bluuebunny/crossref_metadata_2025 huggingface dataset:
Agency and personhood at the onset of the Mycenaean period
Authors: Voutsaki Sofia
Published: May 2010

This paper offers a critical evaluation of the debate on agency and personhood in archaeology. Despite some very interesting and sharp discussions, the debate has suffered from the projection of anachronistic definitions of the person and an overreliance on specific ethnographic readings. In addition, little attempt is made to integrate abstract theoretical discussions with close analyses of empirical data. I would like to suggest that this should be our priority. In the second part of the paper, I will apply these ideas by examining notions of personhood and agency held by the inhabitants of the southern Greek mainland between ca 1800 and 1600 B.C. The analysis will be based on the mortuary practices and imagery of the period.
Picture me dead. Moral choices reimagined
Authors: Tomášková Silvia
Published: May 2010

Shortly before her death, my grandmother expressed a strongly felt sentiment not to lie in the family tomb next to her sister-in-law. It was not quite clear what was to be done with the bones of the woman who by then had occupied the space next to her brother, my grandfather, for some five years. My mother resolved the issue by depositing the urn with my grandmother's ashes on the other side of my grandfather's coffin, stating matter-of-factly, ‘We are not about to toss the aunt out, and we will certainly not build a new tomb.’ Acting in a relational web of moral obligations and duties as a good daughter, my mother also proceeded as a rational modern individual in the universe of limited choices in Eastern Europe. Cremation replaced interment, therefore ‘lying next to’ was no longer an issue in a literal sense. At the same time, the filial duty of a proper burial in the family tomb was conducted with all the necessary ritual, wide kin in attendance. This incident came to my mind when reading about the archaeological dilemma of mortuary analysis described in Voutsaki's essay: to what extent do burials express the will, agency and station in life of the deceased as opposed to those of the wider kin relations responsible for burying them? Do the actions that archaeologists interpret on the basis of burials derive from choices by individual, cognizant agents, or do they represent a moral world in which adherence to certain practices defines a ‘good person’? I wish to address two issues from this presentation, one more philosophical and the other directly addressing the archaeological record of the Mycenaeans. First, I will consider whether the shift from agency to personhood (and back) proposed in this essay solves interpretive problems created by the recent embrace of agency. Second, I am intrigued by the question that Voutsaki poses about why images appear in this period, as it seems to me that a potential answer may lie in her detailed exposition of moral theory if one looks carefully, or extends it slightly beyond the intended meaning.
Approaches to the study of personhood in the early Mycenaean era
Authors: Wright James
Published: May 2010

In the brief space allotted for a comment, with respect to the theoretical discussion I will say only that I find the argument insufficiently developed and would rather that Voutsaki had paid closer attention to Dornan's useful critique of Bourdieu and Giddens and the uses to which their sociological theories have been put by archaeologists (Dornan 2002). As a proponent of adding moral philosophy to the archaeological arsenal of theory, Voutsaki might also have dwelt on Walzer's powerful argument about the interrelationship between ‘thin’ minimizing and ‘thick’ maximalizing moralities, since they disabuse us of the restraints of our local and universal ideologies and help us understand how individual actors and the groups of which they are a part are constrained by a plurality of moral decisions. My thoughts here, however, will focus on the case study, since that is the area of my own primary interest and expertise.
Red blood cells release factors with growth and survival bioactivities for normal and leukemic T cells
Authors: Antunes Ricardo F , Brandão Cláudia , Maia Margarida , Arosa Fernando A
Published: May 2010

Human red blood cells are emerging as a cell type capable to regulate biological processes of neighboring cells. Hereby, we show that human red blood cell conditioned media contains bioactive factors that favor proliferation of normal activated T cells and leukemic Jurkat T cells, and therefore called erythrocyte‐derived growth and survival factors. Flow cytometry and electron microscopy in parallel with bioactivity assays revealed that the erythrocyte factors are present in the vesicle‐free supernatant, which contains up to 20 different proteins. The erythrocyte factors are thermosensitive and do not contain lipids. Native polyacrylamide gel electrophoresis followed by passive elution and mass spectrometry identification reduced the potential erythrocyte factors to hemoglobin and peroxiredoxin II. Two‐dimensional differential gel electrophoresis of the erythrocyte factors revealed the presence of multiple hemoglobin oxy–deoxy states and peroxiredoxin II isoforms differing in their isoelectric point akin to the presence of β‐globin chains. Our results show that red blood cells release protein factors with the capacity to sustain T‐cell growth and survival. These factors may have an unforeseen role in sustaining malignant cell growth and survival in vivo.
CD69 limits early inflammatory diseases associated with immune response to Listeria monocytogenes infection
Authors: Vega‐Ramos Javier , Alari‐Pahissa Elisenda , Valle Juana del , Carrasco‐Marín Eugenio , Esplugues Enric , Borràs Miquel , Martínez‐A Carlos , Lauzurica Pilar
Published: May 2010

