bluuebunny/crossref_metadata_2025 huggingface dataset:
The Civics of Urban Nature: Enacting Hybrid Landscapes
Authors: Karvonen Andrew , Yocom Ken
Published: June 2011

Urban nature is typically managed through top-down, bureaucratic, and expert-driven approaches that tend to rationalize and simplify the interactions between humans and their surroundings. In the last few decades, there has been a significant push in cultural geography and the design disciplines to develop a relational ontology of urban nature, a perspective that emphasizes the hybrid connections between humans and nonhumans, built and unbuilt, social and natural. This perspective offers new and exciting ways of conceptualizing urban nature but it has not produced alternatives to conventional governance. In other words, thinking differently about urban nature has yet to produce different ways of interacting with it. In this paper we argue that civic environmentalism can enact a relational ontology by engaging urban residents in processes of democratic deliberation and action in the reworking of urban nature. We illustrate this approach with a case study of a community-led project to construct a pedestrian trail along an urban creek in Seattle, Washington. The example demonstrates how the concept of civic environmentalism embraces a relational perspective of urban nature, while also producing generative forms of political action.
Neighbourhood Choice and Neighbourhood Reproduction
Authors: Hedman Lina , van Ham Maarten , Manley David
Published: June 2011

Although we know a lot about why households choose certain dwellings, we know relatively little about the mechanisms behind their choice of neighbourhood. Most studies of neighbourhood choice focus only on one or two dimensions of neighbourhoods: typically poverty and ethnicity. In this paper we argue that neighbourhoods have multiple dimensions and that models of neighbourhood choice should take these dimensions into account. We propose the use of a conditional logit model. From this approach we can gain insight into the interaction between individual and neighbourhood characteristics which lead to the choice of a particular neighbourhood over alternative destinations. We use Swedish register data to model neighbourhood choice for all households which moved in the city of Uppsala between 1997 and 2006. Our results show that neighbourhood sorting is a highly structured process where households are very likely to choose neighbourhoods where the neighbourhood population matches their own characteristics. We find that income is the most important driver of the sorting process, although ethnicity and other demographic and socioeconomic characteristics play important roles as well.
Tactical Voting at the 2010 British General Election: Rational Behaviour in Local Contexts?
Authors: Johnston Ron , Pattie Charles
Published: June 2011

Tactical voting is an important element of British electoral behaviour, with approximately one sixth of all voters surveyed indicating that they voted tactically at the 2010 general election. Such voting for one's second preference party rather than one's first in order to prevent a less preferred party winning in a constituency is only rational in certain circumstances, reflecting the local context and electors' perceptions of the tactical situation there. Using 2010 British Election Study Internet survey data, this paper uses three separate definitions of tactical voting (two self-defined by the respondents, one inferred from a separate indication of their preferences) to test whether rational voting models successfully predict such behaviour. The findings are very clear and consistent with the theory, for all three groups.
Tax Doesn't Have to Be Taxing: London's ‘Onshore’ Finance Industry and the Fiscal Spaces of a Global Crisis
Authors: Wainwright Thomas
Published: June 2011

In this paper I will explore London's onshore finance industry and how it facilitates corporate tax avoidance programmes. In doing so, I will discuss how financial elites design transactions and corporate activities so as to minimise their exposure to taxation, and how these structures are shaped by the international geographies of taxation. I will investigate an area of London's financial sector that has previously been neglected by geographers and social scientists. Finally, I turn to illustrate how tax minimisation strategies are implemented, through the example of residential mortgage-backed securitisation, and how tax-minimisation strategies made securitisation a practical tool for financiers. This provides new insights into how taxation elites facilitated the increased financialisation of Britain's economy and the severity of its exposure to the credit crunch.
Competitiveness, Creativity, and Place-Based Development
Authors: Huggins Robert , Clifton Nick
Published: June 2011

This paper seeks to make a link between the concepts of competitiveness and the ‘creative class’ at a place-based level. The paper explores the relationship between creativity and competitiveness at the local level across the UK using a rural–urban framework. A growing competitiveness divide between rural and urban areas is found. Also, the creative class is found to be more evenly distributed than might be anticipated a priori. In conclusion, we argue that city-region approaches to economic development are having a detrimental impact on the competitiveness of rural regions.
Between Rights and Responsibilities: Insurgent Performance in an Invisible Landscape
Authors: Brownlow Alec
Published: June 2011

The rise of voluntary and participatory discourses under neoliberalism has been met with suspicion among scholars who identify within them vulnerabilities to state cooptation and control. A growing body of research suggests, however, that local communities and volunteer organizations are not so easily duped and that the new politics of public participation offer otherwise rare opportunities to pursue and enact alternative political agendas. This paper contributes to this debate by examining voluntarism in a long-marginalized African American community in Philadelphia. Far from being co-opted agents of state agendas, I argue that voluntary participation in the restoration of a local park has been seized upon by local residents in their efforts to reclaim public space, expose racialized injustice, and enact community citizenship. I adopt social theories of insurgency and performance to make my argument. I conclude with a discussion of the significance of devolution to communities whose principal experience with the state is one of political neglect.
Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity againstListeria monocytogenes
Authors: Knowles Heather , Heizer Justin W. , Li Yuan , Chapman Kathryn , Ogden Carol Anne , Andreasen Karl , Shapland Ellen , Kucera Gary , Mogan Jennifer , Humann Jessica , Lenz Laurel L. , Morrison Alastair D. , Perraud Anne-Laure
Published: June 2011

