bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome guardian p53 and viral infections
Authors: Sato Yoshitaka , Tsurumi Tatsuya
Published: December 2012

Because virus infections elicit various cellular responses that inhibit viral replication and growth, viruses must intervene to attenuate antiviral measures in order to thrive. The genome guardian p53 plays a central part not only in DNA damage responses, inducing cell cycle arrest or apoptosis, but also in the innate host immune control of viral infections by orchestrating diverse signaling pathways originating from many different cellular receptors and sensors. Many viruses have acquired sophisticated mechanisms to regulate p53 functions by deploying subversive proteins and modulating its post‐transcriptional status. In this review, we overview the mechanisms by which DNA and RNA viruses manage p53 signaling in favor of their continued survival. Copyright © 2012 John Wiley & Sons, Ltd.
Fulfilling multiple obligations: Preservice elementary teachers’ use of an instructional model while learning to plan and teach science
Authors: GUNCKEL KRISTIN L.
Published: December 2012

Recent efforts to design science methods course frameworks that scaffold preservice teachers in organizing inquiry instructional sequences show promise, yet preservice teachers do not always use these frameworks when they teach in school field placements. This article uses a Discourses lens to explore how two preservice elementary teachers’ sense of obligation shaped their use of an instructional model in their science planning and teaching. The preservice teachers’ course assignments, planned and enacted instructional sequences, and stimulated recall interviews were analyzed to characterize how their sense of obligations as students in a university science methods course and as student teachers in their school field‐placement classrooms enabled and constrained their use of the instructional model. Findings show that the preservice teachers encountered multiple Discourses across communities. These Discourses shaped the obligations that preservice teachers were expected to fulfill. The preservice teachers used the instructional model when it supported them in meeting their obligations to others. These findings have implications for situating teacher orientations in Discourses, understanding the role of mentor teachers in supporting preservice teachers in using instructional models, and framing the function of preservice teachers’ subject‐matter knowledge for using instructional models.
Determination of the second step microstructure for superhydrophobic surfaces
Authors: Zhang Hongyun , Li Wen , Zhang Xiaokai , Miao Fahong , Li Taohai , Liu Haihua
Published: December 2012

A selection of suitable microstructures is critical to fabrication and properties of superhydrophobic surfaces (SHS). In this study, we introduce a three‐dimensional droplet model to thermodynamically analyze the superhydrophobic properties for the purpose of determining the second step of a two‐step microstructure suitable for the SHS based on the common models within the reach of the existing macro‐machining technology. It is found that a sinusoidal microstructure is the most suitable, followed by a cone frustum and a prism in the composite wetting state, as well as the transition from hydrophilic to hydrophobic depends basically on the solid fraction rather than non‐determinative surface microscopic topography. The predictions of the model are found in quite good agreement with the experimental observations. This study will facilitate fabrication of the SHS on how to select the suitable morphology. Copyright © 2012 John Wiley & Sons, Ltd.
Summary of ISO/TC 201 Standard: ISO 16129‐:2012 – Surface chemical analysis — Procedures to assess the day‐to‐day performance of an X‐ray photoelectron spectrometer
Authors: Wolstenholme J.
Published: December 2012

This International Standard is designed to allow the user to simply assess, on a routine basis, several key parameters of an X‐ray photoelectron spectrometer. It is not intended to provide an exhaustive performance check but instead provides a rapid set of tests that may be conducted frequently. Aspects of instrument behaviour covered by this document include the vacuum, measurements of spectra of conductive or non‐conductive samples and the current state of the X‐ray source. Other important aspects of the instrument performance (e.g. lateral resolution) fall outside the scope of this standard. The standard is intended for use with commercial X‐ray photoelectron spectrometers equipped with a monochromated Al Kα X‐ray source or with a unmonochromated Al or Mg Kα X‐ray source. Copyright © 2012 John Wiley & Sons, Ltd.
A Springback Compensation Strategy and Applications to Bending Cases
Authors: Liao Juan , Xue Xin , Zhou Chi , Barlat Frederic , Gracio Jose J.
Published: December 2012

Part shape error due to springback is a manufacturing defect in the sheet metal forming. This problem can be corrected by adjusting the tool shape to an appropriate shape or process optimization. In this paper, a discrete curvature adjustment (DCA) strategy is developed for tool design of channel bending products. This strategy aims at generating the right tool shape in a short time using the measured data from the trial part. A dynamic compensation factor which varies with part geometry and specific process condition will also be used to adjust the tool curvatures. Applications of this method in the tool design of an asymmetrical U‐shaped part, an industrial blade, and a cylindrical part were presented. The experiment results demonstrated that this strategy was able to reduce the trial times of die modification from five or six to one or two, thus saving time and cost in the industry production. Additionally, the comparison of this method with the existing displacement adjustment (DA) method was also discussed.
Using Student Development Theories as Conceptual Frameworks in Leadership Education
Authors: Owen Julie E.
Published: December 2012