Mouse infection with intracellular bacteria induces a potent inflammatory response that requires protective mechanisms to avoid infection‐induced immune pathology. CD69 is expressed in all leukocytes during activation after infection with a wide range of microbial pathogens. This study explores the way in which CD69 affects cell activation after Listeria monocytogenes (Lm) infection and its effects on host protection. We show that infectivity and bacterial clearance capability are unaltered in CD69−/− peritoneal macrophages, bone marrow‐derived macrophages and dendritic cells. We found no major altered cell populations in splenocytes of Lm‐infected CD69−/− mice. However, an increase in the expression of Th1 cytokines was observed after infection, with increased production of type I and II interferon (IFN). In addition, CD69−/− splenocytes showed increased apoptosis, consistent with IFN enhancement of lymphocyte apoptosis in response to Lm infection. CD69−/− mice showed liver and spleen damage, and greatly increased susceptibility to Lm infection, compared with wild‐type controls. Lm‐specific T cells were decreased in CD69−/− mice even if T‐cell cross‐presentation and T‐cell intrinsic priming response were not compromised. As listeriosis was increased as early as day 1 post‐infection but CD69−/−RAG2−/− mice were more efficient at controlling Listeria, we propose that CD69 controls the cross‐talk between innate components and lymphocytes. These results highlight a role for CD69 in preventing infection‐induced immunopathology.
Getting Involved in Plan Making: Participation and Stakeholder Involvement in Local and Regional Spatial Strategies in England
Authors: Baker Mark , Hincks Stephen , Sherriff Graeme
Published: May 2010

In 2004 the English planning system was subject to extensive reforms which introduced a ‘spatial planning’ approach that goes beyond traditional land-use planning in integrating policies for the development and use of land with other policies and programmes which influence the nature of places. At the regional level, regional planning guidance was replaced by regional spatial strategies (RSSs) and, at the local level, existing local land-use planning documents were replaced with a portfolio of documents that make up the new local development framework (LDF). Together, the LDF and RSS make up the statutory development plan for an area. At the heart of the new spatial planning reforms is a heightened emphasis on stakeholder and community involvement. This paper brings together research at two different spatial scales. The ‘Spatial Plans in Practice’ study examined stakeholder involvement in LDF preparation across England. Parallel research examined the experience of stakeholders in the formation of the North West RSS. Drawing on this empirical base, we examine experiences of stakeholder involvement in the reformed spatial planning system and discuss the implications for the future.
Actin-like cytoskeleton filaments contribute to cell mechanics in bacteria
Authors: Wang Siyuan , Arellano-Santoyo Hugo , Combs Peter A. , Shaevitz Joshua W.
Published: May 2010

A filamentous cytoskeleton largely governs the physical shape and mechanical properties of eukaryotic cells. In bacteria, proteins homologous to all three classes of eukaryotic cytoskeletal filaments have recently been discovered. These proteins are essential for the maintenance of bacterial cell shape and have been shown to guide the localization of key cell-wall-modifying enzymes. However, whether the bacterial cytoskeleton is stiff enough to affect the overall mechanical rigidity of a cell has not been probed. Here, we used an optical trap to measure the bending rigidity of live
Escherichia coli
cells. We find that the actin-homolog MreB contributes nearly as much to the stiffness of a cell as the peptidoglycan cell wall. By quantitatively modeling these measurements, our data indicate that the MreB is rigidly linked to the cell wall, increasing the mechanical stiffness of the overall system. These data are the first evidence that the bacterial cytoskeleton contributes to the mechanical integrity of a cell in much the same way as it does in eukaryotes.
Surface-wave-enabled darkfield aperture for background suppression during weak signal detection
Authors: Zheng Guoan , Cui Xiquan , Yang Changhuei
Published: May 2010

Sensitive optical signal detection can often be confounded by the presence of a significant background, and, as such, predetection background suppression is substantively important for weak signal detection. In this paper, we present a novel optical structure design, termed surface-wave-enabled darkfield aperture (SWEDA), which can be directly incorporated onto optical sensors to accomplish predetection background suppression. This SWEDA structure consists of a central hole and a set of groove pattern that channels incident light to the central hole via surface plasmon wave and surface-scattered wave coupling. We show that the surface wave component can mutually cancel the direct transmission component, resulting in near-zero net transmission under uniform normal incidence illumination. Here, we report the implementation of two SWEDA structures. The first structure, circular-groove-based SWEDA, is able to provide polarization-independent suppression of uniform illumination with a suppression factor of 1230. The second structure, linear-groove-based SWEDA, is able to provide a suppression factor of 5080 for transverse-magnetic wave and can serve as a highly compact (5.5 micrometer length) polarization sensor (the measured transmission ratio of two orthogonal polarizations is 6100). Because the exact destructive interference balance is highly delicate and can be easily disrupted by the nonuniformity of the localized light field or light field deviation from normal incidence, the SWEDA can therefore be used to suppress a bright background and allow for sensitive darkfield sensing and imaging (observed image contrast enhancement of 27 dB for the first SWEDA).
Bayesian species delimitation using multilocus sequence data
Authors: Yang Ziheng , Rannala Bruce
Published: May 2010

