bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of core circadian feedback loop in suprachiasmatic nucleus of
mCry1-luc
transgenic reporter mouse
Authors: Maywood Elizabeth S. , Drynan Lesley , Chesham Johanna E. , Edwards Mathew D. , Dardente Hugues , Fustin Jean-Michel , Hazlerigg David G. , O’Neill John S. , Codner Gemma F. , Smyllie Nicola J. , Brancaccio Marco , Hastings Michael H.
Published: May 2013

The suprachiasmatic nucleus (SCN) coordinates circadian rhythms that adapt the individual to solar time. SCN pacemaking revolves around feedback loops in which expression of
Period
(
Per
) and
Cryptochrome
(
Cry
) genes is periodically suppressed by their protein products. Specifically, PER/CRY complexes act at E-box sequences in
Per
and
Cry
to inhibit their transactivation by CLOCK/BMAL1 heterodimers. To function effectively, these closed intracellular loops need to be synchronized between SCN cells and to the light/dark cycle. For
Per
expression, this is mediated by neuropeptidergic and glutamatergic extracellular cues acting via cAMP/calcium-responsive elements (CREs) in
Per
genes.
Cry
genes, however, carry no CREs, and how CRY-dependent SCN pacemaking is synchronized remains unclear. Furthermore, whereas reporter lines are available to explore
Per
circadian expression in real time, no
Cry
equivalent exists. We therefore created a mouse, B6.Cg-Tg(Cry1-luc)01Ld, carrying a transgene (
mCry1-luc
) consisting of
mCry1
elements containing an E-box and E′-box driving firefly luciferase.
mCry1-luc
organotypic SCN slices exhibited stable circadian bioluminescence rhythms with appropriate phase, period, profile, and spatial organization. In SCN lacking vasoactive intestinal peptide or its receptor,
mCry1
expression was damped and desynchronized between cells. Despite the absence of CREs,
mCry1-luc
expression was nevertheless (indirectly) sensitive to manipulation of cAMP-dependent signaling. In
mPer1/2
-null SCN,
mCry1-luc
bioluminescence was arrhythmic and no longer suppressed by elevation of cAMP. Finally, an SCN graft procedure showed that PER-independent as well as PER-dependent mechanisms could sustain circadian expression of
mCry1
. The
mCry1-luc
mouse therefore reports circadian
mCry1
expression and its interactions with vasoactive intestinal peptide, cAMP, and PER at the heart of the SCN pacemaker.
Deciphering the impacts of vaccination and immunity on pertussis epidemiology in Thailand
Authors: Blackwood Julie C. , Cummings Derek A. T. , Broutin Hélène , Iamsirithaworn Sopon , Rohani Pejman
Published: May 2013

Pertussis is a highly infectious respiratory disease that is currently responsible for nearly 300,000 annual deaths worldwide, primarily in infants in developing countries. Despite sustained high vaccine uptake, a resurgence in pertussis incidence has been reported in a number of countries. This resurgence has led to critical questions regarding the transmission impacts of vaccination and pertussis immunology. We analyzed pertussis incidence in Thailand—both age-stratified and longitudinal aggregate reports—over the past 30 y. To dissect the contributions of waning pertussis immunity and repeat infections to pertussis epidemiology in Thailand following a pronounced increase in vaccine uptake, we used likelihood-based statistical inference methods to evaluate the support for multiple competing transmission models. We found that, in contrast to other settings, there is no evidence for pertussis resurgence in Thailand, with each model examined pointing to a substantial rise in herd immunity over the past 30 y. Using a variety of empirical metrics, we verified our findings by documenting signatures of changing herd immunity over the study period. Importantly, this work leads to the conclusion that repeat infections have played little role in shaping pertussis epidemiology in Thailand. Our results are surprisingly emphatic in support of measurable impact of herd immunity given the uncertainty associated with pertussis epidemiology.
Stable nematic droplets with handles
Authors: Pairam Ekapop , Vallamkondu Jayalakshmi , Koning Vinzenz , van Zuiden Benjamin C. , Ellis Perry W. , Bates Martin A. , Vitelli Vincenzo , Fernandez-Nieves Alberto
Published: May 2013

We stabilize nematic droplets with handles against surface tension-driven instabilities, using a yield-stress material as outer fluid, and study the complex nematic textures and defect structures that result from the competition between topological constraints and the elasticity of the nematic liquid crystal. We uncover a surprisingly persistent twisted configuration of the nematic director inside the droplets when tangential anchoring is established at their boundaries, which we explain after considering the influence of saddle splay on the elastic free energy. For toroidal droplets, we find that the saddle-splay energy screens the twisting energy, resulting in a spontaneous breaking of mirror symmetry; the chiral twisted state persists for aspect ratios as large as ∼20. For droplets with additional handles, we observe in experiments and computer simulations that there are two additional −1 surface defects per handle; these are located in regions with local saddle geometry to minimize the nematic distortions and hence the corresponding elastic free energy.
Simple computation of reaction–diffusion processes on point clouds
Authors: Macdonald Colin B. , Merriman Barry , Ruuth Steven J.
Published: May 2013