This chapter describes the importance of selecting conceptual frameworks to undergird leadership education programs, and connects the selection of theoretical frameworks to principles of intentional design. International Leadership Association overarching Conceptual Framework Guiding Question: “What is the conceptual framework of the leadership education program?”
Yukawa-unified natural supersymmetry
Authors: Baer Howard , Kraml Sabine , Kulkarni Suchita
Published: December 2012

Abstract

Previous work on t − b − τ Yukawa-unified supersymmetry, as expected from SUSY GUT theories based on the gauge group SO(10), tended to have exceedingly large electroweak fine-tuning (EWFT). Here, we examine supersymmetric models where we simultaneously require low EWFT (“natural SUSY”) and a high degree of Yukawa coupling unification, along with a light Higgs scalar with m

h
~ 125 GeV. As Yukawa unification requires large tan β ~ 50, while EWFT requires rather light third generation squarks and low μ ≈ 100 − 250 GeV, B-physics constraints from BR(B → X

s
γ) and BR(B

s
→ μ
+
μ
−) can be severe. We are able to find models with EWFT Δ ≲ 50 − 100 (better than 1–2% EWFT) and with Yukawa unification as low as R
yuk ~ 1.2 (20% unification). The unification is lessened to R
yuk ~ 1.3 when B-physics constraints are imposed. We present several Yukawa-unified natural SUSY (YUNS) benchmark points. LHC searches will be able to access gluinos in the lower 1 – 2 TeV portion of their predicted mass range although much of YUNS parameter space may lie beyond LHC14 reach. If heavy Higgs bosons can be accessed at a high rate, then the rare H, A → μ
+
μ
− decay might allow a determination of tan β ~ 50 as predicted by YUNS models. Finally, the predicted light higgsinos should be accessible to a linear e
+
e
− collider with
$ \sqrt{s}\sim 0.5 $
TeV.
JUSTIFICATION AS ‘WOULD-BE’ KNOWLEDGE
Authors: McGlynn Aidan
Published: December 2012

In light of the failure of attempts to analyse knowledge as a species of justified belief, a number of epistemologists have suggested that we should instead understand justification in terms of knowledge. This paper focuses on accounts of justification as a kind of ‘would-be’ knowledge. According to such accounts a belief is justified just in case any failure to know is due to uncooperative external circumstances. I argue against two recent accounts of this sort due to Alexander Bird and Martin Smith. A further aim is to defend a more traditional conception, according to which justification is a matter of sufficiently high evidential likelihood. In particular, I suggest that this conception of justification offers a plausible account of lottery cases: cases in which one believes a true proposition – for example that one's lottery ticket will lose – on the basis of probabilistic evidence.
Energy expenditure on household, childcare and occupational activities of women from urban poor households
Authors: Sujatha T. , Shatrugna Veena , Venkataramana Y. , Begum Nazeema
Published: December 2012

This present study attempts to measure the energy cost of activities of women from the poor socio-economic group in India. Women in the age group of 18–40 years (n 98) either working for incomes or classified as homemakers were randomly selected. Time disposition studies were conducted by a 24 h observation of their activities on a typical day. Predominant activities were identified from the activity profiles and standardized for posture and duration. The BMR (Douglas bag method) and energy cost of the activities (Kofranyi–Michaelis meter) were measured by indirect calorimetry. The energy consumption during these activities ranged from 2·94–12·51 kJ/min. The tasks were divided into standard, household, childcare, occupational and other activities. Using the criteria, attempts were made to categorize the activities into light, moderate and heavy. It was significant that except for walking, the standard activities and occupational work could be classified into the light category (< 2·2 BMR). Most of the household and childcare activities except cooking were classified into the moderate to heavy (2·2–> 2·8 BMR). The energy expenditure of activities did not differ significantly between women with different occupations. This present study provides an important database on energy costs of activities for computing energy requirements of women involved in similar activity patterns.
Testing Hardy–Weinberg disequilibrium using the generalized linear model
Authors: XU SHIZHONG
Published: December 2012

Current methods for detecting Hardy–Weinberg disequilibrium (HWD) only deal with one locus at a time. We developed a method that can jointly detect HWD for multiple loci. The method was developed under the generalized linear model (GLM) using the probit link function. When applied to a single locus, the new method is more powerful than the exact test. When applied to two or more loci, the method can reduce false positives caused by linkage disequilibrium (LD). We applied the method to 24 single nucleotide polymorphism (SNP) markers of a single human gene and eliminated several false positive HWDs due to LD. We developed an R package ‘hwdglm’ for joint HWD detection, which can be downloaded from our personal website (www.statgen.ucr.edu).
Structural Impediments to African Growth? New Evidence from Real Wages in British Africa, 1880–1965
Authors: Frankema Ewout , Waijenburg Marlous Van
Published: December 2012

Recent literature on the historical determinants of African poverty has emphasized structural impediments to African growth, such as adverse geographical conditions, weak institutions, or ethnic heterogeneity. But has African poverty been a persistent historical phenomenon? This article checks such assumptions against the historical record. We push African income estimates back in time by presenting urban unskilled real wages for nine British African colonies (1880–1965). We find that African real wages were well above subsistence level and that they rose significantly over time. Moreover, in West Africa and Mauritius real wage levels were considerably higher than those in Asia.
Approaching the “cold curve” in laser-driven shock wave experiment of a matter precompressed by a partially perforated diamond anvil
Authors: Nissim N. , Eliezer S. , Werdiger M. , Perelmutter L.
Published: December 2012

