bluuebunny/crossref_metadata_2025 huggingface dataset:
Santander acquires Abbey: The Jack Project
Authors: Busquets Javier , Rodón Joan , Vera Lluís
Published: March 2011

The case, ‘Santander Acquires Abbey: The Jack Project’, applies a general strategic management focus to an analysis of the ‘Jack Project’, the Spanish banking group's IT centric project to acquire Abbey. The case focuses on José María Fuster, chief information officer (CIO) and his perspective in leveraging IT to integrate Abbey. The following issues are explored: (1) the value of IT; (2) the generation of synergies in M&A; and (3) the prioritisation of IT-related options comparing two different realities. At the end of the case, students will examine how Partenón, Grupo Santander's core IT system, leveraged this acquisition and made an impact on the bank's long-term market position.
2.05 µm emission properties and energy transfer mechanism of germanate glass doped with Ho3+, Tm3+, and Er3+
Authors: Xu Rongrong , Wang Meng , Tian Ying , Hu Lili , Zhang Junjie
Published: March 2011

A new GeO2−Ga2O3−Na2O−BaO-La2O3 germanate glass doped with Ho2O3, Tm2O3, and Er2O3 has been investigated for application as a laser material at the 2 μm region. The spectroscopic properties and energy transfer mechanisms of Ho3+ sensitized by Tm3+ and Er3+ are analyzed. Based on the measurement of absorption spectra, the Judd–Ofelt intensity parameters, radiation emission probability, branching ratio, and lifetime of Ho3+ are calculated to evaluate the spectroscopic properties. The maximum value of emission cross section of Ho3+ around 2.05 μm is 8.003×10−21 cm2, which indicates that the germanate glass may provide high gain as a good medium in high-power level laser system. It is also found that the 2.05 μm emission of Ho3+:5I7→5I8 can be greatly enhanced by adding the proper amount of Er2O3 and Tm2O3 under excitation at 808 nm. With the large energy transfer coefficient, the high efficient energy transfer process among Ho3+, Tm3+, and Er3+ ions is proven.
Suppression of the Néel temperature in hydrothermally synthesized α-Fe2O3 nanoparticles
Authors: Wang Jun , Wu Wei , Zhao Fan , Zhao Guo-meng
Published: March 2011

Magnetic measurements up to 1000 K have been performed on hydrothermally synthesized α-Fe2O3 nanoparticles (60 nm) using a Quantum Design vibrating sample magnetometer. A high vacuum environment (1×10−5 Torr) during the magnetic measurement up to 1000 K leads to a complete reduction of α-Fe2O3 to Fe3O4. This precludes the determination of the Néel temperature for the α-Fe2O3 nanoparticles. In contrast, coating α-Fe2O3 nanoparticles with SiO2 stabilizes the α-Fe2O3 phase up to 930 K, which allows us to determine the Néel temperature of the α-Fe2O3 nanoparticles for the first time. The Néel temperature of the 60-nm α-Fe2O3 nanoparticles is found to be 945 K, about 15 K below the bulk value. The small reduction of the Néel temperature of the α-Fe2O3 nanoparticles is consistent with a finite-size scaling theory.
The influence of shear layer thickness on the stability of confined two-dimensional wakes
Authors: Biancofiore L. , Gallaire F.
Published: March 2011

The influence of confinement onto the inviscid and incompressible linear stability of the family of wakes introduced by Monkewitz [Phys. Fluids 31, 999 (1988)] is examined. The nondimensional parameters of the model, the velocity ratio Λ, defined as ratio of the velocity gap to the mean velocity, the profile shape parameter, which controls the shear layer thickness δw, and the confinement parameter, are varied and their effect onto temporal and spatiotemporal stability properties is considered. Particularly, the limit between absolute (A) and convective (C) instability is investigated as a function of the different parameters. For a given confinement, there exists an optimal value of the shear layer thickness for which the absolute instability is maximal. The absolute frequency and complex wavenumber of the mode at the C/A transition are discussed. Furthermore, the continuous profiles are approximated by means of piecewise broken-line profile, with similar spatiotemporal properties. As a typical application, a few nonparallel base flows, computed by direct numerical simulation at Re=500, are analyzed on a weakly nonparallel basis by plotting the locus of the local velocity profile in the (δw,Λ) plane. The absolute frequency at the C/A transition point is seen to predict accurately the frequency prevailing in the nonlinear direct numerical simulations. These results further help interpreting the influence of confinement on the Strouhal number measured experimentally in the wake of confined cylinders.
A new noncovalent force: Comparison of P···N interaction with hydrogen and halogen bonds
Authors: Scheiner Steve
Published: March 2011

When PH3 is paired with NH3, the two molecules are oriented such that the P and N atoms face one another directly, without the intermediacy of a H atom. Quantum calculations indicate that this attraction is due in part to the transfer of electron density from the lone pair of the N atom to the σ* antibond of a P–H covalent bond. Unlike a H-bond, the pertinent hydrogen is oriented about 180° away from, instead of toward, the N, and the N lone pair overlaps with the lobe of the P–H σ* orbital that is closest to the P. In contrast to halogen bonds, there is no requirement of a σ-hole of positive electrostatic potential on the P atom, nor is it necessary for the two interacting atoms to be of differing potential. In fact, the two atoms can be identical, as the global minimum of the PH3 homodimer has the same structure, characterized by a P ⋅⋅⋅ P attraction. Natural bond orbital analysis, energy decomposition, and visualization of total electron density shifts reveal other similarities and differences between the three sorts of molecular interaction.
Defects in low-k organosilicate glass and their response to processing as measured with electron-spin resonance
Authors: Ren H. , Nichols M. T. , Jiang G. , Antonelli G. A. , Nishi Y. , Shohet J. L.
Published: March 2011

