bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of AlN interlayer on the anisotropic electron mobility and the device characteristics of N-polar AlGaN/GaN metal-insulator-semiconductor-high electron mobility transistors grown on vicinal substrates
Authors: Kolluri Seshadri , Keller Stacia , Brown David , Gupta Geetak , Rajan Siddharth , DenBaars Steven P. , Mishra Umesh K.
Published: October 2010

This paper presents an experimental investigation of the influence of an AlN interlayer on the electron mobility and the device characteristics of N-polar AlGaN/GaN metal-insulator-semiconductor-high electron mobility transistors grown by metal-organic chemical vapor deposition on miscut sapphire substrates. Use of miscut substrates leads to the formation of multiatomic steps at the AlGaN/GaN interface and anisotropy in electron transport properties. A combination of van der Pauw Hall, gated transfer length measurements, and capacitance-voltage measurements has been used to study the desired properties in directions parallel and perpendicular to the multiatomic steps and qualitative explanations were provided for the observed trends. Similar to the Ga-polar devices, the introduction of AlN interlayer improved the device performance by increasing both the electron mobility and the two-dimensional electron gas charge density in the devices. Orienting the devices such that the conduction occurred parallel to the multiatomic steps was beneficial for better electron transport and device performance.
Device simulation of low-band gap polymer solar cells: Influence of electron-hole pair dissociation and decay rates on open-circuit voltage
Authors: Shang Yuan , Li Qikai , Meng Lingyi , Wang Dong , Shuai Zhigang
Published: October 2010

We simulated the performance of recently developed highly efficient bulk heterojunction photovoltaic cells with poly [N-9″-hepta-decanyl-2,7-carbazole-alt-5,5-(4′,7′-di-2-thienyl-2′,1′,3′-benzothiadiazole)] as the donor and [6,6]-phenyl C70-butyric acid methyl ester as the acceptor, using a device model. The simulated current-voltage curve is in excellent agreement with the experiment. This enables us to analyze how microscopic processes of excitons and charges govern the device performance. The influence of dissociation rate and decay rate of photoinduced electron-hole pairs on the open-circuit voltage VOC is investigated. It is shown that a high dissociation rate relative to decay rate will lead to enhanced VOC.
Radial junction silicon wire array solar cells fabricated by gold-catalyzed vapor-liquid-solid growth
Authors: Kendrick Chito E. , Yoon Heayong P. , Yuwen Yu A. , Barber Greg D. , Shen Haoting , Mallouk Thomas E. , Dickey Elizabeth C. , Mayer Theresa S. , Redwing Joan M.
Published: October 2010

The fabrication of radial junction silicon (Si) solar cells using Si wire arrays grown by Au-catalyzed vapor-liquid-solid growth on patterned Si substrates was demonstrated. An important step in the fabrication process is the repeated thermal oxidation and oxide etching of the Si wire arrays. The oxidation cleaning process removes residual catalyst material from the wire tips and exposes additional Au embedded in the material. Using this cleaning process and junction formation through POCl3 thermal diffusion, rectifying p-n junctions were obtained that exhibited an efficiency of 2.3% and open circuit voltages up to 0.5 V under Air Mass 1.5G illumination.
Large strain and high energy storage density in orthorhombic perovskite (Pb0.97La0.02)(Zr1−x−ySnxTiy)O3 antiferroelectric thin films
Authors: Sharifzadeh Mirshekarloo Meysam , Yao Kui , Sritharan Thirumany
Published: October 2010

Antiferroelectric (Pb0.97La0.02)(Zr1−x−ySnxTiy)O3 (PLZST) thin films with orthorhombic perovskite structure were prepared on Si substrates by a chemical solution deposition process. A secondary pyrochlore phase, which was not detectable with x-ray diffraction, was revealed with transmission electron microscopy. The pyrochlore phase was effectively suppressed by the introduction of polyethylene glycol (PEG) in the precursor solution and applying PbO capping layer on the surface of the films. With the persistent and detrimental pyrochlore phase removed completely, our PLZST antiferroelectric thin films exhibited excellent electrical and electromechanical properties. A large energy storage density up to 13.7 J/cm3 was exhibited from the polarization measurement, and a strain of 0.49% under the clamping of the substrate was also achieved in the thin film with high Zr content.
Strain-doping coupling dynamics in phosphorus doped Si:C formed by solid phase epitaxial regrowth
Authors: Woon W. Y. , Wang S. H. , Chuang Y. T. , Chuang M. C. , Chen C. L.
Published: October 2010

We investigate the solid phase epitaxial regrowth (SPER) dynamics of phosphorus doped Si:C by time resolved reflectivity and high resolution x-ray diffraction. The effect of SPER kinetics on strain profile and dopant activation is analyzed. The accumulated tensile strain induced by both C and P during SPER synergistically determines the onset of SPER rate retardation and leads to lower strain and electrical conductance near surface. Physical origin for the observed SPER rate evolution is discussed and explained with a strain included solute trapping model. Possibility of tailoring strain and doping profiles is discussed.
Injection locking of the gyrotropic vortex motion in a nanopillar
Authors: Lehndorff R. , Bürgler D. E. , Schneider C. M. , Celinski Z.
Published: October 2010