This paper suggests a novel route to approach the cold compression curve in laser-plasma induced shock waves. This effect is achieved with a precompression in a diamond anvil cell (DAC). In order to keep the necessary structure of one dimensional shock wave it is required to use a diamond anvil cell with a partially perforated diamond anvil. Precompression pressures of about 50 GPa, that are an order of magnitude higher than the currently reported pressures, are possible to obtain with presentley existing diamond anvil cell technology. The precompressed Hugoniot of Al was calculated for different precompression pressures and it was found that at precompression pressure of 50 GPa the Hugoniot follows the “cold curve” up to about 2 Mbar and 5.2 g/cc. Furthermore, the thermal relative contribution on the Hugoniot curves is calculated.
FIGURINES ARE US? THE SOCIAL ORGANIZATION OF JAINA ISLAND, CAMPECHE, MEXICO
Authors: McVicker Donald
Published: December 2012

Despite the recognition by many scholars of the high esthetic value of Jaina-style figurines, they present a number of analytic problems. Their functions remain obscure, and their role in Late Classic period Maya society has not been adequately examined. Throughout southeastern Mesoamerica, with few exceptions, all figurines and fragments are found in domestic contexts, mostly trash heaps; on Jaina, most examples come from graves. This article addresses the question of Jaina exceptionalism. It places its unique features in the broader context of Terminal Classic political and economic developments that were sweeping across the northern Maya Lowlands. Here I argue that the use of figurines in domestic rituals determined their appropriateness for placement in a particular grave, rather than the age, sex, or occupation of the deceased.
The Birth of Anglicanism
Authors: MacCulloch Diarmaid
Published: December 2012

The paper surveys the English Reformation in the wider European context to demonstrate that the concept of ‘Anglicanism’ is hardly appropriate for the post-Reformation English Church in the sixteenth century: it was emphatically Protestant, linked to Reformed rather than Lutheran Protestantism. Henry VIII created a hybrid of a Church after breaking with Rome, but that was not unique in northern Europe. There were widespread attempts to find a ‘middle way’, the model being Cologne under Archbishop Hermann von Wied. Wied's efforts failed, but left admirers like Albert Hardenberg and Jan Laski, and their Reformations gradually moved towards those of central Europe—the first Reformed theologians. Edward VTs Reformation aligned itself with this new grouping, and produced prototypes of liturgy and theological formulary which endure to the present day—with the exception of a proposed reform of canon law, with its provisions for divorce. Elizabeth Ts 1559 religious settlement fossilised Edward's Church from autumn 1552. It made no concessions to Catholics, despite later A nglo- Catholic myth-making: minor adjustments were probably aimed at Lutherans. There is nevertheless a ‘Nicodemite’ association among the leading figures who steered the Settlement through its opening years. Important and unlikely survivals were cathedrals, uniquely preserved in a Protestant context and a source of future ideological Catholic ‘subversion’. Nevertheless the theological tone of the Elizabethan Church was a broadly-based Reformed Protestantism, aligned to Zürich rather than to Geneva. Early seventeenth-century Arminianism or Laudianism represented a new direction, and the Puritanism of New England may better represent the English Reformation than the ‘Anglican’ synthesis which came to fruition in the English Church after Charles II's restoration in 1660. In any case, Anglicanism continues to represent in uneasy but useful tension the two poles of theology contending for mastery in the century after Elizabeth Is coming to power.
Between Class War on All Fronts and Anti-Political Autonomy: The Contested Place of Politics in the Working-Class Movements of Leipzig and Lyon during the Inter-War Years
Authors: HÄBERLEN JOACHIM C.
Published: December 2012

This article investigates the contested boundaries of the political within the working-class movements in Leipzig and Lyon at the end of the Weimar Republic and during the Popular Front. What the appropriate issues and places of politics should be was a question that was highly contested among the organisations of the local working-class movements in both cities. The article argues that an over-politicisation of the left-proletarian milieu in Leipzig contributed to the working-class movement's failure successfully to mobilise against the Nazis, while the dynamics of politicisation in Lyon helped the formation of the Popular Front in Lyon, but then contributed to its rapid collapse.
Surface reflectance of Mars observed by CRISM/MRO: 2. Estimation of surface photometric properties in Gusev Crater and Meridiani Planum
Authors: Fernando J. , Schmidt F. , Ceamanos X. , Pinet P. , Douté S. , Daydou Y.
Published: December 2012