Defect concentrations in low-k organosilicate glass films deposited on high-resistivity silicon were measured with electron-spin resonance. Bulk dangling bonds were detected. Both plasma exposure and ultraviolet exposure were used. During argon electron cyclotron resonance plasma exposure, ion and photon bombardment increased the measured defect concentrations. Ultraviolet lamp exposure was also shown to increase the defect concentrations. Dielectric samples with various dielectric constants were examined showing that as the value of the dielectric constant was lowered, the defect concentrations were shown to increase significantly.
Spaces, Times, and Critical Moments: A Relational Time–Space Analysis of the Impacts of AIDS on Rural Youth in Malawi and Lesotho
Authors: Ansell Nicola , van Blerk Lorraine , Hajdu Flora , Robson Elsbeth
Published: March 2011

Southern Africa's AIDS epidemic is profoundly spatially and temporally structured; so too are the lives of the young people whose families it blights. In this paper we draw on qualitative research with AIDS-affected young people in Malawi and Lesotho, and recent work theorising time–space in human geography, to examine how time–spaces of AIDS-related sickness and death intersect with the time–spaces of young people and, importantly, those of their relations with others to produce differentiated outcomes for young people. We also explore the time–spaces of those outcomes and of young people's responses to them. We conclude that a relational time–space analysis of the impacts of AIDS on young people helps explain the diversity of those young people's experiences and allows AIDS to be contextualised more adequately in relation to everyday life and young people's wider lifecourses and their relationships with others. Moreover, the research points to the significance of the time–space structuring of society in shaping the outcomes of familial sickness and death for young people.
The Aesthetics of Emptiness: Sky Art
Authors: Saito Yuriko
Published: March 2011

The sky and celestial phenomena surround us everywhere, all the time. However, they have not received due attention in philosophical discourses dealing with the environment, or in our daily experience. I explore some examples of recent art projects that facilitate our aesthetic experience of the sky and celestial events. These art pieces are analyzed in terms of the different ways in which they embody the notion of ‘emptiness’, a Buddhist term for reality that is written with the Chinese character for sky.
Preliminary study on the effects of ammonium nicotinate on in vitro ruminal fermentation as determined using rumen simulation technique (Rusitec)
Authors: Soliva Carla R. , Kunz Carmen
Published: March 2011

The objective of the present in vitro study was to investigate the effects of different dietary supplementation levels of ammonium nicotinate (NA-NH4), a precursor product when manufacturing nicotinic acid (NA), on ruminal fermentation traits. Four experimental runs were carried out incubating ruminal fluid from a donor cow by using rumen simulation technique (Rusitec). A low-protein (109 g/kg feed dry matter) basal diet, consisting of maize silage, hay and concentrate, served as the first control. Supplements were NA at 4.7 mg/day (second control), NA-NH4 at supplementation rates of 2.7, 5.4, 10.7 and 21.4 mg/day, or NH4-sulfate at 2.53 mg/day (the third control). All NA-containing treatments were supplemented with the same amount of sulfate as supplied with the third control treatment. None of the NA-supplements affected any of the fermentation traits significantly compared with the first control treatment, except for a decrease in total short-chain fatty acids at the highest supplementation rate of NA-NH4. No differences were found between the treatments containing the same amount of NA, i.e. the second control and the NA-NH4 treatment at 5.4 mg/day. Comparing the different NA-NH4 supplementation rates revealed that 5.4 mg/day of NA-NH4 resulted in a lower amount of nitrogen (N) recovered in ammonia than the highest NA-NH4 supplementation rate, and increased non-ammonia N. The findings confirmed the suitability of NA-NH4, instead of pure NA, as a feed supplement; however, increasing NA-NH4-supplementation above the typical rate for dairy cattle might negatively affect ruminal fermentation.
Casein kinase II-mediated phosphorylation of general repressor Maf1 triggers RNA polymerase III activation
Authors: Graczyk Damian , Dębski Janusz , Muszyńska Grażyna , Bretner Maria , Lefebvre Olivier , Boguta Magdalena
Published: March 2011

Maf1 protein is a global negative regulator of RNA polymerase (Pol) III transcription conserved from yeast to man. We report that phosphorylation of Maf1 by casein kinase II (CK2), a highly evolutionarily conserved eukaryotic kinase, is required for efficient Pol III transcription. Both recombinant human and yeast CK2 were able to phosphorylate purified human or yeast Maf1, indicating that Maf1 can be a direct substrate of CK2. Upon transfer of
Saccharomyces cerevisiae
from repressive to favorable growth conditions, CK2 activity is required for the release of Maf1 from Pol III bound to a tRNA gene and for subsequent activation of tRNA transcription. In a yeast strain lacking Maf1, CK2 inhibition showed no effect on tRNA synthesis, confirming that CK2 activates Pol III via Maf1. Additionally, CK2 was found to associate with tRNA genes, and this association is enhanced in absence of Maf1, especially under repressive conditions. These results corroborate the previously reported TFIIIB–CK2 interaction and indicate an important role of CK2-mediated Maf1 phosphorylation in triggering Pol III activation.
Searching for simplicity in the analysis of neurons and behavior
Authors: Stephens Greg J. , Osborne Leslie C. , Bialek William
Published: March 2011