The generation of reactive oxygen species (ROS) is inherent to immune responses. ROS are crucially involved in host defense against pathogens by promoting bacterial killing, but also as signaling agents coordinating the production of cytokines. Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca2+-permeable channel gated via binding of ADP-ribose, a metabolite formed under conditions of cellular exposure to ROS. Here, we show that TRPM2-deficient mice are extremely susceptible to infection withListeria monocytogenes (Lm), exhibiting an inefficient innate immune response. In a comparison with IFNγR-deficient mice, TRPM2−/−mice shared similar features of uncontrolled bacterial replication and reduced levels of inducible (i)NOS-expressing monocytes, but had intact IFNγ responsiveness. In contrast, we found that levels of cytokines IL-12 and IFNγ were diminished in TRPM2−/−mice followingLminfection, which correlated with their reduced innate activation. Moreover, TRPM2−/−mice displayed a higher degree of susceptibility than IL-12–unresponsive mice, and supplementation with recombinant IFNγ was sufficient to reverse the unrestrained bacterial growth and ultimately the lethal phenotype ofLm-infected TRPM2−/−mice. The severity of listeriosis we observed in TRPM2−/−mice has not been reported for any other ion channel. These findings establish an unsuspected role for ADP-ribose and ROS-mediated cation flux for innate immunity, opening up unique possibilities for immunomodulatory intervention through TRPM2.
Chemotactic cell trapping in controlled alternating gradient fields
Authors: Meier Börn , Zielinski Alejandro , Weber Christoph , Arcizet Delphine , Youssef Simon , Franosch Thomas , Rädler Joachim O. , Heinrich Doris
Published: June 2011

Directed cell migration toward spatio-temporally varying chemotactic stimuli requires rapid cytoskeletal reorganization. Numerous studies provide evidence that actin reorganization is controlled by intracellular redistribution of signaling molecules, such as the PI4,5P2/PI3,4,5P3 gradient. However, exploring underlying mechanisms is difficult and requires careful spatio-temporal control of external chemotactic stimuli. We designed a microfluidic setup to generate alternating chemotactic gradient fields for simultaneous multicell exposure, greatly facilitating statistical analysis. For a quantitative description of intracellular response dynamics, we apply alternating time sequences of spatially homogeneous concentration gradients across 300 μm, reorienting on timescales down to a few seconds.
Dictyostelium discoideum
amoebae respond to gradient switching rates below 0.02 Hz by readapting their migration direction. For faster switching, cellular repolarization ceases and is completely stalled at 0.1 Hz. In this “chemotactically trapped” cell state, external stimuli alternate faster than intracellular feedback is capable to respond by onset of directed migration. To investigate intracellular actin cortex rearrangement during gradient switching, we correlate migratory cell response with actin repolymerization dynamics, quantified by a fluorescence distribution moment of the GFP fusion protein LimEΔcc. We find two fundamentally different cell polarization types and we could reveal the role of PI3-Kinase for cellular repolarization. In the early aggregation phase, PI3-Kinase enhances the capability of
D. discoideum
cells to readjust their polarity in response to spatially alternating gradient fields, whereas in aggregation competent cells the effect of PI3-Kinase perturbation becomes less relevant.
Progressive Cenozoic cooling and the demise of Antarctica’s last refugium
Authors: Anderson John B. , Warny Sophie , Askin Rosemary A. , Wellner Julia S. , Bohaty Steven M. , Kirshner Alexandra E. , Livsey Daniel N. , Simms Alexander R. , Smith Tyler R. , Ehrmann Werner , Lawver Lawrence A. , Barbeau David , Wise Sherwood W. , Kulhanek Denise K. , Weaver Fred M. , Majewski Wojciech
Published: June 2011

The Antarctic Peninsula is considered to be the last region of Antarctica to have been fully glaciated as a result of Cenozoic climatic cooling. As such, it was likely the last refugium for plants and animals that had inhabited the continent since it separated from the Gondwana supercontinent. Drill cores and seismic data acquired during two cruises (SHALDRIL I and II) in the northernmost Peninsula region yield a record that, when combined with existing data, indicates progressive cooling and associated changes in terrestrial vegetation over the course of the past 37 million years. Mountain glaciation began in the latest Eocene (approximately 37–34 Ma), contemporaneous with glaciation elsewhere on the continent and a reduction in atmospheric CO
2
concentrations. This climate cooling was accompanied by a decrease in diversity of the angiosperm-dominated vegetation that inhabited the northern peninsula during the Eocene. A mosaic of southern beech and conifer-dominated woodlands and tundra continued to occupy the region during the Oligocene (approximately 34–23 Ma). By the middle Miocene (approximately 16–11.6 Ma), localized pockets of limited tundra still existed at least until 12.8 Ma. The transition from temperate, alpine glaciation to a dynamic, polythermal ice sheet took place during the middle Miocene. The northernmost Peninsula was overridden by an ice sheet in the early Pliocene (approximately 5.3–3.6 Ma). The long cooling history of the peninsula is consistent with the extended timescales of tectonic evolution of the Antarctic margin, involving the opening of ocean passageways and associated establishment of circumpolar circulation.
Perceptual and neural consequences of rapid motion adaptation
Authors: Glasser Davis M. , Tsui James M. G. , Pack Christopher C. , Tadin Duje
Published: June 2011