The present article proposes an approach to analyze the photometric properties of the surface materials from multi‐angle observations acquired by the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) on‐board the Mars Reconnaissance Orbiter. We estimate photometric parameters using Hapke's model in a Bayesian inversion framework. This work also represents a validation of the atmospheric correction provided by the Multi‐angle Approach for Retrieval of Surface Reflectance from CRISM Observations (MARS‐ReCO) proposed in the companion article. The latter algorithm retrieves photometric curves of surface materials in reflectance units after removing the aerosol contribution. This validation is done by comparing the estimated photometric parameters to those obtained from in situ measurements by Panoramic Camera instrument at the Mars Exploration Rover (MER) Spirit and MER Opportunity landing sites. Consistent photometric parameters with those from in situ measurements are found, demonstrating that MARS‐ReCO gives access to accurate surface reflectance. Moreover, the assumption of a non‐Lambertian surface as included in MARS‐ReCO is shown to be significantly more precise to estimate surface photometric properties from space in comparison to methods based on a Lambertian surface assumption. In the future, the presented method will allow us to map from orbit the surface bidirectional reflectance and the related photometric parameters in order to characterize the Martian surface.
Characterisation of an intrinsically disordered protein complex of Swi5–Sfr1 by ion mobility mass spectrometry and small-angle X-ray scattering
Authors: Saikusa Kazumi , Kuwabara Naoyuki , Kokabu Yuichi , Inoue Yu , Sato Mamoru , Iwasaki Hiroshi , Shimizu Toshiyuki , Ikeguchi Mitsunori , Akashi Satoko
Published: December 2012

Extreme compaction of ID regions in the gas phase was experimentally identified by the combination of IM-MS and SAXS.
Describing sequence–ensemble relationships for intrinsically disordered proteins
Authors: Mao Albert H. , Lyle Nicholas , Pappu Rohit V.
Published: December 2012

Intrinsically disordered proteins participate in important protein–protein and protein–nucleic acid interactions and control cellular phenotypes through their prominence as dynamic organizers of transcriptional, post-transcriptional and signalling networks. These proteins challenge the tenets of the structure–function paradigm and their functional mechanisms remain a mystery given that they fail to fold autonomously into specific structures. Solving this mystery requires a first principles understanding of the quantitative relationships between information encoded in the sequences of disordered proteins and the ensemble of conformations they sample. Advances in quantifying sequence–ensemble relationships have been facilitated through a four-way synergy between bioinformatics, biophysical experiments, computer simulations and polymer physics theories. In the present review we evaluate these advances and the resultant insights that allow us to develop a concise quantitative framework for describing the sequence–ensemble relationships of intrinsically disordered proteins.
Evaluating the performance of endophytes in farm systems to improve farmer outcomes - a review
Authors: Thom Errol R. , Popay Alison J. , Hume David E. , Fletcher Lester R.
Published: December 2012

The main plant species relied on for forage supply to grazing animals in New Zealand and south-eastern Australia is perennial ryegrass (Lolium perenne L.). Perennial ryegrass has evolved with a fungal endophyte (Neotyphodium lolii, Latch, Christensen & Samuals) that occupies intercellular spaces, and is nourished by its host. The endophyte (referred to as standard or wild-type) provides the plant with protection from a range of insect pests by producing alkaloids, some of which are also toxic to grazing animals, causing ryegrass staggers and/or exacerbating heat stress. Over the last 20 years naturally occurring perennial ryegrass endophytes have been found in Europe that produce less of the alkaloids that cause animal health problems but have similar or enhanced effects as the standard endophyte on deterring insect attack on infected plants, when introduced into New Zealand and Australian-bred ryegrasses. This review provides a summary of endophyte research in New Zealand from the perspective of insect pests, plants (particularly perennial ryegrass) and the animals grazed on ryegrass-dominant pastures. The protocols used to evaluate perennial ryegrass/endophyte associations over the past 30 years are also discussed. Future testing of new grass/endophyte associations should include the utilisation of more environments for agronomic and entomological experiments; routinely carrying out small animal toxicology assays, and the running of short-term indoor feeding experiments with sheep and cows. Implementation of these changes provides the minimum requirements for strengthening the evaluation of new endophyte associations so farmers using these technologies, gain optimal benefits from their adoption.
High species turnover of the ant genus Solenopsis (Hymenoptera : Formicidae) along an altitudinal gradient in the Ecuadorian Andes, indicated by a combined DNA sequencing and morphological approach
Authors: Delsinne Thibaut , Sonet Gontran , Nagy Zoltán T. , Wauters Nina , Jacquemin Justine , Leponce Maurice
Published: December 2012

Solenopsis is a widespread ant genus and the identification of its species is notoriously difficult. Hence, investigation of their distribution along elevational gradients is challenging. Our aims were (1) to test the complementarity of the morphological and DNA barcoding approaches for Solenopsis species identification, and (2) to assess species diversity and distribution along an altitudinal gradient in the Ecuadorian Andes. Ants were collected in five localities between 1000 and 3000 m above sea level. In total, 24 morphospecies were identified along the gradient and 14 of them were barcoded. Seven morphospecies were confirmed by the molecular approach. Three others, occurring sympatrically and possessing clear diagnostic characters, showed low genetic divergence. Representatives of a further four morphospecies were split into nine clusters by COI and nuclear wingless genetic markers, suggesting the existence of cryptic species. Examination of gynes revealed potential diagnostic characters for morphological discrimination. Solenopsis species were found up to an altitudinal record of 3000 m. Most morphospecies (20 of 24) were found at a single elevation. Our results suggest a high species turnover along the gradient, and point to the use of morphological and DNA barcoding approaches as necessary for differentiating among Solenopsis species.
Rotational motion during three-dimensional morphogenesis of mammary epithelial acini relates to laminin matrix assembly
Authors: Wang Hui , Lacoche Sam , Huang Ling , Xue Bin , Muthuswamy Senthil K.
Published: December 2012