Spin-torque oscillators (STOs) are a promising application for the spin-transfer torque effect. The major challenge lies in pushing the STO’s microwave output power to useful levels, e.g., by operating an array of STOs in a synchronized, phase-locked mode. Our experiment on metallic, giant magnetoresistance-type nanopillars focuses on the influence of external high-frequency signals on the current-driven vortex dynamics and demonstrates the injection locking of the gyrotropic mode. We find a gap of about three orders of magnitude between the high-frequency power emitted by one oscillator and the power needed for phase-locking.
Visual Rays are Parallel
Authors: Koenderink Jan , van Doorn Andrea , de Ridder Huib , Oomes Stijn
Published: October 2010

We show that human observers using monocular viewing treat the pencil of ‘visual rays’ that diverges from the vantage point as experientally parallel. This oddity becomes very noticeable in the case of wide-angle presentations, where the angle subtended by a pair of visual rays may be as large as the angular size of the display. In our presentations such angles subtended over 100 deg. There are various ways to demonstrate the effect; in this study we measure the attitudes of pictorial objects that appear to be situated in mutually parallel attitudes in pictorial space. Our finding is that such objects appear parallel if they are similarly oriented with respect to the local visual rays. This leads to ‘errors’ in the judgment of mutual orientations of up to 100 deg. Although this appears to be the first quantitative study of the effect, we trace it to qualitative reports by Helmholtz (late 19th century) and Kepler (early 17th century) as well as speculation by early authors (AD 500). The effect has apparently been noticed by visual artists from the late middle ages to the present day.
Dated molecular phylogenies indicate a Miocene origin for
Arabidopsis thaliana
Authors: Beilstein Mark A. , Nagalingum Nathalie S. , Clements Mark D. , Manchester Steven R. , Mathews Sarah
Published: October 2010

Dated molecular phylogenies are the basis for understanding species diversity and for linking changes in rates of diversification with historical events such as restructuring in developmental pathways, genome doubling, or dispersal onto a new continent. Valid fossil calibration points are essential to the accurate estimation of divergence dates, but for many groups of flowering plants fossil evidence is unavailable or limited.
Arabidopsis thaliana
, the primary genetic model in plant biology and the first plant to have its entire genome sequenced, belongs to one such group, the plant family Brassicaceae. Thus, the timing of
A. thaliana
evolution and the history of its genome have been controversial. We bring previously overlooked fossil evidence to bear on these questions and find the split between
A. thaliana
and
Arabidopsis lyrata
occurred about 13 Mya, and that the split between
Arabidopsis
and the
Brassica
complex (broccoli, cabbage, canola) occurred about 43 Mya. These estimates, which are two- to threefold older than previous estimates, indicate that gene, genomic, and developmental evolution occurred much more slowly than previously hypothesized and that
Arabidopsis
evolved during a period of warming rather than of cooling. We detected a 2- to 10-fold shift in species diversification rates on the branch uniting Brassicaceae with its sister families. The timing of this shift suggests a possible impact of the Cretaceous–Paleogene mass extinction on their radiation and that Brassicales codiversified with pierid butterflies that specialize on mustard-oil–producing plants.
Climate mitigation and the future of tropical landscapes
Authors: Thomson Allison M. , Calvin Katherine V. , Chini Louise P. , Hurtt George , Edmonds James A. , Bond-Lamberty Ben , Frolking Steve , Wise Marshall A. , Janetos Anthony C.
Published: October 2010

Land-use change to meet 21st-century demands for food, fuel, and fiber will depend on many interactive factors, including global policies limiting anthropogenic climate change and realized improvements in agricultural productivity. Climate-change mitigation policies will alter the decision-making environment for land management, and changes in agricultural productivity will influence cultivated land expansion. We explore to what extent future increases in agricultural productivity might offset conversion of tropical forest lands to crop lands under a climate mitigation policy and a contrasting no-policy scenario in a global integrated assessment model. The Global Change Assessment Model is applied here to simulate a mitigation policy that stabilizes radiative forcing at 4.5 W m−2(approximately 526 ppm CO2) in the year 2100 by introducing a price for all greenhouse gas emissions, including those from land use. These scenarios are simulated with several cases of future agricultural productivity growth rates and the results downscaled to produce gridded maps of potential land-use change. We find that tropical forests are preserved near their present-day extent, and bioenergy crops emerge as an effective mitigation option, only in cases in which a climate mitigation policy that includes an economic price for land-use emissions is in place, and in which agricultural productivity growth continues throughout the century. We find that idealized land-use emissions price assumptions are most effective at limiting deforestation, even when cropland area must increase to meet future food demand. These findings emphasize the importance of accounting for feedbacks from land-use change emissions in global climate change mitigation strategies.
Somatic sex determination in
Caenorhabditis elegans
is modulated by SUP-26 repression of
tra-2
translation
Authors: Mapes James , Chen Jeng-Ting , Yu Jau-Song , Xue Ding
Published: October 2010

Translational repression mediated by RNA-binding proteins or micro RNAs has emerged as a major regulatory mechanism for fine-tuning important biological processes. In
Caenorhabditis elegans
, translational repression of the key sex-determination gene
tra-2
(
tra
, transformer) is controlled by a 28-nucleotide repeat element, the TRA-2/GLI element (TGE), located in its 3′ untranslated region (UTR). Mutations that disrupt TGE or the germline-specific TGE-binding factor GLD-1 increase TRA-2 protein expression and inhibit sperm production in hermaphrodites. Here we report the characterization of the
sup-26
gene, which regulates sex determination in the soma and encodes an RNA recognition motif (RRM)-containing protein. We show that SUP-26 regulates the level of the TRA-2 protein through TGE in vivo and binds directly to TGE in vitro through its RRM domain. Interestingly, SUP-26 associates with poly(A)-binding protein 1 (PAB-1) in vivo and may repress
tra-2
expression by inhibiting the translation-stimulating activity of PAB-1. Taken together, our results provide further insight into how mRNA-binding factors repress translation and modulate sexual development in different tissues of
C. elegans
.
Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms
Authors: Faust Thomas W. , Chang Eric H. , Kowal Czeslawa , Berlin RoseAnn , Gazaryan Irina G. , Bertini Eva , Zhang Jie , Sanchez-Guerrero Jorge , Fragoso-Loyo Hilda E. , Volpe Bruce T. , Diamond Betty , Huerta Patricio T.
Published: October 2010

Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of neurological disorders. In the case of systemic lupus erythematosus (SLE), patients generate autoantibodies (AAbs) that frequently bind dsDNA. Although some symptoms of SLE may arise from direct reactivity to dsDNA, much of the AAb-mediated damage originates from cross-reactivity with other antigens. We have studied lupus AAbs that bind dsDNA and cross-react with the NR2A and NR2B subunits of the NMDA receptor (NMDAR). In adult mouse models, when the blood–brain barrier is compromised, these NMDAR-reactive AAbs access the brain and elicit neuronal death with ensuing cognitive dysfunction and emotional disturbance. The cellular mechanisms that underlie these deleterious effects remain incompletely understood. Here, we show that, at low concentration, the NMDAR-reactive AAbs are positive modulators of receptor function that increase the size of NMDAR-mediated excitatory postsynaptic potentials, whereas at high concentration, the AAbs promote excitotoxicity through enhanced mitochondrial permeability transition. Other synaptic receptors are completely unaffected by the AAbs. NMDAR activation is required for producing both the synaptic and the mitochondrial effects. Our study thus reveals the mechanisms by which NMDAR-reactive AAbs trigger graded cellular alterations, which are likely to be responsible for the transient and permanent neuropsychiatric symptoms observed in patients with SLE. Our study also provides a model in which local AAb concentration determines the exact nature of the cellular response.
EEG microstate sequences in healthy humans at rest reveal scale-free dynamics
Authors: Van De Ville Dimitri , Britz Juliane , Michel Christoph M.
Published: October 2010

Recent findings identified electroencephalography (EEG) microstates as the electrophysiological correlates of fMRI resting-state networks. Microstates are defined as short periods (100 ms) during which the EEG scalp topography remains quasi-stable; that is, the global topography is fixed but strength might vary and polarity invert. Microstates represent the subsecond coherent activation within global functional brain networks. Surprisingly, these rapidly changing EEG microstates correlate significantly with activity in fMRI resting-state networks after convolution with the hemodynamic response function that constitutes a strong temporal smoothing filter. We postulate here that microstate sequences should reveal scale-free, self-similar dynamics to explain this remarkable effect and thus that microstate time series show dependencies over long time ranges. To that aim, we deploy wavelet-based fractal analysis that allows determining scale-free behavior. We find strong statistical evidence that microstate sequences are scale free over six dyadic scales covering the 256-ms to 16-s range. The degree of long-range dependency is maintained when shuffling the local microstate labels but becomes indistinguishable from white noise when equalizing microstate durations, which indicates that temporal dynamics are their key characteristic. These results advance the understanding of temporal dynamics of brain-scale neuronal network models such as the global workspace model. Whereas microstates can be considered the “atoms of thoughts,” the shortest constituting elements of cognition, they carry a dynamic signature that is reminiscent at characteristic timescales up to multiple seconds. The scale-free dynamics of the microstates might be the basis for the rapid reorganization and adaptation of the functional networks of the brain.
Bird communities in future bioenergy landscapes of the Upper Midwest
Authors: Meehan Timothy D. , Hurlbert Allen H. , Gratton Claudio
Published: October 2010

Mandates for biofuel and renewable electricity are creating incentives for biomass production in agricultural landscapes of the Upper Midwest. Different bioenergy crops are expected to vary in their effects on biodiversity and ecosystem services. Here, we use data from the North American Breeding Bird Survey to forecast the impact of potential bioenergy crops on avian species richness and the number of bird species of conservation concern in Midwestern landscapes. Our analysis suggests that expanded production of annual bioenergy crops (e.g., corn and soybeans) on marginal land will lead to declines in avian richness between 7% and 65% across 20% of the region, and will make managing at-risk species more challenging. In contrast, replacement of annual with diverse perennial bioenergy crops (e.g., mixed grasses and forbs) is expected to bring increases in avian richness between 12% and 207% across 20% of the region, and possibly aid the recovery of several species of conservation concern.
Escherichia coli
condensin MukB stimulates topoisomerase IV activity by a direct physical interaction
Authors: Li Yinyin , Stewart Nichole K. , Berger Anthony J. , Vos Seychelle , Schoeffler Allyn J. , Berger James M. , Chait Brian T. , Oakley Martha G.
Published: October 2010