The study of reaction–diffusion processes is much more complicated on general curved surfaces than on standard Cartesian coordinate spaces. Here we show how to formulate and solve systems of reaction–diffusion equations on surfaces in an extremely simple way, using only the standard Cartesian form of differential operators, and a discrete unorganized point set to represent the surface. Our method decouples surface geometry from the underlying differential operators. As a consequence, it becomes possible to formulate and solve rather general reaction–diffusion equations on general surfaces without having to consider the complexities of differential geometry or sophisticated numerical analysis. To illustrate the generality of the method, computations for surface diffusion, pattern formation, excitable media, and bulk-surface coupling are provided for a variety of complex point cloud surfaces.
Parasitoid wasp venom SERCA regulates
Drosophila
calcium levels and inhibits cellular immunity
Authors: Mortimer Nathan T. , Goecks Jeremy , Kacsoh Balint Z. , Mobley James A. , Bowersock Gregory J. , Taylor James , Schlenke Todd A.
Published: May 2013

Because parasite virulence factors target host immune responses, identification and functional characterization of these factors can provide insight into poorly understood host immune mechanisms. The fruit fly
Drosophila melanogaster
is a model system for understanding humoral innate immunity, but
Drosophila
cellular innate immune responses remain incompletely characterized. Fruit flies are regularly infected by parasitoid wasps in nature and, following infection, flies mount a cellular immune response culminating in the cellular encapsulation of the wasp egg. The mechanistic basis of this response is largely unknown, but wasps use a mixture of virulence proteins derived from the venom gland to suppress cellular encapsulation. To gain insight into the mechanisms underlying wasp virulence and fly cellular immunity, we used a joint transcriptomic/proteomic approach to identify venom genes from
Ganaspis sp.1
(G1), a previously uncharacterized
Drosophila
parasitoid species, and found that G1 venom contains a highly abundant sarco/endoplasmic reticulum calcium ATPase (SERCA) pump. Accordingly, we found that fly immune cells termed plasmatocytes normally undergo a cytoplasmic calcium burst following infection, and that this calcium burst is required for activation of the cellular immune response. We further found that the plasmatocyte calcium burst is suppressed by G1 venom in a SERCA-dependent manner, leading to the failure of plasmatocytes to become activated and migrate toward G1 eggs. Finally, by genetically manipulating plasmatocyte calcium levels, we were able to alter fly immune success against G1 and other parasitoid species. Our characterization of parasitoid wasp venom proteins led us to identify plasmatocyte cytoplasmic calcium bursts as an important aspect of fly cellular immunity.
Orbital pacing and ocean circulation-induced collapses of the Mesoamerican monsoon over the past 22,000 y
Authors: Lachniet Matthew S. , Asmerom Yemane , Bernal Juan Pablo , Polyak Victor J. , Vazquez-Selem Lorenzo
Published: May 2013

The dominant controls on global paleomonsoon strength include summer insolation driven by precession cycles, ocean circulation through its influence on atmospheric circulation, and sea-surface temperatures. However, few records from the summer North American Monsoon system are available to test for a synchronous response with other global monsoons to shared forcings. In particular, the monsoon response to widespread atmospheric reorganizations associated with disruptions of the Atlantic Meridional Overturning Circulation (AMOC) during the deglacial period remains unconstrained. Here, we present a high-resolution and radiometrically dated monsoon rainfall reconstruction over the past 22,000 y from speleothems of tropical southwestern Mexico. The data document an active Last Glacial Maximum (18–24 cal ka B.P.) monsoon with similar δ
18
O values to the modern, and that the monsoon collapsed during periods of weakened AMOC during Heinrich stadial 1 (
ca
. 17 ka) and the Younger Dryas (12.9–11.5 ka). The Holocene was marked by a trend to a weaker monsoon that was paced by orbital insolation. We conclude that the Mesoamerican monsoon responded in concert with other global monsoon regions, and that monsoon strength was driven by variations in the strength and latitudinal position of the Intertropical Convergence Zone, which was forced by AMOC variations in the North Atlantic Ocean. The surprising observation of an active Last Glacial Maximum monsoon is attributed to an active but shallow AMOC and proximity to the Intertropical Convergence Zone. The emergence of agriculture in southwestern Mexico was likely only possible after monsoon strengthening in the Early Holocene at
ca
. 11 ka.
Methionine oxidation activates a transcription factor in response to oxidative stress
Authors: Drazic Adrian , Miura Haruko , Peschek Jirka , Le Yan , Bach Nina C. , Kriehuber Thomas , Winter Jeannette
Published: May 2013