What fascinates us about animal behavior is its richness and complexity, but understanding behavior and its neural basis requires a simpler description. Traditionally, simplification has been imposed by training animals to engage in a limited set of behaviors, by hand scoring behaviors into discrete classes, or by limiting the sensory experience of the organism. An alternative is to ask whether we can search through the dynamics of natural behaviors to find explicit evidence that these behaviors are simpler than they might have been. We review two mathematical approaches to simplification, dimensionality reduction and the maximum entropy method, and we draw on examples from different levels of biological organization, from the crawling behavior of
Caenorhabditis elegans
to the control of smooth pursuit eye movements in primates, and from the coding of natural scenes by networks of neurons in the retina to the rules of English spelling. In each case, we argue that the explicit search for simplicity uncovers new and unexpected features of the biological system and that the evidence for simplification gives us a language with which to phrase new questions for the next generation of experiments. The fact that similar mathematical structures succeed in taming the complexity of very different biological systems hints that there is something more general to be discovered.
Phonon softening and metallization of a narrow-gap semiconductor by thermal disorder
Authors: Delaire Olivier , Marty Karol , Stone Matthew B. , Kent Paul R. C. , Lucas Matthew S. , Abernathy Douglas L. , Mandrus David , Sales Brian C.
Published: March 2011

The vibrations of ions in solids at finite temperature depend on interatomic force–constants that result from electrostatic interactions between ions, and the response of the electron density to atomic displacements. At high temperatures, vibration amplitudes are substantial, and electronic states are affected, thus modifying the screening properties of the electron density. By combining inelastic neutron scattering measurements of Fe

1-
x

Co

x

Si as a function of temperature, and finite-temperature first-principles calculations including thermal disorder effects, we show that the coupling between phonons and electronic structure results in an anomalous temperature dependence of phonons. The strong concomitant renormalization of the electronic structure induces the semiconductor-to-metal transition that occurs with increasing temperature in FeSi. Our results show that for systems with rapidly changing electronic densities of states at the Fermi level, there are likely to be significant phonon–electron interactions, resulting in anomalous temperature-dependent properties.
Diversity-oriented synthesis of macrocyclic peptidomimetics
Authors: Isidro-Llobet Albert , Murillo Tiffanie , Bello Paula , Cilibrizzi Agostino , Hodgkinson James T. , Galloway Warren R. J. D. , Bender Andreas , Welch Martin , Spring David R.
Published: March 2011

Structurally diverse libraries of novel small molecules represent important sources of biologically active agents. In this paper we report the development of a diversity-oriented synthesis strategy for the generation of diverse small molecules based around a common macrocyclic peptidomimetic framework, containing structural motifs present in many naturally occurring bioactive compounds. Macrocyclic peptidomimetics are largely underrepresented in current small-molecule screening collections owing primarily to synthetic intractability; thus novel molecules based around these structures represent targets of significant interest, both from a biological and a synthetic perspective. In a proof-of-concept study, the synthesis of a library of 14 such compounds was achieved. Analysis of chemical space coverage confirmed that the compound structures indeed occupy underrepresented areas of chemistry in screening collections. Crucial to the success of this approach was the development of novel methodologies for the macrocyclic ring closure of chiral α-azido acids and for the synthesis of diketopiperazines using solid-supported
N
methylmorpholine. Owing to their robust and flexible natures, it is envisaged that both new methodologies will prove to be valuable in a wider synthetic context.
Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways
Authors: Chou Tsui-Fen , Brown Steve J. , Minond Dmitriy , Nordin Brian E. , Li Kelin , Jones Amanda C. , Chase Peter , Porubsky Patrick R. , Stoltz Brian M. , Schoenen Frank J. , Patricelli Matthew P. , Hodder Peter , Rosen Hugh , Deshaies Raymond J.
Published: March 2011

A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen.

N
2
,N
4

-
d
i
be
nzyl
q
uinazoline-2,4-diamine (DBeQ) was identified as a selective, potent, reversible, and ATP-competitive p97 inhibitor. DBeQ blocks multiple processes that have been shown by RNAi to depend on p97, including degradation of ubiquitin fusion degradation and endoplasmic reticulum-associated degradation pathway reporters, as well as autophagosome maturation. DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy.
Biosynthesis of the immunosuppressants FK506, FK520, and rapamycin involves a previously undescribed family of enzymes acting on chorismate
Authors: Andexer Jennifer N. , Kendrew Steven G. , Nur-e-Alam Mohammad , Lazos Orestis , Foster Teresa A. , Zimmermann Anna-Sophie , Warneck Tony D. , Suthar Dipen , Coates Nigel J. , Koehn Frank E. , Skotnicki Jerauld S. , Carter Guy T. , Gregory Matthew A. , Martin Christine J. , Moss Steven J. , Leadlay Peter F. , Wilkinson Barrie
Published: March 2011