Our understanding of the mechanisms by which ducts and lobules develop is derived from model organisms and three-dimensional (3D) cell culture models wherein mammalian epithelial cells undergo morphogenesis to form multicellular spheres with a hollow central lumen. However, the mechanophysical properties associated with epithelial morphogenesis are poorly understood. We performed multidimensional live-cell imaging analysis to track the morphogenetic process starting from a single cell to the development of a multicellular, spherical structure composed of polarized epithelial cells surrounding a hollow lumen. We report that in addition to actively maintaining apicobasal polarity, the structures underwent rotational motions at rates of 15–20 μm/h and the structures rotated 360° every 4 h during the early phase of morphogenesis. Rotational motion was independent of the cell cycle, but was blocked by loss of the epithelial polarity proteins Scribble or Pard3, or by inhibition of dynein-based microtubule motors. Interestingly, none of the structures derived from human cancer underwent rotational motion. We found a direct relationship between rotational motion and assembly of endogenous basement membrane matrix around the 3D structures, and that structures that failed to rotate were defective in weaving exogenous laminin matrix. Dissolution of basement membrane around mature, nonrotating acini restored rotational movement and the ability to assemble exogenous laminin. Thus, coordinated rotational movement is a unique mechanophysical process observed during normal 3D morphogenesis that regulates laminin matrix assembly and is lost in cancer-derived epithelial cells.
NMR imaging of cell phone radiation absorption in brain tissue
Authors: Gultekin David H. , Moeller Lothar
Published: December 2012

A method is described for measuring absorbed electromagnetic energy radiated from cell phone antennae into ex vivo brain tissue. NMR images the 3D thermal dynamics inside ex vivo bovine brain tissue and equivalent gel under exposure to power and irradiation time-varying radio frequency (RF) fields. The absorbed RF energy in brain tissue converts into Joule heat and affects the nuclear magnetic shielding and the Larmor precession. The resultant temperature increase is measured by the resonance frequency shift of hydrogen protons in brain tissue. This proposed application of NMR thermometry offers sufficient spatial and temporal resolution to characterize the hot spots from absorbed cell phone radiation in aqueous media and biological tissues. Specific absorption rate measurements averaged over 1 mg and 10 s in the brain tissue cover the total absorption volume. Reference measurements with fiber optic temperature sensors confirm the accuracy of the NMR thermometry.
Birth–death skyline plot reveals temporal changes of epidemic spread in HIV and hepatitis C virus (HCV)
Authors: Stadler Tanja , Kühnert Denise , Bonhoeffer Sebastian , Drummond Alexei J.
Published: December 2012

Phylogenetic trees can be used to infer the processes that generated them. Here, we introduce a model, the Bayesian birth–death skyline plot, which explicitly estimates the rate of transmission, recovery, and sampling and thus allows inference of the effective reproductive number directly from genetic data. Our method allows these parameters to vary through time in a piecewise fashion and is implemented within the B
EAST
2 software framework. The method is a powerful alternative to the existing coalescent skyline plot, providing insight into the differing roles of incidence and prevalence in an epidemic. We apply this method to data from the United Kingdom HIV-1 epidemic and Egyptian hepatitis C virus (HCV) epidemic. The analysis reveals temporal changes of the effective reproductive number that highlight the effect of past public health interventions.
CpG underrepresentation and the bacterial CpG-specific DNA methyltransferase M.MpeI
Authors: Wojciechowski Marek , Czapinska Honorata , Bochtler Matthias
Published: December 2012

Cytosine methylation promotes deamination. In eukaryotes, CpG methylation is thought to account for CpG underrepresentation. Whether scarcity of CpGs in prokaryotic genomes is diagnostic for methylation is not clear. Here, we report that Mycoplasms tend to be CpG depleted and to harbor a family of constitutively expressed or phase variable CpG-specific DNA methyltransferases. The very CpG poor
Mycoplasma penetrans
and its constitutively active CpG-specific methyltransferase M.MpeI were chosen for further characterization. Genome-wide sequencing of bisulfite-converted DNA indicated that M.MpeI methylated CpG target sites both in vivo and in vitro in a locus-nonselective manner. A crystal structure of M.MpeI with DNA at 2.15-Å resolution showed that the substrate base was flipped and that its place in the DNA stack was taken by a glutamine residue. A phenylalanine residue was intercalated into the “weak” CpG step of the nonsubstrate strand, indicating mechanistic similarities in the recognition of the short CpG target sequence by prokaryotic and eukaryotic DNA methyltransferases.
Millisecond spatiotemporal dynamics of FRET biosensors by the pair correlation function and the phasor approach to FLIM
Authors: Hinde Elizabeth , Digman Michelle A. , Hahn Klaus M. , Gratton Enrico
Published: December 2012