Oxidant-mediated antibacterial response systems are broadly used to control bacterial proliferation. Hypochlorite (HOCl) is an important component of the innate immune system produced in neutrophils and specific epithelia. Its antimicrobial activity is due to damaging cellular macromolecules. Little is known about how bacteria escape HOCl-inflicted damage. Recently, the transcription factor YjiE was identified that specifically protects
Escherichia coli
from HOCl killing. According to its function, YjiE is now renamed HypT (hypochlorite-responsive transcription factor). Here we unravel that HypT is activated by methionine oxidation to methionine sulfoxide. Interestingly, so far only inactivation of cellular proteins by methionine oxidation has been reported. Mutational analysis revealed three methionines that are essential to confer HOCl resistance. Their simultaneous substitution by glutamine, mimicking the methionine sulfoxide state, increased the viability of
E. coli
cells upon HOCl stress. Triple glutamine substitution generates a constitutively active HypT that regulates target genes independently of HOCl stress and permanently down-regulates intracellular iron levels. Inactivation of HypT depends on the methionine sulfoxide reductases A/B. Thus, microbial protection mechanisms have evolved along the evolution of antimicrobial control systems, allowing bacteria to survive within the host environment.
Surviving rapid climate change in the deep sea during the Paleogene hyperthermals
Authors: Foster Laura C. , Schmidt Daniela N. , Thomas Ellen , Arndt Sandra , Ridgwell Andy
Published: May 2013

Predicting the impact of ongoing anthropogenic CO
2
emissions on calcifying marine organisms is complex, owing to the synergy between direct changes (acidification) and indirect changes through climate change (e.g., warming, changes in ocean circulation, and deoxygenation). Laboratory experiments, particularly on longer-lived organisms, tend to be too short to reveal the potential of organisms to acclimatize, adapt, or evolve and usually do not incorporate multiple stressors. We studied two examples of rapid carbon release in the geological record, Eocene Thermal Maximum 2 (∼53.2 Ma) and the Paleocene Eocene Thermal Maximum (PETM, ∼55.5 Ma), the best analogs over the last 65 Ma for future ocean acidification related to high atmospheric CO
2
levels. We use benthic foraminifers, which suffered severe extinction during the PETM, as a model group. Using synchrotron radiation X-ray tomographic microscopy, we reconstruct the calcification response of survivor species and find, contrary to expectations, that calcification significantly increased during the PETM. In contrast, there was no significant response to the smaller Eocene Thermal Maximum 2, which was associated with a minor change in diversity only. These observations suggest that there is a response threshold for extinction and calcification response, while highlighting the utility of the geological record in helping constrain the sensitivity of biotic response to environmental change.
Brain homogenates from human tauopathies induce tau inclusions in mouse brain
Authors: Clavaguera Florence , Akatsu Hiroyasu , Fraser Graham , Crowther R. Anthony , Frank Stephan , Hench Jürgen , Probst Alphonse , Winkler David T. , Reichwald Julia , Staufenbiel Matthias , Ghetti Bernardino , Goedert Michel , Tolnay Markus
Published: May 2013

Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer’s disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer’s disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.
Mapping microbubble viscosity using fluorescence lifetime imaging of molecular rotors
Authors: Hosny Neveen A. , Mohamedi Graciela , Rademeyer Paul , Owen Joshua , Wu Yilei , Tang Meng-Xing , Eckersley Robert J. , Stride Eleanor , Kuimova Marina K.
Published: May 2013

Encapsulated microbubbles are well established as highly effective contrast agents for ultrasound imaging. There remain, however, some significant challenges to fully realize the potential of microbubbles in advanced applications such as perfusion mapping, targeted drug delivery, and gene therapy. A key requirement is accurate characterization of the viscoelastic surface properties of the microbubbles, but methods for independent, nondestructive quantification and mapping of these properties are currently lacking. We present here a strategy for performing these measurements that uses a small fluorophore termed a “molecular rotor” embedded in the microbubble surface, whose fluorescence lifetime is directly related to the viscosity of its surroundings. We apply fluorescence lifetime imaging to show that shell viscosities vary widely across the population of the microbubbles and are influenced by the shell composition and the manufacturing process. We also demonstrate that heterogeneous viscosity distributions exist within individual microbubble shells even with a single surfactant component.
Direct observation of ground-state lactam–lactim tautomerization using temperature-jump transient 2D IR spectroscopy
Authors: Peng Chunte Sam , Baiz Carlos R. , Tokmakoff Andrei
Published: May 2013

We provide a systematic characterization of the nanosecond ground-state lactam–lactim tautomerization of pyridone derivatives in aqueous solution under ambient conditions using temperature-jump transient 2D IR spectroscopy. Although electronic excited-state tautomerization has been widely studied, experimental work on the ground electronic state, most relevant to chemistry and biology, is lacking. Using 2D IR spectroscopy, lactam and lactim tautomers of 6-chloro-2-pyridone and 2-chloro-4-pyridone are unambiguously identified by their unique cross-peak patterns. Monitoring the correlated exponential relaxation of these signals in response to a laser temperature jump provides a direct measurement of the nanosecond tautomerization kinetics. By studying the temperature, concentration, solvent, and pH dependence, we extract a thermodynamic and kinetic characterization and conclude that the tautomerization proceeds through a two-state concerted mechanism. We find that the intramolecular proton transfer is mediated by bridging water molecules and the reaction barrier is dictated by the release of a proton from pyridone, as would be expected for an efficient Grothuss-type proton transfer mechanism.
The lipopolysaccharide modification regulator PmrA limitsSalmonellavirulence by repressing the type three-secretion system Spi/Ssa
Authors: Choi Jeongjoon , Groisman Eduardo A.
Published: May 2013