The macrocyclic polyketides FK506, FK520, and rapamycin are potent immunosuppressants that prevent T-cell proliferation through initial binding to the immunophilin FKBP12. Analogs of these molecules are of considerable interest as therapeutics in both metastatic and inflammatory disease. For these polyketides the starter unit for chain assembly is (4
R
,5
R
)-4,5-dihydroxycyclohex-1-enecarboxylic acid derived from the shikimate pathway. We show here that the first committed step in its formation is hydrolysis of chorismate to form (4
R
,5
R
)-4,5-dihydroxycyclohexa-1,5-dienecarboxylic acid. This chorismatase activity is encoded by
fkbO
in the FK506 and FK520 biosynthetic gene clusters, and by
rapK
in the rapamycin gene cluster of
Streptomyces hygroscopicus
. Purified recombinant FkbO (from FK520) efficiently catalyzed the chorismatase reaction in vitro, as judged by HPLC-MS and NMR analysis. Complementation using
fkbO
from either the FK506 or the FK520 gene cluster of a strain of
S. hygroscopicus
specifically deleted in
rapK
(BIOT-4010) restored rapamycin production, as did supplementation with (4
R
,5
R
)-4,5-dihydroxycyclohexa-1,5-dienecarboxylic acid. Although BIOT-4010 produced no rapamycin, it did produce low levels of BC325, a rapamycin analog containing a 3-hydroxybenzoate starter unit. This led us to identify the
rapK
homolog
hyg5
as encoding a chorismatase/3-hydroxybenzoate synthase. Similar enzymes in other bacteria include the product of the
bra8
gene from the pathway to the terpenoid natural product brasilicardin. Expression of either
hyg5
or
bra8
in BIOT-4010 led to increased levels of BC325. Also, purified Hyg5 catalyzed the predicted conversion of chorismate into 3-hydroxybenzoate. FkbO, RapK, Hyg5, and Bra8 are thus founder members of a previously unrecognized family of enzymes acting on chorismate.
Membrane nanotubes induced by aqueous phase separation and stabilized by spontaneous curvature
Authors: Li Yanhong , Lipowsky Reinhard , Dimova Rumiana
Published: March 2011

Tubular membrane structures are widespread in eukaryotic cells, but the mechanisms underlying their formation and stability are not well understood. Previous work has focused on tube extrusion from cells and model membranes under the application of external forces. Here, we present novel membrane/polymer systems, where stable tubes form in the absence of externally applied forces. Solutions of two water-soluble polymers, polyethylene glycol and dextran, were encapsulated in giant lipid vesicles, cell-size model systems. Hypertonic deflation induced phase separation of the enclosed solution. The excess membrane area created during the deflation process was stored in a large number of membrane nanotubes inside the vesicle. The tubes had a diameter below optical resolution and became visible only when fluorescently labeled. The tubes were rather stable: In the absence of external forces, they existed for several days. A theoretical analysis of the shapes of the deflated vesicles reveals that these shapes would be unstable if the membranes had no spontaneous curvature. Using the large separation of length scales between the tube diameter and the overall size of the vesicles, the spontaneous curvature can be calculated and is found to be about -1/(240 nm) for a certain range of polymer concentrations. The nanotubes could also be retracted back into the mother vesicle by increasing the membrane tension via micropipette aspiration of the vesicle. Membrane tubes, which can form and be retracted easily, should be relevant for lipid storage in cells.
Golgi nucleotide sugar transporter modulates cell wall biosynthesis and plant growth in rice
Authors: Zhang Baocai , Liu Xiangling , Qian Qian , Liu Lifeng , Dong Guojun , Xiong Guangyan , Zeng Dali , Zhou Yihua
Published: March 2011

Golgi-localized nucleotide sugar transporters (NSTs) are considered essential for the biosynthesis of wall polysaccharides and glycoproteins based on their characteristic transport of a large number of nucleotide sugars to the Golgi lumen. The lack of NST mutants in plants has prevented evaluation of this hypothesis in plants. A previously undescribed Golgi NST mutant,
brittle culm14
(
bc14
), displays reduced mechanical strength caused by decreased cellulose content and altered wall structure, and exhibits abnormalities in plant development. Map-based cloning revealed that all of the observed mutant phenotypes result from a missense mutation in a putative NST gene,
Oryza sativa Nucleotide Sugar Transporter1
(
OsNST1
). OsNST1 was identified as a Golgi-localized transporter by analysis of a fluorescence-tagged OsNST1 expressed in rice protoplast cells and demonstration of UDP-glucose transport activity via uptake assays in yeast. Compositional sugar analyses in total and fractionated wall residues of wild-type and
bc14
culms showed a deficiency in the synthesis of glucoconjugated polysaccharides in
bc14
, indicating that OsNST1 supplies the glucosyl substrate for the formation of matrix polysaccharides, and thereby modulates cellulose biosynthesis.
OsNST1
is ubiquitously expressed, with high expression in mechanical tissues. The inferior mechanical strength and abnormal development of
bc14
plants suggest that OsNST1 has pleiotropic effects on cell wall biosynthesis and plant growth. Identification of OsNST1 has improved our understanding of how cell wall polysaccharide synthesis is regulated by Golgi NSTs in plants.
Complex interactions in EML cell stimulation by stem cell factor and IL-3
Authors: Ye Zhi-jia , Gulcicek Erol , Stone Kathryn , Lam Tukiet , Schulz Vincent , Weissman Sherman M.
Published: March 2011