In contrast to the current state of knowledge in the field of eukaryotic chromosome segregation, relatively little is known about the mechanisms coordinating the appropriate segregation of bacterial chromosomes. In
Escherichia coli
, the MukB/E/F complex and topoisomerase IV (Topo IV) are both crucial players in this process. Topo IV removes DNA entanglements following the replication of the chromosome, whereas MukB, a member of the structural maintenance of chromosomes protein family, serves as a bacterial condensin. We demonstrate here a direct physical interaction between the dimerization domain of MukB and the C-terminal domain of the ParC subunit of Topo IV. In addition, we find that MukB alters the activity of Topo IV in vitro. Finally, we isolate a MukB mutant, D692A, that is deficient in its interaction with ParC and show that this mutant fails to rescue the temperature-sensitive growth phenotype of a
mukB
-
strain. These results show that MukB and Topo IV are linked physically and functionally and indicate that the activities of these proteins are not limited to chromosome segregation but likely also play a key role in the control of higher-order bacterial chromosome structure.
Sequential action of
Caenorhabditis elegans
Rab GTPases regulates phagolysosome formation during apoptotic cell degradation
Authors: Guo Pengfei , Hu Tianjing , Zhang Juan , Jiang Shanya , Wang Xiaochen
Published: October 2010

Phagocytosis of apoptotic cells requires recognition of cell corpses followed by internalization and enclosure within plasma membrane-derived phagosomes. Phagosomes undergo maturation to generate phagolysosomes in which cell corpses are degraded; however, regulation of the maturation process is poorly understood. Here, we identified Rab GTPase 14, which regulates apoptotic cell degradation in
Caenorhabditis elegans
.
rab-14
mutants accumulate many persistent cell corpses owing to defective cell corpse clearance. Loss of
rab-14
function affects several steps of phagosome maturation including phagosomal acidification and phagolysosome formation. RAB-14 and UNC-108/RAB2 are recruited to phagosomes at a similar stage and function redundantly to regulate phagosome maturation. Three Rabs, RAB-14, UNC-108/RAB2, and RAB-7, act in sequential steps to control phagolysosome formation. RAB-14 and UNC-108 recruit lysosomes, whereas RAB-7 mediates fusion of lysosomes to phagosomes. Our data reveal the sequential action of Rab GTPases in regulating tethering, docking, and fusion of lysosomes to apoptotic cell-containing phagosomes.
Duration of antigen receptor signaling determines T-cell tolerance or activation
Authors: Katzman Shoshana D. , O'Gorman William E. , Villarino Alejandro V. , Gallo Eugenio , Friedman Rachel S. , Krummel Matthew F. , Nolan Garry P. , Abbas Abul K.
Published: October 2010

The early events that determine the decision between lymphocyte tolerance and activation are not well-understood. Using a model of systemic self-antigen recognition by CD4
+
T cells, we show, using single-cell biochemical analyses, that tolerance is characterized by transient signaling events downstream of T-cell receptor engagement in the mammalian target of rapamycin (mTOR) and NF-κB pathways. Parallel studies done by live cell imaging show that the key difference between tolerance and activation is the duration of the T cell–antigen presenting cell (APC) interaction, as revealed by stable T-cell immobilization on antigen encounter. Brief T cell–APC interactions result in tolerance, and prolonged interactions are associated with activation and the development of effector cells. These studies show that the duration of T cell–APC interactions and magnitude of associated TCR-mediated signaling are key determinants of lymphocyte tolerance vs. activation.
Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy
Authors: Kolishetti Nagesh , Dhar Shanta , Valencia Pedro M. , Lin Lucy Q. , Karnik Rohit , Lippard Stephen J. , Langer Robert , Farokhzad Omid C.
Published: October 2010

The genomic revolution has identified therapeutic targets for a plethora of diseases, creating a need to develop robust technologies for combination drug therapy. In the present work, we describe a self-assembled polymeric nanoparticle (NP) platform to target and control precisely the codelivery of drugs with varying physicochemical properties to cancer cells. As proof of concept, we codelivered cisplatin and docetaxel (Dtxl) to prostate cancer cells with synergistic cytotoxicity. A polylactide (PLA) derivative with pendant hydroxyl groups was prepared and conjugated to a platinum(IV) [Pt(IV)] prodrug,c,t,c-[Pt(NH3)2(O2CCH2CH2COOH)(OH)Cl2] [PLA-Pt(IV)]. A blend of PLA-Pt(IV) functionalized polymer and carboxyl-terminated poly(d,l-lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer in the presence or absence of Dtxl, was converted, in microfluidic channels, to NPs with a diameter of ∼100 nm. This process resulted in excellent encapsulation efficiency (EE) and high loading of both hydrophilic platinum prodrug and hydrophobic Dtxl with reproducible EEs and loadings. The surface of the NPs was derivatized with the A10 aptamer, which binds to the prostate-specific membrane antigen (PSMA) on prostate cancer cells. These NPs undergo controlled release of both drugs over a period of 48–72 h. Targeted NPs were internalized by the PSMA-expressing LNCaP cells via endocytosis, and formation of cisplatin 1,2-d(GpG) intrastrand cross-links on nuclear DNA was verified. In vitro toxicities demonstrated superiority of the targeted dual-drug combination NPs over NPs with single drug or nontargeted NPs. This work reveals the potential of a single, programmable nanoparticle to blend and deliver a combination of drugs for cancer treatment.
Nucleosome depletion at yeast terminators is not intrinsic and can occur by a transcriptional mechanism linked to 3’-end formation
Authors: Fan Xiaochun , Moqtaderi Zarmik , Jin Yi , Zhang Yong , Liu X. Shirley , Struhl Kevin
Published: October 2010