The regulatory protein PmrA controls expression of lipopolysaccharide (LPS) modification genes inSalmonella entericaserovar Typhimurium, the etiologic agent of human gastroenteritis and murine typhoid fever. PmrA-dependent LPS modifications confer resistance to serum, Fe3+, and several antimicrobial peptides, suggesting that thepmrAgene is required forSalmonellavirulence. We now report that, surprisingly, apmrAnull mutant is actually hypervirulent when inoculated i.p. into C3H/HeN mice. We establish that the PmrA protein binds to the promoter and represses transcription ofssrB, a virulence regulatory gene required for expression of the Spi/Ssa type three-secretion system inside macrophages. ThepmrAmutant displayed heightened expression of SsrB-dependent genes and faster Spi/Ssa-dependent macrophage killing than wild-typeSalmonella. A mutation in thessrBpromoter that abolished repression by the PmrA protein renderedSalmonellaas hypervirulent as thepmrAnull mutant. The antivirulence function of the PmrA protein may limit the acute phase ofSalmonellainfection, thereby enhancing pathogen persistence in host tissues.
Mass spectrometry reveals synergistic effects of nucleotides, lipids, and drugs binding to a multidrug resistance efflux pump
Authors: Marcoux Julien , Wang Sheila C. , Politis Argyris , Reading Eamonn , Ma Jerome , Biggin Philip C. , Zhou Min , Tao Houchao , Zhang Qinghai , Chang Geoffrey , Morgner Nina , Robinson Carol V.
Published: May 2013

Multidrug resistance is a serious barrier to successful treatment of many human diseases, including cancer, wherein chemotherapeutics are exported from target cells by membrane-embedded pumps. The most prevalent of these pumps, the ATP-Binding Cassette transporter P-glycoprotein (P-gp), consists of two homologous halves each comprising one nucleotide-binding domain and six transmembrane helices. The transmembrane region encapsulates a hydrophobic cavity, accessed by portals in the membrane, that binds cytotoxic compounds as well as lipids and peptides. Here we use mass spectrometry (MS) to probe the intact P-gp small molecule-bound complex in a detergent micelle. Activation in the gas phase leads to formation of ions, largely devoid of detergent, yet retaining drug molecules as well as charged or zwitterionic lipids. Measuring the rates of lipid binding and calculating apparent
K

D

values shows that up to six negatively charged diacylglycerides bind more favorably than zwitterionic lipids. Similar experiments confirm binding of cardiolipins and show that prior binding of the immunosuppressant and antifungal antibiotic cyclosporin A enhances subsequent binding of cardiolipin. Ion mobility MS reveals that P-gp exists in an equilibrium between different states, readily interconverted by ligand binding. Overall these MS results show how concerted small molecule binding leads to synergistic effects on binding affinities and conformations of a multidrug efflux pump.
Differential effects of cocaine on histone posttranslational modifications in identified populations of striatal neurons
Authors: Jordi Emmanuelle , Heiman Myriam , Marion-Poll Lucile , Guermonprez Pierre , Cheng Shuk Kei , Nairn Angus C. , Greengard Paul , Girault Jean-Antoine
Published: May 2013

Drugs of abuse, such as cocaine, induce changes in gene expression and epigenetic marks including alterations in histone posttranslational modifications in striatal neurons. These changes are thought to participate in physiological memory mechanisms and to be critical for long-term behavioral alterations. However, the striatum is composed of multiple cell types, including two distinct populations of medium-sized spiny neurons, and little is known concerning the cell-type specificity of epigenetic modifications. To address this question we used bacterial artificial chromosome transgenic mice, which express EGFP fused to the N-terminus of the large subunit ribosomal protein L10a driven by the D1 or D2 dopamine receptor (D1R, D2R) promoter, respectively. Fluorescence in nucleoli was used to sort nuclei from D1R- or D2R-expressing neurons and to quantify by flow cytometry the cocaine-induced changes in histone acetylation and methylation specifically in these two types of nuclei. The two populations of medium-sized spiny neurons displayed different patterns of histone modifications 15 min or 24 h after a single injection of cocaine or 24 h after seven daily injections. In particular, acetylation of histone 3 on Lys 14 and of histone 4 on Lys 5 and 12, and methylation of histone 3 on Lys 9 exhibited distinct and persistent changes in the two cell types. Our data provide insights into the differential epigenetic responses to cocaine in D1R- and D2R-positive neurons and their potential regulation, which may participate in the persistent effects of cocaine in these neurons. The method described should have general utility for studying nuclear modifications in different types of neuronal or nonneuronal cell types.
Ultrastructural analysis of hepatitis C virus particles
Authors: Catanese Maria Teresa , Uryu Kunihiro , Kopp Martina , Edwards Thomas J. , Andrus Linda , Rice William J. , Silvestry Mariena , Kuhn Richard J. , Rice Charles M.
Published: May 2013