Erythroid myeloid lymphoid (EML) cells are an established multipotent hematopoietic precursor cell line that can be maintained in medium including stem cell factor (SCF). EML cultures contain a heterogeneous mixture of cells, including a lineage-negative, CD34
+
subset of cells that propagate rapidly in SCF and can clonally regenerate the mixed population. A second major subset of EML cells consists of lineage-negative. CD34
−
cells that can be propagated in IL-3 but grow slowly, if at all, in SCF, although they express the SCF receptor (c-kit). The response of these cells to IL-3 is stimulated synergistically by SCF, and we present evidence that both the synergy and the inhibition of c-kit responses may be mediated by direct interaction with IL-3 receptor. Further, the relative level of tyrosine phosphorylation of various substrates by either cytokine alone differs from that produced by the combination of the two cytokines, suggesting that cell signaling by the combination of the two cytokines differs from that produced by either alone.
Helicobacter pylori
genome evolution during human infection
Authors: Kennemann Lynn , Didelot Xavier , Aebischer Toni , Kuhn Stefanie , Drescher Bernd , Droege Marcus , Reinhardt Richard , Correa Pelayo , Meyer Thomas F. , Josenhans Christine , Falush Daniel , Suerbaum Sebastian
Published: March 2011

High genetic diversity is a hallmark of the gastric pathogen
Helicobacter pylori
. We used 454 sequencing technology to perform whole-genome comparisons for five sets of
H. pylori
strains that had been sequentially cultured from four chronically infected Colombians (isolation intervals = 3–16 y) and one human volunteer experimentally infected with
H. pylori
as part of a vaccine trial. The four sets of genomes from Colombian
H. pylori
differed by 27–232 isolated SNPs and 16–441 imported clusters of polymorphisms resulting from recombination. Imports (mean length = 394 bp) were distributed nonrandomly over the chromosome and frequently occurred in groups, suggesting that
H. pylori
first takes up long DNA fragments, which subsequently become partially integrated in multiple shorter pieces. Imports were present at significantly increased frequency in members of the
hop
family of outer membrane gene paralogues, some of which are involved in bacterial adhesion, suggesting diversifying selection. No evidence of recombination and few other differences were identified in the strain pair from an infected volunteer, indicating that the
H. pylori
genome is stable in the absence of mixed infection. Among these few differences was an OFF/ON switch in the phase-variable adhesin gene
hopZ
, suggesting strong in vivo selection for this putative adhesin during early colonization.
Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma
Authors: Arroyo Jason D. , Chevillet John R. , Kroh Evan M. , Ruf Ingrid K. , Pritchard Colin C. , Gibson Donald F. , Mitchell Patrick S. , Bennett Christopher F. , Pogosova-Agadjanyan Era L. , Stirewalt Derek L. , Tait Jonathan F. , Tewari Muneesh
Published: March 2011

MicroRNAs (miRNAs) circulate in the bloodstream in a highly stable, extracellular form and are being developed as blood-based biomarkers for cancer and other diseases. However, the mechanism underlying their remarkable stability in the RNase-rich environment of blood is not well understood. The current model in the literature posits that circulating miRNAs are protected by encapsulation in membrane-bound vesicles such as exosomes, but this has not been systematically studied. We used differential centrifugation and size-exclusion chromatography as orthogonal approaches to characterize circulating miRNA complexes in human plasma and serum. We found, surprisingly, that the majority of circulating miRNAs cofractionated with protein complexes rather than with vesicles. miRNAs were also sensitive to protease treatment of plasma, indicating that protein complexes protect circulating miRNAs from plasma RNases. Further characterization revealed that Argonaute2 (Ago2), the key effector protein of miRNA-mediated silencing, was present in human plasma and eluted with plasma miRNAs in size-exclusion chromatography. Furthermore, immunoprecipitation of Ago2 from plasma readily recovered non–vesicle-associated plasma miRNAs. The majority of miRNAs studied copurified with the Ago2 ribonucleoprotein complex, but a minority of specific miRNAs associated predominantly with vesicles. Our results reveal two populations of circulating miRNAs and suggest that circulating Ago2 complexes are a mechanism responsible for the stability of plasma miRNAs. Our study has important implications for the development of biomarker approaches based on capture and analysis of circulating miRNAs. In addition, identification of extracellular Ago2–miRNA complexes in plasma raises the possibility that cells release a functional miRNA-induced silencing complex into the circulation.
Protein farnesylation inhibitors cause donut-shaped cell nuclei attributable to a centrosome separation defect
Authors: Verstraeten Valerie L. R. M. , Peckham Lana A. , Olive Michelle , Capell Brian C. , Collins Francis S. , Nabel Elizabeth G. , Young Stephen G. , Fong Loren G. , Lammerding Jan
Published: March 2011

Despite the success of protein farnesyltransferase inhibitors (FTIs) in the treatment of certain malignancies, their mode of action is incompletely understood. Dissecting the molecular pathways affected by FTIs is important, particularly because this group of drugs is now being tested for the treatment of Hutchinson–Gilford progeria syndrome. In the current study, we show that FTI treatment causes a centrosome separation defect, leading to the formation of donut-shaped nuclei in nontransformed cell lines, tumor cell lines, and tissues of FTI-treated mice. Donut-shaped nuclei arise during chromatin decondensation in late mitosis; subsequently, cells with donut-shaped nuclei exhibit defects in karyokinesis, develop aneuploidy, and are often binucleated. Binucleated cells proliferate slowly. We identified lamin B1 and proteasome-mediated degradation of pericentrin as critical components in FTI-induced “donut formation” and binucleation. Reducing pericentrin expression or ectopic expression of nonfarnesylated lamin B1 was sufficient to elicit donut formation and binucleated cells, whereas blocking proteasomal degradation eliminated FTI-induced donut formation. Our studies have uncovered an important role of FTIs on centrosome separation and define pericentrin as a (indirect) target of FTIs affecting centrosome position and bipolar spindle formation, likely explaining some of the anticancer effects of these drugs.
Temporal coding of odor mixtures in an olfactory receptor neuron
Authors: Su Chih-Ying , Martelli Carlotta , Emonet Thierry , Carlson John R.
Published: March 2011