Genome-wide mapping of nucleosomes generated by micrococcal nuclease (MNase) suggests that yeast promoter and terminator regions are very depleted of nucleosomes, predominantly because their DNA sequences intrinsically disfavor nucleosome formation. However, MNase has strong DNA sequence specificity that favors cleavage at promoters and terminators and accounts for some of the correlation between occupancy patterns of nucleosomes assembled in vivo and in vitro. Using an improved method for measuring nucleosome occupancy in vivo that does not involve MNase, we confirm that promoter regions are strongly depleted of nucleosomes, but find that terminator regions are much less depleted than expected. Unlike at promoter regions, nucleosome occupancy at terminators is strongly correlated with the orientation of and distance to adjacent genes. In addition, nucleosome occupancy at terminators is strongly affected by growth conditions, indicating that it is not primarily determined by intrinsic histone–DNA interactions. Rapid removal of RNA polymerase II (pol II) causes increased nucleosome occupancy at terminators, strongly suggesting a transcription-based mechanism of nucleosome depletion. However, the distinct behavior of terminator regions and their corresponding coding regions suggests that nucleosome depletion at terminators is not simply associated with passage of pol II, but rather involves a distinct mechanism linked to 3’-end formation.
Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation
Authors: Araki Koichi , Gangappa Shivaprakash , Dillehay Dirck L. , Rouse Barry T. , Larsen Christian P. , Ahmed Rafi
Published: October 2010

Recently, several cases of fatal lymphocytic choriomeningitis virus (LCMV) infection occurred in transplant recipients being treated with the immunosuppressive calcineurin inhibitor FK506. These findings were surprising because LCMV is a noncytolytic virus. To understand how a noncytolytic virus can cause disease under conditions of immunosuppression, we used the mouse LCMV model and found that, similar to the observations in human transplant recipients, LCMV infection of FK506-treated mice resulted in a lethal disease characterized by viremia, lack of seroconversion, and minimal lymphocytic infiltrates in the tissues. However, despite the apparent absence of an antiviral immune response, this disease was orchestrated by virus-specific T cells. FK506 did not prevent the generation and proliferation of LCMV-specific T cells but instead altered their differentiation so that these effector T cells lost the ability to control virus but were still capable of mediating disease. These pathogenic T cells initiated a cytokine storm characterized by high levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6), and depletion of T cells or blockade of these inflammatory cytokines prevented the lethal disease. Our study shows that inhibiting calcineurin can generate pathogenic T cells and indicates that T cell–mediated viral disease can occur even under conditions of immunosuppression. Furthermore, we identify a potential strategy (blockade of TNF and IL-6) for treatment of transplant recipients who have acute complications of viral infection.
Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy
Authors: Weiss Jonathan M. , Ridnour Lisa A. , Back Tim , Hussain S. Perwez , He Peijun , Maciag Anna E. , Keefer Larry K. , Murphy William J. , Harris Curtis C. , Wink David A. , Wiltrout Robert H.
Published: October 2010

Using an orthotopic model of renal cell carcinoma, we showed previously that IL-2/anti-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or α-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/α-CD40, but not IL-2 or α-CD40, induced significant nitric oxide synthase (NOS) 2 expression in tumor-associated macrophages. In control-treated mice (low NO), NOS2 inhibition reduced tumor burden. However, during immunotherapy (high NO), NOS2 inhibition or macrophage depletion reversed the ability of IL-2/α-CD40 treatment to reduce lung metastases but had no effect on primary tumor burden. Furthermore, IL-2/α-CD40 induced the IFN-γ– and NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with increases in tissue inhibitor of metalloproteinase (TIMP) 1 and E-cadherin expression within tumors. Finally, treatment of tumor-bearing mice with the NO donor JS-K significantly reduced metastases. These data differentiate the mechanism for primary anti-tumor effects of IL-2/α-CD40 immunotherapy, which are independent of NO, from the NO-dependent inhibition of metastases. Furthermore, reduced MMP9 activity implicates M1-polarized macrophages within the tumor microenvironment as critical components of therapeutic response. Our data demonstrate the mechanistic basis for IL-2/α-CD40–mediated control of metastases and suggest that the context-dependent application of NO donors may hold promise for prevention of metastatic disease.
A requirement for FcγR in antibody-mediated bacterial toxin neutralization
Authors: Abboud Nareen , Chow Siu-Kei , Saylor Carolyn , Janda Alena , Ravetch Jeffery V. , Scharff Matthew D. , Casadevall Arturo
Published: October 2010

One important function of humoral immunity is toxin neutralization. The current view posits that neutralization results from antibody-mediated interference with the binding of toxins to their targets, a phenomenon viewed as dependent only on antibody specificity. To investigate the role of antibody constant region function in toxin neutralization, we generated IgG2a and IgG2b variants of the Bacillus anthracis protective antigen–binding IgG1 monoclonal antibody (mAb) 19D9. These antibodies express identical variable regions and display the same specificity. The efficacy of antibody-mediated neutralization was IgG2a > IgG2b > IgG1, and neutralization activity required competent Fcγ receptor (FcγR). The IgG2a mAb prevented lethal toxin cell killing and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase cleavage more efficiently than the IgG1 mAb. Passive immunization with IgG1 and IgG2a mAb protected wild-type mice, but not FcγR-deficient mice, against B. anthracis infection. These results establish that constant region isotype influences toxin neutralization efficacy of certain antibodies through a mechanism that requires engagement of FcγR. These findings highlight a new parameter for evaluating vaccine responses and the possibility of harnessing optimal FcγR interactions in the design of passive immunization strategies.
Excess Length of Stay Due to Central Line–Associated Bloodstream Infection in Intensive Care Units in Argentina, Brazil, and Mexico
Authors: Barnett Adrian G. , Graves Nicholas , Rosenthal Victor D. , Salomao Reinaldo , Rangel-Frausto Manuel Sigfrido
Published: October 2010

Objective.