In the absence of recent admixture between species, bipartitions of individuals in gene trees that are shared across loci can potentially be used to infer the presence of two or more species. This approach to species delimitation via molecular sequence data has been constrained by the fact that genealogies for individual loci are often poorly resolved and that ancestral lineage sorting, hybridization, and other population genetic processes can lead to discordant gene trees. Here we use a Bayesian modeling approach to generate the posterior probabilities of species assignments taking account of uncertainties due to unknown gene trees and the ancestral coalescent process. For tractability, we rely on a user-specified guide tree to avoid integrating over all possible species delimitations. The statistical performance of the method is examined using simulations, and the method is illustrated by analyzing sequence data from rotifers, fence lizards, and human populations.
Peptide antagonism as a mechanism for NK cell activation
Authors: Fadda Lena , Borhis Gwenoline , Ahmed Parvin , Cheent Kuldeep , Pageon Sophie V. , Cazaly Angelica , Stathopoulos Stavros , Middleton Derek , Mulder Arend , Claas Frans H. J. , Elliott Tim , Davis Daniel M. , Purbhoo Marco A. , Khakoo Salim I.
Published: May 2010

Inhibition of natural killer (NK) cells is mediated by MHC class I receptors including the killer cell Ig-like receptor (KIR). We demonstrate that HLA-C binding peptides can function as altered peptide ligands for KIR and antagonize the inhibition mediated by KIR2DL2/KIR2DL3. Antagonistic peptides promote clustering of KIR at the interface of effector and target cells, but do not result in inhibition of NK cells. Our data show that, as for T cells, small changes in the peptide content of MHC class I can regulate NK cell activity.
Circadian control of carbohydrate availability for growth inArabidopsisplants at night
Authors: Graf Alexander , Schlereth Armin , Stitt Mark , Smith Alison M.
Published: May 2010

Plant growth is driven by photosynthetic carbon fixation during the day. Some photosynthate is accumulated, often as starch, to support nocturnal metabolism and growth at night. The rate of starch degradation inArabidopsisleaves at night is essentially linear, and is such that almost all of the starch is used by dawn. We have investigated the timer that matches starch utilization to the duration of the night. The rate of degradation adjusted immediately and appropriately to an unexpected early onset of night. Starch was still degraded in an appropriate manner when the preceding light period was interrupted by a period of darkness. However, whenArabidopsiswas grown in abnormal day lengths (28 h or 17 h) starch was exhausted ∼24 h after the last dawn, irrespective of the actual dawn. A mutant lacking the LHY and CCA1 clock components exhausted its starch at the dawn anticipated by its fast-running circadian clock, rather than the actual dawn. Reduced growth of wild-type plants in 28-h days andlhy/cca1mutants in 24-h days was attributable to the inappropriate rate of starch degradation and the consequent carbon starvation at the end of night. Thus, starch degradation is under circadian control to ensure that carbohydrate availability is maintained until the next anticipated dawn, and this control is necessary for maintaining plant productivity.
Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure
Authors: Jonasson Sara , Eriksson Johan , Berntzon Lotta , Spáčil Zdenĕk , Ilag Leopold L. , Ronnevi Lars-Olof , Rasmussen Ulla , Bergman Birgitta
Published: May 2010

β-methylamino-L-alanine (BMAA), a neurotoxic nonprotein amino acid produced by most cyanobacteria, has been proposed to be the causative agent of devastating neurodegenerative diseases on the island of Guam in the Pacific Ocean. Because cyanobacteria are widespread globally, we hypothesized that BMAA might occur and bioaccumulate in other ecosystems. Here we demonstrate, based on a recently developed extraction and HPLC-MS/MS method and long-term monitoring of BMAA in cyanobacterial populations of a temperate aquatic ecosystem (Baltic Sea, 2007–2008), that BMAA is biosynthesized by cyanobacterial genera dominating the massive surface blooms of this water body. BMAA also was found at higher concentrations in organisms of higher trophic levels that directly or indirectly feed on cyanobacteria, such as zooplankton and various vertebrates (fish) and invertebrates (mussels, oysters). Pelagic and benthic fish species used for human consumption were included. The highest BMAA levels were detected in the muscle and brain of bottom-dwelling fishes. The discovery of regular biosynthesis of the neurotoxin BMAA in a large temperate aquatic ecosystem combined with its possible transfer and bioaccumulation within major food webs, some ending in human consumption, is alarming and requires attention.
Identification of protective and broadly conserved vaccine antigens from the genome of extraintestinal pathogenic
Escherichia coli
Authors: Moriel Danilo Gomes , Bertoldi Isabella , Spagnuolo Angela , Marchi Sara , Rosini Roberto , Nesta Barbara , Pastorello Ilaria , Corea Vanja A. Mariani , Torricelli Giulia , Cartocci Elena , Savino Silvana , Scarselli Maria , Dobrindt Ulrich , Hacker Jörg , Tettelin Hervé , Tallon Luke J. , Sullivan Steven , Wieler Lothar H. , Ewers Christa , Pickard Derek , Dougan Gordon , Fontana Maria Rita , Rappuoli Rino , Pizza Mariagrazia , Serino Laura
Published: May 2010