Most natural odors are mixtures and often elicit percepts distinct from those elicited by their constituents. This emergence of a unique odor quality has long been attributed to central processing. Here we show that sophisticated integration of olfactory information begins in olfactory receptor neurons (ORNs) in
Drosophila
. Odor mixtures are encoded in the temporal dynamics as well as in the magnitudes of ORN responses. ORNs can respond to an inhibitory odorant with different durations depending on the level of background excitation. ORNs respond to mixtures with distinctive temporal dynamics that reflect the physicochemical properties of the constituent odorants. The insect repellent DEET (
N
,
N
-diethyl-
m
-toluamide), which attenuates odor responses of multiple ORNs, differs from an ORN-specific inhibitor in its effects on temporal dynamics. Our analysis reveals a means by which integration of information from odor mixtures begins in ORNs and provides insight into the contribution of inhibitory stimuli to sensory coding.
Essential glycan-dependent interactions optimize MHC class I peptide loading
Authors: Wearsch Pamela A. , Peaper David R. , Cresswell Peter
Published: March 2011

In this study we sought to better understand the role of the glycoprotein quality control machinery in the assembly of MHC class I molecules with high-affinity peptides. The lectin-like chaperone calreticulin (CRT) and the thiol oxidoreductase ERp57 participate in the final step of this process as part of the peptide-loading complex (PLC). We provide evidence for an MHC class I/CRT intermediate before PLC engagement and examine the nature of that chaperone interaction in detail. To investigate the mechanism of peptide loading and roles of individual components, we reconstituted a PLC subcomplex, excluding the Transporter Associated with Antigen Processing, from purified, recombinant proteins. ERp57 disulfide linked to the class I-specific chaperone tapasin and CRT were the minimal PLC components required for MHC class I association and peptide loading. Mutations disrupting the interaction of CRT with ERp57 or the class I glycan completely eliminated PLC activity in vitro. By using the purified system, we also provide direct evidence for a role for UDP-glucose:glycoprotein glucosyltransferase 1 in MHC class I assembly. The recombinant
Drosophila
enzyme reglucosylated MHC class I molecules associated with suboptimal ligands and allowed PLC reengagement and high-affinity peptide exchange. Collectively, the data indicate that CRT in the PLC enhances weak tapasin/class I interactions in a manner that is glycan-dependent and regulated by UDP-glucose:glycoprotein glucosyltransferase 1.
Contribution of IL-17–producing γδ T cells to the efficacy of anticancer chemotherapy
Authors: Ma Yuting , Aymeric Laetitia , Locher Clara , Mattarollo Stephen R. , Delahaye Nicolas F. , Pereira Pablo , Boucontet Laurent , Apetoh Lionel , Ghiringhelli François , Casares Noëlia , Lasarte Juan José , Matsuzaki Goro , Ikuta Koichi , Ryffel Bernard , Benlagha Kamel , Tesnière Antoine , Ibrahim Nicolas , Déchanet-Merville Julie , Chaput Nathalie , Smyth Mark J. , Kroemer Guido , Zitvogel Laurence
Published: March 2011

By triggering immunogenic cell death, some anticancer compounds, including anthracyclines and oxaliplatin, elicit tumor-specific, interferon-γ–producing CD8+ αβ T lymphocytes (Tc1 CTLs) that are pivotal for an optimal therapeutic outcome. Here, we demonstrate that chemotherapy induces a rapid and prominent invasion of interleukin (IL)-17–producing γδ (Vγ4+ and Vγ6+) T lymphocytes (γδ T17 cells) that precedes the accumulation of Tc1 CTLs within the tumor bed. In T cell receptor δ−/− or Vγ4/6−/− mice, the therapeutic efficacy of chemotherapy was compromised, no IL-17 was produced by tumor-infiltrating T cells, and Tc1 CTLs failed to invade the tumor after treatment. Although γδ T17 cells could produce both IL-17A and IL-22, the absence of a functional IL-17A–IL-17R pathway significantly reduced tumor-specific T cell responses elicited by tumor cell death, and the efficacy of chemotherapy in four independent transplantable tumor models. Adoptive transfer of γδ T cells restored the efficacy of chemotherapy in IL-17A−/− hosts. The anticancer effect of infused γδ T cells was lost when they lacked either IL-1R1 or IL-17A. Conventional helper CD4+ αβ T cells failed to produce IL-17 after chemotherapy. We conclude that γδ T17 cells play a decisive role in chemotherapy-induced anticancer immune responses.
The Network Approach for Prevention of Healthcare-Associated Infections: Long-Term Effect of Participation in the Duke Infection Control Outreach Network
Authors: Anderson Deverick J. , Miller Becky A. , Chen Luke F. , Adcock Linda H. , Cook Evelyn , Cromer A. Lynn , Louis Susan , Thacker Paul A. , Sexton Daniel J.
Published: March 2011

Objective.

To describe the rates of several key outcomes and healthcare-associated infections (HAIs) among hospitals that participated in the Duke Infection Control Outreach Network (DICON).

Design and Setting.

Prospective, observational cohort study of patients admitted to 24 community hospitals from 2003 through 2009.