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with an estimated 170 million people infected worldwide. Low yields, poor stability, and inefficient binding to conventional EM grids have posed significant challenges to the purification and structural analysis of HCV. In this report, we generated an infectious HCV genome with an affinity tag fused to the E2 envelope glycoprotein. Using affinity grids, previously described to isolate proteins and macromolecular complexes for single-particle EM, we were able to purify enveloped particles directly from cell culture media. This approach allowed for rapid in situ purification of virions and increased particle density that were instrumental for cryo-EM and cryoelectron tomography (cryo-ET). Moreover, it enabled ultrastructural analysis of virions produced by primary human hepatocytes. HCV appears to be the most structurally irregular member of the
Flaviviridae
family. Particles are spherical, with spike-like projections, and heterogeneous in size ranging from 40 to 100 nm in diameter. Exosomes, although isolated from unfractionated culture media, were absent in highly infectious, purified virus preparations. Cryo-ET studies provided low-resolution 3D structural information of highly infectious virions. In addition to apolipoprotein (apo)E, HCV particles also incorporate apoB and apoA-I. In general, host apolipoproteins were more readily accessible to antibody labeling than HCV glycoproteins, suggesting either lower abundance or masking by host proteins.
Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium
Authors: Gao Xia , Vockley Christopher M. , Pauli Florencia , Newberry Kimberly M. , Xue Yan , Randell Scott H. , Reddy Timothy E. , Hogan Brigid L. M.
Published: May 2013

Most of the airways of the human lung are lined by an epithelium made up of ciliated and secretory luminal cells and undifferentiated basal progenitor cells. The integrity of this epithelium and its ability to act as a selective barrier are critical for normal lung function. In other epithelia, there is evidence that transcription factors of the evolutionarily conserved grainyheadlike (GRHL) family play key roles in coordinating multiple cellular processes required for epithelial morphogenesis, differentiation, remodeling, and repair. However, only a few target genes have been identified, and little is known about GRHL function in the adult lung. Here we focus on the role of GRHL2 in primary human bronchial epithelial cells, both as undifferentiated progenitors and as they differentiate in air–liquid interface culture into an organized mucociliary epithelium with transepithelial resistance. Using a dominant-negative protein or shRNA to inhibit GRHL2, we follow changes in epithelial phenotype and gene transcription using RNA sequencing or microarray analysis. We identify several hundreds of genes that are directly or indirectly regulated by GRHL2 in both undifferentiated cells and air–liquid interface cultures. Using ChIP sequencing to map sites of GRHL2 binding in the basal cells, we identify 7,687 potential primary targets and confirm that GRHL2 binding is strongly enriched near GRHL2-regulated genes. Taken together, the results support the hypothesis that GRHL2 plays a key role in regulating many physiological functions of human airway epithelium, including those involving cell morphogenesis, adhesion, and motility.
The evolution of three pragmatic markers
Authors: Claridge Claudia
Published: May 2013

The article traces the development of three pragmatic markers with a hedging function, as it were, so to speak and if you like, back to their origins in the fourteenth century, the mid-seventeenth century and the early nineteenth century, respectively. They all probably started out as full clauses, as adverbial clauses (as it were, if you like) or as complement clause (so to speak), but underwent different degrees of restructuring and shortening. While as it were has lost its whole complement section and has fossilised an older conjunction use, if you like just froze in a fairly usual elliptical form and so to speak may not have changed its form at all. In the case of if you like and so to speak the influence of parallel parenthetical forms seems to have been important. The changes in question are seen as instances of pragmaticalisation and partly also lexicalisation, although they share many features with grammaticalisation.
A defence of the focus hypothesis concerning Late Medieval Greek object clitic pronouns
Authors: Soltic Jorie
Published: May 2013

In this article, I strengthen the contested view that the distribution of Late Medieval Greek object clitic pronouns is not only regulated by a syntactic rule but also by a pragmatic principle, i.e. that fronted focalised information attracts object clitic pronouns into preverbal position. For this purpose, I appeal to the modern concept of “light verbs”, as the direct objects of these semantically weak, unspecific verbs can be assumed to constitute focalised information. By means of a case study of the fourteenth century Chronicle
of
Morea, I demonstrate that almost all the fronted direct objects of the light verbs ποιώ (‘to do’) and δίδω (‘to give’) are indeed associated with preverbal object clitic pronouns. As such, the so-called “focus-hypothesis” can be verified in an objective way.
Pray in Early Modern English drama
Authors: Lutzky Ursula , Demmen Jane
Published: May 2013

This study seeks to provide new insights into the development and use of pray in Early Modern English. The study is based on the sociopragmatically annotated Drama Corpus, which combines the drama text samples of three different Early Modern English corpora, comprising a total of 242,561 words from a time span of 1500 to 1760. We investigate the quantitative distribution of the different forms in which pray appears during this period, and the influence of the variables of social status and gender. The aim of the current study is consequently to shed more light on the sociopragmatic nature of pray forms, and to reach a more profound understanding of their use in the Early Modern English period.
Existential quantifiers in second language acquisition
Authors: Gil Kook-Hee , Heather Marsden
Published: May 2013