Extraintestinal pathogenic
Escherichia coli
(ExPEC) are a common cause of disease in both mammals and birds. A vaccine to prevent such infections would be desirable given the increasing antibiotic resistance of these bacteria. We have determined the genome sequence of ExPEC IHE3034 (ST95) isolated from a case of neonatal meningitis and compared this to available genome sequences of other ExPEC strains and a few nonpathogenic
E. coli
. We found 19 genomic islands present in the genome of IHE3034, which are absent in the nonpathogenic
E. coli
isolates. By using subtractive reverse vaccinology we identified 230 antigens present in ExPEC but absent (or present with low similarity) in nonpathogenic strains. Nine antigens were protective in a mouse challenge model. Some of them were also present in other pathogenic non-ExPEC strains, suggesting that a broadly protective
E. coli
vaccine may be possible. The gene encoding the most protective antigen was detected in most of the
E. coli
isolates, highly conserved in sequence and found to be exported by a type II secretion system which seems to be nonfunctional in nonpathogenic strains.
A domain swap approach reveals a role of the plant wall-associated kinase 1 (WAK1) as a receptor of oligogalacturonides
Authors: Brutus Alexandre , Sicilia Francesca , Macone Alberto , Cervone Felice , De Lorenzo Giulia
Published: May 2010

Oligogalacturonides (OGs) released from the plant cell wall are active both as damage-associated molecular patterns (DAMPs) for the activation of the plant immune response and regulators of plant growth and development. Members of the Wall-Associated Kinase (WAK) family are candidate receptors of OGs, due to their ability to bind in vitro these oligosaccharides. Because lethality and redundancy have hampered the study of WAKs by reverse genetics, we have adopted a chimeric receptor approach to elucidate the role of Arabidopsis WAK1. In a test-of-concept study, we first defined the appropriate chimera design and demonstrated that the Arabidopsis pattern recognition receptor (PRR) EFR is amenable to the construction of functional and resistance-conferring chimeric receptors carrying the ectodomain of another Arabidopsis PRR, FLS2. After, we analyzed chimeras derived from EFR and WAK1. Our results show that, upon stimulation with OGs, the WAK1 ectodomain is capable of activating the EFR kinase domain. On the other hand, upon stimulation with the cognate ligand elf18, the EFR ectodomain activates the WAK1 kinase, triggering defense responses that mirror those normally activated by OGs and are effective against fungal and bacterial pathogens. Finally, we show that transgenic plants overexpressing WAK1 are more resistant to
Botrytis cinerea
.
Chemotaxis signaling protein CheY binds to the rotor protein FliN to control the direction of flagellar rotation in
Escherichia coli
Authors: Sarkar Mayukh K. , Paul Koushik , Blair David
Published: May 2010

The direction of rotation of the
Escherichia coli
flagellum is controlled by an assembly called the switch complex formed from multiple subunits of the proteins FliG, FliM, and FliN. Structurally, the switch complex corresponds to a drum-shaped feature at the bottom of the basal body, termed the C-ring. Stimulus-regulated reversals in flagellar motor rotation are the basis for directed movement such as chemotaxis. In
E. coli
, the motors turn counterclockwise (CCW) in their default state, allowing the several filaments on a cell to join together in a bundle and propel the cell smoothly forward. In response to the chemotaxis signaling molecule phospho-CheY (CheY
P
), the motors can switch to clockwise (CW) rotation, causing dissociation of the filament bundle and reorientation of the cell. CheY
P
has previously been shown to bind to a conserved segment near the N terminus of FliM. Here, we show that this interaction serves to capture CheY
P
and that the switch to CW rotation involves the subsequent interaction of CheY
P
with FliN. FliN is located at the bottom of the C-ring, in close association with the C-terminal domain of FliM (FliM
C
), and the switch to CW rotation has been shown to involve relative movement of FliN and FliM
C
. Using a recently developed structural model for the FliN/FliM
C
array, and the CheY
P
-binding site here identified on FliN, we propose a mechanism by which CheY
P
binding could induce the conformational switch to CW rotation.
Asymmetric phosphorylation through catalytic P(III) phosphoramidite transfer: Enantioselective synthesis of
d
-
myo
-inositol-6-phosphate
Authors: Jordan Peter A. , Kayser-Bricker Katherine J. , Miller Scott J.
Published: May 2010

Despite the ubiquitous use of phosphoramidite chemistry in the synthesis of biophosphates, catalytic asymmetric phosphoramidite transfer remains largely unexplored for phosphate ester synthesis. We have discovered that a tetrazole-functionalized peptide, in the presence of 10-Å molecular sieves, functions as an enantioselective catalyst for phosphite transfer. This chemistry in turn has been used as the key step in a streamlined synthesis of
myo
-inositol-6-phosphate. Mechanistic insights implicate phosphate as a directing group for a highly selective kinetic resolution of a protected inositol monophosphate. This work represents a distinct and efficient method for the selective catalytic phosphorylation of natural products.
Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome
Authors: Hoeft Fumiko , Carter John C. , Lightbody Amy A. , Cody Hazlett Heather , Piven Joseph , Reiss Allan L.
Published: May 2010