Methods.

The following data were collected and analyzed: incidence of central line-associated bloodstream infections (CLABSIs), ventilator-associated pneumonia (VAP), catheter-associated urinary tract infections (CAUTIs), and HAIs caused by methicillin-resistant Staphylococcus aureus (MRSA); employee exposures to bloodborne pathogens (EBBPs); physician EBBPs; patient-days; central line-days; ventilator-days; and urinary catheter-days. Poisson regression was used to determine whether incidence rates of these HAIs and exposures changed during the first 5 and 7 years of participation in DICON; nonrandom clustering of each outcome was controlled for. Cost saved and lives saved were calculated on the basis of published estimates.

Results.

In total, we analyzed 6.5 million patient-days, 4,783 EBPPs, 2,948 HAIs due to MRSA, and 2,076 device-related infections. Rates of employee EBBPs, HAIs due to MRSA, and device-related infections decreased significantly during the first 5 years of participation in DICON (P < .05 for all models; average decrease was approximately 50%); in contrast, physician EBBPs remained unchanged. In aggregate, 210 CLABSIs, 312 cases of VAP, 332 CAUTIs, 1,042 HAIs due to MRSA, and 1,016 employee EBBPs were prevented. Each hospital saved approximately $100,000 per year of participation, and collectively the hospitals may have prevented 52-105 deaths from CLABSI or VAP. The 7-year analysis demonstrated that these trends continued with further participation.

Conclusions.

Hospitals with long-term participation in an infection control network decreased rates of significant HAIs by approximately 50%, decreased costs, and saved lives.
Development and Validation of a Clostridium difficile Infection Risk Prediction Model
Authors: Dubberke Erik R. , Yan Yan , Reske Kimberly A. , Butler Anne M. , Doherty Joshua , Pham Victor , Fraser Victoria J.
Published: March 2011

Objective.

To develop and validate a risk prediction model that could identify patients at high risk for Clostridium difficile infection (CDI) before they develop disease.

Design and Setting.

Retrospective cohort study in a tertiary care medical center.

Patients.

Patients admitted to the hospital for at least 48 hours during the calendar year 2003.

Methods.

Data were collected electronically from the hospital's Medical Informatics database and analyzed with logistic regression to determine variables that best predicted patients' risk for development of CDI. Model discrimination and calibration were calculated. The model was bootstrapped 500 times to validate the predictive accuracy. A receiver operating characteristic curve was calculated to evaluate potential risk cutoffs.

Results.

A total of 35,350 admitted patients, including 329 with CDI, were studied. Variables in the risk prediction model were age, CDI pressure, times admitted to hospital in the previous 60 days, modified Acute Physiology Score, days of treatment with high-risk antibiotics, whether albumin level was low, admission to an intensive care unit, and receipt of laxatives, gastric acid suppressors, or antimotility drugs. The calibration and discrimination of the model were very good to excellent (C index, 0.88; Brier score, 0.009).

Conclusions.

The CDI risk prediction model performed well. Further study is needed to determine whether it could be used in a clinical setting to prevent CDI-associated outcomes and reduce costs.
Emergence of Daptomycin-Resistant VRE: Experience of a Single Institution
Authors: Kamboj Mini , Cohen Nina , Gilhuley Kathleen , Babady N. Esther , Seo Susan K. , Sepkowitz Kent A.
Published: March 2011

Recent surveillance from US hospitals shows that more than 99.5% of vancomycin-resistant enterococci (VRE) isolates remain susceptible to daptomycin. This report describes emergence of daptomycin-resistant VRE at a major cancer center. The percentage of patients with daptomycin-resistant VRE bacteremia increased from 3.4% in 2007 to 15.2% in 2009 (P= .03). Without susceptibility data, empiric daptomycin therapy for VRE infections should be used with caution.
Championing Patient Safety through Mandatory Influenza Vaccination for All Healthcare Personnel and Affiliated Physicians
Authors: Karanfil Lynne V. , Bahner Jan , Hovatter Joan , Thomas William L.
Published: March 2011

Objective.

To determine whether a mandatory seasonal influenza vaccination program will increase vaccination rates among healthcare personnel (HCP) and affiliated physicians.

Setting.

MedStar Health is a not-for-profit regional healthcare organization that includes 9 hospitals with approximately 25,000 HCP and approximately 4,000 affiliated physicians. HCP describes any person employed by MedStar Health.

Methods.

With previous vaccination rates parallel to reported national rates of 54% among HCP, MedStar Health introduced a mandatory seasonal influenza vaccination program promulgated during the 2009–2010 influenza season. HCP and affiliated physicians were given an opportunity to apply for medical or religious exemptions. Noncompliant HCP were terminated. Noncompliant physicians had their privileges administratively suspended for the influenza season.

Results.

HCP compliance (vaccinated and exempt) was 99.9%. The influenza vaccination rate among HCP was 98.5%. There were 338 approved medical exemptions and 18 approved religious exemptions. Only 0.01% of HCP (9 full-time, 2 part-time, and 17 per diem employees) were terminated. Overall, 93% of the affiliated physicians were vaccinated; 7 religious and 99 medical exemptions were granted. In total, 149 physicians (4%) had their admitting privileges suspended during the influenza season.

Conclusion.