Here we present a fluctuation-based approach to biosensor Förster resonance energy transfer (FRET) detection that can measure the molecular flow and signaling activity of proteins in live cells. By simultaneous use of the phasor approach to fluorescence lifetime imaging microscopy (FLIM) and cross–pair correlation function (pCF) analysis along a line scanned in milliseconds, we detect the spatial localization of Rho GTPase activity (biosensor FRET signal) as well as the diffusive route adopted by this active population. In particular we find, for Rac1 and RhoA, distinct gradients of activation (FLIM-FRET) and a molecular flow pattern (pCF analysis) that explains the observed polarized GTPase activity. This multiplexed approach to biosensor FRET detection serves as a unique tool for dissection of the mechanism(s) by which key signaling proteins are spatially and temporally coordinated.
Transcription factor YY1 is essential for regulation of the Th2 cytokine locus and for Th2 cell differentiation
Authors: Hwang Soo Seok , Kim Young Uk , Lee Sumin , Jang Sung Woong , Kim Min Kyung , Koh Byung Hee , Lee Wonyong , Kim Joomyeong , Souabni Abdallah , Busslinger Meinrad , Lee Gap Ryol
Published: December 2012

The Th2 locus control region (LCR) has been shown to be important in efficient and coordinated cytokine gene regulation during Th2 cell differentiation. However, the molecular mechanism for this is poorly understood. To study the molecular mechanism of the Th2 LCR, we searched for proteins binding to it. We discovered that transcription factor YY1 bound to the LCR and the entire Th2 cytokine locus in a Th2-specific manner. Retroviral overexpression of YY1 induced Th2 cytokine expression. CD4-specific knockdown of YY1 in mice caused marked reduction in Th2 cytokine expression, repressed chromatin remodeling, decreased intrachromosomal interactions, and resistance in an animal model of asthma. YY1 physically associated with GATA-binding protein-3 (GATA3) and is required for GATA3 binding to the locus. YY1 bound to the regulatory elements in the locus before GATA3 binding. Thus, YY1 cooperates with GATA3 and is required for regulation of the Th2 cytokine locus and Th2 cell differentiation.
Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome
Authors: Ye Haifeng , Charpin-El Hamri Ghislaine , Zwicky Katharina , Christen Matthias , Folcher Marc , Fussenegger Martin
Published: December 2012

Synthetic biology has significantly advanced the design of genetic devices that can reprogram cellular activities and provide novel treatment strategies for future gene- and cell-based therapies. However, many metabolic disorders are functionally linked while developing distinct diseases that are difficult to treat using a classic one-drug-one-disease intervention scheme. For example, hypertension, hyperglycemia, obesity, and dyslipidemia are interdependent pathologies that are collectively known as the metabolic syndrome, the prime epidemic of the 21st century. We have designed a unique therapeutic strategy in which the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin. Therefore, the signal transduction of a chimeric trace-amine–associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements. Based on this designer signaling cascade, it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc
mIgG
-Leptin, a bifunctional therapeutic peptide hormone that combines the glucagon-like peptide 1 (GLP-1) and leptin via an IgG-Fc linker. In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia. Using a clinically licensed drug to coordinate expression of therapeutic transgenes combines drug- and gene-based therapies for coordinated treatment of functionally related metabolic disorders.
Functional characterization of
piggyBat
from the bat
Myotis lucifugus
unveils an active mammalian DNA transposon
Authors: Mitra Rupak , Li Xianghong , Kapusta Aurélie , Mayhew David , Mitra Robi D. , Feschotte Cédric , Craig Nancy L.
Published: December 2012

A revelation of the genomic age has been the contributions of the mobile DNA segments called transposable elements to chromosome structure, function, and evolution in virtually all organisms. Substantial fractions of vertebrate genomes derive from transposable elements, being dominated by retroelements that move via RNA intermediates. Although many of these elements have been inactivated by mutation, several active retroelements remain. Vertebrate genomes also contain substantial quantities and a high diversity of cut-and-paste DNA transposons, but no active representative of this class has been identified in mammals. Here we show that a cut-and-paste element called
piggyBat,
which has recently invaded the genome of the little brown bat (
Myotis lucifugus
) and is a member of the
piggyBac
superfamily, is active in its native form in transposition assays in bat and human cultured cells, as well as in the yeast
Saccharomyces cerevisiae
. Our study suggests that some DNA transposons are still actively shaping some mammalian genomes and reveals an unprecedented opportunity to study the mechanism, regulation, and genomic impact of cut-and-paste transposition in a natural mammalian host.
Regulation of the actin-activated MgATPase activity ofAcanthamoebamyosin II by phosphorylation of serine 639 in motor domain loop 2
Authors: Liu Xiong , Lee Duck-Yeon , Cai Shutao , Yu Shuhua , Shu Shi , Levine Rodney L. , Korn Edward D.
Published: December 2012