Nervous systems adapt to the prevailing sensory environment, and the consequences of this adaptation can be observed in the responses of single neurons and in perception. Given the variety of timescales underlying events in the natural world, determining the temporal characteristics of adaptation is important to understanding how perception adjusts to its sensory environment. Previous work has shown that neural adaptation can occur on a timescale of milliseconds, but perceptual adaptation has generally been studied over relatively long timescales, typically on the order of seconds. This disparity raises important questions. Can perceptual adaptation be observed at brief, functionally relevant timescales? And if so, how do its properties relate to the rapid adaptation seen in cortical neurons? We address these questions in the context of visual motion processing, a perceptual modality characterized by rapid temporal dynamics. We demonstrate objectively that 25 ms of motion adaptation is sufficient to generate a motion aftereffect, an illusory sensation of movement experienced when a moving stimulus is replaced by a stationary pattern. This rapid adaptation occurs regardless of whether the adapting motion is perceived. In neurophysiological recordings from the middle temporal area of primate visual cortex, we find that brief motion adaptation evokes direction-selective responses to subsequently presented stationary stimuli. A simple model shows that these neural responses can explain the consequences of rapid perceptual adaptation. Overall, we show that the motion aftereffect is not merely an intriguing perceptual illusion, but rather a reflection of rapid neural and perceptual processes that can occur essentially every time we experience motion.
Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures
Authors: Harris Audray , Borgnia Mario J. , Shi Dan , Bartesaghi Alberto , He Haifeng , Pejchal Robert , Kang Yun (Kenneth) , Depetris Rafael , Marozsan Andre J. , Sanders Rogier W. , Klasse Per Johan , Milne Jacqueline L. S. , Wilson Ian A. , Olson William C. , Moore John P. , Subramaniam Sriram
Published: June 2011

The initial step in HIV-1 infection occurs with the binding of cell surface CD4 to trimeric HIV-1 envelope glycoproteins (Env), a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120). The design of soluble versions of trimeric Env that display structural and functional properties similar to those observed on intact viruses is highly desirable from the viewpoint of designing immunogens that could be effective as vaccines against HIV/AIDS. Using cryoelectron tomography combined with subvolume averaging, we have analyzed the structure of SOSIP gp140 trimers, which are cleaved, solubilized versions of the ectodomain of trimeric HIV-1 Env. We show that unliganded gp140 trimers adopt a quaternary arrangement similar to that displayed by native unliganded trimers on the surface of intact HIV-1 virions. When complexed with soluble CD4, Fab 17b, which binds to gp120 at its chemokine coreceptor binding site, or both soluble CD4 and 17b Fab, gp140 trimers display an open conformation in which there is an outward rotation and displacement of each gp120 protomer. We demonstrate that the molecular arrangements of gp120 trimers in the closed and open conformations of the soluble trimer are the same as those observed for the closed and open states, respectively, of trimeric gp120 on intact HIV-1 BaL virions, establishing that soluble gp140 trimers can be designed to mimic the quaternary structural transitions displayed by native trimeric Env.
Biocompatible artificial DNA linker that is read through by DNA polymerases and is functional in
Escherichia coli
Authors: El-Sagheer Afaf H. , Sanzone A. Pia , Gao Rachel , Tavassoli Ali , Brown Tom
Published: June 2011

A triazole mimic of a DNA phosphodiester linkage has been produced by templated chemical ligation of oligonucleotides functionalized with 5′-azide and 3′-alkyne. The individual azide and alkyne oligonucleotides were synthesized by standard phosphoramidite methods and assembled using a straightforward ligation procedure. This highly efficient chemical equivalent of enzymatic DNA ligation has been used to assemble a 300-mer from three 100-mer oligonucleotides, demonstrating the total chemical synthesis of very long oligonucleotides. The base sequences of the DNA strands containing this artificial linkage were copied during PCR with high fidelity and a gene containing the triazole linker was functional in
Escherichia coli
.
Outer membrane adhesion factor multivalent adhesion molecule 7 initiates host cell binding during infection by Gram-negative pathogens
Authors: Krachler Anne Marie , Ham Hyeilin , Orth Kim
Published: June 2011

The initial binding of bacteria to host cells is crucial to the delivery of virulence factors and thus is a key determinant of the pathogen's success. We report a multivalent adhesion molecule (MAM) that enables a wide range of Gram-negative pathogens to establish high-affinity binding to host cells during the early stages of infection. MAM7 binds to the host by engaging in both protein–protein (with fibronectin) and protein–lipid (with phosphatidic acid) interactions with the host cell membrane. We find that MAM7 expression on the outer membrane of a Gram-negative pathogen is necessary for virulence in a nematode infection model and for efficient killing of cultured mammalian host cells. Expression of MAM7 on nonpathogenic strains produced a tool that can be used to impede infection by Gram-negative bacterial pathogens. Targeting or exploiting MAM7 might prove to be important in combating Gram-negative bacterial infections.
Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation
Authors: Apcher Sebastien , Daskalogianni Chrysoula , Lejeune Fabrice , Manoury Bénédicte , Imhoos Gabriela , Heslop Lea , Fåhraeus Robin
Published: June 2011