Lardiere’s (2005,2008,2009) Feature Reassembly Hypothesis proposes that L2 acquisition involves reconfiguring the sets of lexical features that occur in the native language into feature bundles appropriate to the L2. This paper applies the Feature Reassembly Hypothesis to findings from recent research into the L2 acquisition of existential quantifiers. It firstly provides a feature-based, crosslinguistic account of polarity itemanyin English, and its equivalents —wh-existentials — in Chinese, Korean and Japanese. We then test predictions built on the Feature Reassembly Hypothesis, about how learners map target existential quantifiers in the L2 input onto feature sets from their L1, and how they then reassemble these feature sets to better match the target. The findings, which are largely compatible with the predictions, show that research that focuses on the specific processes of first mapping and then feature reassembly promises to lead to a more explanatory account of development in L2 acquisition.
Examining second language development using event-related potentials
Authors: Gabriele Alison , Fiorentino Robert , Bañón José Alemán
Published: May 2013

This cross-sectional study examines the role of L1-L2 differences and structural distance in the processing of gender and number agreement by English-speaking learners of Spanish at three different levels of proficiency. Preliminary results show that differences between the L1 and L2 impact L2 development, as sensitivity to gender agreement violations, as opposed to number agreement violations, emerges only in learners at advanced levels of proficiency. Results also show that the establishment of agreement dependencies is impacted by the structural distance between the agreeing elements for native speakers and for learners at intermediate and advanced levels of proficiency but not for low proficiency. The overall pattern of results suggests that the linguistic factors examined here impact development but do not constrain ultimate attainment; for advanced learners, results suggest that second language processing is qualitatively similar to native processing.
An empirical approach to the use and comprehension of mixed metaphors
Authors: Hilpert Martin
Published: May 2013

So-called mixed metaphors have not received much attention in cognitive linguistic research, despite acknowledgments to the fact that the combination of metaphors is in fact pervasive. This paper makes the case that mixed metaphors present a unique test case for existing theories of metaphor, in particular Conceptual Metaphor Theory and Blending Theory, since these theories make different predictions with regard to the comprehension of mixed metaphors. It will be argued that mixed metaphors selectively combine aspects of semantically conflicting source domains into one figurative meaning. The argument will be made through a two-tiered empirical study that uses quantitative corpus data as well as experimental evidence.
Semantic molecules and semantic complexity
Authors: Goddard Cliff
Published: May 2013

In the NSM approach to semantic analysis, semantic molecules are a well-defined set of non-primitive lexical meanings in a given language that function as intermediate-level units in the structure of complex meanings in that language. After reviewing existing work on the molecules concept (including the notion of levels of nesting), the paper advances a provisional list of about 180 productive semantic molecules for English, suggesting that a small minority of these (about 25) may be universal. It then turns close attention to a set of potentially universal level-one molecules from the “environmental” domain (‘sky’, ‘ground’, ‘sun’, ‘day’, ‘night’ ‘water’ and ‘fire’), proposing a set of original semantic explications for them. Finally, the paper considers the theoretical implications of the molecule theory for our understanding of semantic complexity, cross-linguistic variation in the structure of the lexicon, and the translatability of semantic explications.
The contribution of Herrero Ruiz’sUnderstanding Tropesto the interplay between Cognitive Linguistics and Pragmatics
Authors: Fuertes Olivera Pedro A.
Published: May 2013

This article attempts to give a critical review of Javier Herrero Ruiz’sUnderstanding Tropes. At a Crossroads between Pragmatics and Cognition. It evaluates the book in view of the available literature dealing with the trend towards empiricism adopted by Cognitive Linguistics. It also focuses on the main hypothesis put forward, i.e., tropes such asirony,paradox,oxymoron,overstatement,understatement,euphemism, anddysphemismcan be considered idealised cognitive models, and discusses the main contributions and arguments of the book, especially his idea that these idealised cognitive models are all constructed around the creation of contrast. A few concerns are also raised, mainly regarding corpus methodology. While these may have a negative impact on the reader, they are not severe enough to discredit the rigour with which the book was conceived.
Keratins control intercellular adhesion involving PKC-α–mediated desmoplakin phosphorylation
Authors: Kröger Cornelia , Loschke Fanny , Schwarz Nicole , Windoffer Reinhard , Leube Rudolf E. , Magin Thomas M.
Published: May 2013

Maintenance of epithelial cell adhesion is crucial for epidermal morphogenesis and homeostasis and relies predominantly on the interaction of keratins with desmosomes. Although the importance of desmosomes to epidermal coherence and keratin organization is well established, the significance of keratins in desmosome organization has not been fully resolved. Here, we report that keratinocytes lacking all keratins show elevated, PKC-α–mediated desmoplakin phosphorylation and subsequent destabilization of desmosomes. We find that PKC-α activity is regulated by Rack1–keratin interaction. Without keratins, desmosomes assemble but are endocytosed at accelerated rates, rendering epithelial sheets highly susceptible to mechanical stress. Re-expression of the keratin pair K5/14, inhibition of PKC-α activity, or blocking of endocytosis reconstituted both desmosome localization at the plasma membrane and epithelial adhesion. Our findings identify a hitherto unknown mechanism by which keratins control intercellular adhesion, with potential implications for tumor invasion and keratinopathies, settings in which diminished cell adhesion facilitates tissue fragility and neoplastic growth.
Evolutionary comparisons reveal a positional switch for spindle pole oscillations in Caenorhabditis embryos
Authors: Riche Soizic , Zouak Melissa , Argoul Françoise , Arneodo Alain , Pecreaux Jacques , Delattre Marie
Published: May 2013