Significance

Myosin II from the soil amoebaAcanthamoeba castellaniiis a member of the largest of the 35 classes of the superfamily of molecular motors that, together with actin filaments, convert the energy of hydrolysis of ATP into force or motion that drives numerous cellular and intracellular processes. In this paper we show that the actin-activated ATPase ofAcanthamoebamyosin II is regulated by phosphorylation of a specific serine in a region of the myosin motor domain that is known to be at the myosin–actin interface. No other myosin has been shown to be regulated in this way.
Antibacterial drug leads targeting isoprenoid biosynthesis
Authors: Zhu Wei , Zhang Yonghui , Sinko William , Hensler Mary E. , Olson Joshua , Molohon Katie J. , Lindert Steffen , Cao Rong , Li Kai , Wang Ke , Wang Yang , Liu Yi-Liang , Sankovsky Anna , de Oliveira César Augusto F. , Mitchell Douglas A. , Nizet Victor , McCammon J. Andrew , Oldfield Eric
Published: December 2012

With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. We report here the discovery and X-ray crystallographic structures of 10 chemically diverse compounds (benzoic, diketo, and phosphonic acids, as well as a bisamidine and a bisamine) that inhibit bacterial undecaprenyl diphosphate synthase, an essential enzyme involved in cell wall biosynthesis. The inhibitors bind to one or more of the four undecaprenyl diphosphate synthase inhibitor binding sites identified previously, with the most active leads binding to site 4, outside the catalytic center. The most potent leads are active against
Staphylococcus aureus
[minimal inhibitory concentration (MIC)
90
∼0.25 µg/mL], and one potently synergizes with methicillin (fractional inhibitory concentration index = 0.25) and is protective in a mouse infection model. These results provide numerous leads for antibacterial development and open up the possibility of restoring sensitivity to drugs such as methicillin, using combination therapies.
New methodologies for historical linguistics?
Authors: Donohue Mark , Denham Tim , Oppenheimer Stephen
Published: December 2012

Recent research claims that analysis of lexical cognate classes for a basic wordlist can reproduce linguistic subgroups within the Austronesian family (Gray et al. 2009). The analysis is open to question in two respects. Primarily, the lexically-based classification, primed with pre-established cognate classes of the family it seeks to emulate, fails to differentiate shared retentions from shared innovations. Secondly, languages and language families typically disperse through contiguous regions (especially in the Pacific) which means that geography or social distance should be expected crudely to match phylogeny in most cases. The reproduction fails because of local borrowing between branches not closely related to each other. For instance, when we examine disjunct distributions, cases in which the phylogeny does not match a straightforward geographic spread, we can determine which of these (phylogeny or geography) the lexical cognate approach preferentially detects. Where we find a mismatch between geography and phylogeny, Gray et al.’s approach clusters languages based on human geography (that is, social distance), not linguistic subgroup. In all cases of divergence between Gray et al.’s tree and accepted Austronesian trees, the discrepancy is a product of the former representing social distance rather than historical phylogenetic relationships. In summary, the examination of lexical cognate classes is not a valid proxy for the comparative method, though it is a useful heuristic for detecting pairs of languages that are either lexically conservative, or which show the effects of later lexical diffusion (without discriminating between these two outcomes).
Basic vocabulary and Bayesian phylolinguistics
Authors: Greenhill Simon J. , Gray Russell D.
Published: December 2012

Donohue et al.’s critique of our work on the origins and spread of the Austronesian language family is marred by misunderstandings. We respond to these by noting that our Bayesian phylogenetic approach: (1) distinguishes between retentions and innovations probabilistically, (2) focuses on basic vocabulary not ‘the lexicon’, (3) eliminates known loanwords, (4) produces results that are congruent with the results of the comparative method and conflict with the scenarios requiring unprecedented amounts of language shift postulated by Donohue et al.
Understanding audience affiliation in response to political speeches in Japan
Authors: Feldman Ofer , Bull Peter
Published: December 2012

Affiliative response invitations were analysed in 38 speeches delivered during the 2009 Japanese general election by 18 candidates for the House of Representatives (the lower house of the National Diet of Japan). The results clearly replicated those reported by Bull and Feldman (2011) in their analysis of the 2005 Japanese general election. Highly significant correlations were found between the two studies not only for the overall pattern of affiliative responses, but also for each type of response (applause, laughter and cheering). In both studies, over 70% of affiliative responses occurred in response to explicit invitations from the speaker. This contrasts with British political meetings, where applause occurs principally in response to implicit rhetorical devices. However, the candidates’ electoral success showed no significant correlations either with overall affiliative response rate, or with rates for applause, laughter or cheering. It is proposed that the prime function of affiliative response invitations at these meetings is not so much to win votes as to give the audience the opportunity to express their support both for the candidates and for the political parties they represent.
DOES VOLUNTEERING CAUSE TRUST?
Authors: Sivesind Karl Henrik , Pospíšilová Tereza , Frič Pavol
Published: December 2012