The MHC class I antigen presentation pathway allows the immune system to distinguish between self and nonself. Despite extensive research on the processing of antigenic peptides, little is known about their origin. Here, we show that mRNAs carrying premature stop codons that prevent the production of full-length proteins via the nonsense-mediated decay pathway still produce a majority of peptide substrates for the MHC class I pathway by a noncanonical mRNA translation process. Blocking the interaction of the translation initiation factor eIF4E with the cap structure suppresses the synthesis of full-length proteins but has only a limited effect on the production of antigenic peptides. These results reveal an essential cell biological function for a class of translation products derived during the pioneer round of mRNA translation and will have important implications for understanding how the immune system detects cells harboring pathogens and generates tolerance.
Opposite-sex siblings decrease attraction, but not prosocial attributions, to self-resembling opposite-sex faces
Authors: DeBruine Lisa M. , Jones Benedict C. , Watkins Christopher D. , Roberts S. Craig , Little Anthony C. , Smith Finlay G. , Quist Michelle C.
Published: June 2011

Contextual cues of genetic relatedness to familiar individuals, such as cosocialization and maternal–perinatal association, modulate prosocial and inbreeding-avoidance behaviors toward specific potential siblings. These findings have been interpreted as evidence that contextual cues of kinship indirectly influence social behavior by affecting the perceived probability of genetic relatedness to familiar individuals. Here, we test a more general alternative model in which contextual cues of kinship can influence the kin-recognition system more directly, changing how the mechanisms that regulate social behavior respond to cues of kinship, even in unfamiliar individuals for whom contextual cues of kinship are absent. We show that having opposite-sex siblings influences inbreeding-relevant perceptions of facial resemblance but not prosocial perceptions. Women with brothers were less attracted to self-resembling, unfamiliar male faces than were women without brothers, and both groups found self-resemblance to be equally trustworthy for the same faces. Further analyses suggest that this effect is driven by younger, rather than older, brothers, consistent with the proposal that only younger siblings exhibit the strong kinship cue of maternal–perinatal association. Our findings provide evidence that experience with opposite-sex siblings can directly influence inbreeding-avoidance mechanisms and demonstrate a striking functional dissociation between the mechanisms that regulate inbreeding and the mechanisms that regulate prosocial behavior toward kin.
Systems analysis identifies an essential role for SHANK-associated RH domain-interacting protein (SHARPIN) in macrophage Toll-like receptor 2 (TLR2) responses
Authors: Zak Daniel E. , Schmitz Frank , Gold Elizabeth S. , Diercks Alan H. , Peschon Jacques J. , Valvo Joe S. , Niemistö Antti , Podolsky Irina , Fallen Shannon G. , Suen Rosa , Stolyar Tetyana , Johnson Carrie D. , Kennedy Kathleen A. , Hamilton M. Kristina , Siggs Owen M. , Beutler Bruce , Aderem Alan
Published: June 2011

Precise control of the innate immune response is essential to ensure host defense against infection while avoiding inflammatory disease. Systems-level analyses of Toll-like receptor (TLR)-stimulated macrophages suggested that SHANK-associated RH domain-interacting protein (SHARPIN) might play a role in the TLR pathway. This hypothesis was supported by the observation that macrophages derived from
chronic proliferative dermatitis mutation
(
cpdm
) mice, which harbor a spontaneous null mutation in the
Sharpin
gene, exhibited impaired IL-12 production in response to TLR activation. Systems biology approaches were used to define the SHARPIN-regulated networks. Promoter analysis identified NF-κB and AP-1 as candidate transcription factors downstream of SHARPIN, and network analysis suggested selective attenuation of these pathways. We found that the effects of SHARPIN deficiency on the TLR2-induced transcriptome were strikingly correlated with the effects of the recently described hypomorphic L153P/
panr2
point mutation in
Ikbkg
[
N
F-κB
E
ssential
Mo
dulator (NEMO)], suggesting that SHARPIN and NEMO interact. We confirmed this interaction by co-immunoprecipitation analysis and furthermore found it to be abrogated by panr2. NEMO-dependent signaling was affected by SHARPIN deficiency in a manner similar to the
panr2
mutation, including impaired p105 and ERK phosphorylation and p65 nuclear localization. Interestingly, SHARPIN deficiency had no effect on IκBα degradation and on p38 and JNK phosphorylation. Taken together, these results demonstrate that SHARPIN is an essential adaptor downstream of the branch point defined by the
panr2
mutation in NEMO.
Pathway for lipid A biosynthesis in
Arabidopsis thaliana
resembling that of
Escherichia coli
Authors: Li Chijun , Guan Ziqiang , Liu Dan , Raetz Christian R. H.
Published: June 2011

