the list of potentially haemolytic drugs (which includes rasburicase). It is now clear that it is not good practice to give one of these drugs before testing a person for his/her G6PD status, especially in populations in whom G6PD deficiency is common. We discuss therefore how G6PD testing can be done reconciling safety with cost; this is once again becoming of public health importance, as more countries are moving along the pathway of malaria elimination, that might require mass administration of primaquine. Finally, we sketch the triangular relationship between malaria, antimalarials such as primaquine, and G6PD deficiency: which is to some extent protective against malaria, but also a genetically determined hazard when taking primaquine.
Complement and cytokine response in acute Thrombotic Thrombocytopenic Purpura
Authors: Westwood John‐Paul , Langley Kathryn , Heelas Edward , Machin Samuel J. , Scully Marie
Published: December 2013

Complement dysregulation is key in the pathogenesis of atypical Haemolytic Uraemic Syndrome (aHUS), but no clear role for complement has been identified in Thrombotic Thrombocytopenic Purpura (TTP). We aimed to assess complement activation and cytokine response in acute antibody‐mediated TTP. Complement C3a and C5a and cytokines (interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, tumour necrosis factor, interferon‐γ and IL‐17a) were measured in 20 acute TTP patients and 49 remission cases. Anti‐ADAMTS13 immunoglobulin G (IgG) subtypes were measured in acute patients in order to study the association with complement activation. In acute TTP, median C3a and C5a were significantly elevated compared to remission, C3a 63·9 ng/ml vs. 38·2 ng/ml (P < 0·001) and C5a 16·4 ng/ml vs. 9·29 ng/ml (P < 0·001), respectively. Median IL‐6 and IL‐10 levels were significantly higher in the acute vs. remission groups, IL‐6: 8 pg/ml vs. 2 pg/ml (P = 0·003), IL‐10: 6 pg/ml vs. 2 pg/ml (P < 0·001). C3a levels correlated with both anti‐ADAMTS13 IgG (rs = 0·604, P = 0·017) and IL‐10 (rs = 0·692, P = 0·006). No anti‐ADAMTS13 IgG subtype was associated with higher complement activation, but patients with the highest C3a levels had 3 or 4 IgG subtypes present. These results suggest complement anaphylatoxin levels are higher in acute TTP cases than in remission, and the complement response seen acutely may relate to anti‐ADAMTS13 IgG antibody and IL‐10 levels.