During the first embryonic division in Caenorhabditis elegans, the mitotic spindle is pulled toward the posterior pole of the cell and undergoes vigorous transverse oscillations. We identified variations in spindle trajectories by analyzing the outwardly similar one-cell stage embryo of its close relative Caenorhabditis briggsae. Compared with C. elegans, C. briggsae embryos exhibit an anterior shifting of nuclei in prophase and reduced anaphase spindle oscillations. By combining physical perturbations and mutant analysis in both species, we show that differences can be explained by interspecies changes in the regulation of the cortical Gα–GPR–LIN-5 complex. However, we found that in both species (1) a conserved positional switch controls the onset of spindle oscillations, (2) GPR posterior localization may set this positional switch, and (3) the maximum amplitude of spindle oscillations is determined by the time spent in the oscillating phase. By investigating microevolution of a subcellular process, we identify new mechanisms that are instrumental to decipher spindle positioning.
Live-cell imaging of exocyst links its spatiotemporal dynamics to various stages of vesicle fusion
Authors: Rivera-Molina Felix , Toomre Derek
Published: May 2013

Tethers play ubiquitous roles in membrane trafficking and influence the specificity of vesicle attachment. Unlike soluble N-ethyl-maleimide–sensitive fusion attachment protein receptors (SNAREs), the spatiotemporal dynamics of tethers relative to vesicle fusion are poorly characterized. The most extensively studied tethering complex is the exocyst, which spatially targets vesicles to sites on the plasma membrane. By using a mammalian genetic replacement strategy, we were able to assemble fluorescently tagged Sec8 into the exocyst complex, which was shown to be functional by biochemical, trafficking, and morphological criteria. Ultrasensitive live-cell imaging revealed that Sec8-TagRFP moved to the cell cortex on vesicles, which preferentially originated from the endocytic recycling compartment. Surprisingly, Sec8 remained with vesicles until full dilation of the fusion pore, supporting potential coupling with SNARE fusion machinery. Fluorescence recovery after photobleaching analysis of Sec8 at cell protrusions revealed that a significant fraction was immobile. Additionally, Sec8 dynamically repositioned to the site of membrane expansion, suggesting that it may respond to local cues during early cell polarization.
Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation
Authors: Mielke Lisa A. , Jones Sarah A. , Raverdeau Mathilde , Higgs Rowan , Stefanska Anna , Groom Joanna R. , Misiak Alicja , Dungan Lara S. , Sutton Caroline E. , Streubel Gundula , Bracken Adrian P. , Mills Kingston H.G.
Published: May 2013

Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22–responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti–IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells.
Empirical modelling of benthic species distribution, abundance, and diversity in the Baltic Sea: evaluating the scope for predictive mapping using different modelling approaches
Authors: Bučas M. , Bergström U. , Downie A-L. , Sundblad G. , Gullström M. , von Numers M. , Šiaulys A. , Lindegarth M.
Published: May 2013

Bučas, M., Bergström, U., Downie, A-L., Sundblad, G., Gullström, M., von Numers, M., Šiaulys, A., and Lindegarth, M. 2013. Empirical modelling of benthic species distribution, abundance, and diversity in the Baltic Sea: evaluating the scope for predictive mapping using different modelling approaches. – ICES Journal of Marine Science, 70: 1233–1243. The predictive performance of distribution models of common benthic species in the Baltic Sea was compared using four non-linear methods: generalized additive models (GAMs), multivariate adaptive regression splines, random forest (RF), and maximum entropy modelling (MAXENT). The effects of data traits were also tested. In total, 292 occurrence models and 204 quantitative (abundance and diversity) models were assessed. The main conclusions are that (i) the spatial distribution, abundance, and diversity of benthic species in the Baltic Sea can be successfully predicted using several non-linear predictive modelling techniques; (ii) RF was the most accurate method for both models, closely followed by GAM and MAXENT; (iii) correlation coefficients of predictive performance among the modelling techniques were relatively low, suggesting that the performance of methods is related to specific responses; (iv) the differences in predictive performance among the modelling methods could only partly be explained by data traits; (v) the response prevalence was the most important explanatory variable for predictive accuracy of GAM and MAXENT on occurrence data; (vi) RF on the occurrence data was the only method sensitive to sampling density; (vii) a higher predictive accuracy of abundance models could be achieved by reducing variance in the response data and increasing the sample size.
Perioperative Management of Coagulation in Nontraumatic Intracerebral Hemorrhage
Authors: Degos Vincent , Westbroek Erick M. , Lawton Michael T. , Hemphill J. Claude , del Zoppo Gregory J. , Young William L.
Published: May 2013