The lipid A moiety of
Escherichia coli
lipopolysaccharide is a hexa-acylated disaccharide of glucosamine that makes up the outer monolayer of the outer membrane.
Arabidopsis thaliana
contains nuclear genes encoding orthologs of key enzymes of bacterial lipid A biosynthesis, including LpxA, LpxC, LpxD, LpxB, LpxK and KdtA. Although structurally related lipid A molecules are found in most other Gram-negative bacteria, lipid A and its precursors have not been directly detected in plants previously. However, homozygous insertional knockout mutations or RNAi knock-down constructs of
Arabidopsis
lpx
and
kdtA
mutants revealed accumulation (or disappearance) of the expected monosaccharide or disaccharide lipid A precursors by mass spectrometry of total lipids extracted from 10-day old seedlings of these mutants. In addition, fluorescence microscopy of
lpx-gfp
fusions in transgenic
Arabidopsis
plants suggests that the Lpx and KdtA proteins are expressed and targeted to mitochondria. Although the structure of the lipid A end product generated by plants is still unknown, our work demonstrates that plants synthesize lipid A precursors using the same enzymatic pathway present in
E. coli
.
Neutral and Nonneutral Genetic Markers Revealed the Presence of Inshore and Offshore Stock Components of Atlantic Cod in Greenland Waters
Authors: Pampoulie Christophe , Daníelsdóttir Anna Kristín , Storr‐Paulsen Marie , Hovgård Holger , Hjörleifsson Einar , Steinarsson Björn Ævarr
Published: June 2011

The spawning stock of Atlantic cod Gadus morhua in West Greenland waters was characterized by a drastic decline in the late 1960s and has since exhibited considerable variation. It has been suggested that the cod stock in West Greenland waters is composed of several stock components that include (1) a number of distinct local inshore populations spawning in separate fjord systems, (2) an offshore spawning component located on the fishing banks, and (3) a periodic Icelandic–East Greenland cod influx that mixes with the offshore and inshore West Greenland stock components. In an attempt to clarify the status of Atlantic cod in Greenland waters, we investigated the genetic structure at different inshore and offshore feeding grounds east and west of Greenland. A total of 1,581 genetic samples were collected within North Atlantic Fisheries Organization areas at inshore and offshore locations as well as within the International Council for the Exploration of the Sea area XIVb. Those samples were genotyped for 18 microsatellite loci and the pantophysin (Pan I) locus. Both types of genetic markers gave congruent results and suggest the presence of two distinct genetic components with limited connectivity in Greenland waters, namely, an inshore component and an offshore component.
A Multistate Capture–Recapture Modeling Strategy to Separate True Survival from Permanent Emigration for a Passive Integrated Transponder Tagged Population of Stream Fish
Authors: Horton Gregg E. , Letcher Benjamin H. , Kendall William L.
Published: June 2011

Robust estimates of survival and movement are important for informing the recovery of fish populations as well as for the study of life history, behavior, and population ecology. We present a multistate capture–recapture model that allows separate and simultaneous estimation of true survival and fidelity to the study reach in the presence of imperfect recapture and detection probabilities. The key study design element that permitted this separation was the use of a multiple‐antenna array to detect passive integrated transponder (PIT) tagged individuals as they emigrated from the study area. The modeling approach incorporated live recapture data during discrete sampling occasions with observational data on antenna detections of tagged individuals as they exited the study area between sampling occasions. The multistate emigration model was applied to empirical data from a stream‐dwelling, PIT‐tagged cohort of Atlantic salmon Salmo salar for which emigration was continuously monitored by using a pair of stationary PIT tag antennas. The study design we outline presents a way to inform key management, recovery, and ecological questions. Our analysis showed how estimates of the joint probability of surviving and remaining faithful to the study reach (apparent survival) that were based solely on live recapture data (e.g., from the Cormack–Jolly–Seber model) masked the patterns that were revealed when true survival and emigration were separately estimated with the multistate emigration model. Use of the multistate model also allowed us to consider size dependence in survival and emigration in a straightforward way; the estimated size‐dependent functions support hypotheses regarding the mechanisms leading to survival or emigration responses of Atlantic salmon and other stream‐dwelling salmonids.
Jagesh Shah: A quantitative approach to cell biology
Authors: Sedwick Caitlin
Published: June 2011

Shah uses quantitative modeling to build frameworks for understanding complex cellular systems.
Pak1 regulates focal adhesion strength, myosin IIA distribution, and actin dynamics to optimize cell migration
Authors: Delorme-Walker Violaine D. , Peterson Jeffrey R. , Chernoff Jonathan , Waterman Clare M. , Danuser Gaudenz , DerMardirossian Céline , Bokoch Gary M.
Published: June 2011

Cell motility requires the spatial and temporal coordination of forces in the actomyosin cytoskeleton with extracellular adhesion. The biochemical mechanism that coordinates filamentous actin (F-actin) assembly, myosin contractility, adhesion dynamics, and motility to maintain the balance between adhesion and contraction remains unknown. In this paper, we show that p21-activated kinases (Paks), downstream effectors of the small guanosine triphosphatases Rac and Cdc42, biochemically couple leading-edge actin dynamics to focal adhesion (FA) dynamics. Quantitative live cell microscopy assays revealed that the inhibition of Paks abolished F-actin flow in the lamella, displaced myosin IIA from the cell edge, and decreased FA turnover. We show that, by controlling the dynamics of these three systems, Paks regulate the protrusive activity and migration of epithelial cells. Furthermore, we found that expressing Pak1 was sufficient to overcome the inhibitory effects of excess adhesion strength on cell motility. These findings establish Paks as critical molecules coordinating cytoskeletal systems for efficient cell migration.
The p25 subunit of the dynactin complex is required for dynein–early endosome interaction
Authors: Zhang Jun , Yao Xuanli , Fischer Lauren , Abenza Juan F. , Peñalva Miguel A. , Xiang Xin
Published: June 2011