To estimate the excess length of stay in an intensive care unit (ICU) due to a central line-associated bloodstream infection (CLABSI), using a multistate model that accounts for the timing of infection.

Design.

A cohort of 3,560 patients followed up for 36,806 days in ICUs.

Setting.

Eleven ICUs in 3 Latin American countries: Argentina, Brazil, and Mexico.

Patients.

All patients admitted to the ICU during a defined time period with a central line in place for more than 24 hours.

Results.

The average excess length of stay due to a CLABSI increased in 10 of 11 ICUs and varied from -1.23 days to 4.69 days. A reduction in length of stay in Mexico was probably caused by an increased risk of death due to CLABSI, leading to shorter times to death. Adjusting for patient age and Average Severity of Illness Score tended to increase the estimated excess length of stays due to CLABSI.

Conclusions.

CLABSIs are associated with an excess length of ICU stay. The average excess length of stay varies between ICUs, most likely because of the case-mix of admissions and differences in the ways that hospitals deal with infections.
Patient-Associated Risk Factors for Acquisition of Methicillin-Resistant Staphylococcus aureus in a Tertiary Care Hospital
Authors: Salangsang Jo-anne M. , Harrison Lee H. , Brooks Maria M. , Shutt Kathleen A. , Saul Melissa I. , Muto Carlene A.
Published: October 2010

Background.

Determining risk factors for acquisition of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals is important for defining infection-control measures that may lead to fewer hospital-acquired infections.

Objective.

To determine patient-associated risk factors for acquisition of MRSA in a tertiary care hospital with the goal of identifying modifiable risk factors.

Methods.

A retrospective matched case-control study was performed. Case patients who acquired MRSA during hospitalization and 2 matched control patients were selected among inpatients admitted to target units during the period from 2001 through 2008. The odds of exposure to potential risk factors were compared between case patients and control patients, using matched univariate conditional logistic regression. A single multivariate conditional logistic regression model identifying independent patient-specific risk factors was generated.

Results.

A total of 451 case patients and 866 control patients were analyzed. Factors positively associated with MRSA acquisition were as follows: target unit stay before index culture; primary diagnosis of respiratory disease, digestive tract disease, injury or trauma, or other diagnosis compared with cardiocirculatory disease; peripheral vascular disease; mechanical ventilation with pneumonia; ventricular shunting or ventriculostomy; and ciprofloxacin use. Factors associated with decreased risk were receipt of a solid-organ transplant and use of penicillins, cephalosporins, rifamycins, daptomycin or linezolid, and proton pump inhibitors.

Conclusion.

Among the factors associated with increased risk, few are modifiable. Patients with at-risk conditions could be targeted for intensive surveillance to detect acquisition sooner. The association of MRSA acquisition with target unit exposure argues for rigorous application of hand hygiene, appropriate barriers, environmental control, and strict aseptic technique for all procedures performed on such Patients. Our findings support focusing efforts to prevent MRSA transmission and restriction of ciprofloxacin use.
Characterization of the Interactions Between Cucumber mosaic virus and Potato virus Y in Mixed Infections in Tomato
Authors: Mascia Tiziana , Cillo Fabrizio , Fanelli Vilma , Finetti-Sialer Mariella Matilde , De Stradis Angelo , Palukaitis Peter , Gallitelli Donato
Published: October 2010

Mixed infection with the SON41 strain of Potato virus Y (PVY-SON41) in tomato increased accumulation of RNAs of strains Fny and LS of Cucumber mosaic virus (CMV-Fny and CMV-LS, respectively) and enhanced disease symptoms. By contrast, replication of PVY-SON41 was downregulated by CMV-Fny and this was due to the CMV-Fny 2b protein. The CMV-FnyΔ2b mutant was unable to systemically invade the tomato plant because its movement was blocked at the bundle sheath of the phloem. The function needed for invading the phloem was complemented by PVY-SON41 in plants grown at 22°C whereas this complementation was not necessary in plants grown at 15°C. Mutations in the 2b protein coding sequence of CMV-Fny as well as inhibition of translation of the 2a/2b overlapping region of the 2a protein lessened both the accumulation of viral RNAs and the severity of symptoms. Both of these functions were complemented by PVY-SON41. Infection of CMV-Fny supporting replication of the Tfn-satellite RNA reduced the accumulation of CMV RNA and suppressed symptom expression also in plants mixed-infected with PVY-SON41. The interaction between CMV and PVY-SON41 in tomato exhibited different features from that documented in other hosts. The results of this work are relevant from an ecological and epidemiological perspective due to the frequency of natural mixed infection of CMV and PVY in tomato.
A Host-Factor Interaction and Localization Map for a Plant-Adapted Rhabdovirus Implicates Cytoplasm-Tethered Transcription Activators in Cell-to-Cell Movement
Authors: Min Byoung-Eun , Martin Kathleen , Wang Renyuan , Tafelmeyer Petra , Bridges Max , Goodin Michael
Published: October 2010