This commentary seeks to clarify the recommendations and highlight the debate regarding the perioperative management of hemostasis in intracerebral hemorrhage.
Increased Perioperative B-type Natriuretic Peptide Associates with Heart Failure Hospitalization or Heart Failure Death after Coronary Artery Bypass Graft Surgery
Authors: Fox Amanda A. , Nascimben Luigino , Body Simon C. , Collard Charles D. , Mitani Aya A. , Liu Kuang-Yu , Muehlschlegel Jochen D. , Shernan Stanton K. , Marcantonio Edward R.
Published: May 2013

Background:

Heart failure (HF) is a leading cause of hospitalization and mortality. Plasma B-type natriuretic peptide (BNP) is an established diagnostic and prognostic ambulatory HF biomarker. We hypothesized that increased perioperative BNP independently associates with HF hospitalization or HF death up to 5 yr after coronary artery bypass graft surgery.

Methods:

The authors conducted a two-institution, prospective, observational study of 1,025 subjects (mean age = 64 ± 10 yr SD) undergoing isolated primary coronary artery bypass graft surgery with cardiopulmonary bypass. Plasma BNP was measured preoperatively and on postoperative days 1–5. The study outcome was hospitalization or death from HF, with HF events confirmed by reviewing hospital and death records. Cox proportional hazards analyses were performed with multivariable adjustments for clinical risk factors. Preoperative and peak postoperative BNP were added to the multivariable clinical model in order to assess additional predictive benefit.

Results:

One hundred five subjects experienced an HF event (median time to first event = 1.1 yr). Median follow-up for subjects who did not have an HF event = 4.2 yr. When individually added to the multivariable clinical model, higher preoperative and peak postoperative BNP concentrations each, independently associated with the HF outcome (log10 preoperative BNP hazard ratio = 1.93; 95% CI, 1.30–2.88; P = 0.001; log10 peak postoperative BNP hazard ratio = 3.38; 95% CI, 1.45–7.65; P = 0.003).

Conclusions:

Increased perioperative BNP concentrations independently associate with HF hospitalization or HF death during the 5 yr after primary coronary artery bypass graft surgery. Clinical trials may be warranted to assess whether medical management focused on reducing preoperative and longitudinal postoperative BNP concentrations associates with decreased HF after coronary artery bypass graft surgery.
Glycemia-dependent Nuclear Factor κB Activation Contributes to Mechanical Allodynia in Rats with Chronic Postischemia Pain
Authors: Ross-Huot Marie-Christine , Laferrière André , Khorashadi Mina , Coderre Terence J.
Published: May 2013

Background:

Ischemia–reperfusion injury causes chronic postischemia pain (CPIP), and rats with higher glycemia during ischemia–reperfusion injury exhibit increased allodynia. Glycemia-induced elevation of nuclear factor κB (NFκB) may contribute to increased allodynia.

Methods:

Glycemia during a 3-h ischemia–reperfusion injury was manipulated by: normal feeding; or normal feeding with administration of insulin; dextrose; or insulin/dextrose. In these groups, NFκB was measured in ipsilateral hind paw muscle and spinal dorsal horn by enzyme-linked immunosorbent assay (ELISA), and SN50, an NFκB inhibitor, was administered to determine its differential antiallodynic effects depending on glycemia.

Results:

CPIP fed/insulin rats (12.03 ± 4.9 g, N = 6) had less allodynia than fed, fed/insulin/dextrose, and fed/dextrose rats (6.29 ± 3.37 g, N = 7; 4.57 ± 3.03 g, N = 6; 2.95 ± 1.10 g, N = 9), respectively. Compared with fed rats (0.209 ± 0.022 AU, N = 7), NFκB in ipsilateral plantar muscles was significantly lower for fed/insulin rats, and significantly higher for fed/dextrose rats (0.152 ± 0.053 AU, N = 6; 0.240 ± 0.057 AU, N = 7, respectively). Furthermore, NFκB in the dorsal horn of fed, fed/insulin/dextrose, and fed/dextrose rats (0.293 ± 0.049 AU; 0.267 ± 0.037 AU; 0.315 ± 0.015 AU, respectively, N = 6 for each) was significantly higher than in fed/insulin animals (0.267 ± 0.037 AU, N = 6). The antiallodynic SN50 dose–response curves of CPIP rats in the fed/insulin/dextrose, fed/dextrose, and fed conditions exhibited a rightward shift compared with the fed/insulin group. The threshold SN50 dose of CPIP fed/dextrose, fed/insulin/dextrose, and fed rats (328.94 ± 92.4 ng, 77.80 ± 44.50 ng, and 24.89 ± 17.20 ng, respectively) was higher than that for fed/insulin rats (4.06 ± 7.04 ng).

Conclusions:

NFκB was activated in a glycemia-dependent manner in CPIP rats. Hypoglycemic rats were more sensitive to SN50 than rats with higher glycemia. The finding that SN50 reduces mechanical allodynia suggests that NFκB inhibitors might be useful for treating postischemia pain.