Cytoplasmic dynein transports various cellular cargoes including early endosomes, but how dynein is linked to early endosomes is unclear. We find that the Aspergillus nidulans orthologue of the p25 subunit of dynactin is critical for dynein-mediated early endosome movement but not for dynein-mediated nuclear distribution. In the absence of NUDF/LIS1, p25 deletion abolished the localization of dynein–dynactin to the hyphal tip where early endosomes abnormally accumulate but did not prevent dynein–dynactin localization to microtubule plus ends. Within the dynactin complex, p25 locates at the pointed end of the Arp1 filament with Arp11 and p62, and our data suggest that Arp11 but not p62 is important for p25–dynactin association. Loss of either Arp1 or p25 significantly weakened the physical interaction between dynein and early endosomes, although loss of p25 did not apparently affect the integrity of the Arp1 filament. These results indicate that p25, in conjunction with the rest of the dynactin complex, is important for dynein–early endosome interaction.
E4F1 deficiency results in oxidative stress–mediated cell death of leukemic cells
Authors: Hatchi Elodie , Rodier Genevieve , Lacroix Matthieu , Caramel Julie , Kirsh Olivier , Jacquet Chantal , Schrepfer Emilie , Lagarrigue Sylviane , Linares Laetitia Karine , Lledo Gwendaline , Tondeur Sylvie , Dubus Pierre , Sardet Claude , Le Cam Laurent
Published: June 2011

The multifunctional E4F1 protein was originally discovered as a target of the E1A viral oncoprotein. Growing evidence indicates that E4F1 is involved in key signaling pathways commonly deregulated during cell transformation. In this study, we investigate the influence of E4F1 on tumorigenesis. Wild-type mice injected with fetal liver cells from mice lacking CDKN2A, the gene encoding Ink4a/Arf, developed histiocytic sarcomas (HSs), a tumor originating from the monocytic/macrophagic lineage. Cre-mediated deletion of E4F1 resulted in the death of HS cells and tumor regression in vivo and extended the lifespan of recipient animals. In murine and human HS cell lines, E4F1 inactivation resulted in mitochondrial defects and increased production of reactive oxygen species (ROS) that triggered massive cell death. Notably, these defects of E4F1 depletion were observed in HS cells but not healthy primary macrophages. Short hairpin RNA–mediated depletion of E4F1 induced mitochondrial defects and ROS-mediated death in several human myeloid leukemia cell lines. E4F1 protein is overexpressed in a large subset of human acute myeloid leukemia samples. Together, these data reveal a role for E4F1 in the survival of myeloid leukemic cells and support the notion that targeting E4F1 activities might have therapeutic interest.
FoxM1 mediates the progenitor function of type II epithelial cells in repairing alveolar injury induced by Pseudomonas aeruginosa
Authors: Liu Yuru , Sadikot Ruxana T. , Adami Guy R. , Kalinichenko Vladimir V. , Pendyala Srikanth , Natarajan Viswanathan , Zhao You-yang , Malik Asrar B.
Published: June 2011

The alveolar epithelium is composed of the flat type I cells comprising 95% of the gas-exchange surface area and cuboidal type II cells comprising the rest. Type II cells are described as facultative progenitor cells based on their ability to proliferate and trans-differentiate into type I cells. In this study, we observed that pneumonia induced by intratracheal instillation of Pseudomonas aeruginosa (PA) in mice increased the expression of the forkhead transcription factor FoxM1 in type II cells coincidentally with the induction of alveolar epithelial barrier repair. FoxM1 was preferentially expressed in the Sca-1+ subpopulation of progenitor type II cells. In mice lacking FoxM1 specifically in type II cells, type II cells showed decreased proliferation and impaired trans-differentiation into type I cells. Lungs of these mice also displayed defective alveolar barrier repair after injury. Expression of FoxM1 in the knockout mouse lungs partially rescued the defective trans-differentiation phenotype. Thus, expression of FoxM1 in type II cells is essential for their proliferation and transition into type I cells and for restoring alveolar barrier homeostasis after PA-induced lung injury.
Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44
Authors: Li Yuejuan , Jiang Dianhua , Liang Jiurong , Meltzer Eric B. , Gray Alice , Miura Riu , Wogensen Lise , Yamaguchi Yu , Noble Paul W.
Published: June 2011

Tissue fibrosis is a major cause of morbidity, and idiopathic pulmonary fibrosis (IPF) is a terminal illness characterized by unremitting matrix deposition in the lung. The mechanisms that control progressive fibrosis are unknown. Myofibroblasts accumulate at sites of tissue remodeling and produce extracellular matrix components such as collagen and hyaluronan (HA) that ultimately compromise organ function. We found that targeted overexpression of HAS2 (HA synthase 2) by myofibroblasts produced an aggressive phenotype leading to severe lung fibrosis and death after bleomycin-induced injury. Fibroblasts isolated from transgenic mice overexpressing HAS2 showed a greater capacity to invade matrix. Conditional deletion of HAS2 in mesenchymal cells abrogated the invasive fibroblast phenotype, impeded myofibroblast accumulation, and inhibited the development of lung fibrosis. Both the invasive phenotype and the progressive fibrosis were inhibited in the absence of CD44. Treatment with a blocking antibody to CD44 reduced lung fibrosis in mice in vivo. Finally, fibroblasts isolated from patients with IPF exhibited an invasive phenotype that was also dependent on HAS2 and CD44. Understanding the mechanisms leading to an invasive fibroblast phenotype could lead to novel approaches to the treatment of disorders characterized by severe tissue fibrosis.
The aminobisphosphonate pamidronate controls influenza pathogenesis by expanding a γδ T cell population in humanized mice
Authors: Tu Wenwei , Zheng Jian , Liu Yinping , Sia Sin Fun , Liu Ming , Qin Gang , Ng Iris H.Y. , Xiang Zheng , Lam Kwok-Tai , Peiris J.S. Malik , Lau Yu-Lung
Published: June 2011