To identify host factors that play critical roles in processes, including cell-to-cell movement of plant-adapted rhabdoviruses, we constructed and validated a high-resolution Nicotiana benthamiana yeast two-hybrid library. The library was screened with the putative movement protein (sc4), nucleocapsid (N), and matrix (M) proteins of Sonchus yellow net virus (SYNV). This resulted in identification of 31 potential host factors. Steady-state localization studies using autofluorescent protein fusions to full-length clones of interactors were conducted in transgenic N. benthamiana marker lines. Bimolecular fluorescence complementation assays were used to validate two-hybrid interactions. The sc4 interactor, sc4i21, localized to microtubules. The N interactor, Ni67, localized to punctuate loci on the endoplasmic reticulum. These two proteins are 84% identical homologues of the Arabidopsis phloem-associated transcription activator AtVOZ1, and contain functional nuclear localization signals. Sc4i17 is a microtubule-associated motor protein. The M interactor, Mi7, is a nuclear-localized transcription factor. Combined with a binary interaction map for SYNV proteins, our data support a model in which the SYNV nucleocapsids are exported from the nucleus and moved cell-to-cell by transcription activators tethered in the cytoplasm.
All Hands on Deck—The Role of Chloroplasts, Endoplasmic Reticulum, and the Nucleus in Driving Plant Innate Immunity
Authors: Padmanabhan Meenu S. , Dinesh-Kumar S. P.
Published: October 2010

Plant innate immunity is mediated by cell membrane and intracellular immune receptors that function in distinct and overlapping cell-signaling pathways to activate defense responses. It is becoming increasingly evident that immune receptors rely on components from multiple organelles for the generation of appropriate defense responses. This review analyzes the defense-related functions of the chloroplast, nucleus, and endoplasmic reticulum (ER) during plant innate immunity. It details the role of the chloroplasts in synthesizing defense-specific second messengers and discusses the retrograde signal transduction pathways that exist between the chloroplast and nucleus. Because the activities of immune modulators are regulated, in part, by their subcellular localization, the review places special emphasis on the dynamics and nuclear–cytoplasmic transport of immune receptors and regulators and highlights the importance of this process in generating orderly events during an innate immune response. The review also covers the recently discovered contributions of the ER quality-control pathways in ensuring the signaling competency of cell surface immune receptors or immune regulators.
Cross Talk between the KNOX and Ethylene Pathways Is Mediated by Intron-Binding Transcription Factors in Barley
Authors: Osnato Michela , Stile Maria Rosaria , Wang Yamei , Meynard Donaldo , Curiale Serena , Guiderdoni Emmanuel , Liu Yongxiu , Horner David S. , Ouwerkerk Pieter B.F. , Pozzi Carlo , Müller Kai J. , Salamini Francesco , Rossini Laura
Published: October 2010

In the barley (Hordeum vulgare) Hooded (Kap) mutant, the duplication of a 305-bp intron sequence leads to the overexpression of the Barley knox3 (Bkn3) gene, resulting in the development of an extra flower in the spikelet. We used a one-hybrid screen to identify four proteins that bind the intron-located regulatory element (Kap intron-binding proteins). Three of these, Barley Ethylene Response Factor1 (BERF1), Barley Ethylene Insensitive Like1 (BEIL1), and Barley Growth Regulating Factor1 (BGRF1), were characterized and their in vitro DNA-binding capacities verified. Given the homology of BERF1 and BEIL1 to ethylene signaling proteins, we investigated if these factors might play a dual role in intron-mediated regulation and ethylene response. In transgenic rice (Oryza sativa), constitutive expression of the corresponding genes produced phenotypic alterations consistent with perturbations in ethylene levels and variations in the expression of a key gene of ethylene biosynthesis. In barley, ethylene treatment results in partial suppression of the Kap phenotype, accompanied by up-regulation of BERF1 and BEIL1 expression, followed by down-regulation of Bkn3 mRNA levels. In rice protoplasts, BEIL1 activates the expression of a reporter gene driven by the 305-bp intron element, while BERF1 can counteract this activation. Thus, BEIL1 and BERF1, likely in association with other Kap intron-binding proteins, should mediate the fine-tuning of Bkn3 expression by ethylene. We propose a hypothesis for the cross talk between the KNOX and ethylene pathways.
Post‐glacial expansion into the Paleozoic Plateau: evidence of an Ozarkian refugium for the Ozark minnow Notropis nubilus (Teleostei: Cypriniformes)
Authors: Berendzen P. B. , Dugan J. F. , Gamble T.
Published: October 2010

Genetic variation was examined within the Ozark minnow Notropis nubilus using complete mtDNA cytochrome b gene sequences from 160 individuals representing 30 localities to test hypotheses on the origin of the distribution. Phylogenetic analyses revealed three strongly supported clades of haplotypes consistent with geographic distributions: a clade from the Western Ozarks, a clade from the Southern Ozarks and a clade from the Northern Ozarks and upper Mississippi River basin. The estimated mean ages of these clades indicated that they diverged during pre‐Illinoian glacial cycles extending from the late Pliocene into the early Pleistocene. Results of demographic analyses based on coalescent approaches supported the hypothesis that the Paleozoic Plateau was not a refugium for N. nubilus during periodic glacial advances. There is evidence of a genetic signature of northern expansion into the Paleozoic Plateau from a Southern Ozarkian refugium. Populations expanded out of drainages in the Northern Ozarks into the Paleozoic Plateau during the late Pleistocene. Subsequently, the two regions were isolated due to the recent extirpation of intervening populations caused by the loss of suitable habitat.
The rate of decompensation and clinical progression of disease in people with cirrhosis: a cohort study
Authors: Fleming K. M. , Aithal G. P. , Card T. R. , West J.
Published: October 2010

Aliment Pharmacol Ther 2010; 32: 1343–1350

Background  We lack population‐based estimates of the rate of decompensation in people with compensated cirrhosis as well as estimates of the manner in which the disease progresses once identified.