Social capital theory expects volunteering to generate general social trust, while critics point out that there is little evidence to support this claim. The purpose of this article is to show that volunteering can cause trust, depending on the institutional context and the types of organizations for which people volunteer. The data are from representative population surveys conducted in Norway and the Czech Republic in 2009. The analysis shows that in institutional contexts with impartial and reliable institutions, as in the case of Norway, general social trust is very high in comparative perspective, and the experience of volunteering has little additional effect. However, volunteering boosts institutional trust because volunteers get in touch with a political and administrative system that supports and interacts with the voluntary sector. This applies particularly to voluntary organizations in culture, sports, and recreation. In contrast, in an institutional context with elements of clientelism and corruption, as in the case of the Czech Republic, there is no positive effect on institutional trust. However, the level of general social trust is low and the collaborative experience of volunteering can generate social trust. This applies particularly to voluntary organizations that are not associated with the established political culture.
Free-energy relationships in ion channels activated by voltage and ligand
Authors: Chowdhury Sandipan , Chanda Baron
Published: December 2012

Many ion channels are modulated by multiple stimuli, which allow them to integrate a variety of cellular signals and precisely respond to physiological needs. Understanding how these different signaling pathways interact has been a challenge in part because of the complexity of underlying models. In this study, we analyzed the energetic relationships in polymodal ion channels using linkage principles. We first show that in proteins dually modulated by voltage and ligand, the net free-energy change can be obtained by measuring the charge-voltage (Q-V) relationship in zero ligand condition and the ligand binding curve at highly depolarizing membrane voltages. Next, we show that the voltage-dependent changes in ligand occupancy of the protein can be directly obtained by measuring the Q-V curves at multiple ligand concentrations. When a single reference ligand binding curve is available, this relationship allows us to reconstruct ligand binding curves at different voltages. More significantly, we establish that the shift of the Q-V curve between zero and saturating ligand concentration is a direct estimate of the interaction energy between the ligand- and voltage-dependent pathway. These free-energy relationships were tested by numerical simulations of a detailed gating model of the BK channel. Furthermore, as a proof of principle, we estimate the interaction energy between the ligand binding and voltage-dependent pathways for HCN2 channels whose ligand binding curves at various voltages are available. These emerging principles will be useful for high-throughput mutagenesis studies aimed at identifying interaction pathways between various regulatory domains in a polymodal ion channel.
Increased intracellular magnesium attenuates β-adrenergic stimulation of the cardiac CaV1.2 channel
Authors: Brunet Sylvain , Scheuer Todd , Catterall William A.
Published: December 2012

Increases in intracellular Mg2+ (Mg2+i), as observed in transient cardiac ischemia, decrease L-type Ca2+ current of mammalian ventricular myocytes (VMs). However, cardiac ischemia is associated with an increase in sympathetic tone, which could stimulate L-type Ca2+ current. Therefore, the effect of Mg2+i on L-type Ca2+ current in the context of increased sympathetic tone was unclear. We tested the impact of increased Mg2+i on the β-adrenergic stimulation of L-type Ca2+ current. Exposure of acutely dissociated adult VMs to higher Mg2+i concentrations decreased isoproterenol stimulation of the L-type Ca2+ current from 75 ± 13% with 0.8 mM Mg2+i to 20 ± 8% with 2.4 mM Mg2+i. We activated this signaling cascade at different steps to determine the site or sites of Mg2+i action. Exposure of VMs to increased Mg2+i attenuated the stimulation of L-type Ca2+ current induced by activation of adenylyl cyclase with forskolin, inhibition of cyclic nucleotide phosphodiesterases with isobutylmethylxanthine, and inhibition of phosphoprotein phosphatases I and IIA with calyculin A. These experiments ruled out significant effects of Mg2+i on these upstream steps in the signaling cascade and suggested that Mg2+i acts directly on CaV1.2 channels. One possible site of action is the EF-hand in the proximal C-terminal domain, just downstream in the signaling cascade from the site of regulation of CaV1.2 channels by protein phosphorylation on the C terminus. Consistent with this hypothesis, Mg2+i had no effect on enhancement of CaV1.2 channel activity by the dihydropyridine agonist (S)-BayK8644, which activates CaV1.2 channels by binding to a site formed by the transmembrane domains of the channel. Collectively, our results suggest that, in transient ischemia, increased Mg2+i reduces stimulation of L-type Ca2+ current by the β-adrenergic receptor by directly acting on CaV1.2 channels in a cell-autonomous manner, effectively decreasing the metabolic stress imposed on VMs until blood flow can be reestablished.
Revisiting the Role of Education for Agricultural Productivity
Authors: Reimers Malte , Klasen Stephan
Published: December 2012

Various recent cross‐country regressions have detected insignificant or even surprisingly negative effects of schooling on agricultural productivity. Applying advanced panel econometric techniques to a sample of 95 developing and emerging countries from 1961 to 2002, we show that these results are due to a problematic reliance on enrollment and literacy indicators. Using data on educational attainment, we instead find a sizable and significant impact of schooling (avg. increase of approx. 3.2% per year of schooling) on agricultural productivity that is robust to estimation methods and model specification. We also find that returns from schooling are higher in technologically more advanced countries.