There are few antiviral drugs for treating influenza, and the emergence of antiviral resistance has further limited the available therapeutic options. Furthermore, antivirals are not invariably effective in severe influenza, such as that caused by H5N1 viruses. Thus, there is an urgent need to develop alternative therapeutic strategies. Here, we show that human Vγ9Vδ2 T cells expanded by the aminobisphosphonate pamidronate (PAM) kill influenza virus–infected cells and inhibit viral replication in vitro. In Rag2−/−γc−/− immunodeficient mice reconstituted with human peripheral mononuclear cells (huPBMCs), PAM reduces disease severity and mortality caused by human seasonal H1N1 and avian H5N1 influenza virus, and controls the lung inflammation and viral replication. PAM has no such effects in influenza virus–infected Rag2−/−γc−/− mice reconstituted with Vγ9Vδ2 T cell–depleted huPBMCs. Our study provides proof-of-concept of a novel therapeutic strategy for treating influenza by targeting the host rather than the virus, thereby reducing the opportunity for the emergence of drug-resistant viruses. As PAM has been commonly used to treat osteoporosis and Paget’s disease, this new application of an old drug potentially offers a safe and readily available option for treating influenza.
Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis
Authors: Clausen Torben , Nielsen Ole Bækgaard , Clausen Johannes D. , Pedersen Thomas Holm , Hayward Lawrence J.
Published: June 2011

In patients with hyperkalemic periodic paralysis (HyperKPP), attacks of muscle weakness or paralysis are triggered by K+ ingestion or rest after exercise. Force can be restored by muscle work or treatment with β2-adrenoceptor agonists. A missense substitution corresponding to a mutation in the skeletal muscle voltage-gated Na+ channel (Nav1.4, Met1592Val) causing human HyperKPP was targeted into the mouse SCN4A gene (mutants). In soleus muscles prepared from these mutant mice, twitch, tetanic force, and endurance were markedly reduced compared with soleus from wild type (WT), reflecting impaired excitability. In mutant soleus, contractility was considerably more sensitive than WT soleus to inhibition by elevated [K+]o. In resting mutant soleus, tetrodotoxin (TTX)-suppressible 22Na uptake and [Na+]i were increased by 470 and 58%, respectively, and membrane potential was depolarized (by 16 mV, P < 0.0001) and repolarized by TTX. Na+,K+ pump–mediated 86Rb uptake was 83% larger than in WT. Salbutamol stimulated 86Rb uptake and reduced [Na+]i both in mutant and WT soleus. Stimulating Na+,K+ pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL). Increasing [Na+]i with monensin also restored force in soleus. In soleus, EDL, and tibialis anterior muscles of mutant mice, the content of Na+,K+ pumps was 28, 62, and 33% higher than in WT, respectively, possibly reflecting the stimulating effect of elevated [Na+]i on the synthesis of Na+,K+ pumps. The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na+ influx and show that contractility can be restored by acute stimulation of the Na+,K+ pumps. Calcitonin gene-related peptide (CGRP) restored force in mutant soleus but caused no detectable increase in 86Rb uptake. Repeated excitation and capsaicin also restored contractility, possibly because of the release of endogenous CGRP from nerve endings in the isolated muscles. These observations may explain how mild exercise helps locally to prevent severe weakness during an attack of HyperKPP.
Control of plasma properties in capacitively coupled oxygen discharges via the electrical asymmetry effect
Authors: Schüngel E , Zhang Q-Z , Iwashita S , Schulze J , Hou L-J , Wang Y-N , Czarnetzki U
Published: June 2011

Using a combined experimental, numerical and analytical approach, we investigate the control of plasma properties via the electrical asymmetry effect (EAE) in a capacitively coupled oxygen discharge. In particular, we present the first experimental investigation of the EAE in electronegative discharges. A dual-frequency voltage source of 13.56 MHz and 27.12 MHz is applied to the powered electrode and the discharge symmetry is controlled by adjusting the phase angle θ between the two harmonics. It is found that the bulk position and density profiles of positive ions, negative ions, and electrons have a clear dependence on θ, while the peak densities and the electronegativity stay rather constant, largely due to the fact that the time-averaged power absorption by electrons is almost independent of θ. This indicates that the ion flux towards the powered electrode remains almost constant. Meanwhile, the dc self-bias and, consequently, the sheath widths and potential profile can be effectively tuned by varying θ. This enables a flexible control of the ion bombarding energy at the electrode. Therefore, our work proves the effectiveness of the EAE to realize separate control of ion flux and ion energy in electronegative discharges. At low pressure, the strength of resonance oscillations, which are found in the current of asymmetric discharges, can be controlled with θ.
La Collection comme mode discursif dans les relations de voyage françaises aux XVI
e
et XVII
e
siècles
Authors: Kenny Neil
Published: June 2011