Aim  To determine the rate of decompensation and clinical progression of disease in patients with cirrhosis based upon clinical symptoms recorded electronically in general practice data.

Methods  Using Cox proportional hazards regression, we modelled the rate of decompensation for patients from the UK General Practice Research Database with a diagnosis of cirrhosis between 1987 and 2002. We determined the clinical progression in the first year following diagnosis and subsequently categorizing patients through time according to a simple clinical staging system agreed at the Baveno IV consensus conference.

Results  The rate of decompensation in patients with compensated cirrhosis was found to be 11% overall. The rate of decompensation was higher in the first year (at 31% compared with 7.3% afterwards) and in patients with an alcoholic aetiology. Patients with compensated cirrhosis had a 1‐year probability of proceeding directly to death of 7% compared with 20% in patients with decompensated cirrhosis.

Conclusions  Using data recorded in general practice records, it is possible to determine the rate of decompensation and the clinical progression of disease in people with cirrhosis.
Practice patterns for the evaluation and treatment of eosinophilic oesophagitis
Authors: Peery A. F. , Shaheen N. J. , Dellon E. S.
Published: October 2010

Aliment Pharmacol Ther 2010; 32: 1373–1382

Background  Although consensus guidelines for eosinophilic oesophagitis have been published, it remains unclear whether gastroenterologists follow these recommendations.

Aim  To assess academic and community practice patterns for the evaluation and treatment of eosinophilic oesophagitis and to compare these practices with current guidelines.

Methods  This was a prospective study of academic and community gastroenterologists using a self‐administered online survey.

Results  A total of 60% (34 of 57) of academic and 29% (38 of 133) of community gastroenterologists completed the survey. Only 24% of academic and 3% of community gastroenterologists follow consensus guidelines to diagnose eosinophilic oesophagitis (P = 0.007). A proton pump inhibitor trial or negative pH study prior to diagnosis was required by just 25% of all gastroenterologists. A majority (60%) do not use the recommended threshold of 15 eosinophils per high powered field to diagnosis eosinophilic oesophagitis. Half (51%) mistakenly require a positive endoscopic finding. For first‐line treatment, about half of the gastroenterologists surveyed treat with a swallowed topical steroid (53% academic, 56% community; P = N.S.), consistent with the guidelines.

Conclusions  There is variability in practice patterns for both diagnosis and treatment of eosinophilic oesophagitis. Ongoing education and research concerning diagnosis and treatment are needed.
Isolation and preservation of peripheral blood mononuclear cells for analysis of islet antigen-reactive T cell responses: position statement of the T-Cell Workshop Committee of the Immunology of Diabetes Society
Authors: Mallone R , Mannering S I , Brooks-Worrell B M , Durinovic-Belló I , Cilio C M , Wong F S , Schloot N C
Published: October 2010

Autoimmune T cell responses directed against insulin-producing β cells are central to the pathogenesis of type 1 diabetes (T1D). Detection of such responses is therefore critical to provide novel biomarkers for T1D ‘immune staging’ and to understand the mechanisms underlying the disease. While different T cell assays are being developed for these purposes, it is important to optimize and standardize methods for processing human blood samples for these assays. To this end, we review data relevant to critical parameters in peripheral blood mononuclear cell (PBMC) isolation, (cryo)preservation, distribution and usage for detecting antigen-specific T cell responses. Based on these data, we propose recommendations on processing blood samples for T cell assays and identify gaps in knowledge that need to be addressed. These recommendations may be relevant not only for the analysis of T cell responses in autoimmune disease, but also in cancer and infectious disease, particularly in the context of clinical trials.
The relationship between postprandial bile acid concentration, GLP‐1, PYY and ghrelin
Authors: Roberts R. E. , Glicksman C. , Alaghband‐Zadeh J. , Sherwood R. A. , Akuji N. , le Roux C. W.
Published: October 2010

Background  Gut hormones peptide YY (PYY) and glucagon‐like peptide‐1 (GLP‐1) play an integral role in appetite control and energy homeostasis. Entero‐endocrine L‐cells can be stimulated by nutrients and or bile acids to co‐secrete PYY and GLP‐1. The aim of this study was to determine the response of bile acids, PYY, GLP‐1 and ghrelin after a test meal.

Design  Twelve subjects with a BMI of 22·8 (0·52) kg/m2 [mean (SEM)] received a 400 kcal test meal after which blood samples were taken every 30 min from 0 to 180 min. PYY, GLP‐1 and ghrelin were measured by radioimmunoassays. Fractionated bile acids were measured by HPLC‐MSMS.

Results  PYY positively correlated with glycochenodeoxycholic acid (GCDCA) (rs = 0·23, P = 0·03) and taurochenodeoxycholic acid (TCDCA) (rs = 0·26, P = 0·02). GLP‐1 positively correlated with GCDCA (rs = 0·22, P = 0·047) and glycodeoxycholic acid (GDCA) (rs = 0·3, P = 0·005). Ghrelin negatively correlated with GDCA (rs = −0·45, P≤ 0·0001), TCDCA (rs = −0·23, P = 0·034) and taurodeoxycholic acid (TDCA) (rs = −0·44, P≤ 0·0001).

Conclusion  PYY and GLP‐1 responses correlated with chenodeoxycholic acid (CDCA) counterparts, whereas ghrelin negatively correlated with deoxycholic acid (DCA) counterparts. Specific bile acids may thus differentially affect entero‐endocrine cells.