Longitudinal neuroimaging investigation of fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, provides an opportunity to study the influence of a specific genetic factor on neurodevelopment in the living human brain. We examined voxel-wise gray and white matter volumes (GMV, WMV) over a 2-year period in 1- to 3-year-old boys with FXS (
n
= 41) and compared these findings to age- and developmentally matched controls (
n
= 28). We found enlarged GMV in the caudate, thalamus, and fusiform gyri and reduced GMV in the cerebellar vermis in FXS at both timepoints, suggesting early, possibly prenatal, genetically mediated alterations in neurodevelopment. In contrast, regions in which initial GMV was similar, followed by an altered growth trajectory leading to increased size in FXS, such as the orbital gyri, basal forebrain, and thalamus, suggests delayed or otherwise disrupted synaptic pruning occurring postnatally. WMV of striatal-prefrontal regions was greater in FXS compared with controls, and group differences became more exaggerated over time, indicating the possibility that such WM abnormalities are the result of primary FMRP-deficiency-related axonal pathology, as opposed to secondary connectional dysregulation between morphologically atypical brain structures. Our results indicate that structural abnormalities of different brain regions in FXS evolve differently over time reflecting time-dependent effects of FMRP deficiency and provide insight into their neuropathologic underpinnings. The creation of an early and accurate human brain phenotype for FXS in humans will significantly improve our capability to detect whether new disease-specific treatments can “rescue” the FXS phenotype in affected individuals.
Using deep sequencing to characterize the biophysical mechanism of a transcriptional regulatory sequence
Authors: Kinney Justin B. , Murugan Anand , Callan Curtis G. , Cox Edward C.
Published: May 2010

Cells use protein-DNA and protein-protein interactions to regulate transcription. A biophysical understanding of this process has, however, been limited by the lack of methods for quantitatively characterizing the interactions that occur at specific promoters and enhancers in living cells. Here we show how such biophysical information can be revealed by a simple experiment in which a library of partially mutated regulatory sequences are partitioned according to their in vivo transcriptional activities and then sequenced en masse. Computational analysis of the sequence data produced by this experiment can provide precise quantitative information about how the regulatory proteins at a specific arrangement of binding sites work together to regulate transcription. This ability to reliably extract precise information about regulatory biophysics in the face of experimental noise is made possible by a recently identified relationship between likelihood and mutual information. Applying our experimental and computational techniques to the
Escherichia coli lac
promoter, we demonstrate the ability to identify regulatory protein binding sites de novo, determine the sequence-dependent binding energy of the proteins that bind these sites, and, importantly, measure the in vivo interaction energy between RNA polymerase and a DNA-bound transcription factor. Our approach provides a generally applicable method for characterizing the biophysical basis of transcriptional regulation by a specified regulatory sequence. The principles of our method can also be applied to a wide range of other problems in molecular biology.
Unique characteristics of Ca
2+
homeostasis of the
trans
-Golgi compartment
Authors: Lissandron Valentina , Podini Paola , Pizzo Paola , Pozzan Tullio
Published: May 2010

Taking advantage of a fluorescent Ca
2+
indicator selectively targeted to the
trans
-Golgi lumen, we here demonstrate that its Ca
2+
homeostatic mechanisms are distinct from those of the other Golgi subcompartments: (
i
) Ca
2+
uptake depends exclusively on the activity of the secretory pathway Ca
2+
ATPase1 (SPCA1), whereas the sarco-endoplasmic reticulum Ca
2+
ATPase (SERCA) is excluded; (
ii
) IP
3
generated by receptor stimulation causes Ca
2+
uptake rather than release; (
iii
) Ca
2+
release can be triggered by activation of ryanodine receptors in cells endowed with robust expression of the latter channels (e.g., in neonatal cardiac myocyte). Finally, we show that, knocking down the SPCA1, and thus altering the
trans
-Golgi Ca
2+
content, specific functions associated with this subcompartment, such as sorting of proteins to the plasma membrane through the secretory pathway, and the structure of the entire Golgi apparatus are dramatically altered.
Histone H1 phosphorylation is associated with transcription by RNA polymerases I and II
Authors: Zheng Yupeng , John Sam , Pesavento James J. , Schultz-Norton Jennifer R. , Schiltz R. Louis , Baek Sonjoon , Nardulli Ann M. , Hager Gordon L. , Kelleher Neil L. , Mizzen Craig A.
Published: May 2010

Histone H1 phosphorylation affects chromatin condensation and function, but little is known about how specific phosphorylations impact the function of H1 variants in higher eukaryotes. In this study, we show that specific sites in H1.2 and H1.4 of human cells are phosphorylated only during mitosis or during both mitosis and interphase. Antisera generated to individual H1.2/H1.4 interphase phosphorylations reveal that they are distributed throughout nuclei and enriched in nucleoli. Moreover, interphase phosphorylated H1.4 is enriched at active 45S preribosomal RNA gene promoters and is rapidly induced at steroid hormone response elements by hormone treatment. Our results imply that site-specific interphase H1 phosphorylation facilitates transcription by RNA polymerases I and II and has an unanticipated function in ribosome biogenesis and control of cell growth. Differences in the numbers, structure, and locations of interphase phosphorylation sites may contribute to the functional diversity of H1 variants.
The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma
Authors: Pechloff Konstanze , Holch Julian , Ferch Uta , Schweneker Marc , Brunner Kristina , Kremer Markus , Sparwasser Tim , Quintanilla-Martinez Leticia , Zimber-Strobl Ursula , Streubel Berthold , Gewies Andreas , Peschel Christian , Ruland Jürgen
Published: May 2010

Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)–inducible T cell kinase (ITK)–spleen tyrosine kinase (SYK) fusion tyrosine kinase was identified as a recurrent event in PTCL. We show that ITK-SYK associates constitutively with lipid rafts in T cells and triggers antigen-independent phosphorylation of T cell receptor (TCR)–proximal proteins. These events lead to activation of downstream pathways and acute cellular outcomes that correspond to regular TCR ligation, including up-regulation of CD69 or production of IL-2 in vitro or deletion of thymocytes and activation of peripheral T cells in vivo. Ultimately, conditional expression of patient-derived ITK-SYK in mice induces highly malignant PTCLs with 100% penetrance that resemble the human disease. Our work demonstrates that constitutively enforced antigen receptor signaling can, in principle, act as a powerful oncogenic driver. Moreover, we establish a robust clinically relevant and genetically tractable model of human PTCL.
Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis
Authors: Hermansson Andreas , Ketelhuth Daniel F.J. , Strodthoff Daniela , Wurm Marion , Hansson Emil M. , Nicoletti Antonino , Paulsson-Berne Gabrielle , Hansson Göran K.
Published: May 2010

Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100tg) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100. However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4+ T cell hybridomas were MHC class II–restricted and expressed a single T cell receptor (TCR) variable (V) β chain, TRBV31, with different Vα chains. Immunization of huB100tgxLdlr−/− mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4+ T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis.
A low-polynomial algorithm for assembling clusters of orthologous groups from intergenomic symmetric best matches
Authors: Kristensen David M. , Kannan Lavanya , Coleman Michael K. , Wolf Yuri I. , Sorokin Alexander , Koonin Eugene V. , Mushegian Arcady
Published: May 2010

Motivation: Identifying orthologous genes in multiple genomes is a fundamental task in comparative genomics. Construction of intergenomic symmetrical best matches (SymBets) and joining them into clusters is a popular method of ortholog definition, embodied in several software programs. Despite their wide use, the computational complexity of these programs has not been thoroughly examined.

Results: In this work, we show that in the standard approach of iteration through all triangles of SymBets, the memory scales with at least the number of these triangles, O(g3) (where g = number of genomes), and construction time scales with the iteration through each pair, i.e. O(g6). We propose the EdgeSearch algorithm that iterates over edges in the SymBet graph rather than triangles of SymBets, and as a result has a worst-case complexity of only O(g3log g). Several optimizations reduce the run-time even further in realistically sparse graphs. In two real-world datasets of genomes from bacteriophages (POGs) and Mollicutes (MOGs), an implementation of the EdgeSearch algorithm runs about an order of magnitude faster than the original algorithm and scales much better with increasing number of genomes, with only minor differences in the final results, and up to 60 times faster than the popular OrthoMCL program with a 90% overlap between the identified groups of orthologs.

Availability and implementation: C++ source code freely available for download at ftp.ncbi.nih.gov/pub/wolf/COGs/COGsoft/

Contact:  dmk@stowers.org

Supplementary information:  Supplementary materials are available at Bioinformatics online.
Acupuncture Attenuates Anxiety‐Like Behavior by Normalizing Amygdaloid Catecholamines during Ethanol Withdrawal in Rats
Authors: Zhao Zheng Lin , Zhao Guang Wen , Li Hou Zhong , Yang Xu Dong , Wu Yi Yan , Lin Feng , Guan Li Xin , Zhai Feng Guo , Liu Jia Qi , Yang Chae Ha , Kim Sang Chan , Kim Kee Won , Zhao Rong Jie
Published: May 2010

Previously, we demonstrated acupuncture at acupoint HT7 (Shen‐Men) attenuated ethanol withdrawal syndrome by normalizing the dopamine release in nucleus accumbens shell. In the present study, we investigated the effect of acupuncture on anxiety‐like behavior in rats and its relevant mechanism by studying neuro‐endocrine parameters during ethanol withdrawal. Rats were treated with 3 g kg−1day−1of ethanol (20%, w/v) or saline by intraperitoneal injections for 28 days. The rats undergoing ethanol withdrawal exhibited anxiety‐like behavior 72 h after the last dose of ethanol characterized by the decrease of time spent in the open arms of the elevated plus maze compared with the saline‐treated rats (P <.05). Radioimmunoassay exhibited there were notably increased concentrations of plasma corticosterone in ethanol‐withdrawn rats compared with saline‐treated rats (P< .05). Additionally, high performance liquid chromatography analysis also showed the levels of norepinephrine and 3‐methoxy‐4‐hydroxy‐phenylglycol were markedly increased while the levels of dopamine and 3,4‐dihydroxyphenylacetic acid were significantly decreased in the central nucleus of the amygdala of ethanol‐withdrawn rats compared with saline‐treated rats (P< .01). Acupuncture groups were treated with acupuncture at acupoint HT7 or PC6 (Nei‐Guan). Acupuncture at HT7 but not PC6 greatly attenuated the anxiety‐like behavior during ethanol withdrawal as evidenced by significant increases in the percentage of time spent in open arms (P< .05). In the meantime, acupuncture at HT7 also markedly inhibited the alterations of neuro‐endocrine parameters induced by ethanol withdrawal (P< .05). These results suggest that acupuncture may attenuate anxiety‐like behavior during ethanol withdrawal through regulation of neuro‐endocrine system.
Differential Auxin-Transporting Activities of PIN-FORMED Proteins in Arabidopsis Root Hair Cells
Authors: Ganguly Anindya , Lee Sang Ho , Cho Misuk , Lee Ok Ran , Yoo Heejin , Cho Hyung-Taeg
Published: May 2010