A mandatory influenza vaccination program achieves high rates of vaccination among HCP and affiliated physicians.
Highest weight categories arising from Khovanov’s diagram algebra III: category 𝒪
Authors: Brundan Jonathan , Stroppel Catharina
Published: March 2011

We prove that integral blocks of parabolic category

O

\mathcal {O}

associated to the subalgebra

g
l

m

(

C

)
⊕

g
l

n

(

C

)

\mathfrak {gl}_m(\mathbb {C}) \oplus \mathfrak {gl}_n(\mathbb {C})

of

g
l

m
+
n

(

C

)

\mathfrak {gl}_{m+n}(\mathbb {C})

are Morita equivalent to quasi-hereditary covers of generalised Khovanov algebras. Although this result is in principle known, the existing proof is quite indirect, going via perverse sheaves on Grassmannians. Our new approach is completely algebraic, exploiting Schur-Weyl duality for higher levels. As a by-product we get a concrete combinatorial construction of

2
2

-Kac-Moody representations in the sense of Rouquier corresponding to level two weights in finite type

A
A

.
Use of Phytases in Ethanol Production from E‐Mill Corn Processing
Authors: Khullar Esha , Shetty Jay K. , Rausch Kent D. , Tumbleson M. E. , Singh Vijay
Published: March 2011

Effects of phytase addition, germ, and pericarp fiber recovery were evaluated for the E‐Mill dry grind corn process. In the E‐Mill process, corn was soaked in water followed by incubation with starch hydrolyzing enzymes. For each phytase treatment, an additional phytase incubation step was performed before incubation with starch hydrolyzing enzymes. Germ and pericarp fiber were recovered after incubation with starch hydrolyzing enzymes. Preliminary studies on phytase addition resulted in germ with higher oil (40.9%), protein (20.0%), and lower residual starch (12.2%) contents compared to oil (39.1%), protein (19.2%), and starch (18.1%) in germ from the E‐Mill process without phytase addition. Phytase treatment resulted in lower residual starch contents in pericarp fiber (19.9%) compared to pericarp fiber without phytase addition (27.4%). Results obtained led to further investigation of effects of phytase on final ethanol concentrations, germ, pericarp fiber, and DDGS recovery. Final ethanol concentrations were higher in E‐Mill processing with phytase addition (17.4% v/v) than without addition of phytase (16.6% v/v). Incubation with phytases resulted in germ with 4.3% higher oil and 2.5% lower residual starch content compared to control process. Phytase treatment also resulted in lower residual starch and higher protein contents (6.58 and 36.5%, respectively) in DDGS compared to DDGS without phytase incubations (8.14 and 34.2%, respectively). Phytase incubation in E‐Mill processing may assist in increasing coproduct values as well as lead to increased ethanol concentrations.
A Numerical Study of Combined Use of Two Biocontrol Agents with Different Biocontrol Mechanisms in Controlling Foliar Pathogens
Authors: Xu X.-M. , Jeffries P. , Pautasso M. , Jeger M. J.
Published: March 2011

Effective use of biocontrol agents is an important component of sustainable agriculture. A previous numerical study of a generic model showed that biocontrol efficacy was greatest for a single biocontrol agent (BCA) combining competition with mycoparasitism or antibiosis. This study uses the same mathematical model to investigate whether the biocontrol efficacy of combined use of two BCAs with different biocontrol mechanisms is greater than that of a single BCA with either or both of the two mechanisms, assuming that two BCAs occupy the same host tissue as the pathogen. Within the parameter values considered, a BCA with two biocontrol mechanisms always outperformed the combined use of two BCAs with a single but different biocontrol mechanism. Similarly, combined use of two BCAs with a single but different biocontrol mechanism is shown to be far less effective than that of a single BCA with both mechanisms. Disease suppression from combined use of two BCAs was very similar to that achieved by the more efficacious one. As expected, a higher BCA introduction rate led to increased disease suppression. Incorporation of interactions between two BCAs did not greatly affect the disease dynamics except when a mycoparasitic and, to a lesser extent, an antibiotic-producing BCA was involved. Increasing the competitiveness of a mycoparasitic BCA over a BCA whose biocontrol mechanism is either competition or antibiosis may lead to improved biocontrol initially and reduced fluctuations in disease dynamics. The present study suggests that, under the model assumptions, combined use of two BCAs with different biocontrol mechanisms in most cases only results in control efficacies similar to using the more efficacious one alone. These predictions are consistent with published experimental results, suggesting that combined use of BCAs should not be recommended without clear understanding of their main biocontrol mechanisms and relative competitiveness, and experimental evaluation.
Drag reduction by riblets
Authors: García-Mayoral Ricardo , Jiménez Javier
Published: March 2011

The interaction of the overlying turbulent flow with riblets, and its impact on their drag reduction properties are analysed. In the so-called viscous regime of vanishing riblet spacing, the drag reduction is proportional to the riblet size, but for larger riblets the proportionality breaks down, and the drag reduction eventually becomes an increase. It is found that the groove cross section
A
+
g
is a better characterization of this breakdown than the riblet spacing, with an optimum

. It is also found that the breakdown is not associated with the lodging of quasi-streamwise vortices inside the riblet grooves, or with the inapplicability of the Stokes hypothesis to the flow along the grooves, but with the appearance of quasi-two-dimensional spanwise vortices below
y
+
≈30, with typical streamwise wavelengths

. They are connected with a Kelvin–Helmholtz-like instability of the mean velocity profile, also found in flows over plant canopies and other surfaces with transpiration. A simplified stability model for the ribbed surface approximately accounts for the scaling of the viscous breakdown with 
A
+
g
.