L'expression
récit de voyage
peut laisser présupposer un mode discursif dominant, celui de la narration. Cependant, dans le genre viatique du seizième au dix-huitième siècle, la narration se conjuguait constamment avec un deuxième mode discursif, que certains critiques ont appelé l'inventaire ou la description. Reste pourtant à mettre en évidence une autre dimension de ce mode non-narratif — la collection. Tout en étant intimement liée à la description et à l'inventaire, la collection ne leur était pas coextensive. De nombreux textes viatiques se présentaient à divers niveaux comme des collections. La collecte était en effet dans ces relations l'un des modes fondamentaux de production et d'organisation du savoir. Celles-ci ne se contentaient pas de retracer l'itinéraire du voyageur, mais elles permettaient de donner à voir les lieux parcourus à travers le prisme de la collection. Ce phénomène a pris toute son ampleur à une époque caractérisée par l'essor de la collection d'objets matériels comme pratique sociale ou philosophique en Europe, et particulièrement célèbre pour ses innombrables cabinets. De plus, cette pratique matérielle alimentait (ou, réciproquement, était alimentée par) des emplois métaphoriques de la notion de collection dans des discours très diversifiés, dont les relations de voyage.
Oxford Handbook of Medical Statistics
Authors: Peacock Janet , Peacock Philip
Published: June 2011

Written in an easily accessible style, the Oxford Handbook of Medical Statistics provides doctors and medical students with a concise and thorough account of this often difficult subject. It promotes understanding and interpretation of statistical methods across a wide range of topics, from study design and sample size considerations, through t- and chi-squared tests, to complex multifactorial analyses, using examples from published research.
The Cytokinin Receptors of Arabidopsis Are Located Mainly to the Endoplasmic Reticulum
Authors: Wulfetange Klaas , Lomin Sergey N. , Romanov Georgy A. , Stolz Andrea , Heyl Alexander , Schmülling Thomas
Published: June 2011

The plant hormone cytokinin is perceived by membrane-located sensor histidine kinases. Arabidopsis (Arabidopsis thaliana) possesses three cytokinin receptors: ARABIDOPSIS HISTIDINE KINASE2 (AHK2), AHK3, and CYTOKININ RESPONSE1/AHK4. The current model predicts perception of the cytokinin signal at the plasma membrane. However, cytokinin-binding studies with membrane fractions separated by two-phase partitioning showed that in the wild type, as well as in mutants retaining only single cytokinin receptors, the major part of specific cytokinin binding was associated with endomembranes. Leaf epidermal cells of tobacco (Nicotiana benthamiana) expressing receptor-green fluorescent protein fusion proteins and bimolecular fluorescence complementation analysis showed strong fluorescence of the endoplasmic reticulum (ER) network for all three receptors. Furthermore, separation of the microsomal fraction of Arabidopsis plants expressing Myc-tagged AHK2 and AHK3 receptors by sucrose gradient centrifugation followed by immunoblotting displayed the Mg2+-dependent density shift typical of ER membrane proteins. Cytokinin-binding assays, fluorescent fusion proteins, and biochemical fractionation all showed that the large majority of cytokinin receptors are localized to the ER, suggesting a central role of this compartment in cytokinin signaling. A modified model for cytokinin signaling is proposed.
Australian Judicial Biography: Past, Present and Future
Authors: Burnside Sarah
Published: June 2011

This article posits that biographical writing on High Court judges generates insights that may otherwise be overlooked in explorations of national history and politics. Firstly, the article addresses the relative scarcity of such biographies in Australia. It then explores themes common to the existing works and the ways in which they are evoked. The article canvasses some possibilities inherent in judicial biography, expanding briefly on the themes of national and gender identity, before surveying some of the minor controversies of the genre, including the question of who is best qualified to write it. The discussion concludes with the suggestion that the development of this genre would provide nuanced material for legal scholars, historians and political scientists alike.
Far More than Market‐Based: Rethinking the Impact of the Dutch Viswijzer (Good Fish Guide) on Fisheries' Governance
Authors: de Vos Birgit I. , Bush Simon R.
Published: June 2011

The sustainable seafood movement has given greater credence to non‐governmental organisation (NGO) involvement in fisheries' governance through a series of market‐based tools and strategies, including consumer awareness campaigns and seafood certification schemes. Despite their proliferation in recent years, the market‐based translation of consumer demand directly steering fishermen towards more sustainable practices, we argue, limits our understanding of the wider patterns of interaction that these tools can engender. Using the case of the Dutch Good Fish Guide or Viswijzer, we contend that market‐based tools can be effective in creating both horizontal and vertical spaces of interaction between key actors in the Dutch fishery sector. We conclude that while market‐based impacts may be negligible, the Viswijzer presents a powerful communicative instrument that has succeeded in fostering more face‐to‐face interaction and deliberation between otherwise disparate actors. Constructive collaboration between NGOs and industry can therefore create the requisite level of trust in the transition towards sustainable fisheries.