The Arabidopsis (Arabidopsis thaliana) genome includes eight PIN-FORMED (PIN) members that are molecularly diverged. To comparatively examine their differences in auxin-transporting activity and subcellular behaviors, we expressed seven PIN proteins specifically in Arabidopsis root hairs and analyzed their activities in terms of the degree of PIN-mediated root hair inhibition or enhancement and determined their subcellular localization. Expression of six PINs (PIN1–PIN4, PIN7, and PIN8) in root hair cells greatly inhibited root hair growth, most likely by lowering auxin levels in the root hair cell by their auxin efflux activities. The auxin efflux activity of PIN8, which had not been previously demonstrated, was further confirmed using a tobacco (Nicotiana tabacum) cell assay system. In accordance with these results, those PINs were localized in the plasma membrane, where they likely export auxin to the apoplast and formed internal compartments in response to brefeldin A. These six PINs conferred different degrees of root hair inhibition and sensitivities to auxin or auxin transport inhibitors. Conversely, PIN5 mostly localized to internal compartments, and its expression in root hair cells rather slightly stimulated hair growth, implying that PIN5 enhanced internal auxin availability. These results suggest that different PINs behave differentially in catalyzing auxin transport depending upon their molecular activity and subcellular localization in the root hair cell.
Similarity of pharmacodynamic effects of a single injection of insulin glargine, insulin detemir and NPH insulin on glucose metabolism assessed by 24‐h euglycaemic clamp studies in healthy humans
Authors: Sørensen L. P. , Brock B. , Mengel A. , Rungby J. , Moller N. , Nielsen S. , Vølund A. , Schmitz O.
Published: May 2010

Diabet. Med. 27, 830–837 (2010)

Aims  Two long‐acting insulin analogues, insulin glargine and insulin detemir, have been developed as alternatives to neutral protamine Hagedorn (NPH) insulin, which has been the preferred basal insulin preparation for decades. The aim was to directly compare the pharmacodynamic properties of the long‐acting insulin analogues and NPH insulin after a single subcutaneous injection.

Methods  The study was conducted as a double‐blind, controlled, three‐arm, crossover study including 10 healthy lean male volunteers. On three different occasions, each subject was challenged with 0.4 U kg−1 of either insulin glargine, insulin detemir or NPH insulin. Plasma glucose was maintained at 0.3 mmol l−1 below fasting level by glucose clamping for 24 h. C‐peptide, insulin, free fatty acids (FFAs) and counter regulatory hormones were measured throughout the clamp period, whereas endogenous glucose release (EGR) was assessed by isotope dilution technique (3‐3H‐glucose).

Results  The mean glucose infusion rate (GIR)–time profiles revealed no significant differences between the three preparations in the primary endpoints: Maximal GIR of approximately 3.4 mg kg−1 min−1 (P = 0.68), time to maximal GIR of approximately 10 h (TRmax) (P = 0.35) and area under the GIR curve (GIRAUC) (P = 0.81). Compared with the other insulin preparations, EGR (see above)was lower for insulin detemir at the beginning of the clamp period (330–360 min) (P = 0.007) while GIR was lower (P = 0.005) and FFA concentrations were higher (P = 0.005) during the last 4 h of the clamp.

Conclusions  In this experimental design, only minor pharmacodynamic differences were demonstrated between insulin detemir, insulin glargine and NPH insulin.
Association between cardiac autonomic neuropathy and hypertension and its potential influence on diabetic complications
Authors: Ayad F. , Belhadj M. , Pariés J. , Attali J. R. , Valensi P.
Published: May 2010

Diabet. Med. 27, 804–811 (2010)

Aims  To examine the association between cardiac autonomic neuropathy and hypertension and the role of this association in diabetic complications.

Methods  We included 310 patients, 138 with Type 1 and 172 with Type 2 diabetes, 62 of them with hypertension. Cardiac autonomic neuropathy was assessed by analysing heart rate variations during three standard tests (deep breathing, lying to standing and Valsalva) and looking for postural hypotension.

Results  Cardiac autonomic neuropathy was present in 123 patients and 39 also had hypertension. The prevalence of a cardiac autonomic neuropathy/hypertension association was higher in Type 2 patients (P < 0.002). The prevalence of hypertension increased with the severity of cardiac autonomic neuropathy. In multiple logistic regression analysis, cardiac autonomic neuropathy was an independent risk factor for hypertension [odds ratio 2.86 (1.54–5.32); P < 0.001]. Only confirmed or severe cardiac autonomic neuropathy (two or more abnormal function tests, respectively) were independent risk factors for hypertension (P < 0.005 and < 0.0001). Cardiac autonomic neuropathy was found in most of the patients with macrovascular complications, retinopathy or nephropathy, but a large majority of the patients with these complications exhibited the cardiac autonomic neuropathy/hypertension profile. This profile was more prevalent among the patients with coronary or peripheral artery disease or antecedent stroke than among those free of these complications (P < 0.001). In logistic regression analyses, the cardiac autonomic neuropathy/hypertension profile associated significantly with macro‐ and microvascular complications.

Conclusions  These data are strongly in favour of the role of cardiac autonomic neuropathy in hypertension in diabetic patients. The association of the cardiac autonomic neuropathy/hypertension profile with vascular complications is consistent with a deleterious effect on vascular hemodynamics and structure, additional to the effects of hypertension.
Depressive symptoms in the first year from diagnosis of Type 2 diabetes: results from the DESMOND trial
Authors: Skinner T. C. , Carey M. E. , Cradock S. , Dallosso H. M. , Daly H. , Davies M. J. , Doherty Y. , Heller S. , Khunti K. , Oliver L. ,   on behalf of The DESMOND Collaborative
Published: May 2010

Diabet. Med. 27, 965–967 (2010)

Aims  To describe the course of depressive symptoms during the first year after diagnosis of Type 2 diabetes.

Methods  Post hoc analysis of data from a randomized controlled trial of self‐management education for 824 individuals newly diagnosed with Type 2 diabetes. Participants completed the Depression scale of the Hospital Anxiety and Depression Scale after diagnosis and at 4, 8 and 12 months follow‐up. Participants also completed the Problem Areas in Diabetes scale at 8 and 12 months follow‐up. We present descriptive statistics on prevalence and persistence of depressive symptoms. Logistic regression is used to predict possible depression cases, and multiple regression to predict depressive symptomatology.

Results  The prevalence of depressive symptoms in individuals recently diagnosed with diabetes (18–22% over the year) was not significantly different from normative data for the general population (12%) in the UK. Over 20% of participants indicated some degrees of depressive symptoms over the first year of living with Type 2 diabetes; these were mostly transient episodes, with 5% (1% severe) reporting having depressive symptoms throughout the year. At 12 months post diagnosis, after controlling for baseline depressive symptoms, diabetes‐specific emotional distress was predictive of depressive symptomatology.

Conclusions  The increased prevalence of depressive symptoms in diabetes is not manifest until at least 1 year post diagnosis in this cohort. However, there are a significant number of people with persistent depressive symptoms in the early stages of diabetes, and diabetes‐specific distress may be contributing to subsequent development of depressive symptoms in people with Type 2 diabetes.
INTER‐ETHICS: TOWARDS AN INTERACTIVE AND INTERDEPENDENT BIOETHICS
Authors: ABMA TINEKE A. , BAUR VIVIANNE E. , MOLEWIJK BERT , WIDDERSHOVEN GUY A.M.
Published: May 2010

Since its origin bioethics has been a specialized, academic discipline, focussing on moral issues, using a vast set of globalized principles and rational techniques to evaluate and guide healthcare practices. With the emergence of a plural society, the loss of faith in experts and authorities and the decline of overarching grand narratives and shared moralities, a new approach to bioethics is needed. This approach implies a shift from an external critique of practices towards embedded ethics and interactive practice improvement, and from a legal defence of rights towards fostering interdependent practices of responsibility. This article describes these transitions within bioethics in relation to the broader societal and cultural dynamics within Western societies, and traces the implications for the methodologies and changing roles of the bioethicist. The bioethicist we foresee is not just a clever expert but also a relationally sensitive person who engages stakeholders in reciprocal dialogues about their practice of responsibility and helps to integrate various sorts of knowledge (embodied, experiential, visual, and cognitive‐scientific). In order to illustrate this new approach, we present a case study. It concerns a project focusing on an innovation in elderly care, based on the participation of various stakeholders, especially older people themselves.
7. Respondent-Driven Sampling: An Assessment of Current Methodology
Authors: Gile Krista J. , Handcock Mark S.
Published: May 2010

Respondent-driven sampling (RDS) employs a variant of a link-tracing network sampling strategy to collect data from hard-to-reach populations. By tracing the links in the underlying social network, the process exploits the social structure to expand the sample and reduce its dependence on the initial (convenience) sample.

The current estimators of population averages make strong assumptions in order to treat the data as a probability sample. We evaluate three critical sensitivities of the estimators: (1) to bias induced by the initial sample, (2) to uncontrollable features of respondent behavior, and (3) to the without-replacement structure of sampling.

Our analysis indicates: (1) that the convenience sample of seeds can induce bias, and the number of sample waves typically used in RDS is likely insufficient for the type of nodal mixing required to obtain the reputed asymptotic unbiasedness; (2) that preferential referral behavior by respondents leads to bias; (3) that when a substantial fraction of the target population is sampled the current estimators can have substantial bias.

This paper sounds a cautionary note for the users of RDS. While current RDS methodology is powerful and clever, the favorable statistical properties claimed for the current estimates are shown to be heavily dependent on often unrealistic assumptions. We recommend ways to improve the methodology.